Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Strategic guidance on VPD surveillance in the WHO South-East Asia Region)

September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region OVERVIEW MODULE: STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Strategic guidance on VPD surveillance in the WHO South-East Asia Region) ISBN 978-92-9021-009-2 © World Health Organization 2022 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization (http://www.wipo.int/amc/en/mediation/rules/). Suggested citation. Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Strategic guidance on VPD surveillance in the WHO South-East Asia Region). New Delhi: World Health Organization, Regional Office for South-East Asia; 2022. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party- owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. Cover Photo by: WHO/Nepal Printed in India CONTENTS Foreword 4 Background 7 Vision 7 Objectives 7 Guiding principles 8 Current situation of VPD surveillance in the Region 9 Design characteristics of VPD surveillance 10 Passive surveillance 10 Active surveillance 11 Community-based surveillance 11 Additional surveillance activities 11 Minimum requirements for VPD surveillance 12 Laboratory network 13 Integration of VPD surveillance 13 Syndromic surveillance platform 14 Key steps in conducting surveillance in the Region 15 Prioritization of VPDs for surveillance 15 Strengthening VPD surveillance in South-East Asia Region 17 The way forward 17 Minimum surveillance requirement for VPDs in countries in SEA Region 18 References 19 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Foreword Overwhelming evidence demonstrates the benefits of immunization as one of the most successful and cost-effective public health interventions ever known. Over the past several decades, immunization has achieved many milestones, including the eradication of smallpox, an accomplishment that has been called one of humanity’s greatest triumphs. Vaccines have saved countless lives, lowered the global incidence of polio by 99% and reduced illness, disability and death from diphtheria, tetanus, whooping cough, measles, Haemophilus influenzae type b disease and epidemic meningococcal A meningitis. We have been able to make the Region free of polio for the last 10 years, eliminate maternal and neonatal tetanus and eliminate measles in five countries and eliminate rubella in 2 countries. . We have vaccines against more than 25 diseases in the present-day world, and this has increased the need for better surveillance against these diseases to control or eliminate them. As the essence of this subject matter, I would like to highlight that high vaccination coverage may not necessarily indicate the caseload or disease burden in a population. We need to look into the surveillance performance as the key indicators progress towards disease control and/ or elimination. 5STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION A functional vaccine-preventable disease surveillance system is a key part of public health decision-making in all countries. Thus, there is an urgent need to build on the current efforts to strengthen vaccine-preventable disease surveillance with the latest state-of-the- art technologies at subnational and national levels. I hope that this second edition of the vaccine-preventable diseases surveillance guide will be well translated into respective national programmes and add to the efforts to have a high-quality surveillance system for priority vaccine-preventable diseases and accelerate progress towards strengthening vaccine-preventable disease surveillance in our Region. Finally, every individual in our Region deserves our best work. We all agree that every family, no matter where residing, has the right to all immunization and health services that are provided by the respective government, in the spirit of universal health coverage contributing towards Sustainable Development Goals, especially Goal 3 on health. Dr. Poonam Khetrapal Singh Regional Director, WHO South-East Asia Region Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 7STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION Strategic guidance on VPD surveillance in the WHO South-East Asia Region Background Public health surveillance is the continuous and systematic collection, analysis and interpretation of health-related data needed for the planning, implementation, and evaluation of public health practice (1). Surveillance for vaccine-preventable diseases (VPDs) is similar to other types of disease surveillance in the matter of design (2). VPD surveillance is of vital importance for its potential to inform policy. It is also of great value in the monitoring of immunization programmes, including the introduction and coverage of vaccines and their potential use in outbreak response. Surveillance also helps to detect changes in the epidemiology of VPDs over time due to vaccination and other preventive measures. As the burden of a VPD decreases, the objectives and design of the surveillance system may shift. This document provides standards for the design and implementation of VPD surveillance to meet the objectives of immunization programmes. Vision All countries in the Region have sustainable, high-quality VPD surveillance systems which are supported by efficient laboratories that detect and confirm cases and generate useful data to guide outbreak prevention and response, immunization programme management, and vaccine policy. Objectives The key objectives of VPD surveillance in the Region are: z monitoring disease elimination or eradication efforts; z detecting outbreaks and new pathogens; z collecting evidence for the introduction of new vaccines or the optimization of vaccine schedules; z evaluating the performance of immunization programmes and defining the need for supplementary immunization; z evaluating the effectiveness of vaccines and their impact on the disease burden; and z detecting changes in the strains or nature of disease (for example, flu). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Guiding principles A VPD surveillance system must be: z comprehensive z country-led and country-owned z high quality z sustainable z tailored to the needs of a country z evidence-informed z integrated across diseases z accountable z flexible z efficient z useful for programme and policy decisions 9STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION Current situation of VPD surveillance in the Region Table-1: Current situation of VPD surveillance by country (June 2022) Laboratory supported case-based Nationwide case-based Nationwide aggregateNationwide Sentinel Bangladesh Polio; MR; CRS; JE/AES; IBD; Rota NNT; Diphtheria; Pertussis; Bhutan Polio; MR; CRS; JE/AES; Rota Diphtheria; Pertussis; NNT DPR Korea Polio; MR; CRS; Diphtheria; Pertussis NNT: Rota India Polio; MR; JE/AES CRS ; IBD; Rota, Typhoid Diphtheria, Pertussis , NNT Indonesia Polio; MR; Diphtheria, Pertussis CRS ; JE/AES; Rota NNT Maldives Polio; MR; CRS; Rota Diphtheria, Pertussis , NNT Myanmar Polio; MR ; JE/AES CRS ;Rota Diphtheria; NNT Nepal Polio; MR ; JE/AES CRS; IBD; Rota NNT Diphtheria, Pertussis Sri Lanka Polio; MR; CRS Diphtheria; Pertussis; NNT; JE/AES IBD, Typhoid Thailand Polio; MR; CRS Diphtheria; Pertussis; NNT; JE/AES Timor-Leste Polio ; MR Diphtheria, Pertussis , NNT AES: acute encephalitis syndrome; CRS: congenital rubella syndrome; IBD: invasive bacterial diseases; JE: Japanese encephalitis; MR: measles rubella; NNT: Neonatal tetanus; Polio: poliomyelitis; Rota: Rotavirus Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 Design characteristics of VPD surveillance Once the objectives of surveillance are set, it is necessary to create a surveillance system design that meets the objectives. The following questions must be considered for the process: z Is it necessary to capture all cases, or is a subset or fraction acceptable? If the elimination or eradication of the VPD is the goals, then all cases must be captured. z What level of detailed case information is necessary to inform public health action? z Are the resources adequate for obtaining detailed information for every case, or would it be more efficient to have focused surveillance in high-yield scenarios, or to integrate with other surveillance systems? The following characteristics could be considered during the designing process. These may depend on the existing public health system and infrastructure in a country. Although these have been presented as either/or, many surveillance systems contain a mixture of elements, for example, a system may have both passive and active elements, or be both facility- and community-based. z Aggregate/case-based z Nationwide/subnational: When controlling a VPD is the goal, subnational surveillance may be acceptable to determine the risk factors or evaluate the impact of a vaccine. However, if elimination or eradication is the goal, nationwide surveillance that strives to detect all cases is essential. z Population-based/sentinel z Facility-based/community-based z Active/passive z Clinical/laboratory-based Passive surveillance In this type of surveillance, data/reports are sent routinely by designated health facilities (reporting sites) or individuals. Weekly reports are sent even if no cases have been detected ( zero reports). The reporting network for passive surveillance should consist of the following sites: z public sector facilities, such as medical colleges, district hospitals and subdistrict health facilities; z private sector health facilities that VPD cases are most likely to visit (personnel should be trained to identify cases); and 11 STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION z community-based informants, such as village-level health extension workers/ volunteers, teachers, members of nongovernmental organizations (NGOs) and civil society organizations (CSOs). The reporting sites should be regularly reviewed and assessed for performance and new sites should be included as required. There should be a mechanism to provide feedback to the reporting sites. Active surveillance In this type of surveillance, designated surveillance officers visit health facilities to search for and investigate unreported cases through: z a review of health facility records; z interviews with health workers; and z visits to wards. Surveillance sites should be prioritized according to the probability of finding VPD cases. In other words, those which have a higher probability of having VPD cases should be visited more regularly. Every surveillance officer should have a list of surveillance sites and a schedule of the visits to be made. Each surveillance visit should be documented. Community-based surveillance The systematic detection and reporting of events of public health significance within a community-by-community members is called community-based surveillance. This is especially important in areas where the health system is weak or non-existent, such as areas with compromised security. Trained community members (e.g., informants, volunteers) are engaged to report suspected cases, based on a simplified case definition tailored for use by community members, to a designated focal person who is part of the surveillance system. Additional surveillance activities Additional surveillance activities are undertaken in areas with underreporting or no reporting (‘silent’). These help to assess the sensitivity of the VPD surveillance system. Some examples are as follows. Retrospective record review: A limited number of international classification of diseases (ICD) codes is used to categorize all patients. Their records are reviewed for any sign of Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 the targeted VPD. The review is conducted for a minimum period of one year in selected health-care facilities. The objectives of the review are to: z identify missed cases; z determine the sensitivity of the surveillance system; z identify factors contributing to inadequate surveillance; and z raise awareness of the importance of VPD surveillance through the involvement of key local personnel. Active case search: In this case, health officials contact key persons in the community to find out about VPD events in the community. The key persons could be community leaders, schoolteachers, social workers, leaders of women’s organizations, traditional healers, and religious leaders. Active case finding (ACS) is conducted in: z districts that have been silent for one or more years; z high-risk populations; and z areas that have reported outbreaks/increased transmission for diseases that are close to elimination/eradication/control. Minimum requirements for VPD surveillance Starting a surveillance requires the following: z planning a strategy and partner coordination; z defining standards for surveillance and information systems (interoperable or well- integrated with the existing system) to support the collection, analysis, sharing and programmatic use of data; z a workforce that is appropriately trained in the core competencies of surveillance, including data analysis; z a laboratory network (where applicable); z technical support for implementation; and z sustainable financing. 13 STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION Laboratory network A laboratory result confirming a VPD case is the starting point of surveillance for many diseases. Laboratories or hospitals report these cases to public health authorities, either as part of national disease reporting requirements or sentinel surveillance networks. This approach is best implemented when a majority of patients with specified signs and symptoms are laboratory tested as part of the existing clinical practice. Data management systems are essential for linking laboratory and epidemiological (clinic-based) data. WHO coordinates global and regional laboratory networks to support surveillance for several VPDs, including polio, measles–rubella, Japanese encephalitis (JE), rotavirus and invasive bacterial diseases (IBD). Global laboratory networks engender confidence in the data used in eradication and elimination programmes and for national and global vaccine policy decisions. They also allow for valid comparison of VPD epidemiology and incidence across countries. National laboratory personnel are trained to test for a VPD and are supported by regional reference laboratories for confirmatory testing and quality assurance/control. A few global specialized and regional reference laboratories conduct advanced testing, such as molecular typing. A network of laboratories has been established in the Region to support case-based surveillance for priority VPDs (polio, measles–rubella, JE, IBD) and ensure the reporting of quality assured results of surveillance specimens. Laboratory quality assurance (QA) procedures relate to the testing process (for example, external quality assurance, proficiency panel testing, periodic retesting, and regular site visits), while quality control (QC) procedures relate to laboratory results, such as internal assay controls. Both are encouraged as part of the laboratory component of surveillance. Integration of VPD surveillance The integration of VPD surveillance into existing communicable disease surveillance systems or the linking of one VPD surveillance system to another has clear advantages. The integration of disease surveillance capitalizes on an economy of scale and can be less resource-intensive than starting a new disease-specific surveillance system. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 VPD surveillance can be integrated into existing surveillance in three main ways. 1. Use the existing system as is. If the existing surveillance system already captures the complement of cases and data elements from the desired population, then the system might already be sufficient to meet the standards for some VPDs as outlined in this document. 2. Add more VPDs to an existing VPD platform. An existing VPD surveillance platform might be adapted to meet the surveillance standards for additional VPDs. An example is the adaptation of measles case definitions and testing algorithms to allow integrated surveillance with rubella. 3. Integrate surveillance activities instead of systems. If separate VPD-specific surveillance is required, the team can integrate surveillance activities in areas of overlap between the two surveillance systems. The integration of VPD surveillance activities with existing surveillance efforts will require integration in the following areas: z policy, including regulations, prioritization, and standards; z financing, including costing, funding, and sustainability plans; z infrastructure, including facilities, equipment, supplies, and maintenance; z workforce, including staffing, retention plans and cross-cutting training; z field logistics, including case investigations, supervision, active surveillance visits and transport of laboratory samples; z laboratory, including expansion and diversification of global networks, shared procurement processes and quality management systems (for example, external quality assessment); and z monitoring and evaluation, including information systems and performance indicators. Syndromic surveillance platform In the context of VPD surveillance, syndromic surveillance refers to the use of a clinical syndrome – a constellation of symptoms and signs – as the case definition for the detection of suspect cases of a VPD. Using syndromic surveillance platforms for multiple VPDs can be more efficient than doing surveillance for a single disease. 15 STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION Key steps in conducting surveillance in the Region Following are the key steps proposed for conduction VDP surveillance in the Region. However, countries will need to adopt and adapt to the respective surveillance system. Figure1: Key steps in conducting surveillance in the Region Prioritization of VPDs for surveillance Not all VPDs are prioritized for surveillance. WHO specifies a set of criteria for prioritizing the surveillance of communicable diseases (3). Many VPDs would be prioritized according to these, partially because they have a proven method of control and prevention – namely vaccination. The following points must be taken into consideration when deciding whether to undertake surveillance for a particular VPD: z whether it is a VPD with a global surveillance mandate, for example, diseases as defined by International Health Regulations; and z whether surveillance data will inform key vaccine policy and immunization strategy decisions. z The following questions related to resources must be considered when deciding the type of surveillance to be conducted. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 z Can surveillance objectives be met by using the existing integrated surveillance platforms, with a minimal increase in resources, or is disease-specific surveillance required? z Is there sufficient technical capacity, including epidemiological staff and laboratory infrastructure? z Is there adequate funding and other resources to conduct a high-quality surveillance that addresses the objectives of the immunization programme? If not, the decision to conduct surveillance for the VPD should be reconsidered. Poor-quality surveillance can be worse than no surveillance because it can lead to decision- making based on erroneous or incomplete data. Table 2 lists the current recommendations of WHO for comprehensive VPD surveillance on the basis of a country’s resources and disease burden. Table 2: WHO global recommendations for comprehensive VPD surveillance Tier Country characteristics Recommended strategy Tier - 1 z Limited surveillance capacity z High communicable disease burden and risk, including polio z Fragile Minimum surveillance standards for at least 5 VPDs (polio, measles, rubella, congenital rubella syndrome and neonatal tetanus) Tier - 2 z Moderate surveillance capacity z High communicable disease burden and risk Minimum surveillance standards for at least 7 VPDs (polio, measles, rubella, congenital rubella syndrome, neonatal tetanus, diphtheria and pertussis ) Tier - 3 z Adequate surveillance capacity z Moderate communicable disease burden and risk; support needed for specific VPDs Minimum or enhanced surveillance standards for priority VPDs (at least 10, including invasive bacterial diseases, rotavirus, and Japanese encephalitis) Tier - 4 z High surveillance capacity z Low communicable disease burden and risk A national system beyond minimum VPD surveillance standards (for at least 15 VPDs) that coordinates with other communicable disease surveillance systems and supranational entities 17 STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION Strengthening VPD surveillance in South-East Asia Region A regular review of VPD surveillance should be conducted to identify good practices, and issues and challenges, to guide the future course of action and strengthen VPD surveillance. The following key activities are essential to strengthen VPD surveillance. 1. Case detection in the public and private sectors must be enhanced through z regular review and updating of reporting sites; z the addition of informants; community based as well as health facility based (private and public) z linkage with other surveillance systems. 2. Surveillance guides and standard operating procedures must be updated. 3. The surveillance workforce must receive initial and refresher training. 4. Effective and efficient laboratory support must be ensured, and the laboratory network expanded to increase access. 5. Sustainability must be ensured by z making provisions in the national and local budget; z having a dedicated workforce; and z establishing a mechanism for accountability at all levels 6. Adequate technical assistance must be ensured for the implementation of the surveillance programme. 7. The quality of data must be enhanced, and the data must be used for further action. 8. Surveillance functions must be integrated. 9. Other activities may be identified during the review of the programme. The way forward The following actions will be required to further strengthen surveillance. z Ensure that the existing system meets the standards for VPD surveillance (captures data and information required), for example, aggregate facility-based surveillance for non-neonatal tetanus. z Adapt the existing surveillance platform to meet the surveillance standards for additional VPDs. z Integrate activities in functional areas of overlap, even if separate surveillance is required for specific VPDs. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 Minimum surveillance requirement for VPDs in countries in SEA Region A set of VPDs has been recommended for surveillance in the Region. This includes, at a minimum, all VPDs with global surveillance mandates, including diseases as defined by International Health Regulations (4), and other regional and country priorities. Table 5: VPDs identified for surveillance in the Region Nationwide, laboratory- supported, case-based Nationwide, aggregate Sentinel, case-based with laboratory confirmation of every case In all countries Poliomyelitis, measles and rubella Diphtheria, pertussis , neonatal tetanus Congenital rubella syndrome, In selected countries Japanese encephalitis/ AES Non-NT, Hepatitis B Invasive bacterial diseases Rotavirus The guidance and minimum core variables to be recorded and reported along with key performance indicators for each of these VPDS have been defined and available in respective modules. Module1 – Measles and rubella Module 2 – Congenital rubella syndrome Module 3 – Poliomyelitis Module 4 – Diphtheria Module 5 – Pertussis Module 6 – Neonatal tetanus Module 7 – Non-neonatal tetanus Module 8 – Hepatitis B Module 9 – Rotavirus Module 10 – Japanese encephalitis Module 11 – Invasive bacterial vaccine-preventable diseases 19 STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION References 1. WHO. Public Health Surveillance [website]. WHO Regional Office for the Eastern Mediterranean; 2014 (http://www.emro.who.int/health-topics/public-health- sur veillance/index.html#:~:text=Photo%20credit%3AWHOPublic%20 health,a%20position%20to%20take%20action, accessed 21 July 2022). 2. Gregg MB. Field Epidemiology. New York: Oxford University Press; 2008. DOI:10.1093/acprof:oso/9780195313802.001.0001. 3. World Health Organization. Setting priorities in communicable disease surveillance. Geneva: World Health Organization; 2006 (https://apps.who.int/iris/ handle/10665/69332, accessed 21 July 2022). 4. International Health Regulations. Geneva: World Health Organization; 2005 (https:// www.who.int/health-topics/international-health-regulations, accessed 21 July 2022). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

MODULE-1 MEASLES AND RUBELLA Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Measles And Rubella) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Measles And Rubella). New Delhi: World Health Organization, Regional Office for South-East Asia; 2023. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party- owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Printed in India Cover and inside photo credit: WHO CONTENTS Introduction 5 Objectives 5 Types of surveillance 6 Case detection 6 Definition of suspected case 6 Description of terms 6 Response to suspected case 7 Investigation of suspected case 7 Case investigation form 7 Unique ID 7 Specimen collection 7 Types of specimens 8 For MR-specific IgM antibody detection 8 For virus detection and isolation 8 Case confirmation 9 Algorithm for testing serum specimens in the laboratory: 9 Algorithm for testing throat/NP swabs and urine specimens in the laboratory: 10 Case classification 11 Laboratory-confirmed case 11 Epidemiologically linked case 11 Clinically compatible measles case 11 Clinically compatible rubella case 11 Non-measles non-rubella case 11 Vaccine-associated illness 12 Acute measles-related death 12 Classification by source of transmission 12 Endemic cases 12 Imported cases 13 Import-related cases 13 Cases with unknown source of infection 13 Contact tracing 13 Active case search 14 Clinical management 14 Case management 14 Management of contacts 15 Outbreak 16 Definition 16 Chain of transmission 16 Large outbreak 16 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 End of an outbreak 16 Preparedness and response 17 Investigation of outbreak 17 Modification of surveillance during large outbreaks 17 Public health response 18 When to initiate a public health response 18 Steps to be taken when a measles/rubella outbreak is suspected 19 Describing the outbreak 22 Assessing severity of outbreak 22 Evaluating effectiveness of vaccine, if possible 22 Disseminating messages to the public 23 Tools for outbreak response 24 Data management 24 Reporting requirements 24 Unique ID 24 Recommended data elements 25 Data analysis 25 Using data for decision-making 26 Indicators for surveillance performance 26 Risk assessment 31 Annex 1: Disease epidemiology – measles and rubella 33 Background 33 Annexes 33 Vaccines 34 Disease burden 34 Annex 2: Case investigation form 35 Annex 3: Collection, storage and transport of specimens 39 Venous blood collection 39 Alternative specimen collection 39 How to collect throat swabs or NP/oropharyngeal swabs 40 Alternative specimen collection for molecular tests 41 Annex 4: Tools for public health response to measles and rubella outbreaks 44 Annex 4a: Assessment of vaccine effectiveness using a nomogram 44 Annex 4b: Contact tracing form 45 Annex 4c: Community census form 47 Annex 4d: Analysis of data and outbreak severity 49 Annex 4e: Template for reporting an outbreak 50 Annex 4f: Line list for large outbreak 53 Annex 5: Checklist for outbreak preparedness 54 Further reading 59 5MEASLES AND RUBELLA Measles and Rubella surveillance Introduction In September 2019, the Seventy-second session of the World Health Organization (WHO) Regional Committee for South-East Asia endorsed resolution SEA/RC72/R3, in which the Member States of the Region adopted the updated goal of the elimination of measles and rubella by 2023. “Measles and rubella elimination by 2023” has been one of the Flagship Priority Programmes of the Region since 2014. The Strategic Plan for Measles and Rubella Elimination in the WHO South-East Asia Region 2020–2024 has been developed to ensure the provision of adequate technical guidance to accelerate progress towards the goal. Surveillance is one of the major strategic priority areas in this plan. In the setting of the elimination of measles and rubella, surveillance must be sufficiently sensitive to detect endemic measles and rubella cases and imported/import-related chains of transmission. The surveillance system must also be adequately equipped for timely and proper case investigation and laboratory analysis. The credibility of measles and rubella elimination depends on the quality of epidemiological and laboratory surveillance. Objectives The objectives of the surveillance system are to: z detect, notify and investigate suspected cases and outbreaks; z correctly classify cases as confirmed or discarded; z determine if the cases z were due to the failure of the implementation of the programme (e.g. should have been vaccinated but were not); z due to vaccine failure; or z because vaccination was not recommended; and z guide actions that reduce morbidity and mortality and prevent further transmission of the virus. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 Types of surveillance Surveillance should be nationwide and case-based, and should include all health facilities (both private and public). The system of zero reporting (reporting the absence of cases) should be followed. If desired and provided that there are sufficient resources, the implementation of community- based surveillance (such as notification of cases by community health workers or teachers) should be considered in areas that are at risk for measles/rubella during outbreaks, and for populations among which not all measles cases seek care in health facilities. Active surveillance in health facilities, such as regular review of the logbooks of clinics for missed cases, is essential so that no case is missed. Case detection Definition of suspected case A suspected case is defined as: z a patient with a fever and maculopapular (non-vesicular) rash; or z a patient whom a health-care worker suspects of having measles or rubella, irrespective of his/her age A syndromic approach is recommended for measles and rubella surveillance. Description of terms Fever: Typically, the fever increases during the prodromal phase and peaks (generally > 39 °C) around the onset of the rash. Rash: It is a red, blotchy, maculopapular (erythematous macules) rash, which is not filled with fluid (non-vesicular), not itchy and not painful. It appears first on the face, close to the hairline and behind the ears coalescing , spreads over the neck, chest and abdomen, and finally affects the hands and feet, involving the entire body by day 3. The rash lasts for 3–7 days and gradually fades in the order of appearance. As it disappears, it becomes non-blanching and brownish yellow. There can be intensive peeling for 1–2 weeks. Associated differentiating symptoms: Cough, a running nose and sneezing (coryzal symptoms) and red inflamed and watery eyes (conjunctivitis) are specific symptoms that differentiate measles from many other influenza-like illnesses. Similarly, cervical, suboccipital or postauricular adenopathy or arthralgia/arthritis differentiate measles from many other cases of fever and rashes. 7MEASLES AND RUBELLA Response to suspected case Specially trained staff or an epidemiologist should start investigating a suspected case within 48 hours of the time of reporting of the case. Investigation of suspected case Case investigation form A standard case investigation form should be used to investigate each suspected case (see Annex 2 for a sample form). Adequate investigation: An adequate investigation includes the collection of the following data elements from each suspected case: name or identifiers, place of residence, place where the infection was contracted (at least to the district level), age (or date of birth), sex, date of onset of rash, date of specimen collection, status of vaccination, dates of all measles–rubella or measles–mumps–rubella vaccinations, date of notification of the case, date of investigation and travel history. Unique ID Each suspected case should be assigned a unique identification number (UID). Every form, biological specimen label and communication related to the suspected case should bear this number. The UID should consist of the following: z Name of the disease (MR for measles/rubella) z Country code z State/province code z District code z Year in which suspected case was reported (YY) z Serial number of the case (in three digits, e.g. 001) MR- _______/____________/__________/____/_____ Country code/ Province code/District code/ Year/serial number Specimen collection The specimen should be collected on the very first contact with the suspected case. Waiting for the most appropriate time may result in the loss of the case. The timing of the initiation investigation influences the types of specimen to be collected. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Types of specimens For MR-specific IgM antibody detection Blood may be obtained by venepuncture, or through a finger prick and then dried on filter paper (dried blood spots or DBS). Alternatively, oral fluid can be obtained using oral fluid collection devices. The preferred specimen for laboratory confirmation is serum. Specimen for the detection of IgM antibody should be collected within 28 days of the onset of rash. In the first three days, the sensitivity of the test might be less than 30% for measles and 50% for rubella. For virus detection and isolation The specimens that can be collected for the isolation of the virus or detection of its RNA are a throat or nasopharyngeal (NP) swab, nasal aspirate, oral fluid or urine. Throat swabs are preferred due to the ease of collection and high success rate in molecular tests. Specimens for virus detection by molecular methods should be collected within 7 days of the rash onset. Though the virus can be detected in throat swab samples collected in the second week after the onset of rash, the success rate is much lower. For the isolation of the virus by cell culture methods, it is recommended that samples be collected within 5 days, preferably within the first 3 days of the onset of rash. These specimens can be used for genotype characterization of measles and rubella viruses, which helps in the identification of transmission chains and genetic linkages. In countries that have been verified as having eliminated measles and/or rubella or have re-established transmission, every suspected case should have samples collected both for serology and virus detection. In countries that are endemic for measles and/or rubella: z serum specimen (gold standard) should be collected from all suspected cases for laboratory confirmation of measles or rubella diagnosis; and z throat or NP swab or urine should be collected from at least 80% of the sporadic cases and all outbreaks for genotype characterization of circulating measles and rubella viruses. Annex 3 presents the details of the methods of collection, storage and transport of samples. 9MEASLES AND RUBELLA Case confirmation A case can be confirmed as one of measles if the following test results are obtained in the laboratory: z detection of anti-measles IgM antibody by enzyme immunoassay (EIA) z detection of measles or rubella RNA by reverse transcription-polymerase chain reaction (RT-PCR) or z isolation of measles and rubella viruses in cell culture (Fig. 1.1a); and z a diagnostically significant titre changes in IgG antibody level in acute or convalescent sera, or documented seroconversion (IgG-negative to IgG-positive) (Fig.1.1b and 1.1c). Algorithm for testing serum specimens in the laboratory: The countries that have been verified as measles or rubella eliminated or achieved low disease incidence and are targeting for measles or rubella verification status should adopt parallel testing of serum specimens for measles and rubella. Countries that are experiencing high incidence of measles disease may consider adopting sequential test algorithm (Figure 1). Figure 1: Laboratory testing algorithms for serum specimen. Serum sp. Measles IgM Rubella IgM Serum sp. Measles IgM Rubella IgM (countries with high measles incidence ) Parallel (countries eliminated or achieved low measles incidence) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 Algorithm for testing throat/NP swabs and urine specimens in the laboratory: Throat or NP swabs and urine specimens can be tested by real time RT-PCR for measles and rubella case confirmation or by end-point RT-PCR for genotype characterisation. The choice of RT-PCR test on throat swabs and urine specimens should be based on country requirements, that vary as per their current status for achieving measles elimination, Figure 2. Figure 2: Choice of measles rubella serology and molecular tests based on country status of measles rubella elimination. 1. Cases with no adequate serum specimen (serum specimen could not be collected due to parents’ denial, infants, logistic issues, etc) 2. Serum specimen collected close to rash onset date when IgM serology results are expected to be negative (sample collection within 2 days of rash onset) 3. Poor quality serum specimen: grossly hemolyzed or contaminated or less quantity 4. IgM results are not conclusive: dual reactive, equivocal or doubtful based on epidemiology and clinical information) 5. Trouble shooting genotype PCR results, for e.g. measles or rubella IgM positive serum with negative results in corresponding end-point genotype RT-PCR assay or vice versa *Specific scenarios for undertaking real time RT-PCR test: Endemic Countries • Serology is mainly used • RT-PCR assay, a costly test, not advised • End-point RT-PCR done genotype • Serology remain the primary method for case • add value in specific scenarios* • End-point RT-PCR in genotype Eliminated Measles • No measles transmission in the country • should be based on both PCR assay results • , efforts should be made for genotype virus. For dual reactive serum specimens or doubtful results, it is recommended that the regional laboratory coordinator be consulted to determine if additional testing is warranted and feasible. 11 MEASLES AND RUBELLA Case classification Laboratory-confirmed case A laboratory-confirmed case is a suspected case which has been confirmed to be positive through testing in a proficient laboratory, and which has not been caused by vaccine- associated illness. A proficient laboratory is one that is WHO-accredited or has recognized quality assurance certification, such as by the International Organization for Standards (ISO) or Clinical Laboratory Improvement Amendments (CLIA). If a case is found to be equivocal during laboratory testing, the laboratory should follow the WHO MR laboratory guidelines for the interpretation of equivocal cases. This includes the collection of repeat samples, when indicated. Epidemiologically linked case This is a suspected case of measles that has not been confirmed by a laboratory but is geographically and temporally related with a laboratory-confirmed case or another epidemiologically linked case. For measles, the onset of rash should occur 7–23 days apart from a laboratory-confirmed case or another epidemiologically linked case, and for rubella, 12–23 days. Clinically compatible measles case This refers to a suspected case with fever, maculopapular (non-vesicular) rash and one of the symptoms of cough, coryza and conjunctivitis, for which no adequate clinical specimen was taken, and which has not been linked epidemiologically to a laboratory-confirmed case of measles/rubella or another laboratory-confirmed communicable disease. Clinically compatible rubella case This refers to a case with maculopapular (non-vesicular) rash, fever (if measured) and one of arthritis/arthralgia and lymphadenopathy, for which no adequate clinical specimen was taken, and which has not been linked epidemiologically to a laboratory-confirmed case of rubella/measles or another laboratory-confirmed communicable disease. Non-measles non-rubella case A suspected case that has been investigated and discarded is termed a non-measles, non- rubella case if any of the following is true: z An adequate specimen collected during the proper time period after the onset of rash has tested negative in a proficient laboratory. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 z There is an epidemiological linkage to a laboratory-confirmed outbreak of another communicable disease that is not measles or rubella. z Another aetiology has been confirmed, regardless of whether it meets the definition of an epidemiological linkage. z The case does not match the definition of a clinically compatible measles/rubella case. Vaccine-associated illness A person with illness associated with the measles vaccine is a suspected case who meets all five of the following criteria. z The patient had an illness marked by rashes, with or without fever, but did not have a cough or other respiratory symptoms related to the rash. z The rash began 7–14 days after vaccination with a measles-containing vaccine. z The blood specimen, which was positive for measles IgM, was collected 8–56 days after vaccination. z Thorough field investigation did not identify any secondary cases. z Field and laboratory investigations failed to identify other causes. Acute measles-related death This denotes any death occurring within 30 days of the onset of rash in a measles case (confirmed, epidemiologically linked or clinical) that is related to a complication of measles, such as pneumonia. The complications of measles occur mostly after the second week of the onset of rash. Rare deaths from post-infectious encephalitis and subacute sclerosing panencephalitis occur months to years after the measles infection and surveillance for acute measles illness would not be able to detect these conditions. Classification by source of transmission Laboratory-confirmed or epidemiologically confirmed cases should be further classified as imported cases, import-related cases and cases with an unknown source according to the source of the infection. Endemic cases The endemic transmission of measles denotes the existence of any continuous indigenous chain or re-established chain of transmission of measles/rubella virus that has persisted for > 1 year in any defined geographical area. An endemic measles case is a laboratory- confirmed or epidemiologically confirmed measles case resulting from endemic transmission of the measles virus. As for rubella, any case that cannot be proved to be imported is considered endemic. 13 MEASLES AND RUBELLA Imported cases An imported measles case is a confirmed case who, as supported by epidemiological and/or virological evidence, was exposed to a measles case outside the country or region 7–21 days prior to the onset of rash. For rubella, the time frame is 12–23 days. The patient must have a history that demonstrates travel to an area where measles/rubella occurs and during a plausible time frame; the results of molecular sequencing of the virus isolated from the cases should be compatible with the areas/countries visited. A thorough community investigation must be carried out to exclude the possibility of local exposure to measles/rubella. Import-related cases An import-related case is a confirmed case who, as supported by epidemiological and/or virological evidence, has locally acquired infection as part of a transmission chain related to an imported case. A chain of transmission consists of two or more confirmed cases who are epidemiologically linked. The investigation should thus demonstrate that the import- related case had direct contact with an imported case or another import-related case 7–21 days before the onset of rash (12–23 days for rubella). The molecular sequencing data of the isolated virus, if available, could support the link. Cases with unknown source of infection These are confirmed cases for which the source of infection was not identified. It is possible that an epidemiological link to an imported case or an import-related case cannot be found even after a thorough investigation, and sporadic cases with an unknown source of infection are not necessarily indicative of endemic transmission. However, the identification of sporadic cases might indicate gaps in surveillance. The pattern of occurrence of these cases (e.g. the number of transmission chains, number of cases involved, geographical and temporal distribution) is as important as their number. Contact tracing Since both measles and rubella are highly infectious, contact tracing must be undertaken both to determine the source of the infection (endemic or imported/import-related), as well as to identify those whom the case may have subsequently infected. A line list must be made of all persons with whom the suspected case had contact during the infectious period (for measles: 4 days before to 4 days after the appearance of the rash; for rubella: 7 days before to 7 days after the rash appeared). The public health authorities should monitor all contacts for 23 days since their last contact with the confirmed case. “Contact” refers to sharing the same airspace, usually an enclosed area (living in the same household or being in the same room, school, health facility waiting room, office or transport), for any length of time with a case during the infectious period of the case. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 The following are a few examples of the categories of people among whom contact tracing should be conducted: z household contacts z students and employees of educational centres z child care / day-care contacts z workplace contacts z health-care facilities. When conducting contact tracing, it should be kept in mind that the virus remains contagious in the air or on infected surfaces for up to two hours. Hence, transmission can occur even if the contact was not in the same room as the case at the exact same time. In some investigations, contacts are considered those who occupied an enclosed airspace within two hours of when the case was there. Active case search To ensure that all cases are identified and reported, active case searches should be conducted in response to confirmed cases of measles or rubella. Active case searches are conducted by asking key people in the community and in schools if they know of anyone with fever and rash. This activity can be aided by using pictures of measles/rubella patients with a maculopapular rash. Such searches are usually conducted within a radius of 100–1000 m from the confirmed case. This may be within the perimeter of an entire village, in a cluster of villages, a ward of a town or an entire town, and so on, depending on a local epidemiological assessment. In addition, active case searches must cover health facilities. The staff of the health facilities should be interviewed, and registration records, discharge diagnoses and hospital charts must be reviewed so as to identify patients with illnesses marked by fever and rash and learn of their final diagnosis. During and following rubella outbreaks, active surveillance should be conducted in the affected area for congenital rubella syndrome (CRS), with special focus on the investigation and active follow-up of pregnant women with an illness marked by rashes. Additional measures could include the investigation and vaccination of susceptible contacts to reduce the risk of exposure to pregnant women. Clinical management Case management There is no specific treatment for measles. Case management focuses on supportive care, as well as the prevention and treatment of complications and secondary infections. 15 MEASLES AND RUBELLA Supportive care includes providing relief from the common symptoms of fever, cough, nasal congestion or rhinorrhoea, conjunctivitis and sore mouth. Since measles is highly contagious, an important intervention is to isolate the patient to prevent further spread of the virus. Increasing population immunity through vaccination is the most effective way to prevent outbreaks. z Nutritional support is recommended to reduce the risk of malnutrition due to the diarrhoea, vomiting and poor appetite associated with measles. Breastfeeding should be encouraged, where appropriate. Oral rehydration salts should be used to prevent dehydration, when necessary. z Vitamin A should be administered to all acute cases, irrespective of the timing of the previous doses of vitamin A. The patient should be given an oral dose of vitamin A immediately on diagnosis and again the next day. Infants < 6 months of age should be given 50 000 IU, infants of the age of 6–11 months 100 000 IU, and children ≥ 12 months 200 000 IU. If the child has clinical ophthalmic signs of vitamin A deficiency, such as Bitot’s spots, a third dose should be administered 4–6 weeks later (5). z The complications of measles, such as otitis media, pneumonia and diarrhoea, should be managed using the Integrated Management of Childhood Illness (IMCI) case management algorithm or on the basis of the recommendations in the country. z Severe measles cases, such as those with severe pneumonia, dehydration or seizures, require specific treatment (antibiotics, rehydration, anticonvulsants) and should be treated as inpatients due to the increased risk of mortality. IMCI specifically recommends the assessment and treatment of children with eye and mouth complications. z Measles cases should be isolated from non-measles cases in inpatient facilities. Non-hospitalized measles cases should be isolated in the home until four days after the onset of rash. Management of contacts The following steps should be taken to minimize the spread of disease. z Contacts without documented evidence of measles and/or rubella vaccination should be vaccinated, and the symptoms of measles and rubella should be explained to them. z A contact should be instructed to stay at home during the second week after exposure, and at the first sign of fever and maculopapular rashes. z A contact should be followed up to determine if he/she subsequently fell ill. If so, laboratory specimens should be collected from the person. z A pregnant woman with suspected rubella should be followed until the completion of her pregnancy to document the outcome (e.g. normal, CRS, miscarriage, stillbirth), especially if the outbreak has been labelled as one of rubella. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 z Unvaccinated contacts who are ≥ 6 months of age and eligible for vaccination should be vaccinated for prophylaxis within 72 hours of exposure, if possible. This can prevent measles infection. However, if disease does develop despite post-exposure prophylaxis, the symptoms are usually not severe and the duration of the illness is relatively shorter. z If a person is given a dose before reaching the age at which the routine first dose of measles-containing vaccine (MCV1) is administered (at 9–12 months of age), the dose is referred to as MCV0 and does not count. z As for contacts who have contraindications to the measles vaccine, human immune globulin may be administered intramuscularly within 6 days of exposure. These contacts include pregnant women, infants < 6 months of age and individuals with impaired immune systems. If administered within 6 days of exposure, this method of passive immunization can prevent illness or reduce its severity. Outbreak Definition The definition of a confirmed measles outbreak recommended by WHO’s Strategic Advisory Group on Immunization (SAGE) is: “… a single laboratory-confirmed measles case”. Similarly, “A single laboratory-confirmed rubella case is also considered to be a confirmed rubella outbreak.” [World Health Organization. Framework for verifying elimination of measles and rubella. Weekly Epidemiol Rec 2013; 88:89-98] Chain of transmission Two or more laboratory-confirmed cases that are temporally related (with the dates of the onset of rash occurring 7–23 days apart) and epidemiologically and/or virologically linked constitute a chain of transmission. Large outbreak If within a period of 1 month, the chain of transmission includes 5 or more cases in a population of more than 100 000, an appropriate response should be launched. The definition of the response may vary from country to country on the basis of the local epidemiology and transmission level of the disease. End of an outbreak An outbreak is considered over after there have been no further epidemiologically or virologically linked cases for two incubation periods (46 days) from the date of the onset of symptoms of the last case, provided there is a well -performing surveillance system. 17 MEASLES AND RUBELLA Preparedness and response z Countries should have a detailed plan in place to respond to outbreaks and the plan should be put into action. It should include the delineation of a hierarchy to respond to incidents; subgroups and their responsibilities and pre-identified roles; and rapid response teams. It should set out standard operating procedures, including procedures for response activation, information management and flow, and response deactivation. Further, it should make provisions for contingency plans, such as on surge capacity. z The plan should be readily available and accessible to all levels of the health system. z The country should have adequate capacity (both at the national and state/ provincial levels) to rapidly respond to an outbreak. z Contingency funds should be available at the national level, and there should be established systems for their rapid transfer to the state /province or district level in case of a suspected outbreak. z An assessment of outbreak preparedness should be conducted at the national as well as subnational levels, using the WHO checklist (adapted, if required) on outbreak preparedness assessment. Investigation of outbreak For details on this, see the section on public health response. Modification of surveillance during large outbreaks z When outbreaks become too large to allow for the maintenance of normal case investigation protocols, contact tracing should be deprioritized and a large public health response should be given priority instead. z Line listing of cases should be considered and the number of elements required to be collected for each individual case should be decreased. However, at a minimum, the UID, name, age, vaccination status, travel history and residence must continue to be collected. When possible, an outbreak ID should also be assigned to all cases associated with the outbreak. More detailed information, such as potential sources of infection (medical settings, school settings, etc.), should be collected on a sample of cases to help determine the major transmitters and transmission settings. z Laboratory specimens should be collected from approximately the first 5–10 suspected cases in an outbreak. z If 2 or more specimens are positive for measles IgM and less than 2 for rubella IgM, or measles virus is isolated/detected from any sample, the outbreak is classified as a measles outbreak. z If 2 or more specimens are positive for rubella IgM and less than 2 for measles IgM, or rubella virus is isolated/detected from any sample, the outbreak is classified as a rubella outbreak. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 z If 2 or more specimens are positive for measles IgM and 2 or more for rubella IgM, the outbreak is classified as a mixed measles and rubella outbreak or co-circulation of measles and rubella. z If less than 2 samples are positive for measles or rubella IgM, the outbreak is discarded, and the cases are treated as sporadic cases. The public health response is initiated accordingly. Specimens are not required from suspected cases who satisfy the clinical case definition of epidemiologically linked to a laboratory-confirmed or other epidemiologically linked case. z Epidemiological linkage should be the primary means of classifying new cases during a confirmed outbreak. z However, the criteria for epidemiological linkage must be strict enough to provide confidence of a high positive predictive value for the epidemiologically linked case to be a true measles case. The criteria for epidemiological linkage include: z being a known contact; and z being in the same physical setting as the case during their infectious period (shared enclosed airspace, such as at home, school and workplace). z If no epidemiological link is established, the suspected case should undergo laboratory tests. z If an outbreak continues over a protracted period, another 5–10 samples should be collected every 2 months to ascertain whether the outbreak is still one of measles. Genotyping becomes particularly important when the duration of an outbreak is approaching 12 months in a country in which measles had previously been eliminated. This helps to determine whether the cases are a part of the same outbreak or due to new importation of a different measles virus strain. z To characterize the extent of the outbreak, intensified passive reporting and active surveillance should be established in the neighbouring villages, districts and possibly, provinces, in response to laboratory-confirmed cases or outbreaks. z Epidemiological data should be analysed rapidly to identify vulnerable groups with low immunity and to target immunization activities appropriately. Public health response When to initiate a public health response According to the Regional guidelines, a public health response should be initiated as soon as there is a laboratory-confirmed case. However, considering that laboratory reporting may be delayed, a decision needs to be taken on whether to initiate a response to HOT CASES. A HOT CASE: z has a fever, rash and the three Cs (coryza, cough and conjunctivitis); 19 MEASLES AND RUBELLA z has no history of vaccination; and z has a confirmed history of travel to an area with an ongoing outbreak. Steps to be taken when a measles/rubella outbreak is suspected z Investigating cases (Annex 2, Annex 4f) z Undertaking clinical case management z Tracing contacts (Annex 4b) z Surveying immunity gaps in the population (Annex 4c) z Stepping up surveillance z Closing gaps in population’s immunity (outbreak response immunization [ORI]) z Isolating suspected cases z Analysing outbreak data (Annex 4d) z Disseminating messages to the public z Reporting the outbreak (Annex 4e) z Declaring the end of the outbreak z Conducting a root cause analysis and drawing up a recovery plan z Special considerations on dealing with large outbreaks Case investigation z The case investigation form must be completed for all cases (Annex 2). z A blood sample must be collected at the first opportunity, and so must throat/ NP swabs be collected to identify the virus genotype/molecular sequence. z The pregnancy status of female cases must be determined. Pregnant women infected with or exposed to rubella must be followed up. A pregnant woman with confirmed rubella should be followed up till the completion of her pregnancy to document the outcome and the newborn should be evaluated for CRS. z At the end of the investigation, cases must be classified on the basis of laboratory results and the source of infection. Clinical case management z Currently, there is no specific antiviral treatment for measles or rubella. z The patient should be treated for complications of measles. z All cases do not require hospitalization and uncomplicated cases can be managed at home. For these cases, fluids (such as oral rehydration solution), antipyretics and nutritional therapy are commonly indicated. z The administration of vitamin A to children with measles decreases both the severity of the disease and the case fatality rate. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Contact tracing A contact is a person associated with the patient in time and place: z in the same room while the case is present and up to 2 hours afterwards z in the same house, workplace, school, gumba/church/mosque/ temple, village, district. There are two types of contacts. Those who infected the case 7–21 days ago in the case of measles, and 12–23 days ago in the case of rubella. In such cases, it is necessary to determine the source of the virus (imported, import-related, endemic), identify other cases and ascertain the extent of transmission. z Those who were potentially infected by the case 4 days before to 4 days after the onset of rash in the case of measles and 7 days before to 5 days after in the case of rubella. They should be followed up to prevent further transmission of the virus. Survey of population immunity z The trend in the coverage of MRCV1 and MRCV2 must be reviewed. z It is necessary to review the coverage of any supplementary immunization activities (SIA) or other periodic intensification of routine immunization activities related to MCV in the area. z The vaccination status of the contacts must be reviewed. z Any immunity gaps should be identified, with a special focus on hard-to-reach populations. z A community census of the local catchment area must be conducted to look into the immunity profile of the population. Enhancing surveillance z A search must be conducted for additional unreported cases during the community survey. z A search must be conducted for persons with fever and rash within a radius of 100–1000 m from the confirmed case. This could mean an entire village, a cluster of villages, etc., depending on a local epidemiological assessment. z Active case searches should also cover health facilities. The staff should be interviewed, and registration records, discharge diagnoses and hospital charts should be reviewed to identify patients with an illness marked by fever and rash and to learn of their final diagnosis. z The case search should be repeated after four weeks to ascertain that the outbreak is over. 21 MEASLES AND RUBELLA Closing gaps in immunity of population z An ORI or SIA must be conducted on the basis of the epidemiological data. To determine the nature of the response, it is necessary to determine the following. z Extent of transmission:  duration of transmission, number of generations;  number of cases – total and in each generation of transmission; and  number and location of the villages, districts and provinces affected. z Epidemiology:  ages affected;  vaccination status;  travel;  occupation; and  other risks. z Immunity of the population in the affected and surrounding areas z Quality of surveillance in the affected and surrounding areas z Response capacity:  vaccine, logistics, cold chain, staff, training of staff, transport for possible ORI; and  Vitamin A, antibiotics and oral rehydration solution for case management. z In low-risk areas (i.e. for people with documentation of prior vaccination), the following should be selectively vaccinated: z children who are 6 months to 14 years old and have presented to health facilities nearby or outreach sites; and z health facility staff in affected and nearby areas. z Non-selective immunization should be considered in the case of a large outbreak or if the area is a high-risk one. z Routine immunization should be reinforced by: z identifying low-coverage areas nearby; z intensifying routine work plan activities; z conducting additional outreach services, if necessary; and z providing additional staff, if required. z International visitors should be screened and vaccinated if they do not have documentation of immunity to measles. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 Isolation of suspected cases z Suspected measles patients should be isolated until 4 days after the appearance of the rash and suspected rubella patients, until 5 days after the onset of rash. z During the second week after exposure and at the first sign of fever and maculopapular rashes, the contact should be instructed to stay at home. z In hospital settings, the staff should take care to use proper infection control practices (e.g. isolation, negative pressure), as measles is extremely contagious. z There is a high risk of nosocomial transmission among non-immune health-care workers and other patients, including unimmunized infants. Data analysis An analysis of the data on an outbreak consists of the following components. Describing the outbreak z Time: epidemic curve (at least 2 incubation periods before and after the first and last case) z Place: spot map z Person: age/age group, stacked by vaccination status on bar chart or tables z Calculate incidence if population data available Assessing severity of outbreak z Deaths (case fatality ratio = dead cases/all cases) z Proportion of cases hospitalized z Proportion of cases with complications z For female rubella patients: incidence of CRS 6–9 months later z Economic cost of outbreak Evaluating effectiveness of vaccine, if possible z Determine directly by z Case control study (1 - odds ratio) VE=1-OR=1-AD/BC z Cohort study (1 - risk ratio) or [(ARU-ARV)/ARU)] ARV=attack rate among vaccinated = A/A+B ARU=attack rate among unvaccinated = C/C+D VE= 1-RR=1-(ARV/ARU) = (ARU_ARV)/ARU. z Determine indirectly with the help of nomogram that uses proportion of cases vaccinated versus proportion of population vaccinated (Annex 4a). 23 MEASLES AND RUBELLA Disseminating messages to the public z Inform the public about the existence of the outbreak. z Explain the seriousness of measles and rubella. z Describe the signs and symptoms of the disease. z Encourage persons with symptoms and signs of measles or rubella to seek medical advice as soon as possible. z Inform the public about the benefits of vaccination against measles and rubella. z Inform the public about the efforts that should be made to control the disease. z Explain who should receive MRCV (in accordance with the relevant public health guidelines), and where and when they can receive the vaccine. z Highlight the importance of evaluating pregnant women who have had contact with a rubella case. Reporting an outbreak z Initial report: This should contain data analysis and recommendations for launching an immediate response. z Interim report: The report focuses on the progress of the implementation of the response measures. z End report: This contains immediate -, medium- and long-term recommendations, and includes a root cause analysis to prevent further outbreaks. Annex 4e contains a sample reporting format. Declaring the end of an outbreak An outbreak can be declared to have ended when no new cases have been reported after 2 incubation periods have elapsed, i.e. 42 days. A prerequisite for declaring the end of the outbreak is a well-performing surveillance system that fulfills all the surveillance performance indicators. In addition, an active case search should have been conducted. Root cause analysis and recovery plan As part of post-outbreak recovery, a root cause analysis should be conducted and a strategy developed to ensure that the immunization system recovers following the outbreak and that the recovery is sustained. The root cause analysis may include the following features. z The failure to vaccinate a large number of unvaccinated people due to: z low routine coverage, or z low coverage of the campaign (<95%) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24 z Vaccine failure (vaccine did not work): z Expected – up to 15% primary vaccine failure (i.e. 85% vaccine effectiveness) when vaccine is given at 9 months of age z Unexpected – e.g. cold chain problems and vaccine of poor quality z Other factors: z Failure of policy or schedule – targeting of wrong age group during SIA and long interval between MCV1 and MCV2 (e.g. administered at 7 years) z Migration – massive influx of susceptible populations and importation of cases z Children born to HIV+ women Tools for outbreak response z Form 1: Case investigation form (Annex 2) z Form 2: Contact tracing (Annex 4b) z Form 3: Community census (Annex 4c) z Form 4: Analysis of data and outbreak severity (Annex 4d) z Form 5: Reporting of MR outbreak (Annex 4e) z Form X: Line list for large outbreaks (Annex 4f) Data management Reporting requirements It is necessary to report and analyse case-based data on all suspected cases, regardless of the final classification, from the local to the national level, to facilitate quality epidemiological analysis. Measles cases should be reported regularly to the next level within the ministry of health (at least monthly, preferably weekly). This should include zero reporting. Every WHO Member State uses the Joint Reporting Form to report confirmed cases of measles annually. In addition, WHO recommends that all countries submit monthly case- based data to it. Measles is currently not a notifiable disease under the International Health Regulations (IHR); however, measles outbreaks may be considered as events involving epidemic-prone diseases of special national or regional concern that “have demonstrated the ability to cause a serious public health impact and to spread rapidly internationally”. As such, they may be reported through IHR mechanisms. Unique ID As explained earlier, every suspected case should be assigned a UID. 25 MEASLES AND RUBELLA Recommended data elements z Demographic information z Reporting source z Clinical information z Laboratory methods and results z Vaccination status z Contact tracing z Epidemiological data z Final case classification (laboratory-confirmed, epidemiologically linked, clinically compatible, discarded) z Source (imported, import-related, unknown, endemic) Note: A time period of 7–23 days is counted as the exposure periods of both measles and rubella. Details of these data elements are given in the case investigation form in Annex 2. Data analysis The factors to be taken into account in the data analysis are: z number of suspected and confirmed cases by age, date of onset of illness (by month and year at a minimum, by week in an outbreak setting), and geographical area; z incidence per million population by 12-month period and by geographical area (it is not appropriate to calculate the incidence for shorter periods of time because of seasonality); z incidence rates specific to age, sex and district; z proportion of confirmed cases by age group and immunization status (suggested groups: < 6 months, 6–8 months, 9–11 months, 1–4 years, 5–9 years, 10– 14 years, 15–19 years, 20–24 years, 25–29 years, 30–44 years and ≥ 45 years; may vary depending on epidemiology, vaccination schedule and vaccine programme); z measles vaccine status of confirmed and discarded cases by year and geographical area; z epidemiological curve showing cases over time by genotype/named strain; z proportion of cases by final classification and source; z maps of cases; Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 26 z proportion of complications and death, stratified by age; z proportion of cases that were preventable (e.g. age ≥ that of first recommended dose), separated into vaccine failures and programmatic failures, and the proportion of cases not preventable by vaccination (age below that of first recommended dose); and z data summaries of endemic and imported virus genotype and lineage characterization. Using data for decision-making Regular epidemiological analysis and synthesis of data, based on local knowledge of the context, are necessary to capture patterns of disease and any immunity gaps. Such analysis indicates whether there are likely to be any future issues that may require action, and whether the control and elimination status will be sustained. The analysis should include an epidemiological description of who is infecting who, particularly with respect to the source of infection for infants, and where immunity gaps seem to be the most evident among birth cohorts or underserved populations. The synthesis should be derived from and informed by an analysis of surveillance data. The most important uses of data are to: z identify the proportion of disease due to endemic circulation and that due to importation; z characterize transmission patterns, including the age groups that are the main transmitters of infection to infants, and the effectiveness of methods to interrupt transmission; z determine the risk factors for infection, complications and death; z determine the major reasons for which cases are non-immune and take action to fill gaps in the vaccination programme or modify it; z verify if an outbreak has been eliminated and assess the sustainability of elimination; z identify birth cohorts with immunity gaps, assess the risk of the spread of an outbreak and protect the neighbouring areas; and z confirm cases and outbreaks to take appropriate action to prevent further transmission. Indicators for surveillance performance Table 1.1 lists indicators, established by WHO, against which the measles surveillance system can be evaluated in order to help pinpoint problems and make improvements. 27 MEASLES AND RUBELLA Table 1.1: Indicators for the quality of field and laboratory surveillance for measles (and rubella) Attribute Indicator Target How to calculate Comments Timeliness of reporting Proportion of surveillance units reporting to the national level on time, even in the absence of cases ≥ 80% (Number of surveillance units in the country reporting by the deadline / number of surveillance units in the country) x 100 At each level, reports should be received on or before the requested date. Timeliness of reporting (WHO Region ) Proportion of countries reporting to their respective Regional Offices on time, even in the absence of cases 100% (Number of countries in the Region reporting to WHO by the deadline / number of countries in the Region) x 100 At each level, reports should be received on or before the requested date. Timeliness and completeness of investigation Proportion of all suspected measles and rubella cases for which an adequate investigation was initiated within 48 hours of notification ≥ 80% (Number of suspected cases of measles or rubella for which an adequate investigation was initiated within 48 hours of notification / number of suspected measles and rubella cases) x 100 An adequate investigation includes the collection of all the following data elements from each suspected measles or rubella case: name or identifiers, age (or date of birth), sex, place of residence, place of infection (at least to the district level), age (or date of birth), sex, date of rash onset of rash, date of specimen collection, measles-–rubella vaccination status, date of all measles-–rubella or measles-–mumps–-rubella vaccinations, date of notification, date of investigation and travel history. Some variables may not be required for cases that are confirmed by epidemiological linkage (e.g.for example, date of specimen collection). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 28 Proportion of all suspected measles and rubella cases for which an adequate investigation was initiated within 48 hours of notification ≥ 80% (Number of suspected cases of measles or rubella for which an adequate investigation was initiated within 48 hours of notification / number of suspected measles and rubella cases) x 100 Note 1 and Note 2 Case investigation Proportion of confirmed cases for which source of transmission is classified as endemic, imported or import-related ≥ 80% (Number of confirmed cases for which source of transmission is classified as endemic, imported or import-related / total number of confirmed cases) x100 The minimum number of cases should be classified as having an unknown source of transmission, but such cases are bound to occur despite thorough field investigations. It might not be possible to identify the source in large outbreaks. Representativeness Proportion of subnational administrative units reporting at least 2 discarded non-measles non-rubella cases per 100 000 population per year ≥ 80% (Number of subnational units achieving discard rates ≥ 2 per 100 000 / number of subnational units) x 100 If the administrative unit has a population < 100 000, the rate should be calculated by combining data over more than a year or combining neighbouring administrative units to achieve ≥ 100 000 person-years of observation. An administrative unit should take into account all cases reported from its catchment area, including imported and import-related cases, and cases residing in neighbouring administrative units but reported in this one. 29 MEASLES AND RUBELLA Adequacy of specimen collection and testing Proportion of suspected cases with adequate specimens collected and tested by a proficient laboratory ≥ 80% (Suspected cases with an adequate specimen tested by a proficient laboratory / suspected cases not tested by a laboratory and (a) confirmed as measles or rubella by epidemiological linkage, or (b) discarded as non-measles and non- rubella by epidemiological linkage to another laboratory- confirmed communicable disease case) x 100 Adequate specimens are: a blood sample collected by venepuncture in a sterile tube with a volume of at least 1 mL for older children and adults, and 0.5 mL for infants and younger children; a dried blood sample filling at least 3 full circles on a filter-paper collection device; an oral fluid sample obtained by using a sponge collection device that is rubbed along the gums for > 1 minute to ensure that the device is thoroughly wet; and a properly collected upper respiratory tract specimen for RT-PCR. Adequate samples for antibody detection are those that are collected within 28 days of the onset of rash, and for RT-PCR within 5 days of the onset of rash. A proficient laboratory is one that is WHO-accredited and/or has recognized quality assurance certification, such as by the ISO or CLIA. Detection of virus Proportion of laboratory- confirmed outbreaks with adequate samples collected and tested, in an accredited laboratory, for the detection of measles virus ≥ 80% (Number of outbreaks with adequate samples submitted for viral detection / number of outbreaks identified) x 100 Where possible, samples should be collected from at least 5–10 cases early in a chain of transmission and every 2–3 months thereafter if transmission continues. Adequate throat or urine samples for the isolation of the virus are those collected within 5 days of the onset of rash. For virus detection using molecular techniques, an adequate throat sample is one that is collected up to 14 days after the onset of rash, and an adequate oral fluid sample one collected up to 21 days after the onset of rash. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 30 Timeliness of specimen transport Proportion of specimens received by laboratory within 5 days of collection ≥ 80% (Number of specimens received by laboratory within 5 days of collection / number of specimens collected) x 100 This indicator applies only to public laboratories. Timeliness of reporting of laboratory results Proportion of IgM test results reported to national public health authorities by laboratory within 4 days of receipt of specimen ≥ 80% (Number of IgM test results reported within 4 days of receipt of specimen / number of specimens received by laboratory) x 100 This indicator applies only to public laboratories. 31 MEASLES AND RUBELLA Risk assessment The WHO Measles Programmatic Risk Assessment Tool has been drafted to help national programmes to: z identify areas in which the targets of the measles programme are not being met; z use the findings to guide and strengthen the activities of the measles elimination programme; and z reduce the risk of outbreaks. This tool triangulates data from surveillance and the immunization programme to give a more complete map of the subnational risk of measles outbreaks. One limitation of the tool is that it focuses primarily on early childhood risk. The WHO Measles Programmatic Risk Assessment Tool can be accessed at: https://www.who.int/teams/immunization-vaccines-and-biologicals/immunization- analysis-and-insights/surveillance/measles-programmatic-risk-assessment-tool 32 33 MEASLES AND RUBELLA Annex 1: Disease epidemiology – measles and rubella Background The measles virus is one of the world’s most contagious human viruses known. Rubella is of public health importance because of the teratogenic potential of infections acquired during pregnancy. The rubella virus is generally recognized as the most common infectious cause of birth defects, account¬ing for an estimated 100 000 infants born with CRS worldwide each year. The elimination of measles is estimated to have prevented at least 1.1 million cases of measles in the South-East Asia Region every year and for each case prevented, approximately 2 weeks of disability-adjusted life years are averted. In addition, a combination of various strategies can avert approximately 1.1 million deaths due to measles by 2023, at an average cost of US$ 1373 per death averted. It is estimated that the elimination of rubella is preventing 52 118 cases of CRS annually in the Region. The disability-adjusted life years averted for every CRS case prevented range from 27 years in low- and middle- income countries to 18 years in high-income countries. Table 1.A1: Disease epidemiology Epidemiological features Measles Rubella Infectious agent Morbillivirus genus Rubivirus genus Reservoir Humans Humans Mode of transmission Airborne, by droplet spread Direct contact with nasal and throat secretions of infected person Less commonly, through articles freshly soiled with nose and throat secretions Airborne, by droplet spread Direct contact with NP secretions of infected persons Incubation period About 10 days (range 7–21 days) 15 days (range 14–23 days) Period of communicability Infectiousness Before the beginning of the prodromal phase, 4 days before the onset of rash to 4 days after Extremely infectious – a single case may infect an average of 15–20 individuals in a totally susceptible population About 1 week before the appearance of the rash to 4 days after Case fatality ratio 3–6% Annexes Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 34 Vaccines Measles vaccine: Several live attenuated measles vaccines are available, most of them originating from the Edmonston strain of the measles virus. These are either monovalent vaccines, or polyvalent, i.e. combined with the rubella, mumps or varicella vaccine or some combination of these. With the combined measles–rubella (MR) vaccine, measles– mumps–rubella (MMR) vaccine, or measles–mumps–rubella–varicella (MMRV) vaccine, the protective immune response to each individual vaccine antigen is largely unchanged. Rubella vaccine: Most currently licensed rubella vaccines are based on the live attenuated RA 27/3 strain. Most of these vaccines are available in a monovalent formulation and also in polyvalent combinations, as a component of the MR, MMR and MMRV vaccines. In countries with a high incidence of and mortality from measles, the recommended age of administration of RCV (as a combined MR or MMR vaccine) is 9 months onwards. Manufacturers recommend that the age of vaccination be shifted to 12–15 months in countries with a low incidence of measles and consequently, a lower risk to infants and with use of MMRV. A second dose of MR, MMR or MMRV should be given to ensure protection against measles. RCV can also be administered to older children, adolescents and adults, depending on the product. The immune response to the rubella antigen is not affected by the other components of the MR, MMR or MMRV vaccines, and the serocon¬version rates are similar with different formulations of the RA 27/3 vaccine when it is given concurrently with other live or inactivated vaccines. The RCV (containing the RA 27/3 strain) have shown 97% vaccine effec¬tiveness (95% CI, 92–99%). Generally, the adverse events following immunization with the RA 27/3 rubella vaccine, whether monovalent or in a polyvalent combination, are mild, particularly among children. In principle, pregnancy is a contraindication to vaccination because of a theoretical risk of teratogenic outcomes, though there is no evidence that the rubella vaccine can cause CRS. Disease burden In 2020, a total of 159 067 cases of measles were reported to WHO. Almost three-quarters of these came from the African Region (115 369, 73%); the Region of the Americas, European Region and South-East Asia Region contributed about 6% each; and the Eastern Mediterranean Region and Western Pacific Region accounted for 4% each. India reported the highest number of cases (5604, 60%) in the South-East Asia Region, followed by Bangladesh (2410, 26%). Indonesia Nepal and Myanmar contributed 4–5% each. Genotypes of viruses: During 2020, 47 (46%) of 102 countries reported the isolation of the measles virus from persons with measles, compared to 88 (62%) of 141 countries in 35 MEASLES AND RUBELLA 2019. The number of genotypes detected per year decreased from 13 in 2002 to 3 in 2020 – a sign of progress towards elimination. Among the 1268 reported sequences in 2020, 947 (75%) were D8, 307 (24%) B3, and 14 (1%) D4. Mortality estimates: According to updated annual data and revised models, there was a 79% decrease in the estimated number of measles cases from 2000 to 2020 (36 763 000 to 7 549 000). In the same period, the estimated number of annual deaths due to measles decreased by 94%, from 1 072 800 to 60 700. Compared with no measles vaccination, measles vaccination prevented an esti¬mated 31.7 million deaths globally during these two decades. Annex 2: Case investigation form Patient information Case identification number: MR- _______/____________/__________/____/_____ Country code/ Province code/District code/ Year/Serial number Name of health facility: Patient’s name: Date of birth (DOB): Age (if DOB not available): __________ Gender: Male Female Place of residence House no. Street: Village/town District/province: Country: Pin code: Patient’s contact no. /parent’s mobile no.: (dd/mm/yyyy) Date of birth: _____/______/_____ Date of onset of fever: _____/______/_____ Date of onset of rash: _____/__/_____ Date of notification: _____/______/_____ Date of Investigation: _____/______/_____ Vaccination status (by card / history) No. of doses Date of 1st dose Date of 2nd dose Measles-containing vaccine _______ dd/mm/yyyy dd/mm/yyyy Rubella-containing vaccine _______ dd/mm/yyyy dd/mm/yyyy Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 36 Clinical information Fever Yes No Unknown Maculopapular rash Yes No Unknown Adenopathy Yes No Unknown If yes, place……………………. Cough Yes No Unknown Arthralgia Yes No Unknown If yes, joint……………………. Coryza Yes No Unknown Pregnancy Yes No Unknown If yes, weeks……. Conjunctivitis Yes No Unknown Others: Patient’s status Hospitalization Yes No If yes, name of hospital: Date of admission: _____/_____/______ Date of discharge: _____/_____/______ Final status  Recovered  Referred  Died  Unknown Epidemiological information Any similar illness in family/community Yes No If yes, number…………. Travel history (7–21 days before onset of rash): Yes No If yes, place/country visited: Travel dates: From _____/_____/______ to _____/_____/______ Name of the investigator with designation: Laboratory information To be filled at specimen collection point To be filled by testing laboratory 37 MEASLES AND RUBELLA F. Serology samples and test results Was a specimen collected? Yes No If yes, type of specimen  Serum  DBS Date of collection: ______/______/________ Specimen collected by: Sample shipment date: ______/______/________ Sample sent by: Date of receipt of sample: _____/_______/________ Sample received by: Sample status:  Satisfactory  Unsatisfactory If unsatisfactory, give details: Serology result Specimen ID:___________ Test done by: Date of test: ______/______/_______ Date of report to National program*: ______/______/_______ Measles:  Positive  Negative  Equivocal  Test not done Rubella:  Positive  Negative  Equivocal  Test not done G. Virology samples and test results Was a specimen collected? Yes No If yes, type of specimen  Throat swab  Urine  Other: Date of collection: ______/______/________ Specimen collected by: Sample shipment date: ______/______/________ Sample sent by: Date of receipt of sample: _____/_______/________ Sample received by: Sample status: Satisfactory Unsatisfactory If unsatisfactory, give details: Virology result Specimen ID:___________ Test done by: Date of test: ______/______/_______ Date of report to National program: ______/______/_______  Measles-positive  Rubella-positive  Negative  Test not done 38 Genotyping Was a specimen submitted for genotyping?  Yes  No If yes, date on which specimen was sent: ____/______/______ Genotyping result Measles: ____ Rubella:_____ Date on which result was received by laboratory ____/____/______ Date on which result was received by Surveillance program unit: ____/____/______ Classification (to be filled in by the VPDP) Final classification:  Confirmed measles  Confirmed rubella  Discarded Basis for classification:  Laboratory  Epidemiological linked  Clinical Source of infection:  Endemic  Imported  Import-related  Unknown Reason for discarding………………………………………. Follow-up Was an active case search done?  Yes  No If yes, number of additional suspected cases detected: ________ Outcome at 30 days’ follow-up:  Alive  Died  Lost to follow-up Investigator’s name: Designation: Institution: Telephone (mobile): Email: Date: Signature: 39 MEASLES AND RUBELLA Annex 3: Collection, storage and transport of specimens Serology Whenever measles/rubella is suspected, the designated personnel should obtain specimens for laboratory confirmation. An adequate* blood sample should be collected on first contact with the patient during the case investigation. A NP/throat swab should be obtained for molecular tests, along with the serology specimen. The likelihood of detecting IgM antibodies is high if the blood specimen is collected between 3 and 28 days after the onset of rash. The sample should be shipped to a recognized laboratory as soon as possible, maintaining an appropriate cold chain (4–8 °C). Venous blood collection 1. Blood collected through venepuncture should be stored in a sterile labelled tube (3–5 mL for older children and adults and 1 mL for infants and younger children). 2. Whole blood can be stored at 4–8 °C for up to 24 hours before the serum is separated. 3. Whole blood should be allowed to clot, and then centrifuged at 1000 × g for 10 minutes to separate the serum. 4. The serum should be carefully removed with a fine-bore pipette to avoid extracting red cells and transferred aseptically to a sterile labelled vial. 5. The serum should be stored at 4–8 °C until shipment, but only for a maximum of 5 days. If kept for longer periods, serum samples should be frozen at a temperature of –20 °C. Alternative specimen collection The collection of blood through vene puncture is the preferred method of specimen collection; however, it is not always feasible in circumstances in which conducting venepuncture is problematic, or if there are geographical challenges to transportation or difficulties in the maintenance of a cold chain when transporting samples to the laboratory. Therefore, the alternative use of DBS and oral fluid samples has been validated by the WHO Measles and Rubella Laboratory Network. Antibody is stable in DBS, so the use of DBS is particularly valuable if the lack of a cold chain is a problem. Oral fluid samples have a higher sensitivity for viral detection than dried blood samples and easy to collect; though easy to collect, however, cold chain requirements have to be met. Dried blood spot collection z A sterile lancet should be used to puncture the skin on the finger or heel (for young children who have not started to walk). z Up to 4 full circles of whole blood should be collected on standardized filter paper (Perkin Elmer filter card). For the specimen to be adequate, each circle must be Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 40 filled completely. One to two drops need to be collected to completely fill each circle and each card should be properly labelled. z The filter paper should be dried thoroughly, and then enclosed in a plastic bag or envelope. It should be stored with a desiccant so that it remains dry. z Samples do not need to be kept refrigerated or frozen during transport. It is advisable to store them in a cool, dry place and transport them to the laboratory at room temperatures as soon as possible, preferably within 5 days. z Thoroughly dried blood spot samples are no longer subject to the International Air Transport Association’s regulations on dangerous goods. Oral fluid collection z A special swab (such as a toothbrush) should be used to collect crevicular fluid from the gum area of the mouth. The swab should be rubbed along the gum for at least 1 minute until the device is thoroughly wet. z The wet swab should be placed inside a clear plastic tube available for the purpose and should be labelled. z The samples should be shipped to the laboratory within 48 hours. They should be kept in a refrigerator until shipment, and should be shipped together with ice packs. z The samples are usually not considered biohazardous and the site of collection can ship them to the laboratory without special documentation. z Specific instructions provided by the device manufacturer should be followed. * For serology, adequate specimens are those which are collected within 28 days of the onset of rash and which consist of ≥ 0.5 mL serum or ≥ 3 fully filled circles of dried blood on a filter paper, or oral fluid. For oral fluid samples, the sponge collection device should be rubbed along the gum for at least 1 minute until the device is thoroughly wet. Molecular tests Data on viral genotypes are critical for the identification of the source of cases, and for the determination of whether they are indigenous or imported, as well as the place of origin, if imported. Therefore, specimens for viral detection and isolation should be collected on first contact with every suspected case and collection should be repeated periodically during large outbreaks. Throat/nasopharyngeal swabs or urine specimen should be collected within 7 days of the rash onset for measles and rubella viral detection/isolation. How to collect throat swabs or NP/oropharyngeal swabs z Sterile cotton swabs should be used to firmly rub the NP/oropharyngeal passage and back of the throat to dislodge epithelial cells. 41 MEASLES AND RUBELLA z The swabs should be placed in a sterile viral transport medium in labelled screw-capped tubes. z NP/oropharyngeal specimens should be refrigerated and shipped to the laboratory with ice packs (4–8 °C) and should arrive at the testing laboratory within 48 hours. z If arrangements cannot be made for rapid shipment, the swabs should be shaken in the medium to elute the cells and then removed. The medium or nasal aspirate should be centrifuged at 500 × g (approximately 1500 rpm) for 5 minutes, preferably at 4 °C, and the resulting pellet should be re-suspended in cell culture medium. The suspended pellet and the supernatant should be stored separately at –70 °C. They should be shipped to the testing laboratory on wet ice (4–8 °C) and reach within 48 hours, or preferably on dry ice in well- sealed screw-capped vials. Alternative specimen collection for molecular tests Urine samples z In acute cases, the measles virus is present in cells that are sloughed off in the urinary tract. Thus, urine is collected for virus detection or isolation if a throat swab is difficult to obtain. It is preferable to obtain the first urine passed in the morning. z About 10–50 mL of urine should be collected in a sterile container and held at 4–8 °C before centrifugation. z The virus is concentrated by centrifugation of the urine and the cell pellet re- suspended in a suitable viral transport medium. z Urine must NOT be frozen before the concentration procedure is carried out. z Whole urine samples may be shipped in well-sealed containers at 4 °C, but centrifugation within 24 hours of collection is preferable. z Centrifugation should be performed at 500 x g (approximately 1500 rpm) for 5–10 minutes, preferably at 4 °C. The supernatant should be discarded and the sediment re-suspended in a 2–3 mL sterile transport medium, tissue culture medium or phosphate-buffered saline. z The re-suspended pellet may be stored at 4 °C and shipped within 48 hours to a measles reference laboratory. Alternatively, it may be frozen at –70 °C in a viral transport medium and shipped on dry ice, in a well-sealed screw-capped vial. Oral fluid The procedure to be followed for oral fluid is similar to that described earlier for serology. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 42 Table 1.A2: Summary of types of samples to be collected for laboratory diagnosis of measles and rubella Type of specimen Type of test Volume to be collected Timing of collection Storage conditions Whole blood/ serum (by venepuncture) Antibody detection* (measles-specific IgM, paired sera to document IgG seroconversion or significant rise in IgG, between acute- and convalescent- phase sera) 4–7 mL of blood from older children and adults, 1 mL from younger children, 0.5mL from infants ≤ 28 days after onset of rash Paired sera are normally collected 10–20 days apart. The interval between the two samples can be shorter if virus- specific IgG is not detected in the first serum sample. Whole blood: 4–8oC (never to be frozen) for up to 24 hours, or 6 hours at 20–25°C before the serum is separated from clotted blood through centrifugation To be stored at 4–8oC until shipment to laboratory, ideally for no longer than 7 days Alternative specimen: DBS (whole blood) Antibody detection (measles-specific IgM, paired sera to document IgG seroconversion or significant rise in IgG) Detection of viral RNA by RT-PCR At least 3 fully filled circles on a filter paper collection device ≤ 28 days after onset of rash Cold chain not required Should be dried at low humidity before storage Throat (recommended), or nasopharyngeal (NP) swabs or nasopharyngeal aspirates** Viral isolation by cell culture Detection of viral RNA by RT- PCR*** Swab or NP aspirate Within 7 days of onset of rash for viral isolation (cell culture) RT-PCR for virus detection 4–8oC 43 MEASLES AND RUBELLA Type of specimen Type of test Volume to be collected Timing of collection Storage conditions Oral fluid (OF) Antibody detection (measles-specific IgM) Detection of viral RNA by RT-PCR ~0.5 mL of crevicular fluid, using a sponge collection device that is rubbed along the gums for >1 minute to ensure that it is thoroughly wet Up to 14 days after onset of rash if using RT-PCR for virus detection Up to 28 days for antibody testing Cold chain not required if ambient temperature is < 22oC and if shipped to laboratory within 24 hours. At higher temperatures, samples should be kept at 4–8°C until shipped, using cold packs. Urine Viral isolation by cell culture Detection of viral RNA by RT-PCR Minimum 10 mL, preferably from first morning void (chance of detection higher with larger volume) Within 7 days of onset of rash for viral isolation or virus detection by RT-PCR Stored at 4–8°C until urine can be centrifuged; original sample should not be frozen prior to centrifugation. * Adequate samples are those collected within 28 days of the onset of rash. However, IgM detection by enzyme immunoassay (EIA) for measles is more sensitive when collected 4–28 days after the onset of the rash. A negative result may be obtained for IgM from up to 30% of measles cases in the first 72 hours after the appearance of the rash. A second serum sample may be required for additional testing under the following circumstances: z either if RT-PCR for the detection of virus-specific RNA is unavailable or the results were inconclusive; z repeat testing of the initial serum specimen fails to resolve an equivocal result for IgM. ** Some laboratories consider the testing of properly collected serum for IgM as the only adequate means of ruling out measles. A negative RT-PCR from the upper respiratory tract is not considered to rule out measles because the timing and quality of the specimen collection are of critical importance. However, some countries collect only upper respiratory tract specimens from infants because of the difficulty of drawing blood. In some countries with a very low prevalence of measles, these samples can be a significant fraction of the total. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 44 Type of specimen Type of test Volume to be collected Timing of collection Storage conditions *** Since the virus is more likely to be isolated (and the RNA detection rate is higher) when the specimen is collected early, the collection of should not be delayed until laboratory confirmation of a suspected case is obtained by antibody detection. Samples for antibody and viral detection should be collected at first contact with a suspected case. Annex 4: Tools for public health response to measles and rubella outbreaks Annex 4a: Assessment of vaccine effectiveness using a nomogram Fig. 1.A1: Assessment of vaccine effectiveness using a nomogram Chen RT, Orenstein WA. Epidemiologic methods in immunization programs. Epidemiol Rev 1996; 18 (2): 99-117 45 MEASLES AND RUBELLA M ea sl es o ut br ea k in ve st ig at io n : C O N TA CT T R AC K IN G F O R M S D is tri ct :_ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ _ B lo ck /w ar d/ ha m le t:_ __ __ __ __ __ __ __ __ Su pe rv is or n am e: __ __ __ __ __ __ __ __ __ __ __ __ __ __ _ In ve st ig at or n am e: __ __ __ __ __ __ __ __ __ __ __ _ O ut br ea k ID :_ __ __ __ __ __ __ __ __ __ __ Su rv ey D at es : _ __ __ __ __ __ CO N TA CT S fo ur d ay s be fo re to fo ur d ay s af te r t he ra sh o ns et "O N LY S U SP EC TE D C AS ES (O ns et b et w ee n __ __ __ _ & _ __ __ __ )" (1 ) (2 ) (3 ) (4 ) (5 ) (6 ) (7 ) (8 ) (9 ) (1 0) N am e Ag e Se x (M /F ) To ta l nu m be r o f m ea sl es va cc in e do se s D at e of la st d os e "S us pe ct ed m ea sl es ca se (f ev er , r as h, 3 C' s) (Y es /N o) " D at e of ra sh o ns et Sa m pl es ta ke n: (s er um , th ro at sw ab , ) Pl ac es vi si te d fo ur d ay s be fo re to fo ur d ay s af te r r as h on se t D at e( s) o f in ve st ig at io n of p la ce s de sc rib ed in co lu m n 10 G eo -c oo rd in at es , if av ai la bl e An ne x 4b : Co nt ac t tr ac in g fo rm Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 46 Ex po su re to s us pe ct ed c as es 7 -2 1 da ys b ef or e th e on se t o f r as h (d at ed b et w ee n __ __ __ __ _& __ __ __ __ __ __ _) (1 ) (2 ) (3 ) (4 ) (5 ) (6 ) (7 ) (8 ) (9 ) (1 0) N am e an d ad dr es s B irt h da te /A ge in y ea rs Se x (M /F ) To ta l nu m be r o f m ea sl es va cc in e do se s D at e of la st d os e "S us pe ct ed m ea sl es ca se (f ev er , r as h, 3 C' s) (Y es /N o) " D at e of ra sh o ns et Sa m pl es ta ke n: (s er um , th ro at sw ab , ) Pl ac es vi si te d 7- 21 d ay s be fo re ra sh o ns et (p os si bl e ex po su re si te s) D at e( s) o f in ve st ig at io n of p la ce s de sc rib ed in co lu m n 8 G eo -c or di na te s of th e co nt ac t, if av ai la bl e R em ar ks 47 MEASLES AND RUBELLA M R O B F O R M -3 C O M M U N IT Y CE N SU S FO R M Vi lla ge / Lo ca lit y na m e: D at e of c en su s __ __ __ __ __ __ _ Te am N o. : _ __ __ __ __ __ _ W ar d: _ __ __ __ __ __ __ __ __ _ D is tri ct : _ __ __ __ __ __ __ __ __ __ _ Se ar ch d on e by : _ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ _ __ _ Su rv ey or s N am es : 1 2 3 N ot e- D ur in g co m m un ity s ur ve y, p le as e as k fo r a ny ca se s w ith fe ve r m ac ul op ap ul ar ra sh es a nd in cl ud e th em in th e co nt ac t t ra ci ng fo rm Ag e G ro up M R va cc in at io n st at us B y ca rd o r hi st or y H ou se N o. : 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 To ta l 9- 11 m on th s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 1- 4 ye ar s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 5- 9 ye ar s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 10 -1 4 ye ar s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 An ne x 4c : Co m m un ity c en su s fo rm Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 48 Ag e G ro up M R va cc in at io n st at us B y ca rd o r hi st or y U nk no w n 0 15 -1 9 ye ar s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 20 -2 4 ye ar s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 25 -2 9 ye ar s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 30 -3 4 ye ar s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 35 -3 9 ye ar s Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 40 + y ea rs Ze ro d os e 0 1 do se 0 2 or m or e do se s 0 U nk no w n 0 N ot e: M R O B F O R M -4 M ea sl es O ut br ea k An al yt ic al e pi de m io lo gy D at a an al ys is o f o ut br ea k in ve st ig at io n O ut br ea k ID :_ Ag e G ro up N um be r of m ea sl es ca se s re ce iv ed m ea sl es va cc in e N um be r of m ea sl es ca se s no t re ce iv ed m ea sl es va cc in e N um be r of m ea sl es ca se s w ith un kn ow n va cc in at io n st at us N um be r o f no n- m ea sl es re ce iv ed m ea sl es va cc in e N um be r o f no n- m ea sl es no t r ec ei ve d m ea sl es va cc in e N um be r of n on - m ea sl es w ith un kn ow n va cc in at io n st at us N um be r o f de at hs d ue to m ea sl es (D ea th s m us t be in cl ud ed in c as e co un ts ) To ta l po pu la tio n Ag e sp ec ifi c at ta ck ra te A ge w is e di st rib ut io n of m ea sl es c as es (% ) At ta ck ra te am on g `u nv ac ci na te d (A R U ) At ta ck ra te am on g va cc in at ed (A R V) Va cc in e Ef fe ct iv en es s (% ) Ca se F at al ity ra te (C FR ) A B C D E F G H = Su m (A :F ) J = (( A+ B + C) /H ) *1 00 K = (A + B + C) / (L + M + N ) *1 00 AR U = B / (B + E) AR V = A / (A + D ) (A R U -A R V) / AR U *1 00 CF R = G / (A + B + C) *1 00 < 1 y ea r 1 - 4 y ea rs 5 - 9 y ea rs 10 - 14 y ea rs > = 15 y ea rs To ta l L M N N ot e: H ig hl ig ht ed c ol um ns to b e co m pl et ed o nl y w he n po pu la tio n da ta (m ea sl es c as es a nd n on c as es ) i s co lle ct ed u si ng F or m 3 An y ot he r r el ev an t d et ai ls e. g. Is it a n im po rt ed /i m po rt -r el at ed /e nd em ic o r u nk no w n so ur ce o f o rig in ? An ne x 4d : An al ys is o f d at a an d ou tb re ak s ev er ity Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 50 Annex 4e: Template for reporting an outbreak Outbreak ID Location Date of reporting of outbreak Date of investigation Names of members of investigating team 1. 2. 3. 4. 5. Notification Source of notification EWARS§  Weekly report  Active case search  Others  (specify) Date of notification Of index case Duration of outbreak Index case reported by Designation §Early Warning, Alert and Response System Location of outbreak Name of village/ urban locality Health facility / satellite clinic/ hospital District Cross-notification Yes  No  Descriptive epidemiology Epidemic curve of all confirmed measles cases by date of onset (stacked bar with laboratory-confirmed, epidemiologically linked, clinically compatible) Mapping of suspected measles cases (with geographical coordinates) Bar chart of measles cases (by age) stratified by vaccination status (0 dose, 1 dose, > 1 dose, unknown) 51 MEASLES AND RUBELLA Measles–rubella immunization coverage in the affected catchment area for last 5 years Year Routine EPI (MR) MCV-1 MCV-2 History of SIA (catch-up, follow-up, ORI) Year Coverage Target Line list of suspected measles cases in large outbreaks (attach as annex) Summary of contact tracing findings (attach contact tracing form as annex) z Key features Summary of community survey z Comment on immunity gaps z Any new cases found during community survey z Community survey form (attach as annex) Mapping of transmission pattern z Travel history of index and primary cases z Types of contacts z Efforts made to identify source Summary of analytical epidemiology z Case fatality rate, attack rates, age-specific attack rate, vaccine effectiveness z Calculation sheet (attach as annex) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 52 List of pregnant women possibly exposed during rubella outbreak Name Age Village/ district Contact phone no. Last menstrual period Estimated gestational age (trimester) Expected date of delivery Exposure to patient with rash (yes/no/ unknown) If yes, relationship Date of delivery (dd/mm/yyyy) Birth outcome* * 1. normal delivery, 2. miscarriage, 3. fetal death, 4. cataract, 5. deafness, 6. heart murmurs, 7. microcephaly, 8. any other abnormality (specify) List the responses (e.g. vaccination, Vitamin A distribution, other treatment) If ORI conducted, number of children vaccinated (selective and/or non-selective ORI), and geographical scope of ORI Efforts to intensify surveillance Efforts to strengthen routine immunization Root cause analysis of outbreak Information on status of confirmed cases at 30 days’ follow-up Any additional cases found in 30 days’ follow-up Conclusion Source of outbreak (imported/import-related) Salient features (attack rate, case fatality rate, vaccine effectiveness) What was the cause of the outbreak (outcome of root cause analysis) – vaccine failure or failure to vaccinate? The main responses recommended and carried out Lessons learnt Recommendations Immediate: Long-term: 53 MEASLES AND RUBELLA Annex 4f: Line list for large outbreak Line listing of suspected Measles / Rubella cases District: ____________________ Line List (year): _____ R ep or t D at e: _ _/ __ /_ __ _ R ep or te d by : _ __ __ __ __ __ __ _ Sr . N o. Ep id N um be r D is tri ct B lo ck D at e of n ot ifi ca tio n D at e of in ve st ig at io n D at e of ra sh o ns et D at e of b irt h Ag e in m on th s Se x (M / F) R el ig io n (H / M / O ) M ea sl es v ac ci ne re ce iv ed th ro ug h ro ut in e U IP (b ef or e ra sh o ns et ) - A N um be r o f m ea sl es v ac ci ne re ce iv ed th ro ug h SI A ca m pa ig ns (b ef or e ra sh o ns et ) - B To ta l M CV d os es (A + B ) D at e of la st d os e of M CV (b ef or e ra sh o ns et ) D at e of la st d os e of M CV (b ef or e bl oo d co lle ct io n) Ty pe o f v ac ci ne u se d as M CV 1 (M / M R / M M R / M M R V) Ty pe o f v ac ci ne u se d as M CV 2 (M / M R / M M R / M M R V) Fe ve r ( Y / N / U ) Co ug h (Y / N / U ) Co ry za (Y / N / U ) Co nj uv tiv iti s (Y / N / U ) Co m pl ec at io n (Y / N / U ) D at e sp ec im en c ol le ct io n La bo ra to ry re su lt If su sp ec te d ca se is p re gn an t w om an th en d at e of fo llo w -u p O ut co m e 30 -d ay s fo llo w -u p (A liv e / D ea th / Lo st ) If di ed , t he n da te o f d ea th Co m pl ic at io n pr es en t a t 3 0- da ys fo llo w u p (Y / N ) Po te nt ia l C R S ca se (Y / N ) Fi na l c la ss ifi ca tio n If di sc ar de d, th en fi na l d ia gn os is Ty pe o f c as e (S po ra di c / C lu st er ed in a n ou tb re ak ) If ca se b el on gs to a n ou tb re ak , t he n pr ov id e ou tb re ak -id D at e M CV 1 re ce iv ed D at e M CV 2 re ce iv ed B lo od N as op ha ry ng ea l S w ab Th ro at S w ab U rin e B lo od N as op ha ry ng ea l S w ab Th ro at S w ab U rin e Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 54 Readiness Indicator Complete/ Ready Incomplete/ Not Realized In- Process/ Not fully realized Leadership and Coordination Are national, regional and local measles outbreak preparedness and responses coordination mechanisms functional (or can be reactivated quickly)? Does the health coordination mechanism (inclusive of partners) have an established mandate and defined roles and responsibilities to coordinate measles readiness and response actions Partner capability to support measles outbreak response is well-mapped (including # persons, type of support, duration of support, time to mobilize surge support)/ 4 W Matrix PHEOC is functional and ready to support measles response coordination activities. The PHEOC is well linked to all coordination mechanisms at the national and subnational level Preparedness and Response Planning Has a national plan for measles outbreak preparedness and response been developed in consultation with key stakeholders? Does the national measles preparedness and response plan define the roles and responsibilities of the subnational and local levels (or the response plans)? Planning for continuity of essential services during the measles outbreak response and recovery phases Is a list of high-risk areas for measles outbreaks regularly updated, based upon surveillance and immunization performance data? Does the country have national legal framework defining public health emergency response authorities and measures? Contingency Finance The country has an established contingency fund mechanism to support emergency response (i.e. measles) with clear description on national, subnational and local requesting Measles treatment is free with clear communication on costs disseminated within the community Country has clear policy/protocol for cost of treatment/user fees including (lab tests, outpatient care, hospitalization, referral, medical exam and pharmaceuticals) for suspect measles cases, which is disseminated to public and private facilities and the community Annex 5: Checklist for outbreak preparedness 55 MEASLES AND RUBELLA Readiness Indicator Complete/ Ready Incomplete/ Not Realized In- Process/ Not fully realized Early Warnings, Epidemiological and Lab Surveillance The risk for measles outbreaks, inclusive of vulnerability analysis, is well-assessed and mapped Vaccination coverage rates are well-mapped (for 1 dose and 2 dose) in-country Country has analyzed and described the historical measles outbreak pattern, including identifying areas at high risk for measles outbreak The country's surveillance system for measles detection and reporting is well-functioning The measles surveillance reporting system has integrated private and public facility data in its regular reporting Standard case definition for measles is well-established and disseminated throughout the health sector Standard data collection forms and means of case reporting are available at all levels (local, regional and national) Subnational areas have rumor reporting analysis or event based surveillance capability in the event of high measles outbreak risk Country has sufficient laboratory capacity or access to laboratory testing to confirm measles outbreak Laboratory capacity for specimen testing for measles within the country has been mapped (national and subnational levels) The laboratory circuit for collecting, transporting, and testing samples for measles and rubella and the reporting results is well- functioning Country has collaboration mechanism with an international reference laboratory for measles (as required) Designated measles testing sites have all required lab testing materials and laboratory equipment including sufficient supply of reagent Rapid Response Team(s) or outbreak investigation team(s) are well-trained, equipped, and ready to investigate suspicion of measles outbreak (within <24 hours of alert) Case investigation form for measles is developed and available to relevant personnel and partners Rapid Response team or outbreak investigation team includes at minimum 1 clinical team member (i.e. doctor, nurse or clinical officer) to support collection of sample and patient referrals if additional suspect cases are identified during investigation Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 56 Readiness Indicator Complete/ Ready Incomplete/ Not Realized In- Process/ Not fully realized Standard Operating Procedures (add references) Are national standard operating procedures for outbreak preparedness and response have been developed and disseminated to respondents at all relevant levels of the health sector? SOPs for outbreak prevention and control SOPs for clinical management (including co-morbidities), triage and infection, prevention and control (IPC) SOPs for effective communication and public awareness SOPs for microplanning/vaccination campaigns (inclusive of waste management plan and cold-chain and IPC for COVID-19) SOPs for routine immunization, including safe infection SOPs for laboratory surveillance Risk Communi- cations Existing community-based health interventions within the country health system are in place and well-functioning Key persons within community-based programs within the country health system have been identified and mapped (i.e. national, subnational and local) Gaps in coverage of community-based health interventions have been identified and mapped Community-based health system has capacity to expand activities during an emergency response Are communication systems and plan(s) developed to ensure communities are engaged in surveillance and case management and vaccination, including during outbreak immunization response campaigns? Clear, practical public health messages and information that are tailored to affected population(s) are available (in languages) based on community feedback and assessment(s) Feedback loop for patient communication is well established and functioning The health sector has identified and trained a key spokesperson(s) on measles outbreak communication to the public Social media communication strategy is developed to address the rumors and myths on social media (e.g. Facebook, Weibo, Twitter, etc.) with evidence-based engagement 57 MEASLES AND RUBELLA Readiness Indicator Complete/ Ready Incomplete/ Not Realized In- Process/ Not fully realized Vulnerable Populations for measles have been mapped as part of the risk communication and community engagement strategy link to geographic areas Knowledge, Attitudes and Practices of Communities for measles vaccination and seeking treatment for measles-like symptoms are well-understood, documented and disseminated Health Workforce Is there Country health workforce and surge capacity available and ready to respond to measles outbreaks for protracted periods? Medical surge capacity health workforce is well-trained and ready to respond to measles outbreak Staff roster and surge capacity roster (including retired staff) listing is available to mobilize workforce with contact information, availability and described skillset Country Emergency Medical Teams are ready to respond to support measles case management or vaccination response as needed All health workers have presumptive evidence of immunity to measles (2 documented MCV doses, history of disease or evidence of immunity through serologic verification) Are there mechanisms for signaling for and managing external emergency health workforce surge? SOPs or Policies/Procedures are in place to manage external workforce support for emergency response HFs have established mechanism to request additional health workforce resources to relevant health authorities in the event of an outbreak National FETP program provides surge capacity Health Structure Health structures (public, private) are well-mapped (including type of facility, health services and staffing, and isolation capacity in at-risk areas) and regularly updated Referral mechanisms for measles cases with complications are well-established, inclusive of roles and responsibilities for all indicated actors (i.e. ambulance services, emergency dispatchers, etc.) Strategy for accelerated Implementation of IPC core components are developed and put in place at the points of care Health structures have capacity to treat complications associated with measles (pneumonia, diarrhea, malnutrition, etc) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 58 Readiness Indicator Complete/ Ready Incomplete/ Not Realized In- Process/ Not fully realized Logistics/ Supply Chain Do public health systems have access to vaccines and treatments for outbreak response at the point of care? Country has mapped cold chain capacity to support emergency response vaccination Country has established vaccine supply pipeline and injection supplies in the event of emergency measles vaccination response Country has sufficient waste management materials to support measles emergency response vaccination Country has adequate and appropriate medical supplies for measles case management available There are sufficient medical emergency stockpiles for severe and non-severe measles case management both at the national level and designated high-risk areas for outbreak (as appropriate) The country has adequate stockpile for Vitamin A distribution for case management There is capacity to produce a regular gap analysis and pre- positioning of the required stock at the sub-national level There is adequate storage and warehousing for PPE and other medical supplies in support of a scaled-up measles emergency response Country has defined a clear pre-positioning strategy for medical supplies in health facilities at high risk for receiving measles cases The country's supply chain and movement of supplies and personnel is well-mapped and functional Developed measles readiness/response tools, including case investigation forms, cases and contact line-list forms, lab specimens, are readily available and in sufficient quantity at points of care 59 MEASLES AND RUBELLA Further reading 1. Brown DW, Warrener L, Scobie HM, Donadel M, Waku-Kouomou D, Mulders MN et al. Rapid diagnostic tests to address challenges for global measles surveillance. Curr Opin Virol. 2020;41:77–84 (https://doi.org/10.1016/j. coviro.2020.05.007, accessed 28 August 2022). 2. Gastanaduy PA, Redd SB, Clemmons NS, Lee AD, Hickman CJ, Rota PA et al. Measles. In Roush SW, Baldy LM, Hall MAK, editors. Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases, Atlanta, GA (https://www.cdc.gov/vaccines/pubs/surv-manual/chpt07-measles.html, accessed 28 August 2022). 3. Lanzieri T, Redd S, Abernathy E, Icenogle J. Rubella. In Roush SW, Baldy LM, Hall MAK, editors. Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases, Atlanta, GA (https://www.cdc.gov/ vaccines/pubs/surv-manual/chpt14-rubella.html, accessed 28 August 2022). 4. Cherian T, Arora N, MacDonald NE. The global vaccine action plan monitoring and evaluation/accountability framework: perspective. Vaccine. 2020;38(33):5384– 86. doi: 10.1016/j.vaccine.2020.04.036. 5. Dixon MG, Ferraru M, Antoni S, Portnoy A, Lambert B, Hauryski S et al. Progress towards regional measles elimination – worldwide, 2000–2020. MMWR Morb Mortal Wkly Rep. 2021;70:1563–9. DOI: http://dx.doi.org/10.15585/mmwr. mm7045a1. 6. Durrheim DN. Measles eradication – retreating is not an option. Lancet Infect Dis. 2020;20(6):e138–e141. doi:10.1016/S1473-3099(20)30052-9. 7. Gastañaduy, PA, Goodson JL, Panagiotakopoulos L, Rota PA, Orenstein WA, Patel M. Measles in the 21st century: progress toward achieving and sustaining elimination. 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Cherian T, Hwang A, Mantel C, Veira C, Malvolti S, MacDonald N et al. Global vaccine action plan lessons learned III: monitoring and evaluation/accountability framework. Vaccine. 2020;38, 5379–83. doi: 10.1016/j.vaccine.2020.05.028. 12. Measles vaccines: WHO position paper – April 2017. Wkly Epidemiol Rec. 2017; 92(17):205–27. 13. [World Health Organization. Framework for verifying elimination of measles and rubella. Weekly Epidemiol Rec 2013; 88:89-98] 14. The role of extended and whole genome sequencing for tracking transmission of measles and rubella viruses: report from the Global Measles and Rubella Laboratory Network meeting, 2017. Wkly Epidemiol Rec. 2018;93(6): 55–9. 15. World Health Organization. Regional Office for South-East Asia. Strategic plan for measles and rubella elimination in WHO South-East Asia Region: 2020–2024. World Health Organization. Regional Office for South-East Asia; 2019 License: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/handle/10665/330356, accessed 28 August 2022). 16. World Health Organization. Guide for clinical case management and infection prevention and control during a measles outbreak. World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/ handle/10665/331599, accessed 28 August 2022). 17. World Health Organization. Measles and rubella strategic framework 2021–2030. Geneva: World Health Organization; 2020. (https://www.who.int/publications/i/ item/measles-and-rubella-strategic-framework-2021-2030, accessed 28 August 2022). 18. World Health Organization. The immunological basis for immunization series. Module 7: measles. Update 2020. Geneva: World Health Organization; 2020 (https://www.who.int/publications/i/item/9789241516655, accessed 28 August 2022). 19. World Health Organization. Rubella vaccines: WHO position paper – July 2020. Wkly Epidemiol Rec. 2020;95 (27):306–24. World Health Organization (https:// apps.who.int/iris/handle/10665/332952, accessed 28 August 2022). 20. World Health Organization. Regional Office for South-East Asia. Framework for verification of measles and rubella elimination in the WHO South-East Asia Region. World Health Organization. Regional Office for South-East Asia; 2020 (https://apps.who.int/iris/handle/10665/332737, accessed 28 August 2022). 61 MEASLES AND RUBELLA 21. World Health Organization. Regional Office for South-East Asia. Surveillance guide for vaccine-preventable diseases in the WHO South-East Asia Region. World Health Organization. Regional Office for South-East Asia; 2017 (https://apps. who.int/iris/handle/10665/277459, accessed 28 August 2022). Module -1. Measles and Rubella (https://apps.who.int/iris/ b i ts t r eam/handle /10665/277459/Module1-Measles%26Rubel la . pdf?sequence=1&isAllowed=y) 22. World Health Organization. Measles – Surveillance standards for vaccine- preventable diseases, 2nd ed. World Health Organization; 2018 (https://www. who.int/publications/m/item/vaccine-preventable-diseases-surveillance- standards-measles, accessed 28 August 2022). 23. World Health Organization. Rubella – Surveillance standards for vaccine- preventable diseases, 2nd ed. World Health Organization; 2018 (https://www. who.int/publications/m/item/vaccine-preventable-diseases-surveillance- standards-rubella, accessed 28 August 2022). 24. World Health Organization. Maintaining essential health services: operational guidance for the COVID-19 context: interim guidance, 1 June 2020. World Health Organization; 2020. License: CC BY-NC-SA 3.0 IGO (https://apps.who. int/iris/handle/10665/332240, accessed 28 August 2022). 25. World Health Organization. Measles programmatic risk assessment tool. Geneva: World Health Organization; 2014 (https://www.who.int/teams/immunization- vaccines-and-biologicals/immunization-analysis-and-insights/surveillance/ measles-programmatic-risk-assessment-tool, accessed 28 August 2022). 26. World Health Organization. Vaccination in acute humanitarian emergencies: a framework for decision making. Geneva: World Health Organization; 2017. License: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/handle/10665/255575, accessed 28 August 2022). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

MODULE-2 CONGENITAL RUBELLA SYNDROME (CRS) Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region September 2023 Cover and inside photo credit: WHO Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Congenital Rubella Syndrome (CRS)) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. 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Printed in India 3CRS CONTENTS Introduction 5 Objectives 5 Why CRS and rubella surveillance are treated separately 5 Types of surveillance 6 Case detection 6 Definition of suspected case 6 Case definition 6 Case reporting 7 Nodal person 7 Linkages with other surveillance programmes 7 Investigation of suspected case 8 Case investigation form 8 Unique ID 8 Specimen collection 8 Detection / isolation of virus 9 Detection of antibodies 9 Laboratory testing 9 Case classification 10 Case management 12 Outbreak 12 Definition 12 Measures to be taken 12 Public health response 12 Special considerations 13 Retrospective review of medical records 13 Serological survey of women of reproductive age 13 Data management 14 Reporting requirements 14 Unique case ID 14 Recommended data elements 14 Data analysis 15 4Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Monitoring indicators 16 Public health measures 17 Annex 1: Disease epidemiology 19 Background 19 Essential epidemiology 20 Vaccines 20 Annex 2: Steps to establish CRS surveillance system 21 National CRS surveillance coordinators 21 Identification of health-care facilities for reporting CRS 21 Initial and refresher training for participating providers 22 Initiation of surveillance activities 23 Quality assessment and monitoring of surveillance 23 Analysis of CRS surveillance data 23 Expansion of CRS surveillance 24 Feedback for stakeholders 24 Infection control measures 24 Annex 3: Case investigation form 25 Annex 4: Collection, storage and transport of specimens 28 Collection of specimens 28 For detection/ isolation of virus 28 Urine 29 For detection of antibodies 29 Collection of blood for dried blood spots 30 Annex 5: Indicators of performance of CRS surveillance 31 Further reading 34 5CRS Congenital Rubella Syndrome (CRS) surveillance Introduction Rubella surveillance cannot capture every case of rubella since the disease is frequently mild or asymptomatic. Congenital rubella syndrome (CRS) is the most severe outcome of rubella and its prevention is the primary objective of rubella vaccination. CRS surveillance allows for the detection of infants with clinically apparent manifestations and can be standardized for regional and global reporting, and for comparison. The early detection of infants with CRS is necessary to control the infection and prevent it from spreading further, as infants with CRS may shed the virus for a prolonged period (up to 1 year of age or longer). An immediate diagnosis of CRS also facilitates early intervention for specific defects. Objectives The key objective of CRS surveillance is to provide data in support of the pursuit of the national goals related to rubella vaccination, including monitoring progress to achieve and maintain elimination of the disease. The objectives are to: z monitor the impact of the rubella vaccine on the reduction of the incidence of CRS; z detect and isolate affected infants rapidly; z mitigate the consequences of the disease for infants and their families through the early provision of appropriate medical care; and z demonstrate the elimination of rubella and CRS. Why CRS and rubella surveillance are treated separately Both rubella and CRS are manifestations of infection with the rubella virus. However, though they are linked in terms of public health significance and as far as implications for vaccination are concerned, the surveillance systems for the two differ substantially in terms of: z case definitions; z age groups of interest; and z sites of case detection. All Member States in the South-East Asia Region should develop a CRS surveillance system that captures the majority of infants with suspected CRS within the country. If there is no surveillance in place, countries may opt to first establish CRS surveillance in a few sentinel sites, then add additional sites to cover a larger proportion of the population. 6Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Types of surveillance Minimal surveillance: The minimal surveillance recommended for CSR is case-based at sentinel sites, with laboratory confirmation in select health facilities. The main target age group for the surveillance is infants < 12 months of age. As CRS is a combination of congenital abnormalities that may have other causes, the surveillance requires a high level of specificity. Thus, laboratory confirmation is critical. Enhanced surveillance: In the case of enhanced surveillance, a national case-based surveillance system (passive, active or both), together with laboratory confirmation at health facilities, is recommended. Case detection Definition of suspected case A health worker should suspect CRS in the case of an infant <12 months of age with: z congenital heart disease (most commonly, patent ductus arteriosus or peripheral pulmonary artery stenosis); and/or z suspicion of hearing impairment; and/or z one or more of the listed eye signs – z white pupil (cataract); z larger eyeball (congenital glaucoma); or z loss of night vision and/or side vision. A health worker may suspect CRS in any infant <12 months of age even without apparent signs of CRS, in case of maternal history of suspected or confirmed rubella infection during pregnancy. Case definition The mother may complain that her child does not react to loud sounds; does not seek out or detect the direction from which sound is coming; does not react to voices; has stopped babbling and trying to make sounds; or still babbles but is not progressing towards more understandable speech. The lens of the eye may be clouded at birth. There may be excessive tearing, or the child may not open his/her eyes in bright light, or may have a large, cloudy cornea (the normally clear front surface of the eye). The child’s vision at night or in low light may be decreased and there may be loss of side vision (tunnel vision). The mother may complain that her child is not growing at the normal pace. Besides, the child may suffer from heavy and fast breathing. 7CRS Case reporting The most common type of surveillance for CRS is passive reporting from sentinel sites. The success of the programme depends on the selection of appropriate reporting sites. As the defects associated with CRS are most likely to be evaluated and treated at secondary and tertiary care facilities, it is these facilities that should be chosen as reporting sites or sentinel sites in the beginning of CRS surveillance. Some examples are: z secondary care providers/facilities, particularly ophthalmologists, cardiologists, audiologists and neonatologists; z tertiary care facilities, particularly those that provide paediatric surgical services for the eyes, ears and heart; z speciality care centres (e.g. children’s hospitals, and centres for hearing and blindness); and z obstetric centres or private clinics providing care to pregnant women with rubella. Nodal person Since an infant with CRS is likely to be seen in any one of several specialities – for example, paediatrics, obstetrics, otorhinolaryngology, cardiology and ophthalmology – there is a need to have a nodal person who will be able to coordinate between these departments. The nodal person should: z ensure the collection of the clinical and epidemiological data of the infants, as also the completion of case investigation forms; z be responsible for the appropriate collection and transportation of specimens and ensure that laboratory data can be linked to clinical and epidemiological information; z maintain a line list of suspected CRS cases in the assigned facilities; z communicate regularly with the national coordinator on the identification and follow-up of suspected cases identified in the area. The steps to be taken for the establishment of a CRS surveillance system are detailed in Annex 2. For more details, please refer to Introducing rubella vaccine into national immunization programmes: a step-by-step guide.[1] Linkages with other surveillance programmes The World Health Organization Regional Office for South-East Asia created an online integrated surveillance database for newborn birth defects (SEAR-NBBD) in 2014, to support the management of data on birth defects detected at birth, in stillbirths and among 1 World Health Organization. Introducing rubella vaccine into national immunization programmes: a step- by-step guide. World Health Organization; 2015 (https://apps.who.int/iris/handle/10665/184174) 8Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion newborns in hospital settings. A network of hospitals with a high client load of childbirth has been set up in the countries in consultation with the Ministries of Health. The hospital staff has been trained in surveillance on birth defects and stillbirths. Suspected cases of CRS should be reported through this network and also, to this network. Investigation of suspected case Case investigation form Suspected cases should be investigated within 48 hours of being reported. A case investigation form should be filled in following a clinical evaluation for CRS-related signs/ symptoms by different specialities. A sample case investigation form is given in Annex 3. For children between 6 and 11 months of age, it is important to record the history of the receipt of doses of the measles–rubella (MR) vaccine. This will help to understand laboratory results for the classification of cases. Unique ID Each suspected case should be assigned a unique case identification number (UID). The case number should begin with one or more three-letter combinations designating the geographical location, followed by the year and serial number of the case. All communications and forms related to the case should cite the UID. For example: CRS – suspected CRS case code COU – country code PRO – province code DIS – district code 2022 – year of onset 001 – serial number of case in the province The UID would be CRS-COU-PRO-DIS-22-001. Specimen collection Specimens should be collected for laboratory confirmation of all suspected cases. Two types of biological specimens should be collected – one for the detection / isolation of the virus and the second for the detection of antibody levels. 9CRS Detection / isolation of virus Nasopharyngeal swabs are the most preferred method of isolating the virus. A sample of urine (5–20 mL) is also collected frequently because of the ease of collection. However, contamination is a potential problem and decreases the specificity of virus isolation. Other methods which are acceptable include throat swabs, nasal swabs, blood samples (1 mL) and cerebrospinal fluid samples (1 mL). Dried blood spots are an option in remote locations where the transport of serum sample is not possible maintaining a cold chain. Detection of antibodies A blood sample of approximately 1 mL should be drawn (0.5 mL from very small infants, or dried blood spots ≥ 3 fully filled circles are acceptable). This should be centrifuged to separate out the serum, which should then be stored under refrigeration, at 2–8 ⁰C for up to 24 hours, or at 20–25 ⁰C for 6 hours. Dried blood spots can be used when it is not possible to perform venepuncture, or if a cold chain or economical method to ship serum samples is not available. For details of sample collection, storage and transport, refer to Annex 4. Laboratory testing A laboratory-confirmed case of congenital rubella infection (CRI) or syndrome in an infant meets one of the following criteria. z For infants < 6 months of age: rubella IgM antibody is detected; and z For infants between 6 and 12 months of age: rubella IgM and IgG antibody are detected, OR there is a sustained rubella IgG antibody level (determined on a minimum of two occasions at least one month apart in the absence of the receipt of rubella vaccine or exposure to wild-type rubella). For infants of any age < 12 months, rubella virus is detected by viral culture OR polymer chain reaction (PCR) in an appropriate clinical sample (throat or nasal swabs, or blood, urine or cerebrospinal fluid specimens). The following points should be noted in relation to laboratory testing. z Serology results cannot be used to confirm CRS after a child with suspected CRS has received rubella-containing vaccine. z Although IgM antibodies may persist for up to one year, about 50% of CRS cases are IgM-negative at 6 months of age, depending on the sensitivity of the test. 10 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Since IgM may not be detectable in some infants tested shortly after birth, IgM- negative infants with suspected CRS should be retested at the age of 1 month or shortly thereafter. z Laboratory confirmation of CRS in an infant older than 6 months of age should not rely on the IgM test alone if the IgM result is negative. In such cases, serial IgG testing should be conducted after at least one month to check if the level of IgG antibody is sustained over several months. z Virus isolation techniques should be used to test if infants with congenital rubella are shedding rubella virus. Congenitally infected infants may shed and transmit rubella virus for up to 1 year of age and thus become a source of rubella outbreaks. Therefore, it is important to continue testing the infant for the virus throughout the first year of life so that infection control measures can continue until virus shedding stops. Whether viral shedding has ceased may be confirmed by two negative results of viral testing of specimens obtained 1 month apart from infants of at least 3 months of age. z Genotyping may provide information on the source of the virus. In an endemic setting, genotype testing should be conducted at least once for every chain of rubella transmission. Case classification The classification of CRS cases depends partly on the identification of the clinical signs mentioned under Group A or Group B in Table 2.1. These signs may be used to classify cases as follows. Clinically compatible CRS: A suspected case where adequate specimen could not be collected and in whose case a qualified clinician detects at least two of the complications listed in Group A or one each from Groups A and B Laboratory-confirmed CRS: A suspected case who has at least one sign from Group A and meets the laboratory criteria for the confirmation of CRS Congenital rubella infection: An infant who has none of the clinical signs of CRS listed in Group A, but who meets the laboratory criteria for CRS Discarded: A suspected case with an adequate specimen who does not meet the definition of a laboratory-confirmed case, or a suspected case who does not have an adequate laboratory specimen and does not meet the clinically compatible case definition 11 CRS Table 2.1: Clinical signs of CRS Fig. 2.1. Classification of suspected cases < 6 months of age Fig. 2.2. Classification of suspected cases 6 – 12 months of age Clinical signs in Congenital Rubella Syndrome 1. Cataract 2. Congenital glaucoma 3. Congenital heart disease 4. Hearing impairment 5. 1. Purpura 2. Splenomegaly 3. Microcephaly 4. Developmental delays 5. 6. Radiolucent bone disease 7. Group AG roup B Suspected CRS case <6 months 6 to<12 months No blood samples Blood samples taken Discarded Does not meet clinical criteria Meets clinical criteria Discard IgM-ve Presence of >1 defect from [A] Within 1st month of life, and high suspicion of CRS IgM-ve Presence of < 1 defect from [A] only (CRI) Confirmed Follow-up test 1-2 months later IgM-ve IgM-ve Discarded Confirmed SUSPECTED CRS CASE 6 TO <12 MONTHS OF AGE > 6 mths of age Blood sample obtained IgG-,IgM-/IgM+ DISCARDED Blood sample not obtained 2nd Blood sample not obtained Clinical criteria for CRS not met Meets clinical criteria for CRS DISCARDED CLINICALLY COMAPITIBLE IgG + IgM + No defect from Gp A > 1 defect from GpA CONFIRMED IgG+ IgM - 2nd sample obtained IgG- IgG+ DISCARDED 12 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Case management Currently, no treatment is available for CRS beyond the clinical management of the related congenital abnormalities. The patient should be looked after and the follow-up done by experienced personnel, according to the national treatment guidelines. Outbreak Definition The number of CRS cases generally increases six to eight months after an outbreak of rubella infection. The detection of an increase in CRS cases can be a sign of relatively wider circulation of rubella virus among the population, indicating the possible occurrence of a past or current rubella outbreak. Measures to be taken z CRS surveillance should be established or strengthened in maternity hospitals, paediatric hospitals and neonatal intensive care units, as well as among specialists who treat infants with cardiac, hearing or eye deficits. z Hospitals located in the area where the outbreak is occurring should become sentinel sites, if not already so. z If a passive surveillance system for CRS is in place, it should be enhanced with active case-finding in facilities located in the areas affected by the outbreak. This can help to identify infants who have CRS or CRI and are prolonging the outbreak by shedding live rubella virus. CRS surveillance should continue for a minimum of nine months after the last rubella case. z If not already in place, a pregnancy registry should be established to document the pregnancy outcomes of infected and exposed women. The outcomes include miscarriages, fetal deaths, CRS cases, infants with CRI, and unaffected infants. Public health response z Infants with CRS or CRI should be considered infectious until two clinical specimens, obtained one month apart, are negative for rubella virus detection or viral isolation. Infection control procedures should be followed until this time. z Infants in hospitals should remain in isolation. z Persons involved in the care of infants should follow universal precautions. z The close contacts, family members and friends involved in the care or handling of such infants should either be immune or be immunized against rubella, in accordance with the national policy 13 CRS z In areas where follow-up testing of confirmed CRS and CRI cases is not feasible, emphasis must be placed on ensuring that close contacts and health-care workers are vaccinated against rubella. z In health-care settings, contact precautions should be implemented for every CRS and CRI case detected. z Pregnant women should not be exposed to infants with CRS or CRI; if exposed, they should be tested for rubella. z An active search should be conducted in the community to detect more CRS cases, as well as to review the vaccination status of children in the locality. Children who are unimmunized or those whose immunization cards or records are not available should be vaccinated with measles- and rubella-containing vaccine, according to the national recommendation. z Contact tracing is recommended in the case of mothers of infants with CRS or CRI to identify the source of the rubella virus in the mother. Special considerations Retrospective review of medical records z A retrospective review of the medical records of health institutes can be done annually to monitor the sensitivity of the CRS surveillance system. z For countries unable to establish or maintain CRS surveillance, a retrospective review can help to identify CRS cases. z A review of the medical records can aid in the estimation of the disease burden or provide the country with baseline data to measure the impact of the introduction of vaccines. z A retrospective review can also be used in special circumstances, e.g. in countries with a small population believed to have achieved the elimination of CRS. z A limitation of this approach is that retrospectively identified cases usually lack laboratory confirmation and, therefore, lack a definitive diagnosis. Serological survey of women of reproductive age z Serological assessments of rubella IgG antibody levels among women of reproductive-age, carried out in a survey setting, may help evaluate population immunity against rubella and protection against CRS in newborns. z Rubella IgG can be acquired both through vaccination and natural infection; therefore, serosurveys are not purely a reflection of the coverage of vaccination. A serological survey is not a substitute for CRS surveillance, but can complement it. 14 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Data management Reporting requirements z CRS cases should be reported separately from clinical rubella cases. z The doctor should transmit the case notification form / set of core information to public health personnel. z Once the case investigation is completed, the case-based data should be transferred from the local level to the higher administrative levels in the surveillance system (state level / national level). z Each Member State of WHO is required to report in the Joint Reporting Form annually. z CRS is currently not reportable under the International Health Regulations (IHR 2005). Unique case ID A unique case identification number should be assigned to each suspected case, as explained earlier. Recommended data elements z Demographic information z Child z Mother z Reporting information z Clinical observations z Whether health-care worker suspects CRS z Signs and symptoms z Outcome z Laboratory methods and results z Maternal history z Classification The sample case registration form for CRS in Annex 3 gives further details of the above. 15 CRS Data analysis z Final case counts by case classification, source of infection (endemic, imported/import-related, unknown), month/year and geographical area z Incidence of CRS (number of cases per 1000 live births) by year z Clinical characteristics (types of birth defects) and outcome z Maternal characteristics, including age group, race/ethnicity, country of birth, location of exposure, vaccination status, gravida/para z Number of cases with maternal history of rubella-like illness in pregnancy (including during a month or week of gestation; whether it was clinically compatible or laboratory-confirmed; and whether the woman was included in a pregnancy registry) z Proportion of cases clustered or associated with a rubella outbreak z Spot maps of confirmed CRS cases by year z Age of CRS case at time of diagnosis (< 1 month, 1–5 months, 6–11 months, ≥ 12 months) z Number of infants with follow-up samples to confirm clearance of virus z CRS surveillance data should be triangulated with rubella surveillance data because after a rubella outbreak among women of childbearing age, the number of CRS cases may increase in that particular area in the following months, usually 6–8 months later. z CRS surveillance systems should be evaluated annually to assess the completeness of reporting at surveillance sites. The evaluation should include a review of hospital records to identify any missed cases. These can be identified by comparing the list of reported cases with that of all cases matching the definition of a suspected case. z Data gathered from evaluations of the CRS surveillance system should be included in the National Verification Committee’s reports for measles/rubella/CRS. 16 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Table 2.2: Using data for decision-making Data Decision Detect CRS cases and isolate infants with CRS to prevent further spread of rubella. Document the burden of CRS to build a case for the introduction of a vaccine in the immunization programme for infants. Document the incidence of CRS after vaccine introduction to monitor the impact of the introduction of the rubella vaccine on the incidence of CRS and identify areas that need strengthening. Collect data on the epidemiology of CRS and burden of CRS on the population and use to inform strategies for immunization against rubella, including addressing the immunity gaps among adolescents and young adults. Determine risk factors for CRS, such as mothers who may have migrated from a country where the rubella vaccine has not been introduced or been recently introduced, to take preventive measures. Review data on CRS in conjunction with that on rubella surveillance to demonstrate the status of achieving or maintaining rubella elimination goals. Monitoring indicators The quality of CRS surveillance data should be evaluated at sentinel sites at least once every six months to assess the completeness of CRS reporting at the surveillance sites. This should include reviews of hospital records to identify any missed cases. The latter can be identified by comparing the list of reported CRS cases with that of all cases matching the definition of a suspected CRS case. The proportion of suspected cases that have been reported but not tested should be identified. The data gathered from evaluations of the CRS surveillance system should be included in the National Verification Committee’s reports for measles/rubella/CRS. Annex 5 presents a list of indicators that may be used for monitoring the performance of surveillance. 17 CRS Public health measures Public health measures to be followed for all sporadic cases of CRS are the same as those for CRS outbreaks. z Infants with CRS and CRI shed live rubella virus for long periods (60% shed in the first four months of life) and can be highly infectious. z They should be considered infectious until two clinical specimens, obtained one month apart, are negative for rubella virus detection/isolation after 3 months of age. Until this time, infection control procedures should be followed. z In hospitals, these infants should remain in isolation. z Persons caring for them should follow universal precautions. z Close contacts, family members and friends involved in the care or handling of such infants should be either immune or be immunized against rubella as per national policy. z In areas where follow-up testing of confirmed CRS and CRI cases is not feasible, emphasis must be placed on ensuring that close contacts and health-care workers are vaccinated for rubella. z In health-care settings, contact precautions should be implemented for every detected CRS and CRI case. z Pregnant women should not be exposed to infants with CRS or CRI; if exposed, they should be tested for rubella. z An active search should be conducted in the community for more CRS cases as well as to review the vaccination status of children in the locality. All children in the same locality who are found to be unimmunized or whose immunization cards or records are not available should be vaccinated with measles- and rubella- containing vaccine according to the national recommendation. z Contact tracing is recommended among mothers of infants with CRS or CRI to identify the source of the rubella virus in the mother. 18 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 19 CRS Annex 1: Disease epidemiology Background Rubella, also known as German measles, is a mild clinical illness that is caused by a virus and affects children and young adults. It usually causes low-grade fever and rash. However, infection during pregnancy, especially during the first trimester, can result in a miscarriage, fetal death or stillbirth, or the infant may be born with congenital malformations, known as congenital rubella syndrome. Rubella virus is a leading cause of vaccine-preventable birth defects. The risk of congenital infection and defects is the highest during the first 12 weeks of gestation and decreases thereafter; defects are rare if the infection occurs in the 20th week of gestation or later. The common congenital defects caused by CRS include cataracts, congenital heart disease, hearing impairment and developmental delay. Infants with CRS often present with more than one of these signs, but may also present with a single defect, most commonly, hearing impairment. Globally, the number of reported CRS cases increased from 302 in 2012 to 603 in 2020, primarily because of the initiation of CRS surveillance and reporting in several populous countries (Bangladesh, India, Indonesia and Pakistan) from 2012 onwards, and changes in reporting in Pakistan in 2020. The number of countries in the South-East Asia Region that reported CRS cases increased from two in 2002 to 10 in 2016. North Korea, Sri Lanka and Thailand report CRS cases as part of their national integrated disease surveillance programmes. The South-East Asia Region has the highest burden of CRS cases. Cases are identified through sentinel site surveillance in eight countries (Bangladesh, since 2012; Indonesia and Nepal, 2014; Maldives, 2015; Bhutan, India, Myanmar and Timor-Leste, 2016). In addition, Bangladesh utilizes population-based CRS surveillance, for which all the reporting sites for vaccine-preventable disease surveillance also report CRS cases. CRS is associated with significant morbidity and mortality. The estimated mortality may range from 20–40%. Infants born with cardiac defects have the highest risk of mortality. The estimated mean incidence rate of CRS in the Region has been 121 per 100 000 live births (95% CI : 31–238) since 2010, and the total annual number of cases, 49 229 (95% CI: 11 204–96 976). Annexes 20 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion The goal of the Region is to achieve “measles and rubella elimination by 2023”. The elimination of rubella in two countries of the Region is estimated to have prevented 52 118 cases of CRS annually. In 2020, Maldives and Sri Lanka were verified to have eliminated rubella, and both sustained their rubella elimination status in 2021. The facility-based surveillance for CRS in India revealed that about one-fifth of suspected CRS patients during 2016–2018 had evidence of laboratory-confirmed rubella infection, indicating continued transmission of rubella in the country. The estimated incidence of CRS in India varies according to the type of model used. In 2016–2018, it was estimated at 65.5 per 100 000 live births using the age-dependent force of infection model and 225.6 per 100 000 live births using the constant force of infection model. This translates into about 14,520–50,028 infants with CRS annually. Essential epidemiology For more information on the rubella virus, please refer to the Surveillance Guide for Measles and Rubella. Vaccines The rubella vaccine is a live attenuated strain. A single dose confers more than 95% long-lasting immunity, and probably lifelong protection, which is similar to that induced by natural infection. Rubella vaccines are available either in monovalent formulations (a vaccine directed at only one pathogen) or more commonly, in combination with other vaccines, such as vaccines against measles (MR), measles and mumps (MMR), or measles, mumps and varicella (MMRV). 21 CRS Annex 2: Steps to establish CRS surveillance system The following steps should be followed to establish CRS surveillance. National CRS surveillance coordinators It is necessary to have two national coordinators, one for epidemiology and the other for laboratories, to manage these components of the system. The epidemiological coordinator plays the following roles: z developing a protocol for CRS surveillance; z developing the requisite training materials and conducting training on CRS surveillance; z monitoring surveillance performance and the quality of data; z ensuring that adequate specimens are collected and transported for laboratory testing; z maintaining the CRS surveillance database; z coordinating with laboratories to ensure linkage of laboratory and epidemiological data; z coordinating activities with the country’s national measles and rubella elimination programme, including reporting to WHO; and z providing feedback on CRS surveillance to the participating health-care providers and facilities and relevant public health authorities. The laboratory coordinator plays the following roles: z ensuring that there is adequate laboratory testing, that standard operating procedures and necessary accreditations are in place, and that there is an ongoing quality assurance programme; z interpreting and reporting test results; z monitoring the duration of shedding of the virus by CRS cases; z coordinating with those engaged in epidemiological activities to ensure linkage of laboratory and epidemiological data; and z providing laboratory-related training. Identification of health-care facilities for reporting CRS Criteria for identification The CRS surveillance system should include facilities at which there is a likelihood of coming across infants with the most common defects associated with CRS – cataracts, heart defects or deafness, as well as those with a maternal history of rubella during pregnancy. 22 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion As these defects are the most likely to be evaluated and treated at secondary and tertiary care facilities, adequate sentinel surveillance for CRS can be conducted at these facilities, without including primary health-care providers and facilities in the CRS surveillance system. The facilities/providers that are most likely to evaluate and treat infants with CRS are: z secondary care providers, particularly ophthalmologists, cardiologists, audiologists and neonatologists; z tertiary care facilities, particularly those that provide surgical services for the eyes, ears and heart; z speciality care centres (e.g. children’s hospitals, centres for hearing and blindness); and z obstetric centres or private clinics involved in the care of pregnant women with rubella. Considering that an infant with CRS is likely to be seen in any of several specialities, there is a need for a nodal person who can coordinate between the various departments in each health facility. The local surveillance coordinators at sentinel sites play the following roles: z ensuring adherence to the national protocol and SOPs for CRS surveillance; z assisting in the training of health-care providers and the staff of facilities, when necessary; z ensuring the collection of clinical and epidemiological data and the completion of case investigation forms (Annex 3); z ensuring the appropriate collection and transportation of specimens and ensuring that laboratory data can be linked to clinical and epidemiological information; z maintaining a line list of suspected CRS cases in the assigned facilities; z providing periodic feedback to health-care providers; and z maintaining contact with the national coordinator regarding the identification and follow-up of suspected cases in the area. Initial and refresher training for participating providers z The providers from the sentinel facilities participating in CRS surveillance activities should be trained on an annual basis. z The training should cover information on the clinical features of CRS, the evaluation of infants with suspected CRS, appropriate laboratory testing of suspected cases, follow-up of cases, the importance of completing case investigation forms, infection control measures to prevent the spread of rubella virus from infants with CRS, and the reporting of cases in a timely manner. 23 CRS Initiation of surveillance activities Reporting of suspected CRS cases should be initiated once the coordinator and participating sites have been identified and the participating providers have been trained in the SOPs for CRS surveillance. Quality assessment and monitoring of surveillance z Quality assessments of surveillance need to be conducted at the sentinel sites at least once in six months to assess the completeness of CRS surveillance. The sites-level coordinator can review hospital records to identify any missed cases. z The list of reported CRS cases can be compared with that of all cases matching the criteria for a suspected CRS case to identify missed cases. z The proportion of missed cases at a sentinel site can be assessed as the percentage of missed cases identified by the coordinator among all cases that meet the CRS surveillance inclusion criteria (total of both reported and unreported cases). z The proportion of suspected CRS cases that have been reported but not tested by a laboratory can be assessed as the percentage of reported cases without laboratory testing among all reported suspected CRS cases (both tested and not tested). z CRS surveillance case reports should be assessed for any missing variables. If the records are incomplete, the findings should be discussed with the providers at the site and the need for completeness of data and case reporting should be emphasized. Analysis of CRS surveillance data z The CRS surveillance data should be analysed on an annual basis or more frequently, if necessary. The epidemiological variables that should be assessed include: z the number of cases reported throughout the time frame assessed (e.g. a year); z status of case classification; z the geographical location of CRS cases within the country; z whether or not cases were clustered and/or associated with rubella outbreaks; z maternal characteristics (age, race/ethnicity, country of birth); and z the location of maternal exposure to rubella. 24 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Expansion of CRS surveillance z According to whichever is appropriate, attempts should be made to expand surveillance or include other sites. z If the providers and facilities included in the surveillance system capture the majority of infants with suspected CRS within a country, the system can be considered adequate. z In countries which have conducted limited pilot testing of CRS surveillance systems or in which assessments have shown that the CRS surveillance does not include the majority of infants in the country, the surveillance should be expanded to include more sites, with the ultimate goal of establishing sentinel site surveillance that captures the majority of infants in the country. Feedback for stakeholders Stakeholders involved in the CRS surveillance system need to be provided feedback, which should include information on the status of the epidemiology of CRS and any updates and recommendations for improvement. Infection control measures It is vital to institute infection control measures for infants with CRS since they may shed rubella virus for up to one year and have been the cause of rubella outbreaks. z Only those who are immune to rubella should have contact with affected infants. Among the family members and friends, those involved in the care or handling of the infant should be immune to rubella. z In the hospital, the infant should be in contact isolation. Those caring for the patient should wear a protective gown and gloves, and should be immunized against rubella. 25 CRS Annex 3: Case investigation form UID Country code/ province code/ district code/ year/ serial number of case Date of notification dd/mm/yyyy Date of investigation dd/mm/yyyy Date of reporting dd/mm/yyyy Demographic data Name of child Sex Male  Female  Not known  Date of birth, if not available age in months dd/mm/yyyy Months: Address State/province Town/village District Place of delivery of infant Mother’s name Clinical information Gestational age in weeks Birth weight in grams Group A (fill in all) Group B (fill in all) Condition Yes No Not known Condition Yes No Not known Congenital heart disease (if yes, specify defect) Purpura Cataract Microcephaly Congenital glaucoma Meningoencephalitis Pigmentary retinopathy Jaundice Hearing impairment Splenomegaly Development delays Radiolucent bone disease Other abnormalities: If yes, please describe: Name of physician who examined the infant Address: House no. Street City/ town/ village 26 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Telephone Email Present status of infant Alive  Dead  If dead, cause of death: Was an autopsy conducted? Yes  No  Not known  If yes, date dd/mm/yyyy Autopsy findings Maternal history/ antenatal care Number of previous pregnancies Age Vaccinated against rubella Yes  No  Not known  If yes, give dates Rubella-like illness during pregnancy Yes  No  Not known  If yes, in which week of pregnancy Maculopapular rash Yes  No  Not known  If yes, date of onset: dd/mm/yyyy Swollen lymph nodes Yes  No  Not known  If yes, date of onset: dd/mm/yyyy Arthralgia Yes  No  Not known  If yes, date of onset: dd/mm/yyyy Other complications Yes  No  Not known  If yes, date of onset: dd/mm/yyyy Rubella confirmed Yes  No  Not known  If yes, date of onset: dd/mm/yyyy During pregnancy, was the woman exposed to anyone of any age with fever and maculopapular (not vesicular) rash? Yes  No  Not known  If yes, when: dd/mm/yyyy Weeks of pregnancy: Where? Did the woman travel during pregnancy? Yes  No  Not known  If yes, when: dd/mm/yyyy At how many weeks of pregnancy? Where? 27 CRS Laboratory investigations Fi rs t sp ec im en Specimen collected Yes  No  Not known  Type of specimen collected Serum  Nasopharyngeal/throat swab  Urine  Others  (specify) Date of specimen collection: dd/mm/yyyy Date on which specimen was sent: dd/mm/yyyy Date on which laboratory received specimen: dd/mm/yyyy Rubella IgM Not tested  Positive  Negative  In process  Inconclusive  Rubella IgG Not needed  Not tested  Positive  Negative  In process  Inconclusive  Se co nd s pe ci m en Specimen collected Yes  No  Not known  Type of specimen collected Serum  Nasopharyngeal/throat swab  Urine  Cerebrospinal fluid  Others  (specify) Date of specimen collection: dd/mm/yyyy Date on which specimen was sent: dd/mm/yyyy Date on which laboratory received specimen: dd/mm/yyyy Rubella IgM Not needed  Not tested  Positive  Negative  In process  Inconclusive  Rubella IgG Not needed  Not tested  Positive  Negative  In process  Inconclusive  Sustained IgG levels* Not tested  Yes  No  In process  Rubella virus isolation Not tested  Positive  Negative  In process  Rubella PCR† Not done  Positive  Negative  In process  Genotype Date of first validated laboratory result Final classification CRS  Discarded  If discarded , please specify. Laboratory-confirmed  Clinically compatible  Classification by origin Endemic  Imported  Import-related  Not known  Date of final classification dd/mm/yyyy Investigator’s name Signature with date *Sustained IgG level on at least two occasions between 6 and 12 months of age †PCR: polymerase chain reaction 28 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Annex 4: Collection, storage and transport of specimens Collection of specimens It is necessary to collect two types of biological specimens – one for the detection/ isolation of the virus and the second for the detection of antibody levels. For detection/ isolation of virus z Nasopharyngeal swabs are the most preferred for the isolation of the virus. z The other specimens which are also acceptable include: z throat swabs z nasal swabs z blood (1 mL) z urine (5–20 mL) z cerebrospinal fluid (1 mL) z dried blood spots (DBS) in remote locations where serum transport is not possible. Nasopharyngeal swabs: Though these are ideal, it is relatively difficult to collect them. z Only synthetic fibre swabs with plastic shafts should be used for collection. The use of calcium alginate swabs or swabs with wooden shafts should be avoided as they may contain substances that inactivate viruses and/or inhibit PCR testing. z The nasopharyngeal swab has a flexible shaft. The patient’s head should be tilted back and the swab inserted into the nostril, parallel to the palate. The swab should come in contact with the mucosal surface. The throat swab is collected by swabbing the posterior pharynx, avoiding the tongue. z The sample must be placed in a sterile tube that contains 2–3 mL of viral transport media (VTM) or phosphate-buffered saline. It is important to prevent the swabs from drying out. z The throat and nasopharyngeal swabs may be refrigerated at 2–8 °C for up to 48 hours and shipped on ice/frozen ice packs. z If arrangements for shipment cannot be made within this time frame, it is best to preserve the sample at -70 °C. After freezing at -70 °C, the samples are shipped on dry ice. Freeze/thaw cycles should be avoided. z If facilities for storage at -70 °C are not available, the samples should be stored at -20 °C. Viral viability will be lost, but the integrity of the viral RNA may be maintained and detected by RT-PCR. 29 CRS Urine z A suitable sterile, leak-proof container should be used to collect the sample of urine. z Whole urine samples may be shipped in sealed containers at 4 °C. z If facilities for processing urine samples / centrifugation are available, the sample should be stored at 4–8 °C and centrifuged within 24 hours of collection. The sample must be centrifuged at 500 × g (approximately 1500 rpm) for 5–10 minutes, preferably at 4 °C and with the supernatant removed. Sterile VTM, tissue culture medium or phosphate-buffered saline must be added to the sediment to bring the final volume to 2 mL. If a pellet is not visible, all but 1 mL at the bottom of the centrifuge tube must be removed and mixed with an equal volume of VTM. The processed urine sample should be stored at 4 °C and shipped within 48 hours. z Alternatively, the urine sample may be frozen at -70 °C in VTM and shipped on dry ice. z If facilities for storage at -70 °C are not available, samples can be stored at -20 °C; viral viability will be lost, but the integrity of the viral RNA may be maintained and detected by RT-PCR. z Regardless of the type of specimen collected, all specimens should arrive in the laboratory within five days of collection. For detection of antibodies z A 1 mL sample of blood should be taken. In the case of very small infants, 0.5 mL of blood or DBS (≥ 3 fully filled circles) is also acceptable. z The sample should be centrifuged to separate out the serum, which should be stored at 2–8 °C for up to 24 hours, or 20–25 °C for 6 hours. z Upon clotting (by spinning or letting it stand for I hour), the serum should be transferred to a sterile cryovial to avoid haemolysis. z The serum should be stored at 4– 8 °C until shipment, but not for longer than 7 days. z When the serum samples are to be held for longer than 7 days, they should be frozen at -20 °C or below and transported to the testing laboratory on frozen icepacks. When they are to be stored for longer periods, they should be transported to the laboratory in cold chain. Repeated freezing and thawing can have detrimental effects on the stability of IgM antibodies. z As a general rule, serum specimens should be shipped to the laboratory as soon as possible, and shipment should not be delayed for the collection of additional specimens. 30 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Collection of blood for dried blood spots Dried blood spots can be used when it is not possible to perform venepuncture, or if a cold chain or economical method to ship serum samples is not available. z While venous blood can be collected for DBS, normally DBS are prepared using capillary blood. z Blood should be collected by pricking a finger or the heel with a sterile lancet, preferably a single-use disposable lancet. z Blood specimens that have been spotted on filter paper should be allowed to air dry completely. z Individual cards should be wrapped in wax paper and placed in a sealable plastic bag with a desiccant pack. z DBS should be stored at 4 °C until they can be shipped to the laboratory. z It is acceptable to transport DBS at ambient temperatures of up to 42 °C if they are delivered to the laboratory within 3 days. 31 CRS Annex 5: Indicators of performance of CRS surveillance Surveillance attribute Indicator Target Formula (numerator/ denominator) Comments Ti m el in es s of r ep or tin g Proportion of surveillance units reporting to the national level on time, even in the absence of cases ≥ 80% (Number of designated reporting units reporting by deadline / number of designated reporting units) x 100 At each level, reports should be received on or before the requested date. C om pl et en es s of r ep or tin g Proportion of surveillance units submitting 12 monthly reports per year, even in the absence of cases (zero reporting) ≥ 80% (Number of designated reporting units that submitted 12 reports in the last year / number of designated reporting units) x 100 A de qu ac y of in ve st ig at io n Proportion of suspected cases investigated adequately within 48 hours of notification ≥ 80% (Number of suspected cases for which an adequate investigation was initiated within 48 hours of notification / number of suspected cases) x 100 An adequate investigation of a CRS case includes the collection of the following data elements: name and/or UID, place of residence, date of birth, sex, date of reporting, date of investigation, date of specimen collection, clinical examinations for hearing impairment, cataract and congenital cardiac defects, and clinical outcome at the time of the investigation; mother’s history of rashes, travel and vaccination and her age. Se ns iti vi ty o f C R S su rv ei lla nc e National annual rate of suspected CRS cases ≥ 1 per 10 000 live births (Number of suspected cases / live births) x 10 000 32 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Surveillance attribute Indicator Target Formula (numerator/ denominator) Comments A de qu ac y of s pe ci m en c ol le ct io n an d te st in g Proportion of suspected cases with adequate specimens for detection of rubella infection collected and tested in a proficient laboratory ≥ 80% (Number of suspected cases with an adequate specimen tested in a proficient laboratory/ number of suspected cases) x 100 An adequate specimen is a blood sample of a volume of at least 0.5 mL obtained by venepuncture in a sterile tube. A proficient laboratory is one that is WHO-accredited or has established a recognized quality assurance programme with International Organization for Standards or Clinical Laboratory Improvement Amendments certification. A de qu ac y of s pe ci m en s fo r vi ra l d et ec tio n Proportion of confirmed cases with adequate specimens tested for virus detection/ isolation ≥ 80% (Number of confirmed cases with an adequate specimen for viral detection that was tested in a proficient laboratory/ number of confirmed cases) x 100 An adequate specimen is a throat swab, nasal swab, serum, urine, or clinical specimen based on the symptoms (e.g. cataracts and cerebrospinal fluid specimen). The specimen usually taken is a throat swab. C om pl et en es s of m on ito rin g fo r vi ra l s he dd in g Proportion of confirmed CRS cases demonstrated to no longer be shedding virus ≥ 80% (Number of confirmed CRS cases of the age of ≤ 12 months with at least 2 negative tests for virus detection and samples collected at least a month apart / number of confirmed CRS cases of the age of ≤ 12 months) x 100 Ti m el in es s of c as e de te ct io n Proportion of CRS and CRI cases detected within 3 months of birth ≥ 80% (Number of confirmed CRS and CRI cases detected within 3 months of birth / number of confirmed CRS or CRI cases) x 100 This should include individuals found through active case search both in the numerator and denominator. 33 CRS Surveillance attribute Indicator Target Formula (numerator/ denominator) Comments Ti m el in es s of s pe ci m en tr an sp or t Proportion of specimens received at the laboratory within 5 days of collection ≥ 80% (Number of specimens received by laboratory within 5 days of collection / number of specimens collected) x 100 This indicator applies only to public laboratories. Ti m el in es s of r ep or tin g la bo ra to ry r es ul ts Proportion of serological results reported by the laboratory within 4 days of obtaining specimen ≥ 80% (Number of serological results reported within 4 days of receipt of specimen / number of specimens received by laboratory) x 100 This indicator applies only to public laboratories. 34 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion Further reading 1. World Health Organization. Congenital Rubella Syndrome: Vaccine-Preventable Diseases Surveillance Standards. World Health Organization. (https://cdn.who.int/ media/docs/default-source/immunization/vpd_surveillance/vpd-surveillance- standards-publication/who-surveillancevaccinepreventable-03-crs-r2.pdf?sfvrs n=7d83d274_8&download=true, accessed 21, July 2022). 2. World Health Organization. Module-2, Congenital Rubella – Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region. New Delhi: World Health Organization, Regional Office for South-East Asia; 2017. Licence: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/bitstream/handle/10665/277459/ Module2-CRS.pdf?sequence=4&isAllowed=y, accessed 21 July 2022). 3. Lanzieri T, Redd S, Abernathy E, Icenogle J. Chapter 15: Congenital Rubella Syndrome. In: Roush SW, Baldy LM, Hall MAK (eds). Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention, Atlanta, GA (https://www.cdc.gov/vaccines/pubs/surv-manual/index.html, accessed 21 July 2022). 4. Zimmerman LA, Knapp JK, Antoni S, Grant GB, Reef SE. Progress Toward Rubella and Congenital Rubella Syndrome Control and Elimination – Worldwide, 2012– 2020. MMWR Morb Mortal Wkly Rep. 2022;71(6):196–201. doi: 10.15585/ mmwr.mm7106a2. 5. Khanal S, Bahl S, Sharifuzzaman M, Dhongde D, Pattamadilok S, Reef S et al. Progress Toward Rubella and Congenital Rubella Syndrome Control – South-East Asia Region, 2000–2016. MMWR. Morb Mortal Wkly Rep. 2018; 67(21):602– 6. doi: 10.15585/mmwr.mm6721a3. 6. Shanmugasundaram D, Awasthi S, Dwibedi B, Geetha S, Jain M, Malik S, et al. Burden of congenital rubella syndrome (CRS) in India based on data from cross-sectional serosurveys, 2017 and 2019–20. PLoS Negl Trop Dis 2021;15(7):e0009608. doi.org/10.1371/journal.pntd.0009608. CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region MODULE-3 POLIOMYELITIS September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Poliomyelitis) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO CONTENTS Introduction 7 Objectives 7 Types of surveillance 7 Acute flaccid paralysis surveillance 7 Linkages to other surveillance 8 Case detection 8 Definition of suspected case 8 Date of onset of illness 8 Response to a suspected case 8 Case investigation 8 Case investigation form 8 Unique case identification number 9 Specimen collection and transportation 9 Contact sampling 10 Hot case 11 Reporting laboratory results 12 60-day follow-up examination 13 Cross-notification and tracking of cases 13 Classification of cases 13 Data management 14 Recommended data elements 15 Recommended data analysis 15 Using data for decision-making 16 Monitoring performance 16 Indicators for surveillance performance: 16 Timeliness of case detection, investigation and specimen transport 18 Review of surveillance 19 Public health intervention and response 19 Poliovirus events and outbreak 20 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Clinical management 22 Environmental surveillance 22 Background 22 Role of ES in detecting poliovirus 22 Criteria for selecting sampling sites 23 Location of an environmental site 23 Selecting sampling sites 24 Sample collection schedule 25 Validating an environmental site 26 Closing an environmental site 26 Collecting, packaging and transporting samples 27 Environmental surveillance supervision 27 Data collection and management 28 Site identification number 28 Reporting laboratory results 29 Monitoring and evaluating performance 29 Programme response to WPV or VDPV detection 32 Polio surveillance among people with primary immunodeficiency disorders 35 Background 35 Objectives of surveillance 35 Case detection 35 Case definition for PID patient at risk of poliovirus excretion 35 Case definition for PID patient with confirmed poliovirus excretion 36 PID patients with AFP 38 Case investigation and management 39 Detailed investigation of PID patients with confirmed poliovirus excretion 39 Public health response 40 5POLIOMYELITIS Treatment 41 Other management measures 41 Data analysis 42 Suggested epidemiological analysis 42 Monitoring and evaluation 43 Annex 1: Poliomyelitis 45 Epidemiology 45 Occurrence 45 Infectious agent 45 Transmission 45 Reservoir 46 Immunity 46 Vaccines 46 Oral polio vaccine (OPV) 46 Novel oral poliovirus vaccines (nOPVs) 46 Inactivated poliovirus vaccine (IPV) 46 Vaccine-derived polioviruses (VDPVs) 47 Circulating vaccine-derived poliovirus (cVDPV) 47 Immunodeficiency-related vaccine-derived poliovirus (iVDPV) 47 Ambiguous vaccine-derived poliovirus (aVDPV) 48 Clinical aspects 48 Pathogenesis 48 Clinical features and complications 48 Laboratory diagnosis 49 Vaccine-associated paralytic polio (VAPP) 50 Annex 2: Community-based surveillance 51 Definition and rationale 51 Modalities 51 Needs assessment for CBS 52 Process of establishing CBS 52 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 Annex 3: AFP case investigation form 54 Annex 4: Timeliness 57 Annex 5: Indicators for surveillance: Core and non-core 60 Core Indicators 60 Annex 6: Gender and polio surveillance 66 Gender-related delays in detection 67 Gender in the work environment and organizational culture 70 Actions to consider 70 Annex 7: Environmental sample collection form 72 Annex 8: Site registration form 73 Annex 9: Laboratory request/report form 74 Annex 10: PID case investigation form 75 Further reading 79 7POLIOMYELITIS Poliomyelitis Introduction The WHO South-East Asia Region was declared free of all wild polioviruses (types 1, 2 and 3) in 2014. As of 2022, only wild poliovirus type 1 (WPV1) is globally present and is endemic in just two countries: Afghanistan and Pakistan. Types 2 and 3 were certified to have been eradicated in 2015 and 2019, respectively. However, there is a risk of the importation of WPV1 to the Region from the endemic countries. In addition, circulating vaccine-derived polioviruses (cVDPVs) pose a risk of outbreaks. Surveillance for the detection of the transmission of poliovirus is critical for achieving global polio eradication. High-quality surveillance permits the timely detection of the transmission of WPV and VDPVs, as well as the circulation of Sabin-like viruses. Objectives The poliomyelitis surveillance system is a key pillar of the eradication effort and serves to detect: z the importation of WPV; and z the presence of VDPV in a country. Types of surveillance Poliovirus surveillance has three components: z acute flaccid paralysis (AFP) surveillance; z environmental surveillance (ES); and z surveillance among patients with primary immunodeficiency disorders. Poliovirus surveillance is supported by the Global Poliovirus Laboratory Network (GPLN) and the comprehensive Polio Information System, which permits ready access to data to inform action. The three components of poliovirus surveillance are described in the following sections. Acute flaccid paralysis surveillance Surveillance for AFP is the cornerstone of the polio eradication effort and the gold standard for detecting the circulation of poliovirus anywhere within a country. All countries should be able to detect individuals with suspected AFP from any segment of the population through at least one of three strategies: active surveillance, passive surveillance and community- based surveillance. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Linkages to other surveillance Ideally, AFP surveillance should be linked with case-based surveillance for measles–rubella and integrated surveillance for other vaccine-preventable or outbreak-prone diseases. Countries that conduct immunodeficiency-related vaccine-derived poliovirus (iVDPV) surveillance, enterovirus surveillance, or ES for polio should also link AFP surveillance to these efforts. Case detection Definition of suspected case A suspected case is any case presenting with AFP. An AFP case is defined as a child under 15 years of age presenting with recent or sudden onset of floppy paralysis or muscle weakness due to any cause, or any person of any age with paralytic illness if poliomyelitis is suspected by a doctor. Date of onset of illness The date of the onset of AFP should be considered as the date of the onset of paralysis. Response to a suspected case Case investigation All suspected cases should be investigated within 48 hours of notification by trained health staff/clinicians designated by the public health authority. In the early stages, polio may be difficult to differentiate from other forms of AFP, such as the Guillain–Barré syndrome, transverse myelitis and traumatic neuritis. As such, all children with AFP should be reported and tested for poliovirus even if doctors are confident on clinical grounds that the child does not have polio. Case investigation form The relevant information on the suspected case should be noted in a standard case investigation form. (A sample case investigation form is provided in Annex 3.) The information recorded should include basic demographics; clinical features; findings of the neurological examination; the patient’s medical, travel and vaccination history; and information on the medical services available and risk factors. To identify the possible source of exposure, it is important to ascertain whether the suspected case travelled outside his/her area of residence, or received visitors from outside the area of residence in the 35 days preceding the onset of paralysis. The person’s exposure to anyone with AFP within this 35-day period should be determined. 9POLIOMYELITIS Unique case identification number Each AFP case should be assigned a unique case identification number, also known as epidemiological number (EPID number). The number should begin with one or more three-letter combinations to designate the geographical location, followed by the year and the case number. The EPID number should be cited in all communications and forms related to the case. For example: z POL-- polio z NEP – country code z PR5 – province code z KAP – district code z 22 – year of onset (2022) z 001 – serial number of AFP case of the district z The UID or EPID number would thus be POL-NEP-PR5-KAP-22-001. Specimen collection and transportation Testing for polio entails the analysis of stool specimens for the presence of poliovirus. Adequate stool specimens should be obtained for laboratory confirmation of poliovirus as soon as possible after the onset of paralysis. Since the shedding of the virus is variable, two specimens – taken at least 24 hours apart – are required. It is essential to act fast since the concentration of poliovirus in the stool of an infected individual is the highest during the first two weeks after the onset of paralysis. Ideally, all stool specimens should be collected within 14 days of the onset of paralysis. In case the samples cannot be collected within 14 days, they should be collected until up to 60 days of the onset of paralysis. Stool specimens should be sealed in containers and stored immediately in a refrigerator or packed between frozen ice-packs at 4–8 °C in a cold box, ready for shipment to a laboratory. Undue delays or prolonged exposure to heat on the way to the laboratory may destroy the virus. Specimens should arrive at the laboratory within 72 hours of collection. Otherwise, they must be frozen (at -20 °C) and then shipped frozen, ideally packed with dry ice or cold packs. These procedures are known as the “reverse cold chain”. A laboratory request form must be filled in for each case, and the EPID number should be recorded on the label of the specimen collection container and on the form. Specimens should be sent by the fastest, most reliable means of transport available. In countries without a national polio laboratory, this may necessitate a standing contract with a courier service that accepts clinical specimens. Expertise is required for packaging and Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 documentation that is compliant with the International Air Transport Association (IATA) regulations. In critically ill children who cannot pass stool, samples should be collected with the help of rectal tubes. With this method, however, the volume of stool collected is not sufficient to save a portion for additional testing; also, the virus isolation rate may be low. Adequate stool specimens: The evaluation of the performance of surveillance is based on the collection of adequate stools. This is defined as the collection of two specimens within 14 days of the onset of paralysis and at least 24 hours apart, with each specimen being of adequate volume (8–10 g) and the specimens arriving at a WHO-accredited laboratory in good condition. In “good condition” denotes that there should be no desiccation or leakage, and there should be adequate documentation and evidence that the cold chain was maintained. Contact sampling Contact sampling is the collection and testing of one stool specimen from 3 individuals in contact with an AFP case. AFP contact sampling is used to provide laboratory evidence of poliovirus in an AFP case. The likelihood of asymptomatic infection and virus excretion is higher among individuals who have had contact with AFP cases than those who have not. The collection of stool specimens from the contacts of AFP cases provides an additional means of determining whether poliovirus is the cause of paralysis in an AFP case. If the specimens of the contacts test positive in the laboratory, they are used to confirm poliovirus infection in an AFP case which is otherwise not laboratory confirmed. The following guidelines should be followed for contact sampling: z Children with frequent contact (e.g. touching, sharing toys and sharing food) with an AFP case should be identified for specimen collection. z Contact sampling should be carried out in the case of children, preferably < 5 years who have been in contact with an AFP case within the week prior to and/or 2 weeks after the onset of paralysis. z Some examples of the contacts to be sampled are siblings and other children who live in the same household and/or neighbouring houses and who played with the AFP case during the relevant period. z Stool specimens from the contacts of AFP cases may be collected for up to 60 days after the onset of paralysis, as poliovirus may be excreted for up to 2 months and sometimes longer. z Stool specimens are usually collected from the community of residence of the AFP case. However, if the case stayed elsewhere 1 week prior to and/or 2 weeks after the onset of paralysis, then the collection of specimens from the contacts may be warranted at these locations as well. 11 POLIOMYELITIS As part of AFP surveillance: Contact sampling should be performed as part of the regular AFP surveillance activities. Among the regular AFP surveillance activities, the contacts of AFP cases may need to be sampled in the following situations, especially in high-risk countries: z for all AFP cases with inadequate stool specimens. “Inadequate” signifies:  the collection of 0 or 1 stool specimen;  the collection of at least 1 stool specimen > 14 days after the onset of paralysis;  the collection of 2 stool specimens < 24 hours apart; and  poor condition of stool (e.g. specimen was hot on arrival at the laboratory). z for AFP cases who reside in security-compromised or hard-to-reach areas to take advantage of the limited opportunity to reach these individuals and communities; z if there are “hot” AFP cases; and z if there are any suspicions regarding the process of collecting or handling the index AFP stool specimens. Hot case A “hot case” is an AFP case that is characterized by all three cardinal signs of poliomyelitis: z rapid progression of paralysis; z asymmetrical paralysis; and z fever at onset. Additional criteria, depending on the epidemiology, may include: z being less than five years of age; z having taken fewer than three doses of polio-containing vaccine or having an unknown vaccination status; and z having visited areas where or been in contact with groups among which the virus has been circulating recently. The laboratory must fast-track the processing of specimens if a hot case is identified. The procedures for the collection and transport of contact specimens are the same as those for the AFP case. Each specimen should be labelled clearly as being that of a contact of a case and should have the EPID number of the case. This should be followed by the contact number, e.g. C1, C2 or C3. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 As part of outbreak response: The expansion of AFP contact sampling may be warranted under the following circumstances to enhance AFP surveillance. National surveillance and laboratory personnel must coordinate and collaborate closely in the effort to expand sampling. z Attempts should be made to expand contact sampling to all AFP cases in an outbreak-affected country, to improve the detection of all viruses. z The sampling should cover the contacts of all AFP cases detected outside the subnational outbreak zone, to increase the probability of detecting virus movement beyond the designated outbreak zone. NOTE: The results of AFP contact sampling cannot be used to confirm community-wide transmission of poliovirus. It is not recommended that stool specimens be collected from the contacts of individuals classified as: z WPV, aVDPV, cVDPV, unclassified VDPV, polio-compatible and SL2-positive; z poliovirus-positive; and/or z poliovirus-positive healthy children. Reporting laboratory results The specimens of all AFP cases must be processed in a WHO-accredited laboratory within the GPLN. The GPLN member laboratories follow standardized protocols to: 1) isolate poliovirus; 2) conduct intratypic differentiation; and 3) conduct genomic sequencing (done in specialized laboratories). z Laboratory confirmation is based on the isolation of poliovirus on monolayers of tissue culture cells (RD and L20B). The isolation of non-polio enterovirus (NPEV) may be done as part of testing for poliovirus and the result must be reported separately. z Intratypic differentiation is conducted by reverse transcriptase polymerase chain reaction (RT-PCR) to identify whether the virus is a WPV, a VDPV or a Sabin-like virus, as well as the serotype (1, 2, 3). z Genetic sequencing helps to monitor the pathways of poliovirus transmission by comparing the nucleotide sequence of the VP1-coding region of poliovirus isolates. The laboratory must maintain accurate records for each sample, using the EPID number to identify each specimen. The epidemiological data from the surveillance system and the laboratory data for each case will be linked by this number. The polio laboratory must report the results to the national programme and WHO. 13 POLIOMYELITIS 60-day follow-up examination For certain categories of AFP cases, a 60-day follow-up is conducted between the 60th and 90th day after the onset of paralysis to determine whether or not residual paralysis is present. If it is, it is further evidence that the cause of the paralysis is likely to be poliovirus. The follow-up should not be conducted before the 60th day as there is still a possibility that the paralysis will resolve, which would yield “false positive” examination outcomes. The following categories of AFP cases should undergo a 60-day follow-up: z AFP cases with inadequate stool specimens; z AFP cases in which WPV/VDPV have been isolated; and z AFP cases in which Sabin-type poliovirus or nOPV2 has been isolated. During the 60-day follow-up examination, the investigator must: z verify with the family the developments since the first investigation and confirm that the information on the case investigation form is complete and correct; z clinically assess the child; and z fill in the 60-day follow-up form and send it to the national surveillance unit, according to established procedures. Cross-notification and tracking of cases A child presenting with AFP may first come to the attention of a health official in a district other than that where he/she resides, and may even come from a neighbouring country. Procedures should be established to ensure that cases appearing in districts other than the district of residence are evaluated properly, and that the health staff in the districts concerned are notified about the case immediately. For AFP cases from other countries, the local and regional WHO offices should be notified. Classification of cases AFP cases are classified according to the virological scheme shown in Fig. 3.2. If the person has inadequate stool samples, and has residual paralysis, is lost to follow-up or dead at the time of the 60-day follow-up investigation, the case is classified by a national expert review committee (ERC). The ERC may make a request for more clinical background and hospital documents, and might examine the case to determine whether to classify it as either compatible or discarded. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 Figure 3.2.: Final classification of AFP cases Confirmed: This is a suspected case from whose stool specimens, or those of his/her close contacts, WPV or VDPV has been isolated. Compatible: A compatible case is a suspected case without adequate specimens and in whose stool specimens (in addition to those of the close contacts) WPV or VDPV have not been isolated; and there is residual paralysis after 60 days’ follow-up that the national ERC deems to be clinically and epidemiologically compatible with poliomyelitis. The ERC may classify cases presented to it as compatible with poliomyelitis when there is insufficient clinical and epidemiological data to rule it out. Discarded: A discarded case is one that was adequately investigated (including the collection of adequate stool specimens) and there was no laboratory evidence of WPV or VDPV infection. Cases for which inadequate specimens were collected, are classified as discarded if the weakness resolves within 60 days of the onset of paralysis and/or if the national ERC deems the case not to be compatible with poliomyelitis. Data management An important aspect of a successful polio eradication programme is a well-developed information system that provides programme managers and health workers with the information necessary to take appropriate action. The surveillance data should be reviewed on a weekly basis at the national, state and district levels to detect and quantify the AFP CASE STOOL SPECIMEN WILD POLIO VIRUS/ VACCINE DERIVED POLIO VIRUS NO POLIO VIRUS (WILD OR VACCINE DERIVED) TWO ADEQUATE SAMPLES NO /INADEQAUTE SAMPLES RESIDUAL WEAKNESS/ DIED/ LOST NO RESIDUAL WEAKNESS EXPERT REVIEW DISCARDED DISCARDED DISCARDED COMPATIBLE CONFIRMED Final classifica�on of AFP Cases 15 POLIOMYELITIS occurrence of disease, assess changing disease patterns over time, determine the risks for disease, monitor the progress of the polio eradication programme and evaluate the performance of the AFP surveillance system itself. AFP surveillance data must be analysed to measure the sensitivity and consistency of the surveillance system to ensure that it is functioning at the desired level. The following key indicators should be assessed regularly. Recommended data elements z Case notification z Demographic information z Vaccination status and risk factors z Clinical information z Specimen-related data z Laboratory results The sample case investigation form in Annex 3 gives the details of the data to be collected. Recommended data analysis z Suspected cases by geographical area, month, year, source of notification and health-care contact (names of facilities or traditional healers visited for treatment of AFP) z Classification and type of poliovirus (confirmed WPV or VDPV, polio-compatible, discarded) by geographic area, month and year z Confirmed cases by age group, sex, immunization status and risk factors (such as migrant status) z Percentage of stool samples collected before and after 14 days of onset of paralysis z Percentage of AFP cases with inadequate stool and for which 60-day follow-up investigations were completed z Percentage of non-polio acute flaccid paralysis (NPAFP) cases in the age group of 6–59 months by doses of polio vaccine (0, 1–2, and ≥ 3) z Epi-curve of final classification status by geographical area and year z Spot maps of confirmed cases by poliovirus type (WPV1/3, VDPV1/2/3), polio- compatible cases and positive ES samples z Percentage of subnational areas meeting two key surveillance indicators:  targets for NPAFP rate;  stool adequacy rate. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 Using data for decision-making Data may be used to: z track the circulation of WPV and emergence of VDPV, as well as in the control of an outbreak; z classify suspected cases of AFP as confirmed, compatible or discarded; z identify high-risk populations (e.g. migrants or people of a certain ethnicity) to design appropriate messages and interventions, and investigate the reasons for missed vaccination; z identify high-risk geographical areas where supplementary immunization activities (SIA) and other targeted programme activities can then be conducted; z monitor the impact of interventions, including SIA; z document evidence needed for changes in the immunization policy or strategy and outbreak response (such as on the targeted SIA in areas with low vaccine coverage among NPAFP cases, or the use of the monovalent oral polio vaccine [mOPV] versus the bivalent oral polio vaccine [bOPV]); z monitor surveillance performance and identify areas that need targeted surveillance reviews or strengthening (e.g. for re-assessing the reporting network and prioritizing reporting sites for an active surveillance visit); z provide evidence of the interruption of WPV to the national certification committee and regional commission. Monitoring performance z The performance of surveillance should be monitored using standard indicators and efforts should be focused on areas in which performance is low. z The routine coverage of surveillance should be monitored in all geographical areas, with a focus on those in which performance is low. z During monitoring, high-risk areas should be identified so that they can be given greater attention during efforts to strengthen routine immunization and SIA. Indicators for surveillance performance: Performance indicators are used to monitor the quality of disease surveillance and the performance of laboratories. The indicators for field and logistical activities, as well as processes (notification, investigation and shipment), were reviewed, updated and expanded in 2021, and divided into “core” and “non-core” indicators. For a comprehensive list, see Annex 5. The two indicators that remain the gold standard for the assessment of the quality of AFP surveillance are: z the non-polio AFP rate; and z stool adequacy. 17 POLIOMYELITIS Indicators for the timeliness of activities are of particular importance. These include: z timeliness of the detection of WPV/VDPV (number of cases with final laboratory results ≤ 35 days of onset); z timeliness of notification (number of cases reported within 7 days of onset of paralysis); z timeliness of investigation (number of cases investigated within 48 hours of notification); and z timeliness of sample collection (number of cases with 2 samples collected ≥ 24 hours apart, both within 14 days of the onset of paralysis). Delays in detection can occur at any stage of the field, laboratory or logistical activities. Countries must monitor timeliness at every stage of the process. Annex 4 provides an insight into the causes of delays and the ways in which the programme can address them. Table 3.2: Indicators for performance of AFP surveillance Indicator Description Target Formula Notes Completeness of reporting Proportion of designated sites reporting AFP data, even in the absence of cases ≥ 80% (Number of sites reporting in absence of cases/ number of designated sites for AFP surveillance) x 100 For a given time period, such as 1 month or 6 months Surveillance sensitivity NPAFP rate For South-East Asia Region: ≥ 2 Outbreak settings: ≥ 3 (Number of cases discarded as NPAFP among children < 15 years of age/ number of children < 15 years of age) x 100 000 per year The achievement of the target NPAFP rate indicates that surveillance is sufficiently sensitive to detect WPV/cVDPV cases if poliovirus is circulating. Adequate collection of stool specimens Proportion of AFP cases with 2 stool specimens collected ≥ 24 hours apart, both within 14 days of onset of paralysis ≥ 80% (Number of AFP cases with 2 stool specimens collected ≥ 24 hours apart, within 14 days of onset of paralysis / number of AFP cases reported) x 100 The achievement of the target percentage for stool adequacy indicates the ability to detect poliovirus among AFP cases if poliovirus is circulating. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 Indicator Description Target Formula Notes Specimens in good condition Proportion of AFP cases whose specimens arrived at a WHO- accredited laboratory in good condition ≥ 80% (Number of AFP cases for which 2 stool specimens arrived at a WHO-accredited laboratory in good condition / number of AFP cases reported) x 100 Good condition denotes the maintenance of the reverse cold chain and arrival at the laboratory without leakage or desiccation. Completeness of 60-day follow-up Proportion of AFP cases who underwent a follow-up examination for residual paralysis at 60 days after the onset of paralysis ≥ 80% (Number of AFP cases who had inadequate specimens and underwent a 60-day follow- up examination / number of AFP cases reported to have inadequate specimens) x 100 Timeliness of case detection, investigation and specimen transport A delay in the detection of poliovirus transmission has a negative impact on the timeliness and effectiveness of the response to the outbreak and almost inevitably leads to an increase in transmission. Overall, it is important to identify bottlenecks by conducting regular analyses, making periodic desk reviews and seeking to gain a better understanding of the health-seeking behaviour of AFP cases and their caregivers. This should include the systematic collection and analysis of data disaggregated by sex, age and other factors to support the identification of gender-related barriers to health-seeking behaviour. The findings should be used to introduce effective and timely modifications in AFP surveillance activities, especially those aimed at improving active surveillance, case detection and the transport of specimens. The Global Polio Eradication Initiative (GPEI) strategy has set a targeted timeline for the investigation of cases, while the Global Polio Surveillance Action Plan (GPSAP) 2022– 2024 has elaborated as a 35-day window from the onset of disease to the final laboratory result (Fig. 3.1). 19 POLIOMYELITIS Fig. 3.1: Timeline for the detection of AFP cases AFP: acute flaccid paralysis Source: GPEI: Global Polio Surveillance Action Plan 2022-2024. Annex 4 describes some types of delay in detection, their possible causes and the ways in which the programme can address them. Review of surveillance AFP surveillance should be evaluated through regular periodic national reviews. The surveillance for AFP may be integrated with that for other vaccine-preventable diseases (VPD), including data triangulation (comparisons of coverage, surveillance and other data sources). As part of the quarterly EPI data review meetings, the coverage of the surveillance programme and data on its performance should be reviewed at the national and subnational levels to help identify potential areas in which gaps might exist, or in which surveillance may need to be strengthened. A thorough national review of surveillance that encompasses the field component should be carried out once in five years. In larger countries, provincial reviews should be conducted, with a few provinces being selected every year in a manner that all provinces are covered once in five years. Public health intervention and response All instances of the isolation of WPV, VDPV and all Sabin-like 2 viruses must be reported immediately by the national authority to WHO, regardless of the type of isolate or its source (clinical case, environmental sample, other). The identification of WPV in an area must be followed by an appropriate and timely response. The response should include rapid and thorough epidemiological investigation, strengthening of AFP surveillance in the area, and the immediate implementation of appropriate immunization activities. Timeliness of detection (AFP Cases), 35 days (onset to final lab result) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Poliovirus events and outbreak Definitions of poliovirus events (i.e. no current evidence of transmission) and outbreaks are given in Table 3.1. Table 3.1: Definitions of poliovirus events and outbreaks Typology Source Definition Ev en t (n o ev id en ce o f t ra ns m is si on a s ye t) H um an Detection of VDPV in: single AFP case or asymptomatic person (contact), or one or more personsa with no evidence of further community-level circulation (iVDPV or aVDPV isolates) OR Sabin-like 2 isolate from individual sample(s) OR WPV2 infection in an individual with documented exposure to type 2 virus in a laboratory or vaccine production facility. E nv ir on m en ta l Detection of WPV in single environmental sample without follow-up evidence of virus excretionb OR VDPV without evidence of further transmission, such as: single environmental sample without evidence of prolonged circulation, or an aVDPV OR Sabin-like 2 isolate from environmental sample(s). 21 POLIOMYELITIS Typology Source Definition O ut br ea k H um an Detection of WPV infection in any individual(s),a (in addition, for type 2, without documented exposure to type 2 virus in a laboratory or vaccine production facility) OR cVPDV infection in any individual(s).a E nv ir on m en ta l Detection of two of more separatec environmental samples positive for WPV with genetic sequencing information indicating sustained local transmission OR a single environmental sample positive for WPV with follow- up evidence of virus excretion,b (in addition, for type 2, without documented exposure to type 2 virus in a laboratory or vaccine production facility) OR any cVDPV-positive environmental sample. aVDPV: ambiguous vaccine-derived poliovirus; cVDPV: circulating vaccine-derived poliovirus; iVDPV: immunodeficiency-associated vaccine-derived poliovirus a. The infected person can be an AFP case or an asymptomatic/healthy person. b. Evidence of virus excretion is defined by identification during the follow-up investigation of an individual(s) infected with WPV or VDPV. c. “Separate” means that the samples were collected at more than one distinct ES collection site (no overlapping catchment areas), OR that they were collected from one site but more than two months apart. The following five strategic pillars are of critical importance in the effective interruption of transmission in an outbreak setting: z a fully engaged national government; z rapid risk assessment and the identification of transmission risk zones; z a robust immunization response; z effective communication and social mobilization; and z enhanced surveillance. The national outbreak preparedness and response plan should include the enhancement of surveillance during outbreaks. The national plans should be aligned with the most recent version of the GPEI standard operating procedures on the response to a poliovirus event and outbreak. For greater detail on the requirements of a polio outbreak response, refer to GPEI standard operating procedures (8) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 Clinical management There is no specific treatment for poliomyelitis. Suspected AFP cases should be referred to a hospital immediately for medical care. Any problem with respiration that suggests the involvement of the diaphragm requires immediate attention. Paralytic cases should be managed by a physician and given supportive care. Environmental surveillance Background Six countries in the WHO South-East Asia Region have established Environmental Surveillance (ES) for the detection of poliovirus, as of 2022. These are Bangladesh, India, Indonesia, Myanmar, Nepal and Thailand. Role of ES in detecting poliovirus Poliovirus surveillance continues to rely largely on AFP surveillance, considered the “gold standard”, but ES can be more effective for detecting the circulation of poliovirus in some settings. These include areas with suboptimal AFP surveillance and in populations among whom the vaccination coverage is high or who are receiving inactivated polio vaccine (IPV) in essential immunization schedules. Countries can rely on a combination of ES and AFP surveillance to make sure that the sensitivity and specificity levels of surveillance remain high. In addition, if it is feasible to establish quality ES, it can be employed as part of a polio outbreak investigation. ES has been used for many years to detect and monitor the reintroduction of WPV into polio-free countries, as well as to provide confidence in the successful elimination of the virus in countries with poliovirus transmission. In polio-free countries, ES can supplement AFP surveillance to: z detect the reintroduction of WPV or the emergence of cVDPV, especially in settings where AFP surveillance and/or the use of IPV is non-existent or suboptimal; z document the release of poliovirus from vaccine manufacturing facilities or laboratories; and z monitor the disappearance of Sabin strains following the withdrawal of OPV. In countries that have had a recent polio event or outbreak, ES can: z document the scope of virus transmission to guide immunization activities; z document the effectiveness and impact of vaccination campaigns during an outbreak response; and z confirm the end of an outbreak judging by the disappearance of VDPV or WPV from the environment, in conjunction with negative isolation of poliovirus in stools from AFP cases. 23 POLIOMYELITIS A collaborative effort is required for ES to be successful. The expertise that may be necessary to establish and maintain ES includes: z epidemiologists, and local public health officials both in polio surveillance and immunization programmes; z WHO staff involved in polio surveillance and immunization; z local sanitary engineering authorities and technical staff involved in the maintenance of wastewater and sewage infrastructure; and z staff from the GPLN who will be involved in the processing of samples for polio surveillance. Criteria for selecting sampling sites While AFP surveillance targets the population of the entire country, ES is usually a sentinel surveillance. It is important to keep the following considerations in mind when selecting new ES sites. z The right population centres should be targeted (i.e. with populations at risk of the reintroduction, emergence or transmission of poliovirus). z Efforts should be made to select a collection point with converging sewage from a population large enough to have several individuals shedding poliovirus for several weeks. z It is important to minimize or eliminate factors that may interfere with poliovirus detection during the collection, transport and testing of samples. z Laboratory capacity and resources must be carefully assessed before choosing the testing laboratory, location of the site, sampling schedule and overall number of sampling sites. Location of an environmental site The recommended sampling sites are inlets to sewage treatment plants or other major collector sewers. In some cases, it has also been possible to successfully demonstrate WPV circulation in the relevant population by selecting other systems for the flow of wastewater, such as open canals and water channels. The major challenge to the selection of a representative sampling site is the lack of sewer networks in some of the areas of the highest priority. In such cases, surveillance should be started only if there is adequate knowledge of the major flow routes of wastewater. Criteria for location of new ES sites: The following areas/populations should be prioritized: z areas with populations at an epidemiological risk for poliovirus circulation, on the basis of:  a history of recent VDPV transmission or any WPV importation Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24  a shared border with areas or countries with recent endemic or outbreak transmission; z areas with populations with suspected gaps in immunity due to inadequate access to vaccination (e.g. minorities, temporary workers and undocumented migrants) or high numbers of vaccination refusals; z communities with suboptimal access to sanitation and health care, such as those in slums and illegal urban or peri-urban developments, and areas with a high proportion of minoritized groups; z areas with suboptimal AFP surveillance indicators; z camps and host communities for refugees or internally displaced populations, especially if they are fleeing from areas with a current or recent history of poliovirus circulation; and z hubs of transportation or commerce, or large gatherings (e.g.festivals, markets and pilgrimage sites) with a large presence of women and infants. Types of ES sites: The type of surveillance sites – permanent or temporary – depends on the aim of surveillance. Permanent sites: If the aim is to provide supplementary evidence for the detection of the importation or emergence of polioviruses in a population, a long-term, regular sampling programme for a representative population is preferable. The sampling frequency should be at least once a month. However, it can be increased according to the needs of the programme. Temporary sites: If ES is prompted by an outbreak, the initial plan could be to set up a site for a shorter duration (not less than 12 months) and conduct more frequent sampling, targeted to more select populations. This must always be accompanied by intensified AFP surveillance. The number and location of ES sites can be changed, if necessary, in consultation with public health agencies in the country and the GPEI. Selecting sampling sites Catchment population: The sampling sites chosen for regular monitoring should represent high-risk populations of a preferable size of 100 000 to 300 000 persons. Cities and other urban-like settings such as transit hubs should receive focus to determine feasibility for ES sampling. A sampling site is considered sensitive when enteroviruses (polio or non-polio viruses) are detected in at least 50% of the samples. Types of sewer systems: There may be several options regarding the selection of sampling sites, and each sewer and wastewater system should be evaluated. These could be closed, converging sewage networks, open canals and water channels. In areas where human 25 POLIOMYELITIS waste is disposed into latrines, septic tanks or open fields without a convergent system, ES is not recommended because the number of individuals disposing waste in a certain location is too small. Toxic compounds: Before selecting a sampling site, it is important to explore the wastewater channels to locate points where there is potential drainage of toxic compounds, as these should be avoided. Some factors that must be kept in mind are as follows. z High temperature, exposure to ultraviolet light, high ammonium concentration, low pH and bacterial enzymes are major natural factors that inactivate poliovirus in wastewater, whereas virus adsorption to sewage silts and solids have a protective effect. z Formaldehyde, bleach and other industrial waste may inactivate poliovirus and/or cause toxicity in culture cells. Accessibility: Most sampling is done early in the day to coincide with the toilet-use peak, access should be confirmed during the early morning hours. Areas that are inaccessible part of the year because of flooding, snow or other seasonal considerations should only be considered for ad hoc or temporary environmental sites and only in specific situations, such as an outbreak. As the collectors will need to walk and stand in public areas for 30 minutes to complete the procedures, under no circumstances should sampling sites be placed in areas with dangerous terrain, active conflict or where collectors could be exposed to life-threatening violence. Sample collection schedule Date of collection: Dates for collection should be scheduled to make the most efficient use of transportation and laboratory resources. For example, several sites may collect on the same day of the month or on consecutive days so that samples can be shipped in batches to minimize costs. Optimal time of collection: Generally, there is a greater likelihood of detecting poliovirus if the samples are collected early in the morning, during the hours of peak toilet usage. The exact timing of the peak sewage flow will vary, depending on the distance from the sampling point to the catchment population and the slope of the waterway. Sampling frequency: The minimum frequency of sampling recommended for routine or permanent sites is once a month. Pooled or composite samples: Although ideally, 24-hour pooled or composite samples made from aliquots collected every hour would be more representative, the process is expensive and may not be feasible for sampling points which are located in open sewage canals and to which there is public access. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 26 Validating an environmental site Following the initial assessment of a new environmental site and its selection, the GPLN recommends that the site should go through a validation period of 6–12 months that involves performance analysis, before it is formally included in the network as a routine or permanent site. Closing an environmental site The decision to close a sampling site should be taken after thorough investigations and discussions involving the WHO regional office. The decision could be related to underperformance of the site or the introduction of changes aimed at optimizing sampling sites within a country. The main criteria for closing an ES site are: z The site may no longer meet the programme’s needs, or the initial reason for opening the site may no longer be valid. z The performance of the sampling site is poor for at least six consecutive months. z Limitations in the ES processing capacity may require rationalization of the ES network. Operational framework and decision-making process for closing a site: Assessment is the responsibility of the national programme, which should discuss the proposed closure with the WHO country office and consult the WHO regional office before taking the decision to discontinue sampling. The following decision-making process must be followed systematically. z The national programme should document the need to close one or several sampling sites and share this with the WHO regional office and, if necessary, the WHO headquarters. The proposal (e.g. interim findings from an external monitoring visit) should be prepared in close collaboration with the WHO country office and include the rationale and timeline for the suggested closure of the site(s). z The country could seek the GPEI’s advice on an ad hoc basis and the latter will send back its recommendations within a week. z A site opened in response to an outbreak should be closed in consultation with the lead of the outbreak response. z The WHO country office, regional office and headquarters may hold a final discussion before informing all stakeholders about the decision through a summary report. z When closing a site, the regional office should be informed, and the site data form (electronic, paper-based) updated to reflect the new status in the environmental site database. 27 POLIOMYELITIS Collecting, packaging and transporting samples Collection: Grab sampling is the method currently recommended by WHO for poliovirus surveillance. In this method, a 1-L sample of wastewater is collected at the sampling site on the date and time fixed for collection and specified in the site schedule, in accordance with biosafety measures. An alternative method accepted by WHO and used by several countries is the collection of samples via a bag-mediated filtration system. For the efficient implementation of sample collection, the country programme should ensure that the field personnel are equipped and given training and supervision in a supportive environment. Packaging: Samples should be packaged to prevent contamination and ensure that live enteroviruses within the sample are preserved for laboratory testing. They should be transported to the laboratory in dedicated, robust containers, which should be packed in accordance with the “triple packing” system for biological products or diagnostic specimens. Transporting: From the point of collection to the laboratory, the samples should be maintained and shipped so that they arrive intact, without the appearance of toxicity or bacterial overgrowth and with all enteroviruses preserved for testing. They should reach the laboratory within three days of collection. Seven days is acceptable for samples requiring international shipment. Reverse cold chain: If the samples cannot be shipped to the laboratory on the same day, it is necessary to identify facilities that have a cold storage capacity and can act as intermediary depots, such as the national laboratory or WHO country office. Samples should be stored in a refrigerator at 4°C (range: 2–8°C). When shipping is not going to be immediate, the samples should be stored in a freezer at -20°C and shipped frozen. Sewage samples should not be stored in the same refrigerator as clinical samples for AFP or any other disease because of the high risk of contamination. Environmental surveillance supervision Recognizing the complexity of sewage sampling and its impact on the subsequent procedures, it is of the utmost importance to ensure that all activities – from sampling to the arrival of the samples at the polio laboratory – are carried out in accordance with high quality standards. As an ongoing practice, national programmes should ensure that each sampling site has undergone onsite supervision in the case of at least 80% of sample collections on a quarterly basis. This should be documented. A monitoring tool is available for the evaluation of the performance of sites. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 28 Data collection and management Several forms are available to facilitate the identification and registration of an environmental site and to assist with the collection and sharing of sample data and results. Some of these forms and their uses are mentioned in Table 3.3. Table 3.3: Recommended forms for registration of environmental sites Form Description Registration of characteristics of environmental site This ensures that the core variables are specified and available to create an ES site record. This information should be updated annually, or when the site has undergone major changes (e.g. it has been inactivated/closed, or the sampling location has moved). Digitization of a waterway This involves the electronic collection of descriptive and global positioning system (GPS) coordinates, to determine the flow and accumulation of open waterways. Data are uploaded into an environmental site catalogue. Environmental sample collection form This form contains key information on sample collection (e.g. the time of collection) and the characteristics of a site. It must be filled in for each sample collection. In some circumstances, this form and the laboratory reporting/ request form are the same Site identification number Each ES sample should carry a unique identification code. The code should begin with ENV to denote that it is an environmental sample, followed one or more three-letter combinations to designate the geographical location. Fig. 3.3 shows how to designate an environmental sample. Fig. 3.3: How to designate an ES sample Following sample collection, the corresponding epidemiological identification (EPID) number will include the sample collection year and sample number. ENV= Environmental sample XXX= Admin 0 (country code) YYY= Admin 1 (province/region code ZZZ= Admin 2 (district code) AAA= Site code (name of site) Site Code ENV-THA-TAK-MST-MSA 29 POLIOMYELITIS Reporting laboratory results The results of the tests of environmental samples should be reported by the polio accredited laboratory and uploaded to the database immediately after they have been obtained. The laboratory should ensure that the results are shared with the national programme in a timely and comprehensive manner, and must assist in interpreting the findings and their significance. The flow of information should follow the standard system, as shown in Fig. 3.4. Fig. 3.4: Flow of samples and reporting results Data management: Effective data management entails the efficient collection, transfer and storage of data. z Data may be recorded manually or electronically in prescribed forms. z Several options are available for data entry – MS Access databases, Excel templates, and direct entry into ODK. z Information may be shared at the global level through the Polio Information System. Countries are encouraged to work with WHO regional offices to adopt a fully electronic system of data collection and reporting that includes standardized variables used in national, regional and global databases. Monitoring and evaluating performance Monitoring Indicators: The indicators for monitoring the performance of the surveillance system and their formulas are given in Table 3.4. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 30 Table 3.4: Performance indicators for environmental surveillance Attribute Indicator Target Formula Comments Sensitivity of network Proportion of samples positive for enterovirus (poliovirus or non- polio enterovirus) >50% (Number of samples positive for EV/ number of samples collected during study period) x 100 The aof datahould be conducted for a 6- to 12-month period. Completeness of sample collection Proportion of samples collected out of those scheduled for collection >80% (Number of samples collected / number of samples scheduled for collection) x 100 Each site should have a sampling schedule (i.e. every month, every 2 weeks). Timeliness of sample collection (1) Proportion of samples collected on the scheduled day >80% (Number of samples collected on the scheduled day / number of samples collected) x 100 Each site must have a scheduled day for collection to facilitate transport and ease laboratory workload. Timeliness of sample collection (2) Proportion of samples collected at the scheduled time of day >80% (Number of samples collected at the scheduled time / number of samples collected) x 100 Each site should have a scheduled time for collection that coincides with the peak wastewater flow. Adequacy of sample Proportion of samples arriving at a WHO-accredited laboratory in good condition >80% (Number of samples arriving at the laboratory in good condition / number of samples collected) x 100 Good condition: volume >1 L, reverse cold chain maintained, no leakage Timeliness of shipment of samples Proportion of samples arriving at a WHO-accredited laboratory within 3 days (national) or 7 days (international) of collection >80% (Number of samples arriving at laboratory within 3 or 7 days of collection / number of samples collected) x 100 31 POLIOMYELITIS Attribute Indicator Target Formula Comments Timeliness of reporting laboratory results Proportion of samples for which laboratory results are sent to submitting laboratories/ agencies within a defined period >80% (Number of samples with results available within a defined period / number of samples collected) x 100 Timely reporting: 1. Preliminary results (PV present) within 14 days 2. Type of poliovirus (ITD) within 7 days 3. Sequencing results within 14 days Source: Surveillance standards for vaccine-preventable diseases (1) EV: enterovirus; ITD: intratypic differentiation Periodic evaluation of environmental sites and network: The performance of a country’s ES system should be evaluated periodically and, when possible, integrated with AFP surveillance reviews. Regional and global WHO/GPEI staff can support analysis and field assessments. Interpretation of site evaluation data: The evaluation of a site and the detection of a poliovirus of interest should trigger certain actions. These are mentioned in Table 3.5. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 32 Table 3.5: Site evaluation and corrective action Indicator monitored (6 months of data) Action required Validation of new site Monitoring of existing sites Enterovirus (EV) isolation > 50% Validate site and include in the regular ES sampling schedule. Note: a site registration form should be completed and sent to the WHO regional office. No action is required. However, onsite assessment should be carried out of any site with 3 consecutive months of EV-negative results. EV isolation < 50% and no poliovirus detected 1. Onsite assessment should be conducted. 2. All data must be evaluated. 3. The site should either be discontinued or closed, or a second 6-month sampling should be started. 4. The EV rate should be evaluated after another 3 months. The decision to close a site can be made any time after 6 months, but not later than 12 months. 1. An onsite assessment should be conducted. 2. All data must be evaluated. 3. The site should either be closed or continued to be monitored over the next 6-month sampling period. 4. If there is no improvement after the second 6 months, the site should be closed. EV isolation < 50% and PV detected 1. An onsite assessment should be conducted. 2. Collection should be continued for an additional 6 months. 3. The EV rate should be re- evaluated after 3 months. 4. The decision as to whether to continue or close the site must be taken at 12 months. 1. An onsite assessment should be conducted. 2. All data should be evaluated. 3. The site should either be closed or continued to be monitored over the next 6-month sampling period. 4. The decision to keep a site open when EV detection is low should be periodically re- evaluated and balanced against the availability of resources. Programme response to WPV or VDPV detection The response would be aligned to the global SOPs (23) and according to the national outbreak response plan. When WPV or VDPV is detected in the environment, follow-up investigations must be conducted to determine the significance of the findings. The nature and scope of the programme’s response to the findings are influenced by various factors, including: z the status of the country as polio-free, recently endemic or endemic; z the history of VDPV outbreaks (including in the surrounding geographies); 33 POLIOMYELITIS z the coverage of polio immunization in the population; z the quality of AFP surveillance in the population; z the specific goal of ES; and z the rank of the isolate: the very first or repeated observation. Determining significance of polio detection: In areas that are currently or have recently been polio-endemic, the detection of WPV or VDPV in the environment serves as an impetus for targeting and improving the performance of surveillance and immunization, especially if no concomitant paralytic cases are detected through routine AFP surveillance. In polio-free countries, the detection of WPV or VDPV through either clinical or ES strategies represents a public health emergency that warrants immediate investigation. The following programmatic actions should be taken to determine if there is an outbreak. z Communicating information  All reporting units in the country must be notified within 24 hours of receiving news of a suspected outbreak of poliomyelitis. Rapid communication regarding a possible polio outbreak is the key to initiating appropriate action and preventing further spread. Heightened active surveillance should be sought for AFP cases and strict attention must be paid to the completeness and timeliness of reporting. WHO should be informed within 48 hours that a suspected outbreak is being investigated. z Enhancing environmental sampling  It is important to review information on the population represented by the sampling site and the frequency of environmental sampling to determine whether there are any opportunities to increase the sensitivity of virus detection. If intensified sampling results in the repeated detection of poliovirus, it may be deduced that transmission is ongoing.  Additional sampling sites for surveillance of subpopulations and/or neighbouring or contact populations should be investigated. z Searching for poliovirus-infected persons  Routine surveillance data should be reviewed to determine whether any polio cases may have been missed. The review should cover the previous 12 months and focus on the indicators of the quality of surveillance (non- polio AFP detection rate, timeliness and adequacy of stool collection from cases, proportion of cases with stool specimens tested in a WHO-accredited laboratory and the available laboratory results). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 34  Retrospective records in health facilities in the area of and areas surrounding the suspected outbreak must be reviewed to determine if polio cases were not reported or were inadequately investigated. An active case search should be initiated in the community in which an outbreak is suspected.  The value of stool surveys should be assessed, taking into consideration issues related to timing, representative sampling, logistical arrangements for sample collection/handling, and adequacy of laboratory support. z Assessing coverage of immunization  The coverage of routine and supplemental polio immunization should be reviewed to assess the likelihood of the presence of susceptible populations capable of sustaining the transmission of poliovirus.  Preliminary planning for an immunization response should be started while immunization coverage is being reviewed, focusing on the logistical, operational and financial needs.  The type of vaccine used (OPV, IPV or both) must be considered. z Enhancing virological investigations  Genome characterization of the WPV or VDPV isolates should be expedited to assist in the investigation of their possible source and possible chains of transmission.  To increase population sensitivity, a request should be made for all virus- negative faecal specimens collected during the same time period and untyped or non-typable virus isolates from faecal and environmental samples to be submitted to a WHO-accredited laboratory for further investigations.  All subsequent poliovirus isolates, environmental samples and faecal specimens from the area of the suspected outbreak should be “flagged” for high-priority testing in a WHO-accredited laboratory. Responding to a confirmed outbreak of WPV or VDPV: A suspected outbreak must be investigated as soon as possible to determine whether it is confirmed or whether there is a sufficiently high index of suspicion to warrant an immunization response. If an outbreak is confirmed, countries should notify WHO within 24 hours and the existing immunization services or a special steering group of experts within the ministry of health should offer advice and coordinate response activities nationwide. The response should be appropriate to the outbreak and consistent with the current WHO guidelines on outbreak response. For further details on ES, see Field Guidance for the implementation of Environmental Surveillance for Poliovirus (6). 35 POLIOMYELITIS Polio surveillance among people with primary immunodeficiency disorders Background Individuals with primary immunodeficiency disorders (PIDs) have disorders affecting the B-cell system. Among individuals with PIDs, which are genetically acquired, poliovirus intestinal replication and shedding may persist longer than the usual 4–6 weeks. The prolonged shedding leads to the emergence of VDPVs. VDPVs that evolve in patients with inherited PIDs following exposure to OPV viruses are referred to as immunodeficiency- related vaccine-derived polioviruses (iVDPVs). To mitigate the individual and community risks posed by iVDPVs during the polio endgame and post-eradication era, it is important to identify PID patients excreting polioviruses and to come up with strategies and provide the treatment available to rid both the individual and community of the risk posed by iVDPVs. Acute flaccid paralysis surveillance can only detect transmission through cases of paralysis, and although ES can detect iVDPV shed by asymptomatic carriers, it is unable to identify the individual shedder. There is a need to supplement the AFP and ES systems to help identify all poliovirus excretors and thus, eradicate all polioviruses and maintain eradication. Objectives of surveillance The aim of surveillance is to identify PID patients excreting poliovirus before the virus paralyses them and before they can initiate community transmission. Surveillance should be used to outline effective case management protocols, as well as to propose a public health response for reducing the individual’s risk of developing poliomyelitis and the risk of poliovirus transmission in the community. Case detection Case definition for PID patient at risk of poliovirus excretion A PID patient at risk of poliovirus excretion is defined as an individual who may be of any age and has a primary antibody disorder, or humoral (B-cell) or combined humoral (B-cell) and cellular (T-cell) immunodeficiency disorder, and is confirmed to have immunoglobulin levels below the standards appropriate for his/her age. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 36 Specific PIDs associated with the risk of prolonged poliovirus excretion are: z predominant antibody disorders, such as  common variable immunodeficiency disorder and other primary hypogammaglobulinaemias; and  agammaglobulinaemia, including X-linked agammaglobulinaemia; z immunodeficiencies affecting cellular and humoral immunity, including  severe combined immunodeficiency disorder; and  combined immunodeficiencies, including major histocompatibility complex deficiencies and immunodeficiency centromeric facial anomalies syndrome; and z other immunodeficiencies with hypogammaglobulinaemia or increased susceptibility to viral infection. The programme will identify two types of cases. z Individuals who were previously diagnosed with a PID and match the case definition will be identified through a retroactive search of the national and facility registries. z Individuals newly diagnosed with a PID known to be associated with prolonged poliovirus excretion will be screened for poliovirus excretion shortly after the PID diagnosis has been confirmed. Because of the very low likelihood of prolonged poliovirus excretion, individuals with the following immunodeficiency disorders are not to be included and are not eligible for poliovirus testing in the absence of paralysis: z isolated deficiencies of IgA or IgM, or IgE abnormality; and z transitory or secondary immunodeficiency (i.e. related to infections, including HIV, chronic illness, treatment with immunosuppressive therapy, etc.). Case definition for PID patient with confirmed poliovirus excretion A PID patient with confirmed poliovirus excretion is a PID case who is at risk of prolonged poliovirus shedding – as per the definition above – and whose stool specimen has tested positive for poliovirus, whether it is VDPV, WPV or Sabin viruses. 37 POLIOMYELITIS Table 3.6: Classification of PID patients based on laboratory results Classification Definition 1 PID with VDPV (i.e. iVDPV) This refers to a PID patient in whose stool specimen(s) VDPV has been isolated. It is iVDPV1, iVDPV2 or iVDPV3 depending on the serotype. 2 PID with WPV This refers to a PID patient in whose stool specimen WPV has been isolated. Depending on the serotype, it is WPV1, WPV2 or WPV3. (Note: Although this situation is possible, it is extremely unlikely.) 3 PID with Sabin virus This refers to a PID patient in whose stool specimen(s) Sabin-like poliovirus has been isolated. Depending on the serotype, it will be SL1, SL2 or SL3. 4 PID negative for poliovirus This refers to a PID patient with no laboratory evidence of Sabin, VDPV or WPV in an adequate stool specimen Fiure. 3.5: Classification of PID patients and response It should be noted that PID patients with poliovirus infection may progress from one classification to another. “PID with Sabin” may progress to “PID with VDPV”, and paralysis may also appear in any individual with asymptomatic infection by Sabin or VDPV strains. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 38 PID patients with AFP If paralysis is present at the time of PID diagnosis, the case should be: z reported as an AFP case to the polio surveillance officer and investigated according to the AFP surveillance guidelines; and z included in the PID surveillance database for coordinated treatment, contact sampling and follow-up. If PID patients develop paralysis during follow-up: z their stool samples should be tested for poliovirus as soon as possible after the onset of paralysis and the cases should be classified according to the AFP guidelines; and z the PID surveillance system should record the cases for follow-up and treatment. The case classification of PID patients with AFP is determined per AFP guidelines (Fig 3.6). Figure 3.6: Classification of PID patients who develop paralysis during follow-up Vaccine-associated paralytic poliomyelitis (VAPP) case: This is a PID patient who has AFP and in whose stool specimen Sabin-like poliovirus has been isolated. The patient has residual paralysis at 60 days and beyond. The expert review committee has excluded other causes of AFP for the case on the basis of additional clinical information. iVDPV ‘paralytic’ case: This refers to a PID patient who has AFP and in whose stool specimen VDPV has been isolated. Compatible case: This refers to a PID patient who has AFP but in whose case the number of specimens is inadequate and poliovirus has not been isolated, and who is classified by 39 POLIOMYELITIS the expert review committee as polio-compatible. These individuals should go through a thorough evaluation to rule out other causes of AFP (including NPEV infection). Case investigation and management Follow-up and repeat sampling of PID patients at risk of poliovirus excretion The following schedule is recommended for specimen collection for poliovirus testing. z Initial poliovirus testing is recommended for every individual diagnosed with a PID associated with a risk of prolonged poliovirus excretion. This includes:  previously diagnosed PID patients;  known (registered) PID patients; and  newly diagnosed PID patients. z Repeat testing for follow-up is recommended:  monthly for PID patients with a specimen positive for SL, VDPV or WPV; and  annually for PID patients with negative specimens. Detailed investigation of PID patients with confirmed poliovirus excretion The surveillance officer, in coordination with staff from the sentinel facility, should conduct a case investigation for PID patients with specimens positive for poliovirus, within 48 hours of receiving the laboratory results. The objectives of the investigation are to assess the risk of the circulation of poliovirus in the surrounding community, and to initiate case management and a public health response. The collection of additional information from the patient, his/her close family contacts and the surrounding community should form part of the investigation. Table 3. 7: Investigation guidelines for PID patients with confirmed poliovirus excretion Investigation guidelines Patient The source of exposure of the PID patient to OPV (e.g. travel, visitors, routine immunization and immunization campaigns) should be ascertained on the basis of the estimated time of viral intestinal replication inferred from molecular analysis. The patient’s potential to initiate transmission into the community, such as through attendance of day care or school and admission in a health facility or institution, should be assessed. The availability of sanitation infrastructure must be ascertained. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 40 Close contacts The contact’s polio vaccination status must be determined. It must be ascertained whether the contact has a medical history suggestive of immunodeficiency. Stool samples may be collected from the close (family) contacts or community contacts of a PID patient who is shedding WPV, Sabin or VDPV. The surveillance officer(s) investigating the case should oversee the organization of stool collection. The number of contacts and type of contacts to be sampled should be in accordance with the guidelines for the response to a poliovirus event/outbreak. Community The polio vaccination status (IPV, OPV), especially of children younger than 5 years of age, should be assessed through community surveys and desk review of coverage data. The risk factors for faecal-oral transmission should be assessed. These include high population density, and inadequate sanitation and sewage infrastructure. An active search should be conducted for AFP cases in health facilities and the community. Public health response The scope of the public health response will depend on the type of poliovirus isolated, the sequencing data and the presence of risk factors for community transmission. Table 3.8: Public health response guidelines For Sabin-like poliovirus If Sabin types 1 or 3 is isolated z Testing of specimens should be repeated monthly to monitor the clearance of infection or progression to iVDPV. z Clearance of poliovirus infection should be confirmed by obtaining 2 negative specimens separated by at least 1 month. z Discussions should be initiated with surveillance and public health officials to consider treatment with antivirals. If Sabin type 2 is isolated z The country’s public health authorities and WHO should be notified according to the International Health Regulations (IHR), Annex 2 (2005). z The investigation of the event should be initiated within 48 hours of laboratory confirmation of the results, and a specific public health response should be planned, as explained in the GPEI SOPs (23). z Discussions should be initiated with surveillance and public health officials to consider treatment with antivirals. 41 POLIOMYELITIS For WPV or VDPV or if Sabin strains progress to VDPV in series samples z If WPV or VDPV is identified in any stool sample, the ministry of health (MoH) should notify the public health authorities and WHO, according to the IHR, Annex 2 (2005). z The local surveillance staff should initiate the investigation of the event, enhanced polio surveillance activities and the assessment of the population’s immunity and follow GPEI SOPs (23). The public health response will depend on the detection of community circulation If WPV is isolated An outbreak response should be initiated. If VDPV is isolated z If there is evidence of the circulation of this strain in the community (healthy contacts or environmental samples), it should be considered an outbreak (cVDPV) and vaccination campaigns should be started. The scale of these will depend on the risk to the community. z Discussions should be held with surveillance and public health officials to consider treatment with antivirals. z If there is no evidence of the circulation of this strain in the community, the response may consist of the administration of IPV to the household members and close community contacts. z Discussions should be held with surveillance and public health officials to consider treatment with antivirals. Treatment Treatment with antiviral drugs should be considered for PID patients if: z VDPV is isolated in any of the individual’s stool specimens; z the individual has been excreting Sabin strains for more than 2 months; or z the individual is excreting WPV. Antivirals are not indicated for contacts potentially exposed to polio infection. The clinical immunologist or specialist physician attending to the PID patient should coordinate with the surveillance officers and the appropriate regulatory and public health authorities in the decision-making process and follow-up with antiviral drug developer for implementation procedures for treatment and follow-up. Other management measures The following case management measures should be taken for all patients shedding poliovirus: z The PID and its complications should be treated, e.g. through the administration of intravenous immune globulin or bone marrow transplant, according to the type of PID and the standard of the level of care in the country. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 42 z The patient and his/her family should be counselled and educated to avoid taking live vaccines in the future and to maintain proper hand and toilet hygiene to prevent the transmission of poliovirus to contacts. z Health staff should be vaccinated with IPV and adhere to standard precautions for infection control in health-care facilities or institutions where the PID patient may receive clinical care. z Close contacts of the patient should be vaccinated with IPV, if required. (Like the PID patient, close contacts should never receive OPV.) Data analysis Surveillance data are useful in: z detecting and monitoring PID patients with prolonged excretion of poliovirus; z treating infection and preventing the development of paralysis and other adverse neurological outcomes among patients in the future; z preventing the introduction and circulation of poliovirus excreted by the patient into the community; and z recording the number and geographical location of excretors of Sabin/iVDPV in periodic country risk assessments of polio outbreaks. The main sources of data are: z the case investigation form for PID patients at risk of excreting poliovirus; z the detailed case investigation form for PID patients with confirmed poliovirus excretion; z follow-up forms; z the PID patient registry/line list; z completeness and timeliness of reporting units; and z active surveillance visit forms. Suggested epidemiological analysis It is recommended that the following be included in the epidemiological analysis. z Number of PID patients at risk of poliovirus excretion reported (and tested) by year, sentinel facility and country 43 POLIOMYELITIS z Number of PID patients with negative poliovirus excretion, prolonged Sabin excretion (more than 6 months), asymptomatic iVDPV excretion, VAPP or iVDPV by sentinel facility, country and year z Spot maps of PID patients with poliovirus excretion by geographical area, country and year z Age and sex distribution of PID patients with prolonged Sabin excretion or iVDPV excretion z Distribution of PID patients diagnosed with prolonged Sabin excretion or iVDPV excretion according to duration of shedding (prolonged versus chronic) z Distribution of PID patients diagnosed with prolonged Sabin excretion or iVDPV excretion by PID diagnosis z Percentage of PID individuals diagnosed with prolonged Sabin excretion or iVDPV excretion for whom a detailed investigation (covering contacts and community) was conducted z Results of contact and/or environmental sampling conducted to investigate a PID patient with iVDPV excretion z Percentage of PID patients with prolonged Sabin excretion or iVDPV excretion who received antiviral treatment z Percentage of PID patients who cleared poliovirus excretion after antiviral treatment z Percentage of PID patients with NPEV infection z Outcome of cases (shedding, stopped shedding, died, lost to follow-up) Monitoring and evaluation Surveillance for poliovirus excretion among PID patients should be reviewed quarterly at meetings for the review of polio eradication data, together with data from other polio surveillance systems (AFP, ES). The indicators in Table 3.9 should be reviewed at all levels at least every six months. The data should also be analysed in conjunction with the information provided by AFP and ES for the annual country risk assessments and reports of the National Committee for the Certification of Poliomyelitis Eradication. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 44 Table 3.9: Performance indicators for PID surveillance # Indicator Target 1 Proportion of registered (previously diagnosed) PID patients tested for poliovirus excretion per sentinel facility/country (denominator: from national registry or facility registry of PID patients who match the case definition) > 90% 2 Proportion of newly diagnosed (in the same year) PID patients tested for poliovirus excretion per sentinel facility/country (denominator: from national registry or facility registry of PID patients who meet the case definition) >90% 3 Proportion of PID patients with poliovirus excretion for whom a detailed case investigation (with contact tracing and community assessment) was conducted within 48 hours of laboratory results >80% 4 Proportion of specimens arriving at a WHO-accredited laboratory in good condition >80% 5 Proportion of specimens arriving at a WHO-accredited laboratory within 3 days of collection >80% 6 Proportion of stool specimens for which laboratory results were sent to sentinel facility/submitting agencies within a defined period: within 14 days of receipt of specimen for poliovirus isolation within 7 days of receipt of isolate for intratypic differentiation within 7 days of intratypic differentiation for sequencing results >80% 7 Proportion of follow-up specimens collected out of the expected number >80% 8 Proportion of active surveillance visits implemented out of the planned visits >90% 45 POLIOMYELITIS Annex 1: Poliomyelitis Epidemiology Occurrence In 1988, the World Health Assembly established the GPEI to achieve polio eradication by the year 2000. That was the year when more than 350 000 cases of paralytic poliomyelitis were reported from 125 countries across the globe. The last case of WPV type 2 (WPV2) was reported in October 1999 (India), and that of WPV type 3 (WPV3) in November 2012 (Nigeria). The global eradication of WPV2 was certified on 20 September 2015, and of WPV3 on 24 October 2019. As of October 2022, WPV1 is endemic in only two countries – Afghanistan and Pakistan. Under the International Health Regulations (IHR), the global spread of poliovirus has been declared a public health emergency of international concern (PHEIC) since 2014. The PHEIC status is reviewed every 3 months by the IHR Emergency Committee with respect to the risk of the international spread of WPV1 and cVDPV. Infectious agent Polioviruses are human enteroviruses of the Picornaviridae family. Polioviruses are non- enveloped viruses with a single-stranded ribonucleic acid (RNA) genome and a protein capsid. The three serotypes of polioviruses (types 1, 2 or 3) have different antigenic sites in the capsid proteins. Polioviruses share most of their biochemical and biophysical properties with other enteroviruses. They are resistant to inactivation by many common detergents and disinfectants, including soaps, but are rapidly inactivated by exposure to ultraviolet light. Viral infectivity is stable for months at +4 ºC and for several days at +30 ºC. Transmission Polioviruses are spread by faecal-to-oral and oral-to-oral transmission. Where sanitation is poor, faecal-to-oral transmission predominates, whereas oral-to-oral transmission may be more common where standards of sanitation are high. In most settings, mixed patterns of transmission are likely to occur. Annexes Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 46 Reservoir Humans are the only known reservoir of poliovirus, which is transmitted most frequently by persons with inapparent infections. There is no long-term carrier state in immuno- competent hosts. Immunity Poliovirus infection can provide lifelong immunity against the disease, but this protection is limited to the serotype involved. Infection with one type does not protect an individual against infection with the other two types. Vaccines Oral polio vaccine (OPV) Since the withdrawal of trivalent oral polio vaccine (tOPV) from routine immunization in 2016 (“the switch”),bivalent oral polio vaccine (bOPV, containing Sabin strains types 1 and 3) is used in routine immunization and supplementary immunization activities (SIAs); monovalent OPVs are used in SIAs. Any type 2-containing OPVs (tOPV or mOPV2) are used exclusively in outbreak response to type 2 poliovirus. Novel oral poliovirus vaccines (nOPVs) The strains contained in the novel oral poliovirus vaccines (nOPVs) are modified versions of the Sabin OPV strains with enhanced genetic stability; nOPVs are anticipated to have a significantly reduced risk of reversion. The increased genetic stability is achieved through modifications in the parental genome affecting domain V, cre-element and RNA-dependent RNA polymerase. In November 2020, type 2 nOPV (nOPV2) was recommended under WHO Emergency Use Listing (EUL) for outbreak response to cVDPV2s. The use of nOPV2 in routine immunization is not endorsed. nOPV serotypes 1 and 3 are under clinical development; phase 1 trials began in early 2022. Inactivated poliovirus vaccine (IPV) IPV is given by injection and is commercially available only in trivalent form containing the 3 virus serotypes, PV1, PV2 and PV3. IPV was first developed in 1955 and is currently available as Salk IPV (also referred to as wild/conventional IPV, wIPV or cIPV) containing WPV strains, and as Sabin IPV (sIPV) containing Sabin strains. sIPV has been licensed for use in Japan (2012), China (2015), and the Republic of Korea (2020). The main advantage of sIPV is that there are less stringent biocontainment requirements than for IPV 47 POLIOMYELITIS manufactured from WPV: the consequences of containment breach and escape of Sabin strains into populations would be less serious compared with wild strains. IPV is available as a standalone vaccine, or as a combination product with one or more other vaccine antigens including DTP, hepatitis B, and/or Hib. Vaccine-derived polioviruses (VDPVs) These rare strains of poliovirus have genetically mutated from the strain contained in the oral polio vaccine (OPV). The OPV contains a live, attenuated (weakened) vaccine-virus. When a child/person is vaccinated, the weakened vaccine-virus replicates in the intestine and enters into the bloodstream, triggering a protective immune response in the child/ person. Like WPV, the child/person excretes the vaccine-virus for a period of six to eight weeks. Importantly, as it is excreted, some of the vaccine-virus may no longer be the same as the original vaccine-virus as it has genetically altered during replication. This is called a VDPV and they are identified based on their degree of genetic divergence from the parent OPV viral strain. Strains that are >1% divergent (or >= 10 nucleotide changes/NT, for types 1 and 3) or >0.6% divergent (>= 6 NT changes, for type 2) from the corresponding oral vaccine strain are labelled as VDPVs. VDPVs are classified into three categories: Circulating vaccine-derived poliovirus (cVDPV) On very rare occasions, if a population is seriously under-immunized, there are enough susceptible children/persons for the excreted VDPV to begin circulating in the community. If the vaccine-virus is able to circulate for a prolonged period uninterrupted, it can mutate and, over the course of 12-18 months, reacquire neurovirulence. These viruses are called cVDPV. The lower the population immunity, the longer these viruses survive. The longer they survive, the more they replicate, change, and exchange genetic material with other enteroviruses as they spread through a community. If a population is fully immunized against polio, it will be protected against the spread of both wild and vaccine strains of poliovirus. Immunodeficiency-related vaccine-derived poliovirus (iVDPV) Prolonged replication of VDPVs has been observed in a small number of people with rare immune deficiency disorders. Because they are not able to mount an immune response, these people are not able to clear the intestinal vaccine virus infection, which is usually cleared within six to eight weeks. They therefore excrete iVDPVs for prolonged periods. The occurrence of iVDPVs is very rare. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 48 Ambiguous vaccine-derived poliovirus (aVDPV) This is a classification of exclusion when investigation does not support classification as cVDPV or iVDPV. Isolates may be from persons with no known immunodeficiency or from an environmental sample, without evidence for circulation. For more information on response to WPV/VDPVs please refer to GPEI SOPs for responding to a poliovirus event or outbreak (8) Clinical aspects Pathogenesis Transmission is primarily person-to-person via the faecal-oral route. Poliovirus multiplies at the site of implantation in the pharynx and gastrointestinal tract and is spread through the feces. The virus is intermittently excreted for up to 2 months or more after infection, with maximum excretion occurring just before paralysis and during the first two weeks (14 days) after onset of paralysis. On average, the incubation period from exposure to the virus to the onset of first symptoms is 7–10 days (range, 4–35 days). The virus invades local lymphoid tissue, enters the bloodstream and then may infect cells of the central nervous system. Replication of poliovirus in motor neurons of the anterior horn and brain stem results in cell destruction and causes the typical polio manifestations. Clinical features and complications The incubation period is commonly 7–10 days (range 4–35 days). Most people infected with poliovirus do not have symptoms; viral replication in the pharynx and gastrointestinal tract results in virus excretion in saliva and faeces. Approximately 25% of those infected develop transient minor symptoms, including fever, headache, malaise, nausea, vomiting and sore throat. In some individuals (approximately 4%) with this minor illness, signs of meningeal irritation develop, with neck stiffness, severe headache, and pain in the limbs, back and neck, suggestive of aseptic meningitis (non-paralytic polio). This form of polio lasts between 2 and 10 days and in almost all cases recovery is complete. Paralytic polio is a rare outcome and occurs when poliovirus enters the central nervous system by peripheral or cranial nerve axonal flow and replicates in anterior horn cells (motor neurons) of the spinal cord. It is observed in <1% of poliovirus infections in children <5 years of age, varying with serotype and age. 49 POLIOMYELITIS The ratio of paralytic cases to infections was estimated per 100 infections at approximately 0.5 for serotype 1, 0.05 for serotype 2 and 0.08 for serotype 3, based on data from 15 countries. Depending on the degree and extent to which motor neurons are affected, temporary or permanent paralysis of the affected muscles may ensue. In rare cases, viral destruction of bulbar cells results in respiratory paralysis and death. The typical clinical manifestation of paralytic polio is acute flaccid paralysis (AFP) with the differential diagnosis including - but is not limited to - Guillain-Barre syndrome(GBS), traumatic neuritis and transverse myelitis. These four conditions represent the most common causes of AFP, but the complete differential diagnosis includes numerous etiologies (encephalitis, meningitis, other enterovirus infections, toxins, transient and periodic paralysis caused by metabolic imbalances, tumors and other causes). Distinguishing characteristics of paralytic polio are asymmetric, flaccid paralysis, mostly involving proximal muscles with fever and muscular pain at onset, rapid progression from onset to maximum paralysis (usually <4 days), intact sensory nerve function, and most often, residual (“persistent”) paralysis or weakness after 60 days. However, any disease that presents as AFP, even if diagnosed as a disease other than polio by the physician, must be reported and investigated. The case-fatality rates among paralytic cases range from 5% to 10% in children and from 15% to 30% in adolescents and adults, predominantly associated with bulbar involvement. Post-polio syndrome, with symptoms appearing 15–30 years after recovery from the original paralytic attack, occurs in 25%–50% of cases, with symptoms including acute or increased muscular weakness, pain in the muscles and fatigue. Laboratory diagnosis Virological examination is essential for confirmation of the diagnosis of polio; this involves detection of poliovirus from the stools of patients with AFP and further characterization of the isolated poliovirus to determine whether it is vaccine-associated paralytic polio (VAPP), VDPV or WPV. Molecular diagnostics, such as polymerase chain reaction, are used to differentiate WPV, VDPV and Sabin-like poliovirus. In addition, all discordant poliovirus isolates are partially sequenced to determine their origin and relatedness to other isolates. According to the laboratory results and review by national polio expert committees, cases are further classified as confirmed, polio-compatible or polio-negative (non-polio AFP). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 50 Vaccine-associated paralytic polio (VAPP) OPV is made with live attenuated (weakened) polioviruses that can result in a case of VAPP in approximately 1 in 2.7 million doses of OPV. VAPP is caused by a strain of poliovirus that has genetically changed in the intestine from the original attenuated vaccine strain contained in OPV. Reversion of the small number of substitutions conferring small genetic changes to the attenuated phenotype occurs during OPV replication in humans and is the underlying cause of the rare cases of VAPP in OPV recipients and their close contacts. Sabin strains can replicate in the gut of vaccine recipients and poliovirus maybe excreted for 4 to 6 weeks. During this time, the few attenuating mutations present in the vaccine strains revert rapidly and the virus changes via several mechanisms. These include back mutations, site suppression mutations, recombination and a steady drift in molecular sequence. This reversion of the attenuating mutations during OPV replication in humans is the underlying cause of the rare cases of VAPP observed in OPV recipients and their close contacts. The case definition for VAPP includes the following: z A case of AFP with residual weakness at 60 days after onset of symptoms; z A negative stool sample for wild-type poliovirus but positive for vaccine virus as examined in a WHO accredited laboratory; z Evaluation and confirmation of the case by an expert committee (WHO 1998). The onset of symptoms with VAPP usually occurs 4–30 days following receipt of OPV or within 4–75 days after contact with a recipient of OPV. In immunodeficient individuals (especially those with low antibody – hypogammaglobulinemia) VAPP may occur outside these windows. There are no outbreaks associated with VAPP. 51 POLIOMYELITIS Annex 2: Community-based surveillance Definition and rationale Community-based surveillance (CBS) is the systematic detection and reporting of events of public health significance within a community by community members. Trained community members (e.g. informants, volunteers) are engaged to report suspected AFP cases, based on a simplified case definition of AFP tailored for use by community members, to a designated focal person who is part of the AFP surveillance system (usually a focal point in a network health facility or a surveillance officer). CBS can provide an additional link between communities and the facility-based AFP surveillance system via the designated focal point. It can also increase community engagement in health care and promote the acceptance of immunization and surveillance activities. However, a careful assessment should be made before initiating CBS as it may not be the most efficient option for addressing gaps in surveillance, which could be better addressed by sensitization activities and adjustments to the active surveillance network. Programmes are advised to look first at more sustainable, cost-effective solutions. Modalities The methods or modalities of CBS range from those of low-resource intensity (i.e. building on other existing networks) to those of high-resource intensity (i.e. paying informants and using specialized digital tools). The major cost drivers for CBS include: training (initial and refresher training); supervision; incentives or monthly payment for reporting; and the use of digital technology, mobile phones or other tools (initial and recurring costs). Training, sensitization and supervision are the minimum essential activities for all modalities of CBS. The addition of other activities and an increase in the extent of implementation come with a rise in costs (e.g. the monetary value of reporting incentives can vary, and technology can range from low-cost short message service [SMS] to more expensive smartphones requiring data). When considering CBS, countries should note that the surveillance system may be more cost-effective if used for several diseases rather than a single disease. CBS modalities for polio are referred to as formal or informal: z Formal CBS is a modality of high resource intensity. It requires close supervision and the use of incentives and telecommunication tools (e.g. auto-visual AFP detection and reporting). It usually functions independently of the facility-based surveillance, the informants being directly linked to surveillance officers. z Informal CBS is a modality of low resource intensity. The volunteers are sensitized annually and they receive minimal incentives for reporting verified true AFP cases. The informants are usually linked to focal points within the health facilities nearby, so informal CBS is often closely linked with facility-based surveillance. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 52 Needs assessment for CBS A needs assessment should be conducted to determine whether CBS will be an efficient strategy to improve the sensitivity of AFP surveillance and if so, to decide on the type or modality. The needs assessment is a situational analysis that explores the following questions. z How well does the AFP surveillance system cover or reach special populations or hard-to reach areas? z What are the real factors underlying the gaps in surveillance? Is it a matter of access, utilization or acceptability? z Is linking informants to the existing health facilities an option? Or is it impossible or unacceptable to report through health facilities? z What is the health-seeking behaviour of the communities like and what are the factors that influence it (e.g. gender, ethnicity, belonging to internally displaced populations or having a refugee status, and place of residence)? z Who are the primary reporters of AFP cases in the communities and are they included in the active surveillance network? z Which resources (health-care facilities and providers, humanitarian agencies and nongovernmental organizations) in the geographical area should be involved? Are there any CBS activities currently being conducted (e.g. for other diseases)? z Which existing community networks – particularly women’s groups, community professional and political networks, and grassroots organizations – could be engaged? Process of establishing CBS If the conclusion of the needs assessment is that CBS is the most effective strategy to improve the sensitivity of AFP surveillance and no other strategy can succeed in a specific population or area, the process of establishing CBS must be initiated. The modality must be decided upon and the following steps need to be taken. z Key community actors (community and religious leaders, traditional healers, female leaders) should be identified, sensitized and briefed with a view to engaging them in surveillance activities and encouraging them to assume leadership. z Community volunteers should be selected jointly with community leaders on the basis of certain criteria. The volunteers selected should have the community’s trust and acceptance. Further, they should have a good knowledge of the area, live within the community and speak the local language/dialect. 53 POLIOMYELITIS z It is necessary to identify the gender-related barriers and challenges that the community and/or informants may face and build the support needed to resolve them. The informant’s access to information, literacy level or training, decision- making power and mobility need to be evaluated. Issues related to security and safety should be addressed. The acceptability of tools, equipment and mobility need to be assessed, particularly in the case of female informants. z Concise educational materials should be used to train community volunteers, who should be taught the simplified AFP case definition. They should be trained in the recording and reporting of suspected AFP cases, as well as the procedures for collecting and handling stool specimens. Their roles and responsibilities should be made clear to them. They should be provided materials, such as visual job aids, case investigation forms, tools to record information, focal point contact information and stool collection kits. z The community volunteers will:  actively search for suspected AFP cases in the community through rumours, regular home visits (i.e. biweekly visits), and visits to traditional healers and religious leaders (i.e. weekly visits);  keep records of the vaccination status and basic demographic data of families and children; and  immediately report suspected AFP cases to the designated CBS focal point and/or surveillance officer, who will follow up to confirm that the case matches the AFP case definition, initiate investigation and specimen collection, and notify the district health authority. z An oversight structure should be established to support community volunteers through regular supervisory visits and the provision of feedback. Periodic refresher training should be conducted to ensure that the volunteers maintain their knowledge and skills. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 54 Annex 3: AFP case investigation form EPID number: _________ -_________ -_________ -_________ -_________ Received: _____/______/_______ Country Region/ Province District Year of onset Case no. at national level C as e in ve st ig at io n Region/province: ____________________ District: ____________________ City/town: ____________________ Village: ____________________ Address: ________________________ Phone number: ____________________ Case coordinates (WGS 1984 format): Latitude: ____________________ Longitude: ____________________ Nearest health facility: ____________________ Type: ____________________ Distance (circle): < 5 km / 5–10 km / >10 km Patient’s name: ____________________________ Sex (circle): Male / Female Date of birth (DOB): ____/____/____ Age (if DOB unknown): ______ years ______months Father’s name: ____________________ Mother’s name: ____________________ OR Caregiver’s name: ____________________ N ot ifi ca tio n / i nv es tig at io n Date of case notification: ____/____/____ Notified by (name): ____________________ Title/designation: ____________________ Facility (name): ______________Type of facility (circle appropriate option): Public / Private / Armed Forces / Informal health-care provider / NGO / Other (specify) _________________ Is this facility (circle applicable option): an active surveillance site / a zero reporting site (not an active surveillance site) / Outside network) Date of case investigation: ____/____/____ Investigated by (name): _________________ Title/designation: _________________ Was patient hospitalized? Yes / No Date of admission to hospital, if applicable: ____/____/____ Hospital record #: _________________ Hospital name / address: _________________ Si gn s an d sy m pt om s Fever at onset of paralysis: Yes/No/Unknown Progressive paralysis ≤ 3 days: Yes/ No/ Unknown Site of paralysis: Date of onset of paralysis: ____/____/____ Is paralysis flaccid and acute? Yes / No /Unknown Asymmetrical? Yes / No / Unknown Are paralysed limb(s) sensitive to pain? Yes /No Was any injection administered just before onset of paralysis? Yes / No If “Yes”, mention the site of injection in the table below: Arm Forearm Buttocks Thigh Leg Right Left Provisional diagnosis: __________________________________________________________________________ LA RA LL RL 55 POLIOMYELITIS H ea lth e nc ou nt er s Was help sought at any other place after the parent(s) / caregiver(s) noticed paralysis or weakness in the child and before they came to the current place? Yes / No In chronological order, list the place(s) and/or person(s) the individual visited for health care between the onset of paralysis and visiting the current place (notification). Please fill the table below in chronological order, mentioning the current place [check]. Total number of health encounters for the case____________________________________ Date of visit 1: ____/____/____ 2: ____/____/____ 3: ____/____/____ 4: ____/____/____ 5: ____/____/____ Name of facility or person* Type of facility or person# Location [address] of facility or person, with phone number Is this site a part of the reporting network? Yes / No Yes / No Yes / No Yes / No Yes / No Was the case notified? Yes / No Yes / No Yes / No Yes / No Yes / No Action(s) taken if case was not notified *“Name of person” refers to traditional or faith healer, or other individual. #This includes a) hospital, b) clinic or health centre, c) pharmacy, d) traditional or faith healer, and e) other (specify). A FP ? On investigation, was this found to be true AFP? Yes/ No If not, do not fill the rest of the form and record “6” under final classification. Im m un iz at io n hi st or y Total number of polio vaccine doses (exclude birth dose): _______ OPV dose at birth: ____/____/____ 1st dose: ____/____/____ 2nd dose: ____/____/____ 3rd dose: ____/____/____ 4th dose: ____/____/____ If > 4, last dose: ____/____/____ Total OPV doses received during SIAs: _______ Total OPV doses received through RI: _______ [99=Unknown] Date of last OPV dose received through SIAs: ____/____/____ Type of last OPV received: bOPV/mOPV2/nOPV2/Others_____/Don’t Know Total IPV doses received during SIAs: _______ Total IPV doses received through RI: _______ [99=Unknown] Date of last IPV dose received during SIAs: ____/____/____ Source of information on RI vaccination (circle): Card / Recall Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 56 St oo l s pe ci m en s Date of 1st specimen: ____/____/____ Date of 2nd specimen: ____/____/____ Specimen sent to national level on: ____/____/____ Specimen received at national level on: ____/____/____ Specimen sent to inter-country (I-C)/national laboratory on: ____/____/____ Date of receipt of specimen at I-C/national laboratory: ____/____/____ Was specimen adequate when received by laboratory? Yes / No Date when combined cell culture results became available: ____/____/____ Final cell culture results: _______ [1: suspected poliovirus; 2: negative; 3: NPENT; 4: suspected poliovirus + NPENT] Results sent to national EPI on: ____/____/____ Results received by national EPI on: ____/____/____ Results sent from I-C/national laboratory to regional laboratory on: ____/____/____ I-T differentiation results sent to EPI on: ____/____/____ I-T differentiation results received at EPI on: ____/____/____ Final laboratory results: Isolate sent for sequencing on: ____/____/____ Sequencing results sent to programme on: ____/____/____ Fo llo w - up e xa m Date of follow-up examination: ____/____/____ Results of examination: _______ Residual paralysis? Fi na l cl as si fic at io n Immunocompromised status suspected Yes / No / Unknown Investigator’s name: ___________________________ Investigator’s designation ____________________ Unit: ____________________ Address: __________________________ Telephone: ____________________ W1 W2 W3 1: Yes; 2: No Discordant Sabin Type 1, 2, 3 SL1 SL2 SL3 nOPV2 1: Yes; 2: No (R) NPENT NEV 1: Positive; 2: Negative 57 POLIOMYELITIS Annex 4: Timeliness Possible causes of delay and ways to address them As delays in detection can occur at any stage of field, logistical and laboratory activities, countries must monitor timeliness at every point, particularly at the subnational level and especially in the collection and transport of stool specimens. It is only on the basis of a clear understanding of the delays that swift action can be taken to address the identified bottlenecks. Further, it is advisable to anticipate issues and proactively identify alternatives as part of preparedness. Table 3A.3 highlights certain types of delays, their possible causes and the ways in which the programme can address them. While this table focuses on AFP cases, other human specimens (e.g. from AFP contacts and healthy children) and ES samples may be subject to similar delays, possible causes for delays and solutions. Table 3.A3: Possible delays in detection, their causes and measures for mitigation Stage Target Possible causes Measures for mitigation and possible solutions Care-seeking behaviour AFP cases reported within ≤ 7 days of onset Lack of awareness and sensitization of health- care providers z Make regular supportive supervisory visits to reporting units. z Ensure the training and sensitization of every new staff member. z Provide information, education and communication materials: case definition, reporting requirements and pathway, and surveillance officer’s contact information. Notification to investigation < 48 hours z Lack of training z Absence of qualified person to conduct investigation z Delay in locating the case z Case lost to follow-up z Competing priorities z C h a l l e n g i n g workloads z Ensure that case investigation kits are readily available. z Establish clear responsibilities and ensure reasonable workloads (back-up should be available in the absence of the main surveillance officer). z Conduct regular training for surveillance officers and back-ups (e.g. other public health staff) at the field level. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 58 Stage Target Possible causes Measures for mitigation and possible solutions Investigation to collection of 1st stool specimen < 1 day z Absence of kit z Inability to locate the case (due to discharge, travel, etc.) z Inadequate stool specimen z Death of case z Ensure that case investigation kits are readily available. z Ensure that contact information and address of case are available. z If caregiver has to collect the stool specimens, see to it that it is done properly. 1st stool collection to 2nd stool collection 24 hours z Inadequate stool specimen, or case has died. z Case is no longer at same location (follow- up issues) z Provide clear instructions to nurses and caregivers on collection of stool specimen. z Provide clear instructions on contact sampling if the specimens of the case are inadequate. Collection of 2nd stool to shipment to national level Both stool specimens arrive in laboratory ≤ 3 days after collection of 2nd specimen z No or poor communication on when 2nd specimen was collected z Poor coordination with courier services z Issues related to routes of transport (e.g. lockdowns, route closure) z Batching of specimens z Pilot electronic tracking of stool specimens. z Plan transport ahead of time, including planning for contingencies. z Obtain special permission to transport samples, if necessary. z Identify alternative routes and carriers. z Increase storage capacity and identify storing points. z Do not batch specimens. z Prioritize samples for shipment in the event of suspected cases (“hot” cases). 59 POLIOMYELITIS Stage Target Possible causes Measures for mitigation and possible solutions Shipment to national level to arrival at national level Arrival at national level to shipment to international laboratory Shipment to international laboratory to arrival in international laboratory Both stool specimens arrive in laboratory ≤ 3 days after collection of 2nd specimen Both specimens arrive in laboratory ≤ 3 days after collection of 2nd specimen Both specimens arrive in laboratory ≤ 3 days after collection of 2nd specimen z Poor planning for transport, shipment z Insecurity or road closures z Samples stored at national level until a certain number are collected and shipped in batches z International border closures z Suspension of flights z Pilot electronic tracking of stool specimens. z Make contingency plans specifying alternative routes or laboratory. z Explore ad hoc solutions in case of conflict or insecurity (e.g. using humanitarian flights for transport and sending samples to an alternative WHO-accredited laboratory). Arrival in (inter) national laboratory to final results (i.e. negative results or sequencing results for positive specimens) The specimens are processed according to standard GPLN procedures within defined GPLN target times for all procedures z International border closures z Difficulties with shipping isolates to sequencing laboratory z Shortage of critical reagents z Ambiguities in testing outcomes (e.g. mismatched or missing EPID numbers, suspicion of cross- contamination) z Receipt of large batches of specimens z Ensure a minimum buffer stock (critical consumables and reagents) for a one- year workload when placing orders. z Secure a shipping contract with several in-country couriers. z Develop an alternative domestic and international shipping plan with different sequencing laboratories. AFP: acute flaccid paralysis; GPLN: Global Polio Laboratory Network Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 60 Annex 5: Indicators for surveillance: Core and non-core The global surveillance indicators as per Global Polio Surveillance Action Plan and Global Surveillance Guidelines have been listed in this annexure. Core Indicators Table 3.A4: Overall indicators for timeliness Indicator Calculations (expressed as %) Target Overall detection of WPV/VDPV For AFP Number of AFP cases* with WPV/VDPV final laboratory results ≤ 35 days after onset / number of AFP cases* with WPV/VDPV final laboratory results ≥ 80% For ES Number of ES samples with WPV/VDPV final laboratory results ≤ 35 days after collection / number of ES samples with WPV/VDPV final laboratory results ≥ 80% System capacity Number of WPV and VDPV cases with final laboratory results ≤ 35 days after onset for AFP cases or collection date for ES samples / number of WPV and VDPV cases ≥ 80% AFP detection system Number of AFP cases* with final laboratory results ≤ 35 days after onset / number of AFP cases* ≥ 80% ES detection system Number of ES samples with final laboratory results ≤ 35 days after collection / number of ES samples ≥ 80% AFP : acute flaccid paralysis; ES: environmental surveillance; VDPV: vaccine-derived poliovirus; WPV: wild poliovirus *Aggregated results: all laboratory results (AFP + contacts) used to classify AFP case as confirmed/discarded Table 3.A5: Indicators for timeliness of field activities Indicator Calculations (expressed as %) Target Timeliness of notifications Number of AFP cases reported ≤ 7 days after onset / number of AFP cases ≥ 80% Timeliness of investigations Number of AFP cases investigated ≤ 48 hours after notification / number of AFP cases ≥ 80% Timeliness of field activities Number of AFP cases with 2 stool specimens collected ≥ 24 hrs apart AND ≤ 11 days after onset / number of AFP cases ≥ 80% Timeliness of field and shipment activities Number of AFP cases with 2 stool specimens collected ≥ 24 hours apart AND received in good condition* at a WHO- accredited laboratory AND ≤ 14 days after onset / number of reported AFP cases ≥ 80% Timeliness of stool specimen shipment Number of stool specimens arriving in good condition* in a WHO-accredited laboratory AND ≤ 3 days after specimen collection / number of stool specimens collected ≥ 80% 61 POLIOMYELITIS Timeliness of ES sample shipment Number of sewage samples arriving at a WHO-accredited laboratory ≤ 3 days after sample collection / number of sewage samples collected ≥ 80% AFP: acute flaccid paralysis; ES: environmental surveillance *For calculations: missing stool = poor condition Table 3.A6: Indicators for timeliness of laboratory activities Indicator Calculations (expressed as %) Target AFP: Timeliness of reporting laboratory results (system performance) Number of stool specimens with final laboratory results available ≤ 21 days from a DD country OR ≤ 28 days from a non-DD country after receipt at a WHO-accredited laboratory / number of stool specimens collected ≥ 80% AFP: Timeliness of reporting WPV/VDPV results (detection) Number of stool specimens with final WPV/VDPV laboratory results available ≤ 21 days after receipt from a DD country OR ≤ 28 days after receipt from a non-DD country at a WHO-accredited laboratory / number of stool specimens positive for WPV/VDPV ≥ 80% AFP: Timeliness of reporting laboratory results Number of stool specimens with sequencing results available ≤ 7 days after receipt at a WHO-accredited sequencing laboratory / number of stool specimens positive by ITD requiring sequencing ≥ 80% ES: Timeliness of reporting laboratory results Number of ES samples with final laboratory results available ≤ 32 days after receipt at a WHO-accredited sequencing laboratory / number of ES samples collected with final laboratory results ≥ 80% ES: Timeliness of reporting PV laboratory results PV ES samples with sequencing results available ≤ 7 days after receipt at a WHO-accredited sequencing laboratory / number of PV ES samples positive by ITD requiring sequencing ≥ 80% AFP: acute flaccid paralysis; DD: direct detection; ES: environmental surveillance; ITD: intratypic differentia- tion; VDPV: vaccine-derived poliovirus; WHO: World Health Organization; WPV: wild poliovirus Table 3.A7: Core indicators for quality of AFP surveillance Indicator Calculations Target NPAFP rate* (Number of cases discarded as NPAFP among children < 15 years of age / number of children < 15 years of age) x 100 000 per year Note: Endemic countries are encouraged to have ≥ 3. ≥ 2 NPAFP rate – subnational (Number of districts with ≥ 100 000 children < 15 years of age that meet the NPAFP rate target / number of districts with ≥ 100 000 children < 15 years of age) x100 Note: ≥ 3 per 100 000 need to be reached in all high-risk districts in an outbreak country. ≥ 80% Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 62 Indicator Calculations Target Adequacy of stool specimen (Number of AFP cases with 2 stool specimens collected ≥ 24 hours apart AND ≤ 14 days after onset AND received in good condition‡ in a WHO-accredited laboratory / number of AFP cases) x 100 Note: Certification indicator (14 days) ≥ 80% Adequacy of stool specimen – subnational (Number of districts that reported ≥ 5 AFP cases that meet the stool adequacy target / number of districts that reported ≥ 5 AFP cases) x 100 ≥ 80% Timeliness of stool collection (Number of AFP cases with 2 stool specimens collected ≥ 24 hours apart AND ≤ 14 days after onset / number of reported AFP cases) x 100 Note: Certification indicator (within 14 days of onset) ≥ 80% Condition of stool Number of AFP cases with 2 stool specimens arriving in good condition‡ at a WHO-accredited laboratory / number of reported AFP cases ≥ 80% Composite index – national Population living in districts that meets both NPAFP rate target and stool adequacy target / population living in all districts (Admin2) ≥ 80% Composite index – subnational Number of districts with ≥100,000 children <15 years of age that meet NPAFP rate target and stool adequacy target / number of districts with ≥100 000 children < 15 years of age ≥ 80% Adequacy of active surveillance visits† (2 calculations) 1. # visits to HP sites conducted / # HP site visits planned 2. # HP sites visited / Total # HP sites 1. ≥80% 2. 100% Completeness of 60-day follow-ups Number of inadequate AFP cases with a follow-up examination for residual paralysis completed ≥ 60 days AND ≤ 90 days after onset / number of inadequate AFP cases ≥ 80% Completeness of WZR Number of sites reporting / number of designated reporting sites for AFP surveillance ≥ 80% Timeliness of WZR Number of sites reporting by the deadline / number of designated reporting sites for AFP surveillance ≥ 80% AFP: acute flaccid paralysis; NPAFP: non-polio acute flaccid paralysis; WZR: weekly zero reporting * Rate should be annualized ‡For calculations: missing stool = poor condition †(a) High-priority sites are those facilities where there is a high likelihood of seeing an AFP case; they are visited at least on a weekly basis and sometimes more often, (b) Combination indicator in which “all HP sites have >=1 visit each month” to be used as a flag, (c) Calculated per month 63 POLIOMYELITIS Table 3.A1: Core indicators of community-based surveillance Indicator Calculations Target Proportion of AFP cases reported by CBS (Number of AFP cases (those on line list) identified by community informant / number of AFP cases on line list) x 100 TBD Completeness of WZR or MZR (Number of reports received from community informants / number of reports expected from community informants) x 100 Timeliness of WZR or MZR / number of reports received on time from community informants ≥ 80% Proportion of female informants (Number of female informants / number of informants) x 100 ≥ 50%– 80%* Proportion of informants from local area (Number of local informants / number of informants) x 100 ≥ 80%* Supervision of informants† ‡ (Number of informants who have received at least one supervisory visit in last 3 months / number of informants) x 100 ≥ 80% Informant training‡ § (Number of informants trained within the last year / number of informants) x 100 ≥ 80% Informant turnover rate‡ § ¶ (Number of informants who left during the previous year /number of informants) x 100 TBD AFP: acute flaccid paralysis; TBD: to be decided; MZR; monthly zero reporting; WZR: weekly zero reporting * Target to be adjusted at the country level; priority countries to analyse regularly. * Target to be adjusted at the country level; priority countries to analyse regularly. † To be reviewed quarterly; priority countries to analyse regularly. Suggest results be stratified by supervisor. ‡ Results should be stratified by sex. § To be reviewed annually; priority countries to analyse regularly. ¶ Informant turnover rate is a flag; the target is to be defined at the country level. Table 3.A8: Non-core indicators for AFP surveillance*† Indicator Calculations (expressed as %) Target Unreported AFP cases found during active surveillance Number of unreported AFP cases found in the register during active surveillance visits / month None Percentage of supervised active surveillance visits‡ Number of active surveillance visits supervised per month / number of active surveillance visits conducted per month ≥ 25% Number of supervisory visits in HP sites Number of HP sites with ≥ 1 supervised visit in the last 6 months / number of HP sites 100% Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 64 Indicator Calculations (expressed as %) Target AFP case field validation Note: this would be done by a person higher in station than the one who reported the case Number of AFP cases validated ≤ 14 days of investigation / number of AFP cases ≥ 30% Completeness of AFP contact sampling Number of inadequate AFP cases with contact sampling§ / number of inadequate AFP cases ≥ 80% Timeliness of AFP contact sampling Number of stool specimens of inadequate cases’ contacts collected within ≤ 7 of days of investigation / number of stool specimens of contacts of inadequate cases ≥ 80% AFP: acute flaccid paralysis; HP: high-priority * For priority countries (very high-risk, high-risk and medium-high risk), the indicators should be analysed monthly. † For non-priority countries, the indicators should be reviewed quarterly and included in desk reviews. ‡ Calculated by priority site, by geography and by quarter § 2 or 3 contact samples per inadequate AFP case, as per regional recommendation Table 3.A9: Non-core indicators on health-seeking behaviours*† Indicator Calculation (expressed as a percentage) Target AFP case encounters‡ # of AFP cases with <=2 health encounters between onset and notification / # of AFP cases >=80% Adequacy of notification by designation # of 1st health encounters that led to a notification, by designation [reporting source]§ / # of health encounters by that same designation >=80% Appropriateness of surveillance network # of AFP cases with first health encounters with a reporting site within the AFP surveillance network / # of AFP cases >=80% Late reported AFP cases: Completeness of health encounter information Among AFP cases reported >14 days after paralysis onset: # of AFP cases with no information on health encounters / # AFP cases reported >14 days after paralysis onset >=80% AFP = acute flaccid paralysis * For priority countries (very high risk, high risk, medium-high risk), indicators should be analysed monthly. † For non-priority countries, indicators should be reviewed quarterly and included in desk reviews. ‡ Results should be stratified by sex. § This is the “percentage of 1st encounters by designation (e.g., doctor, nurse, traditional healer, vaccinator, other) that led to the notification of an AFP case.” 65 POLIOMYELITIS Table 3.A10: Non-core indicators on community-based surveillance Indicator Calculation (expressed as a percentage) Target Proportion of AFP cases reported by CBS # of AFP cases (those on linelist) identified by community informant / # of AFP cases on linelist TBD Completeness of weekly/ monthly zero reporting (WZR/MZR) # of reports received from community informants / # of expected reports from community informants >=80% Timeliness of WZR/MZR # of reports received on time from community informants / # of expected reports from community informants >=80% Proportion of female informants # female informants / # informants >=50%-80%* Proportion of informants from local area # local informants / # informants >=80%* Supervision of informants† ‡ # informants who have received at least one supervisory visit in last 3 months / # number of informants >=80% Informant training‡ § # informants with training within the last year / # of informants >=80% Informant turnover rate‡ § ¶ # informants who left during the previous year / # informants TBD AFP = acute flaccid paralysis; CBS = community-based surveillance; MZR = monthly zero reporting; TBD = to be determined; WZR = weekly zero reporting *Target to be adjusted at the country level; priority countries to regularly analyse. † To be reviewed quarterly; priority countries to regularly analyse. Suggest to stratify results by supervisor. ‡ Results should be stratified by sex. § To be reviewed annually; priority countries to regularly analyse. ¶ Informant turnover rate is a flag; the target is to be defined at the country level. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 66 Annex 6: Gender and polio surveillance If gender roles, norms and relations are not adequately understood, analysed and addressed, polio eradication interventions will not be as effective in reaching “every last child”. The GPEI published the Gender Equality Strategy 2019–2023 to provide direction to the efforts to advance gender equality and set out the scope of related activities. It aims to strengthen gender mainstreaming across all interventions, strategies and policies. Table 3.A9 provides definitions that can be useful to the GPEI partners, regional offices and country programmes in their efforts towards achieving greater gender mainstreaming. This is followed by a gender-responsive assessment scale. Table 3.A9: Definitions related to gender Term Definition Se x Typically assigned at birth and refers to the biological characteristics that define a person as female, male or intersex G en de r Gender refers to the socially constructed roles, norms and behaviours that a given society considers appropriate for individuals on the basis of the sex they were assigned at birth. Gender also shapes the relationships between and within groups of women and men. G en de r eq ui ty This is the process of being fair to women and men. It is inherent in the concept of equity that men and women have different needs, power and access to resources, which should be identified and addressed in a manner that rectifies the imbalance. Addressing gender equity leads to equality. G en de r eq ua lit y This denotes the absence of discrimination based on a person’s sex or gender. It means that each person should be provided the same opportunities, including access to and control of social, economic and political resources, and that these rights (such as health services, education and voting rights) should receive protection under the law. G en de r m ai ns tr ea m in g This refers to the process of assessing the implications – for women, men and gender-diverse people – of any planned action within a health system, including legislation, policies, programmes and service delivery, in all technical areas and at all levels. Mainstreaming is a strategy aimed at making the concerns and experiences of gender-diverse people an integral dimension of the design, implementation, and monitoring and evaluation of policies and programmes in all spheres, so that they benefit equally and inequality is not perpetuated. Gender mainstreaming is not an end in itself, but a means, an approach and a strategy for achieving the goal of gender equality. G en de r- un eq ua l Programmes perpetuate gender inequalities by reinforcing unbalanced norms, roles and relations and privileging men over women (or vice versa). G en de r- bl in d Programme ignores gender roles, norms and relations and the differences in opportunities and resource allocations for women and men, girls and boys. 67 POLIOMYELITIS Term Definition G en de r- se ns iti ve Programmes marked by an awareness of gender roles, norms and relations, while not necessarily addressing the inequalities generated by them, may be described as gender-sensitive. No remedial actions are prescribed. G en de r- re sp on si ve Programmes or policies which consider gender norms, roles and inequalities and set out measures to actively address them are gender-responsive. They go beyond gender sensitivity and include gender-specific and gender-transformative actions. G en de r- sp ec ifi c Gender-specific programmes are those that intentionally target a specific group of women or men for a specific purpose, but do not challenge gender roles and norms. G en de r- tr an sf or m at iv e Approaches that attempt to redefine and change the existing gender roles, norms, attitudes and practices may be described as gender-transformative. These interventions tackle the root causes of gender inequality and reshape unequal power relations. Figure 3.A1: WHO gender-responsive assessment scale Gender-related delays in detection In any context, especially in high-risk areas and areas with special populations, the polio surveillance system must be able to identify the stages at which case detection and notification may be affected by gender norms, roles and relations, as well as the existing gender inequalities. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 68 Table 3.A10: Examples of gender-related barriers Stages Possible issues and their causes Possible actions O ns et o f p ar al ys is t o ca re -s ee ki ng Failure to seek care or delay in seeking care: z Women caregivers do not have decision-making power and/or face obstacles/restrictions in terms of mobility (lack of transport, money and time; various household duties; need for authorization to travel to health facility and/or for a male escort/ travelling companion). z Women caregivers have a low level of awareness and literacy rate, and lack access to health information in suitable formats. z The attitude towards health-seeking in the case of female patients is discriminatory (e.g. giving boys access to health care is prioritized / there are delays in seeking care for girls, the quality of services provided by health workers to women are poor). z There is a lack of local female health-care providers. z Conduct gender analysis/assessment to identify gender barriers specific to the context/setting. z Advocate with the local authorities. z Sensitize the community and involve men in the sensitization and outreach activities. z Adapt health services to the needs of women (e.g. the opening times for services, outreach surveillance activities, etc.). N ot ifi ca tio n Delays in notification or no notification because: z women health-care workers do not have sufficient knowledge and training opportunities; z the medical hierarchy is unresponsive when a female worker notifies an AFP case; z active surveillance visits are not conducted regularly and/or adequately due to the absence of suitable modes of transport and/or of male escorts; and z few women serve as community informants due to the existing gender norms and roles. z Ensure that the entire staff receives training. z Engage with women workers to identify and address their needs and challenges, especially those related to safety (e.g. timing of training sessions, location, transport options). z Sensitize the local health workers, including to the issue of security/ safety. z Ensure the availability of safe and adequate transport for personnel. z Reach out to and collaborate with local women’s groups to find solutions. z Modify the composition of the CBS team. 69 POLIOMYELITIS Stages Possible issues and their causes Possible actions C as e in ve st ig at io n an d st oo l co lle ct io n Delays in investigation and/or stool collection due to: z insufficient training opportunities for women surveillance officers; z lack of female surveillance officers needed to enter the homes of AFP cases; z the inability of women caregivers to stay in a health facility overnight when a case is hospitalized; and z safety and security risks faced by women workers. z The training of health-care workers/ surveillance officers should cover gender-related challenges and barriers to women’s participation (e.g. location and timing of training, transport, need for a travelling companion). z Modify the composition of the surveillance team. z Sensitize the local health system and/or community. z Ensure the safety of women working at the frontline. AFP: acute flaccid paralysis The following are some ways of minimizing the risk of gender-related delays in detection. z Programmes should systematically collect and analyse sex-disaggregated data. Adapted case investigation forms and analytical tools should be used for this purpose. It is also important to identify any consistent, recurrent (over a period of 12–24-months) delays in detection, notification and investigation that may be linked to gender barriers. z Surveillance officers and/or programme managers should conduct in-depth assessments with the support of the management and gender specialists and consider possible, locally acceptable actions to address the gaps. When considering actions to inform and support surveillance interventions, it is always essential to: z collaborate with and reach out to women’s groups, women’s health committees, grassroots networks and other organizations with a strong understanding and influence around health-seeking behaviours, gender-related barriers, and children’s health issues. z consult with community authorities, religious leaders, opinion influencers, and elders, including women, to sensitize and negotiate access to women or households and increase women’s participation. z sensitize and promote fathers’ and men’s equal participation in childcare, caregiving, and household responsibilities and tasks; and z ensure communication channels, tools, materials, and messages are context- specific, informed by gender analysis, and free from harmful gender stereotypes. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 70 Gender in the work environment and organizational culture Managers of polio surveillance must ensure that the programme takes gender into account, both to promote gender equality and to address any gender-related barriers or other factors that affect the safety, performance and career advancement of its staff. An organization that does not promote gender equality, respond to the needs of women in its policies and programming, or enhance the meaningful participation of women at all levels cannot provide a safe and enabling work environment and culture and thus, cannot maximize its potential. Actions to consider z Equal and meaningful participation of women should be promoted at all levels in the surveillance workforce and gaps should be identified in the composition of surveillance teams that can contribute to deficiencies in case investigation (e.g. all-men teams not able to access homes in certain contexts). This includes maintaining a gender balance among supervisors. z The specific needs of female frontline workers and the barriers faced by them should be identified to increase women’s participation (e.g. needs or barriers related to mobility, safety, transportation, equipment, literacy [including digital literacy], and training). z Mandatory training should be conducted for all staff members on preventing and responding to sexual exploitation, abuse and harassment. z It is necessary to share information on the existing reporting and support mechanisms and systems to address all forms of sexual exploitation, abuse or harassment. z If not already in place, communication mechanisms should be set up for women involved in polio surveillance to enable them to voice and discuss, in confidence, issues affecting their physical and emotional well-being at work (e.g. mentorship, staff representative). z All polio surveillance training must include the gender module, with a special focus on a description of gender and gender-related barriers in surveillance. z The systematic and regular provision of gender analysis in all reports must be institutionalized. z Training and sensitization sessions should be conducted in health facilities or within communities.  Gender-related barriers to immunization and surveillance should form a part of the sessions. 71 POLIOMYELITIS  Equal parenting and shared caregiving responsibilities need to be highlighted, and equal participation by fathers in childcare, caregiving and household tasks must be promoted.  An effort should be made to ensure that diverse women and men are represented in training visuals and images.  Sex-disaggregated data and gender analysis should be provided whenever possible. The importance of collecting and analysing data disaggregated by sex in all monitoring and evaluation activities must be highlighted.  Efforts should be made to ensure that the training sessions are accessible to all participants. For example, the facilities should be safe and easy to reach, the timing convenient and the seating arrangements appropriate. The organizers and facilitators should know how to facilitate sessions so that everyone participates. Table 3.A11: Gender-related indicators Indicators Calculations (expressed as percentage) AFP detection system Number of AFP cases** by sex with final laboratory results ≤ 35 days after onset / number of AFP cases Timeliness of field activities Number of AFP cases by sex with 2 samples collected ≥ 24 hours apart, both within 11 days of paralysis onset / number of reported AFP cases Timeliness of notification Number of AFP cases by sex reported within 7 days of paralysis onset / number of reported AFP cases Health care encounters Number of AFP cases by sex with ≤ 2 health care encounters between onset and notification / number of AFP cases Professional profile by sex (by category) Number of women / total number of staff or informants (by category: surveillance officer, supervisor, CBS informant) Staff with PRSEAH training Number of surveillance staff with PRSEAH training / number of staff AFP: acute flaccid paralysis; CBS: community-based surveillance; PRSEAH: preventing and responding to sexual exploitation, abuse and harassment **Aggregated results: all laboratory results (AFP cases and contacts) used to classify the case as confirmed/ discarded Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 72 Annex 7: Environmental sample collection form Name of sample collector Location Country State/province District Ward Site identification Name of collection site Site EPID/site collection number Bar code, if available Type of site Sewage plant  Sewage syst  Date and time of sample collection Observations Time of collection Was there good flow rate at the time of collection? Yes ; No  Was the sample collected at the designated point at the site? Yes ; No  Was the sample amount/ volume collected adequate? Yes ; No  Were there any industries or facilities discharging chemical effluent at the time of sample collection Yes  No  Date sample sent to laboratory Intermediary laboratory/health facility, WHO or MoH office Date sample received Person receiving sample in the intermediary laboratory Name, designation, signature Date sample was shipped to the processing laboratory Note any observation during collection. Mention issues such as collection delayed because of rain; description of wastewater colour or smell that could be associated with presence of toxic compounds; and changes in sampling points because access blocked by construction. State whether there was any need to store samples before shipment. 73 POLIOMYELITIS Annex 8: Site registration form Site name Site identification code Site category Permanent  Temporary  Reasons for opening site Geographical location Country Province District City GPS coordinates Map of draining waterways Estimated size and type of catchment population Composite site Yes  No  Estimated total catchment population Catchment geographical area (street boundaries) Type of risk population included Features of sewage system Open  Closed  Others  Flow Yearly  Seasonal  Sampling schedule Date when sampling started Collection frequency Weekly  Fortnightly  Monthly  Scheduled week-year and/or day of week Schedule time or range for sample collection Date when sampling/ site closed Comments Focal person responsible for entering and updating information Addendum for changes in site Date of change Person responsible for change Update New GPS coordinates New catchment area, if changed New population size, if changed Disposition Active  ES samples are being collected as per sample collection schedule Inactive  ES samples are NOT being collected due to temporary or permanent suspension/closure of site Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 74 Annex 9: Laboratory request/report form Site code ENV_____________/___________/__________/_______ Country code/Province code/District code/ Site code Sample collection information Location State District Subdistrict Others Site identification Name of collection site Site code Geographical coordinates Bar code Type of site Date of sample collection dd/mm/yyyy Time of sample collection hr/min Date sample sent to laboratory dd/mm/yyyy Name and phone number of person who collected sample Signature Name and phone number of supervisor during collection Signature Laboratory Date sample received dd/mm/yyyy Sample ID Name and phone number of person who received sample at laboratory Signature Condition of sample at receipt Good  Poor  If poor, specify Temperature of carrier on arrival (0C) Volume of specimen (in litres) Colour of specimen Clear  Cloudy  Dark  Comment: Results Final cell culture results ITD results Sequencing results Date results sent out dd/mm/yyyy Date results received by surveillance (or WHO) dd/mm/yyyy 75 POLIOMYELITIS Annex 10: PID case investigation form NOTIFICATION Case identification Unique case Identifier: PID ___________/____________/___________/____/___________ Country code/ Province code/District code/Year/ Case Number First Name Last Name Parent or legal guardian’s name Physician’s name Physician’s phone number Email: Country Province/ District Health facility name Health facility address Name of reporting person with date Health-facility record number Demographics Date of birth dd/ mm/yyyy Sex 1=Male  2=Female  9=Unknown  Residence Province District Town/Village House #/Street Contact details Email Phone Medical History Date of confirmation of PID Dd/mm/yyyy PID Diagnosis 1.Severe combined immunodeficiency  2.Common variable immunodeficiency  3.Hypogammaglobulinemia  4.Agammaglobulinemia  5. Other  If so, specify: 6.Pending  INVESTIGATIONS Polio Surveillance Team Notification date of conformed PID to Polio Surveillance Team: dd/mm/yyyy Investigation date by polio surveillance team dd/mm/yyyy Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 76 Polio Surveillance Team Paralysis present at the time of first notification 1.Yes  If so, please notify through AFP Surveillance system 2.No  If so, insert AFP EPID Number Initial stool collection Stool 1 Collection date Stool 2 collection date Date stool specimen sent to lab Dd/mm/yyyy Date stool specimen arrived at the laboratory Dd/mm/yyyy Condition of stool on arrival at the laboratory 1.Good  2.Poor  9.Unknown  Laboratory Results Date final culture results sent from laboratory to PID Physician / EPI Dd/mm/yyyy Date intratypic differentiation sent from laboratory to PID Physician/ EPI Dd/mm/yyyy Date genomic sequencing results sent from laboratory to PID physician/ EPI* Dd/mm/yyyy Polio Type 1 isolated 1.Yes  2.No  3.Specimen not processed  If so, specify the type and fill in positive for Polio Form (WPV, VDPV, Sabin-like, mixture, If VDPV, number of nucleotide change 77 POLIOMYELITIS Laboratory Results Polio type 3 isolated? 1.Yes  2.No  3.Specimen not processed  If yes, specify the type and fill in positive for Polio Form (WPV, VDPV, Sabin-like, mixture, If VDPV, number of nucleotide change Non-polio enterovirus (NPEV) isolated? 1.Yes  2.No  3.Specimen not processed  Classification Current Diagnosis & Classification 1-PID with WPV  2-PID with VDPV;  3-PID with Sabin;  4-PID -ve for polio;  5-PID pending polio lab result  Is the child registered for follow up stool testing? 1-Yes  2-No  99-Not applicable/ unknown)  If Yes, when is the date for follow up? (dd/mm/yyyy) DETAILED INVESTIGATION Has the patent received any other treatment for PID IVIG 1.yes  2.No  Bone marrow transplant 1.Yes  2.No  Others (please specify) Immunoglobulin level(__mg/dl) Polio vaccination Number of IPV doses received (Number; 99 if unknown Number and type of OPV doses received (Number; 99 if unknown) Date and type of last OPV dose received* Date Type of OPV Close family members have received OPV doses in last 6 months? 1.Yes  2.No  Date when family member received OPV if yes date Dd/mm/yyyy Date of last OPV campaign in community Dd/mm/yyyy Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 78 Classification Is the child eligible for antiviral polio treatment? 1-Yes  2-No  Is the antiviral polio treatment requested? 1-Yes  2-No  Date start of treatment) (DD/MM/YYYY Date end of treatment (DD/MM/YYYY) Are contact collected 1-Yes  2-No  99-Not applicable/ unknown)  If 1-Yes, fill in PID contact form Comments (e.g. type of antiviral, compliance, etc.) 79 POLIOMYELITIS Further reading 1. World Health Organization. Polio: surveillance standards for vaccine-preventable diseases, 2nd ed. World Health Organization; 2018. (https://www.who.int/ publications/m/item/vaccine-preventable-diseases-surveillance-standards-polio, accessed 15 October 2022) 2. Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region. World Health Organization. Regional Office for South-East Asia; 2017. Licence: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/bitstream/ handle/10665/277459/Module3-Polio.pdf?sequence=9&isAllowed=y, accessed 15 October 2022). 3. Routh JA, Oberste MS, Patel M. Chapter 12: Poliomyletis. In Roush SW, Baldy LM, Hall MAK, editors. Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases (https://www.cdc.gov/vaccines/pubs/surv-manual/chpt12- polio.html, accessed 15 October 2022). 4. Gender Equality Strategy 2019–2023. Geneva: World Health Organization; 2019 (WHO/ POLIO/19.01). Licence: CC BY-NC-SA 3.0 IGO (https://polioeradication.org/ wp-content/uploads/2020/10/Gender-Strategy.pdf, accessed 15 October 2022). 5. Global Polio Surveillance Action Plan 2022–2024. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO (https://polioeradication.org/ wp-content/uploads/2022/04/GPSAP-2022-2024-EN.pdf, accessed 16 October 2022). 6. Global Polio Eradication Initiative. Field Guidance for the implementation of Environmental Surveillance for Poliovirus. Geneva: World Health Organization; 2022 (https://polioeradication.org/wp-content/uploads/2022/09/ES-Field-implementation- guidance-EN.pdf, accessed 16 October 2022). 7. Global Polio Eradication Initiative. Guidelines for implementing Polio Surveillance among patients with Primary Immunodeficiency Disorders (PIDs). 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UNICEF Regional Office for South Asia. Gender toolkit 2018: integrating gender in programming for every child in South Asia. UNICEF ROSA; 2018 (https://www. unicef.org/rosa/reports/regional-office-south-asia-gender-toolkit-2018, accessed 16 October 2022). 26. UNICEF Regional Office for South Asia. Gender-responsive communication for development: guidance, tools, and resources. UNICEF South Asia; 2018 (https:// www.unicef.org/rosa/media/1786/file, accessed 16 October 2022). 27. UNICEF Regional Office for South Asia. Immunization and gender: a practical guide to integrate a gender lens into immunization programmes. UNICEF ROSA; 2019 (https://www.comminit.com/polio/content/immunization-and-gender-practical-guide- integrate-gender-lens-immunization-programmes, accessed 16 October 2022). 28. Global Polio Eradication Initiative. Gender Equality Strategy 2019–2023. Geneva: World Health Organization; 2019 (https://polioeradication.org/wp-content/ uploads/2020/07/Gender_Strategy_EN.pdf, accessed 16 October 2022). 29. Global Polio Eradication Initiative. Technical Brief: Gender. Geneva: World health Organization; 2018 (https://polioeradication.org/wp-content/uploads/2018/07/GPEI- Gender-Technical-Brief-2018.pdf, accessed 16 October 2022). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 82 CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region MODULE-4 DIPHTHERIA September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Diphtheria) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO CONTENTS Introduction 5 Objectives 5 Types of surveillance 5 Case detection 5 Definition of suspected case 5 Description of terms 6 Other associated signs and symptoms 6 Date of onset of illness 6 Response to suspected case 6 Investigation of suspected case 7 Case investigation form 7 Unique ID 7 Specimen collection 8 How to take samples 8 Laboratory testing 9 Confirmation of diagnosis 9 Other tests 9 Classification of cases 9 Laboratory-confirmed case 9 Epidemiologically linked case 9 Clinically compatible case 10 Discarded case 10 Contact tracing 11 Definition of close contacts 11 Duration of monitoring close contacts 11 Prophylactic antibiotics for contacts 12 Vaccination to contacts 12 Laboratory investigations 12 Culture reports 12 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Active case search in community 12 Clinical management of diphtheria cases 13 Diphtheria outbreak 15 Definition 15 Modifications needed in surveillance 15 Public health response 16 Data management 17 Reporting requirements 17 Unique ID 17 Recommended Data elements 17 Data analysis 18 Using data for decision-making 18 Indicators for surveillance performance 19 Annex 1: Disease epidemiology 21 Background 21 Essential epidemiology 21 Vaccines 22 Disease burden 22 Annex 2: Specimen collection 23 Annex 3: Case investigation form 25 Annex 4: Sample contact-tracing form 27 Annex 5: Recommended indicators of surveillance performance 30 Further reading 32 5DIPHTHERIA Diphtheria surveillance Introduction Diphtheria is a vaccine-preventable disease that has the potential to cause epidemics. Recent diphtheria epidemics have highlighted the need for adequate surveillance and epidemic preparedness. Surveillance would provide region-specific epidemiological data that would facilitate the formulation of appropriate control strategies. The data could be used to monitor the levels of immunization coverage (target >90%) and disease as a measure of the impact of immunization programmes. Objectives The objectives of surveillance of diphtheria are to: z monitor the disease burden and define transmission patterns; z identify outbreaks to initiate investigation and prevent further cases; and z determine an appropriate vaccine policy for the country, such as one requiring the introduction of booster doses or a change in the vaccine formulation. Types of surveillance Non-outbreak / non-epidemic situation: The surveillance should be at the national level and facility- and case-based. All health-care providers who diagnose a diphtheria case should report it. Ideally, laboratory testing of all suspected cases should be conducted for case confirmation. Large outbreaks: Case-based surveillance may not be possible during large outbreaks, when laboratory testing of all suspected cases becomes logistically challenging. However, active case search and contact tracing should be prioritized. Case detection Definition of suspected case An illness of the upper respiratory tract characterized by: z pharyngitis, nasopharyngitis, tonsillitis or laryngitis AND z adherent pseudo-membrane of the pharynx, tonsils, larynx and/or nose. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 Description of terms Pharyngitis and/or tonsillitis: fever with pain and redness of the throat and/or tonsils Laryngitis: hoarseness of the voice and cough Pseudo-membrane: Initially, isolated spots of grey or white exudate appear in tonsillar and pharyngeal area. These spots often coalesce within a day to form a confluent sharply demarcated pseudo-membrane that becomes progressively thicker, more tightly adherent to the underlying tissue and darker grey. Dislodging the membrane is likely to cause bleeding. (Note: Unlike the exudate in streptococcal pharyngitis, the diphtheritic pseudo- membrane often extends beyond the margin of the tonsils onto the tonsillar pillars, palate or uvula.) Some countries may expand the definition of a suspected case, especially during high transmission periods /outbreaks, to include: z mild cases without a pseudo-membrane; and z non-healing ulcers in a person with a travel history to a country with endemic disease or one with a diphtheria outbreak. Other associated signs and symptoms Some other signs and symptoms associated with diphtheria are: z dysphagia; z difficulty in breathing; z headache; z change of voice (hoarseness or thick speech); and z nasal regurgitation and serosanguineous nasal discharge. Some patients may also present with “bull neck” diphtheria, which is marked by massive cervical lymphadenopathy with oedematous swelling of the submandibular region and the surrounding areas. Date of onset of illness The date of onset of diphtheria should be considered as the date of onset of sore throat. Response to suspected case Within 24 hours: The clinician who first sees a patient suspected of having diphtheria should notify the public health authorities within 24 hours in order to arrange for the treatment and administration of diphtheria anti-toxin (DAT) to the case. 7DIPHTHERIA Within 48 hours of report of suspected case: The public health authorities should investigate the case, irrespective of the patient’s vaccination status. The process of investigation should be as follows. z A case investigation form should be filled in. z Nasal and pharyngeal swabs should be collected for culture. Once diphtheria is suspected, the swabs should be taken as soon as possible and treatment should not be delayed until the laboratory results arrive. z The samples must be tested in a laboratory. z The case is then confirmed and classified. z The close contacts of the case should be identified, and a case investigation form should be filled for contacts having symptoms of suspected diphtheria. z An active case search should be conducted. Investigation of suspected case Suspected cases should be investigated by the trained health staff/clinician designated by the public health authority. Case investigation form A case investigation form should be filled in for every suspected case within 48 hours of reporting. (See Annex 3 for a sample case investigation form.) Unique ID Each suspected case should be assigned a unique case identification number (UID). The case number should begin with one or more three-letter combinations designating the geographical location, the year and the serial number of the case. All communications and forms related to the case should cite the UID. For example: DTH – code for suspected diphtheria THA – country code BKK – province code BBN – district code 2022 – year of onset 001 – serial number of case in the province The UID would then be DTH-THA-BKK-BBN-22-001. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Specimen collection Two nasal and pharyngeal swabs should be collected from every suspected case at first contact. A trained clinician in a hospital setting may also collect a sample of the pseudomembrane from the patient’s pharynx, if it is discernible. This may not be possible early in the course of the disease as the pseudomembrane takes time to form. How to take samples z Pharyngeal swab: A cotton-tipped applicator must be used. The sample should be obtained under direct visualization, preferably from the edge of or directly beneath the pseudomembrane. z Pseudomembrane: A piece of the pseudomembrane should be removed aseptically, if possible. This should be done only in a hospital setting under the care of an expert clinician. (For details on specimen collection, see Annex 2.) When to collect specimens: Ideally, the biological specimen should be taken prior to starting antibiotics, upto 4 weeks of the onset of the illness. However, samples should be collected even if antibiotics have already been started. Labelling of specimens: A swab should carry a label mentioning the UID and the source of the specimen. Transport media: For the pharyngeal swab specimens, Amies medium or Stuart medium should be used, or the dry swabs should be placed in silica gel sachets. Sterile normal saline, and not formalin, must be used for pseudomembrane samples. Transport temperature: A temperature of 2–8°C must be maintained while transporting the specimens. Ideally, all samples should be sent to the laboratory within 24 hours of collection and arrive at the laboratory within two days of collection, as delays may compromise the ability to isolate the bacteria. 9DIPHTHERIA Laboratory testing Confirmation of diagnosis The diagnosis may be confirmed through: z culture of the organism from the specimen; and z demonstration of toxin production, using an immunoprecipitation reaction (the modified Elek test). Other tests The polymerase chain reaction (PCR) test may also be used to detect the presence of bacterial DNA in throat swab specimens. It can be done directly on swab material to detect the presence of the diphtheria toxin gene (tox). However, it should not replace bacterial culture as the primary and gold standard diagnostic test: z Since the presence of the tox gene does not confirm the production of toxin, positive PCR results should always be confirmed with the Elek test (if there is an isolate) to demonstrate toxin production. z Specimens can be PCR-positive and culture-negative (for example, those taken post-antibiotics, those of poor quality or those for which testing has been delayed due to delays in transportation). These cases should be reviewed to determine their classification. Classification of cases Laboratory-confirmed case A laboratory-confirmed case is a suspected case with Corynebacterium spp., isolated by culture and positive for toxin production (confirmed by the phenotypic Elek test), regardless of the symptoms. PCR-positive results can complement surveillance and may qualify as laboratory-confirmed, in combination with the epidemiological and clinical manifestations of the case. Epidemiologically linked case An epidemiologically linked case meets the definition of a suspected case and is linked epidemiologically to a laboratory-confirmed case. In other words, the person has had intimate respiratory or physical contact with a laboratory-confirmed case within 14 days prior to the onset of sore throat. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 Clinically compatible case A clinically compatible case meets the definition of a suspected case but has neither a confirmatory laboratory test result, nor an epidemiological linkage to a laboratory- confirmed case. Discarded case This is a suspected case that meets either of these criteria: z the culture grows Corynebacterium spp. but the Elek test is negative (non- toxigenic Corynebacterium); or z the PCR is negative for the tox gene. Figure 1: Classification of suspected cases when samples are collected for laboratory confirmation Sample collected Culture: Posi�ve ELEK : Culture: Nega�ve PCR : Nega�ve Non-toxigenic Corynebacteriu Discard Discard Culture: Nega�ve PCR : Posi�ve Culture: Posi�ve ELEK : Posi�ve No contact with cases Contact with lab-confirmed Toxigenic Corynebacteriu Review Epidemiologicall Epidemiologically linked case Lab-confirmed case 11 DIPHTHERIA Figure 2: Classification of suspected cases when samples are not collected for laboratory confirmation Contact tracing Definition of close contacts At a minimum, close contacts are considered to be household members and others with a history of direct contact. They include: z all those who slept under the same roof during the five days prior to the onset of sore throat and fever in the source case; z caretakers, relatives, sexual contacts, fellow students and friends who regularly visit the home, and spent more than an hour there in close contact (within a metre) with the source case; and z medical staff exposed to the case’s oral or respiratory secretions or wound. Duration of monitoring close contacts Close contacts should be monitored for signs and symptoms for 10 days from the date of the last contact with a confirmed case. Ideally, surveillance staff should communicate daily with contacts to learn of any new symptoms, but the extent of monitoring is determined by public health resources. Sample not collected Yes No/Unknown Close contact with a lab-confirmed case Epidemiologically linked case Clinically compa�ble case Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 Prophylactic antibiotics for contacts Close contacts should be administered a 7-day course of penicillin or a 10-day course of erythromycin. They should restrict their movement until 48 hours have elapsed since the initiation of chemoprophylaxis. For example, they should avoid mass gatherings, such as prayer meetings and celebrations. If a close contact develops symptoms of respiratory tract infection, especially sore throat or fever, then he/she should go/ be taken to a health centre immediately. Vaccination to contacts If the person has received fewer than three doses of vaccination or their vaccination status is unknown, they should be administered a dose of diphtheria toxoid containing vaccine immediately, followed by the complete primary series, according to the schedule. Ensure that three dose of primary series and three dose of booster doses are completed as per the WHO recommendation. Laboratory investigations Two pharyngeal swab should be taken from all close contacts with symptoms before antibiotic prophylaxis is started. Culture reports z Culture-positive for toxigenic Corynebacterium spp: The contact is now classified as a laboratory-confirmed case and proper case management, including isolation, must be started. The person must be started on treatment with a two-week antibiotic course. DAT is not needed for asymptomatic cases or those without a pseudomembrane. The contacts of this case should be investigated. z Culture-positive for non-toxigenic Corynebacterium spp.: The contact must complete the course of antibiotics and be retested. This, however, is not classified as a laboratory-confirmed case. z Culture-negative for Corynebacterium spp.: Antibiotics and monitoring can be stopped. The form shown in Annex 4 can be used to document the tracing of contacts. Active case search in community It is very important to conduct an active case search (ACS) in response to the identification of diphtheria cases in the community as there is a probability of finding additional cases 13 DIPHTHERIA among the contacts of diphtheria cases. Attempts should be made to conduct the ACS preferably within 48 hours of the confirmation of the case. Besides covering the household and neighbourhood inhabited by the diphtheria case, his/her contacts in the workplace or school should also be actively assessed. A thorough ACS in the community will identify any clustering of cases, and timely interventions can reduce outbreaks, as well as case morbidity and mortality. The ACS in the community should also include an assessment of the immunization status of the community members. Clinical management of diphtheria cases The clinical management of a case should be started as soon as diphtheria is suspected, without waiting for confirmation of the case. (Information on case management can be accessed at https://openwho.org/courses/diphtheria-clinical-management.) Isolation: Respiratory droplet isolation is required in the case of patients with respiratory diphtheria, and contact precautions must be taken by those with cutaneous diphtheria. The patient must remain in isolation until the elimination of the organism is demonstrated by negative cultures of two samples, obtained at least 24 hours apart after the completion of antimicrobial therapy. If facilities for droplet isolation are not available, screens should be placed between patients to minimize the possibility of transmission and restrict contact between the case and other patients in the health facility. DAT: The mainstay of treatment is DAT. The course and outcome of the disease depend on how early antitoxin treatment is started after the onset of the disease. After about three days from onset, the risk of complications and a fatal outcome increases with each day that DAT administration is delayed. As mentioned already, if diphtheria is strongly suspected, DAT treatment should be started immediately, without waiting for the laboratory results. Preferably, it should be given intravenously in serious cases and intramuscularly otherwise. The dose of DAT varies according to the site and extent of the infection, time since the onset of the disease and severity of the infection. Diphtheria antitoxin is not recommended as post-exposure prophylaxis among contacts as there is limited evidence of its benefit. Antibiotic treatment: Antibiotics (penicillin or erythromycin) eliminate the bacteria and toxin production, prevent further transmission and limit carriage, which can persist even after clinical recovery. Treatment should be continued for two weeks, and given parenterally until the patient can swallow with ease. Studies show that the in vitro effectiveness of azithromycin against diphtheria is similar to that of erythromycin and it can be a reasonable alternative for those who cannot tolerate erythromycin or when the drug is not available. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 Recommended regimen: z infants <6 months old: 10 mg/kg per day for 5 days; z infants and children >6 months old: 10 mg/kg (maximum 500 mg/dose) on day 1, followed by 5 mg/kg per day (maximum 250 mg/dose) on days 2–5; and z adults: 500 mg on day 1, followed by 250 mg per day on days 2–5. Immunization during convalescence: Protective immunity does not always develop after recovery from the disease. Therefore, individuals recovering from diphtheria should complete the age-appropriate recommended course of diphtheria toxoid vaccination during convalescence. Unvaccinated contacts should be given a full course of diphtheria toxoid-containing vaccine. Those who have not been administered the full course should be given the doses needed to complete the vaccination series. Children under 6 years of age should be administered a single dose of diphtheria toxoid containing vaccine, such as diphtheria-pertussis-tetanus (DPT), if they have not received such a vaccine in the previous five years. Those above the age of 6 years should not be given DPT because of the adverse effects of the pertussis component. They can instead be administered the diphtheria and tetanus (DT) vaccine, Td (tetanus toxoid with low-dose diphtheria antigen) or Tdap (tetanus toxoid with low-dose diphtheria and acellular antigens), according to their availability. As an example, children above the age of 7 years can be given 2 doses of DT at an interval of 4 weeks and a third dose after 6 months. Figure 3: Prophylactic management of close contacts with respiratory symptoms AGE VACCINE CHEMO-PROPHYLAXIS ANTIBIOTIC DOSE ROUTE DURATION Less than 6 yrs DPT Penicillin G benzathine 600 000 units Intramuscular Intramuscular Single dose OR Erythromycin Erythromycin 40mgs/kg in 4 divided doses Oral 7-10 days More than 6 yrs DT/Td/Tdap as per availability Penicillin G benzathine 1.2 million units Single dose OR 1Gm/day in 4 divided doses Oral 7-10 days 15 DIPHTHERIA Figure 4: Case management and contact-tracing SUSPECTED DIPHTHERIA • ISOLATION • OBTAIN NASAL/ PHARYNGEAL SWABS FOR CULTURE • TREATMENT WITH DIPHTHERIA ANTITOXIN (not needed for without a pseudomembrane ) • TREATMENT WITH ANTIBIOTICS (2 weeks) • IMMUNIZE WITH DIPHTHERIA TOXOID VACCINE DURING CONVALESCENCE • RECULTURE AFTER ANTIBIOTICS FINISHED (2x 24hrs apart) • MONITOR FOR COMPLICATIONS IDENTIFY CLOSE CONTACTS NONE YES MONITOR 10 DAYS LAB INVESTIGATIONS SIGN AND SYMPTOMS +VE TEST RESULTS NEGATIVE TEST RESULTS POSITIVE ANTIBIOTICS x10-14 DAYS VACCINATION STATUS IF UNVACCINATED Provide full course IF UNDERVACCINATED Complete series NO PUBLIC HEALTH ACTION NEEDED NO PUBLIC HEALTH ACTION NEEDED Diphtheria outbreak Definition A single laboratory-confirmed case of diphtheria should trigger a public health response. The finding of two temporally and geographically linked cases, of which at least one is laboratory-confirmed, is considered an outbreak of diphtheria. Modifications needed in surveillance Identifying additional cases: Once laboratory reports have confirmed initial cases of diphtheria, additional cases may be identified by clinical diagnosis on the basis of typical pseudomembranous pharyngitis without laboratory confirmation. Laboratory investigation of suspected cases is strongly recommended. The investigation of contacts might reveal asymptomatic cases, mild respiratory cases without a pseudomembrane or cases with nonrespiratory manifestations. These cases should be identified and counted as laboratory- confirmed or epidemiologically linked cases. If the size of the outbreak is large: z To avoid overwhelming the laboratory, all suspected cases need not be tested. z The definition of an epidemiologically linked case can be extended to include linkage to another epidemiologically linked case, rather than to a laboratory- confirmed case. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 z This chain of epidemiologically linked cases should not be continued beyond two to three incubation periods (about three weeks), after which any new cases identified should be tested to confirm that the toxigenic diphtheria outbreak is continuing. z Once five cases are confirmed to be toxigenic diphtheria, epidemiological linking to other epidemiologically linked cases can continue. z The process of reconfirming diphtheria among new cases should continue every two to three incubation periods. However, do not delay treatment pending laboratory confirmation. z Culture and Elek testing is critical in large outbreaks. They should be undertaken if new suspected cases are identified in a new area with no epidemiological link to the current outbreak. If the size of the outbreak is very large: z Cases should be line listed. Modifications may need to be made to the case investigation form to capture new risk factors. z PCR could be used as the standalone confirmatory test provided toxigenic diphtheria has been confirmed by culture and Elek testing in at least five cases. z In outbreaks lasting for an extended period, at least five samples from suspected cases with no epidemiological link to a PCR-confirmed case should be tested by culture and Elek every month. This is helpful in settings with limited resources and field challenges that are most likely to experience a diphtheria outbreak. This requires relatively lower resources to confirm that a toxigenic diphtheria outbreak is still ongoing. z Case-based surveillance and contact-tracing may not be feasible, and aggregate surveillance may be undertaken instead. Countries should make this decision based on epidemiology and resources. However, case-based surveillance is always preferable because contact-tracing and post-exposure prophylaxis are a preventive strategy that can save lives. z All laboratory-confirmed cases, their contacts and epidemiologically linked cases should be treated. Public health response The public health response should follow all the steps mentioned in the section ‘Response to suspected case of diphtheria’, in addition to the following. In a highly vaccinated population: If the first case or a small cluster of cases occurs in a highly vaccinated population, the contacts of the case/s should be monitored for the development of disease, their specimens should be collected, and they should be treated and vaccinated as described earlier. Contacts who test positive should be monitored until two subsequent cultures after treatment are negative. 17 DIPHTHERIA In a poorly vaccinated population: The same steps should be followed as in a highly vaccinated population, but the urgent initiation of a large mass immunization campaign must be considered. The vaccination strategy should be based on the epidemiology of the disease and might include adult vaccination. Door-to-door vaccination, fixed vaccination posts and in-school vaccination may be considered. Data management Reporting requirements z Designated reporting sites at all levels should report suspected, laboratory- confirmed, epidemiologically linked and clinically compatible cases at a specified frequency, such as weekly or monthly, even if there are zero cases (often referred to as ‘zero reporting’). z Diphtheria is included in the WHO/UNICEF Joint Reporting Form, which should be completed annually. z The International Health Regulations do not require the reporting of diphtheria cases. Unique ID A unique case identification number should be assigned to each suspected case, as explained earlier. Recommended Data elements z Demographic information z Reporting information z Clinical information z Hospitalization status z Outcome z Treatment type z Laboratory investigations and results z Vaccination status z Epidemiological data z Case classification These data elements have been put together in the Case Investigation Form (Annex 3). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 Data analysis z Total diphtheria cases: sum of laboratory-confirmed, epidemiologically linked and clinically compatible cases z Number of cases by final classification by month, year, and geographical area z Incidence rates by month, year, and geographical area z Number of cases by sex and age groups (suggested age groups: < 1; 1–4; 5–9; 10–14; 15–19; 20–29; 30–39; 40–49; 50–64; and ≥ 65) z In addition, cases could be analysed by year of birth to look for a cohort effect over time. In some areas, there might be too few cases for a quality data analysis. Therefore, cases from multiple years might have to be evaluated together to understand the epidemiological picture. z Overall, age-specific, and second administrative unit-specific incidence rates by month and year z Cases by number of vaccine doses received, laboratory results, and treatment type (Immunization status should be categorized by number of doses, where possible, because the designation of partial or full vaccination status cannot be compared easily across countries implementing different vaccination schedules.) z Time since last vaccine dose z Case fatality ratio z Percentage of cases who receive DAT z Percentage of cases by Corynebacterium spp. z Percentage of cases by subclassification (classic respiratory, mild/asymptomatic, cutaneous) Using data for decision-making Surveillance data should be used in conjunction with immunization coverage data and, if available, serosurvey data by geographical area to identify areas of poor programme performance (Table 4.2). 19 DIPHTHERIA Table 4.2: Examples of using data to guide decisions Indicators for surveillance performance Surveillance should be evaluated at least annually to ensure that the country is able to meet the objectives of surveillance adequately. Some surveillance performance indicators that could be used are: z Completeness of reporting z Timeliness of reporting z Adequacy of investigation z Timeliness of investigation z Specimen collection-adequacy, timeliness z Timeliness of specimen collection z Toxigenicity testing rate z Timeliness of specimen transport z Timeliness of reporting laboratory results (For more details on the indicators and method of calculation, please see Annex 5) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 21 DIPHTHERIA Annex 1: Disease epidemiology Background Diphtheria is a disease mostly of the upper respiratory tract, caused by bacteria belonging to the family Corynebacteriaceae. The commonest species of the family that causes illness in humans is Corynebacterium diphtheriae. Rarely, some species, such as C. ulcerans and C. pseudotuberculosis, can jump from animals to humans and cause illness. A toxin produced by these bacteria leads to the formation of a pseudomembrane that adheres to the tonsils and adjoining areas in the upper respiratory tract. The bacteria also damage the heart, kidneys and peripheral nerves. If the illness is left untreated, the patient may die due to complications resulting in acute respiratory obstruction, systemic toxicity, myocarditis and neurological conditions. In addition, the bacteria can affect the skin and in rare instances, involvement of the extra-respiratory mucous membranes of the genitalia, ear and conjunctiva have been reported. This vaccine-preventable disease causes outbreaks and epidemics, and conducting regular surveillance helps in the early identification of outbreaks. Surveillance also helps to monitor the disease burden and determine the impact of vaccination. This document focuses on classical respiratory diphtheria, which accounts for the majority of clinical cases, is the most severe form of clinical diphtheria and is more amenable to detection by a surveillance system. Essential epidemiology Infectious agents: These are the three biotypes of Corynebacterium diphtheriae – gravis, mitis and intermedius, when infected by a corynebacteriophage containing the gene tox. Non-toxigenic strains rarely produce local lesions. They cause less severe disease and are not vaccine-preventable. Reservoir of infection: Mostly humans and rarely animals constitute the reservoir of infection. (A wide range of animal species, including dairy cows, dogs, cats and horses, are involved in zoonotic transmission.) Mode of transmission: Corynebacterium diphtheriae is transmitted from person to person through respiratory droplets or direct contact with respiratory secretions upon contact with a person or a carrier. Rarely, it spreads through contact with articles soiled with discharge from the lesions of an infected person. Cutaneous and other mucosal disease can transmit the bacteria, particularly in tropical and underdeveloped settings. In zoonotic infections, there is no transmission from person to person. Incubation period: 1–5 days (range 1–10 days) Annexes Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 Period of communicability: In the case of respiratory illness, a person (not under treatment) is infectious to others for usually two weeks from the onset of the symptoms. This period can even exceed six weeks if the respiratory secretions contain virulent bacteria. Skin lesions are infectious for longer periods. Carrier stage: Some people infected with diphtheria develop only a mild illness, or no obvious signs and symptoms at all. Those who are unaware of their illness are known as carriers of diphtheria. They are called carriers because they can spread the infection without being sick themselves. Case fatality ratio: The case fatality ratio can be up to 10% during outbreaks, or even higher in settings where DAT is not available Vaccines Currently, for paediatric use, diphtheria toxoid is available almost exclusively in combination with tetanus toxoid (T) as DT, or with tetanus and pertussis antigens (DTP). The pertussis component is specified as whole-cell (wP) or acellular (aP) (DTwP and DTaP), depending on whether it contains killed pertussis organisms or one or more highly purified individual pertussis antigens. DTwP or DTaP may also be combined with additional vaccine antigens, such as hepatitis B surface antigen (HBsAg) and Haemophilus influenzae type b (Hib) conjugates in pentavalent vaccines, and with inactivated polio vaccine (IPV) in hexavalent vaccines. For the routine immunization of infants, these combination vaccines are licensed to be used in a three-dose series starting from 6 weeks of age, with a minimum interval of 4 weeks between doses, followed by a booster dose at the age of 15–18 months, depending on the product. Disease burden Diphtheria is endemic in some low- and middle-income countries with suboptimal vaccination coverage of the DTP primary series. In 2020, a total of 10 137 cases of diphtheria were reported to WHO. A little over half of these were from the African Region and 40% from the South-East Asia Region of WHO. Of the South-East Asian countries, India (87%), Indonesia (7%) and Myanmar (4%) accounted for 98% of all cases. After 2000, the number of reported cases in the South-East Asia Region decreased from an average of 6387 cases per year in 2001–2005 to 4016 in 2006–2010. After 2011, the average number of cases per year increased from 4676 in 2011– 23 DIPHTHERIA 2015 to 7105 in 2016–2020. In 2006–2010, the average number of cases was 4016 and in 2016–2020, it was 7105 – an increase of 77%. Recent outbreaks have been reported from Indonesia, Bangladesh (among Rohingya refugees from Myanmar), India and Nepal. Annex 2: Specimen collection Window period from onset 2 days–4 weeks Type of specimen Nasal/pharyngeal swab (pieces of pseudomembrane, if possible in hospital setting) Number 2 Transport media Amies /Stuart transport medium/silica gel Storage and transportation 2–8 °C z Universal infection prevention precautions should be taken by the person collecting the samples. z Any throat swab made of cotton, polyester or Dacron may be used. z The specimen tube must be labelled with the unique identification code, patient’s name and date of collection. z The expiry date on the tube and transport media must be checked to ensure acceptability of the material to be used for sample collection. z If the subject is a child and is to be held by the parent, the parent must be masked. The patient must sit with head against a wall or a support as patients have a tendency to pull away during this procedure. The procedure must be explained to the parents or patient. The person collecting the sample must put on gloves after the subject is situated and ready for the swab. z The inflamed area of tonsils, and posterior pharynx must be swabbed. If the membrane is visible, the swab must be rubbed beneath the membrane. z The swab must not come in contact with other parts of the buccal cavity. z A piece of the membrane may also be collected on the swab. z The throat swab sample must be placed in the silica gel sachet/Amies transport media immediately. z The same procedure must be used for the second swab. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24 z To use Amies/Stuart transport media: z the swab must be inserted into the bottom of the media immediately; z if the swab is capped, the cap of the tube must be thrown; z if the swab is uncapped, the shaft of the swab must be cut to fit into the tube and the tube capped securely. z To use a silica gel sachet: z the sachet must be cut from the top; z the granules inside the packet must be blue; if they are pink, the sachet is not fit for use; z the loaded throat swab must be placed inside the sachet as shown in Fig. A2.1; z the top of the sachet must be folded and secured with adhesive tape. Fig. A2.1: Packing throat swab in silica gel sachet for transportation to laboratory z The sample must be transported to the laboratory at 2–8 °C. 25 DIPHTHERIA Annex 3: Case investigation form Recommended data elements Remarks Demographic information Name Unique case identifier Date of birth (DOB) (dd/mm/yyyy) Age (if DOB not available) Sex M/F/O Place of residence House no: Street name: Village/town: District/province: Country: Pin/zip code: Contact Mobile: Email: Reporting information Date of notification to public health department (dd/mm/yyyy) Date of investigation (dd/mm/yyyy) Clinical Signs and symptoms Date of onset (first day with sore throat) (dd/mm/yyyy) Pharyngitis  Nasopharyngitis  Tonsillitis  Laryngitis  Adherent pseudomembrane  If yes, describe location: Fever  Systemic disease  If yes, describe: Cutaneous lesions  Other non-respiratory involvement  If yes, describe: Hospitalization status Admitted  Not admitted  If yes, date of hospital admission: (dd/mm/yyyy) Outcome Survived  Died  If yes, date: Unknown  Treatment type Antibiotic  If yes, type: Date of first dose: Antitoxin  If yes, date: Laboratory methods and results Specimen collected Yes  No  If yes, date: Whether collected before initiating antibiotics Yes  No  Type of specimen collected Nasal swab  Pharyangeal swab  Wound swab  Pseudomembrane  Others (specify)  Date on which specimen was received in laboratory (dd/mm/yyyy) Processed  Not processed  Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 26 Recommended data elements Remarks Culture results Positive  Negative  Unknown / intermediate:  If positive: C. diphtheriae  C. ulcerans  C. pseudotuberculosis  Not done  Elek test Positive  Negative  Unknown / intermediate  Not done  PCR Positive  Negative  Unknown / intermediate  Not done  Specify whether PCR targets C. diphtheriae or tox Vaccination status Type of diphtheria vaccine received DT  DTwP  Date of dose 1: Td  Tdap  Date of dose 2: DTwP  Others  Date of dose 3: Date of dose 4: Date of dose 5: Date of dose 6: Epidemiological data History of contact Contact with a laboratory- confirmed case Yes  No  If yes, write case ID: Close contact with anyone who travelled in the week before the onset of illness Yes  No  If yes, where (give details): Contact with animals Yes  No  Ingestion of unpasteurized dairy products Yes  No  Travel within 10 days prior to illness onset Yes  No  If yes, where (give details): Classification Final classification of case Laboratory- confirmed  Epidemiologically linked and clinically compatible  Discarded  27 DIPHTHERIA Annex 4: Sample contact-tracing form Demographic information of case Name Unique case identifier Date of birth (DOB) (dd/mm/yyyy) Age (if DOB not available) Sex M/F/U Place of residence House no: Street name: Village/town: District /province: Country: Pin/zip code: Contact Mobile: Email: Contact information Availability of contacts Yes  No  If none, no further action needed If yes, follow up actions conducted Demographic information of contact Name Date of birth (DOB) (dd/mm/yyyy) Age (if DOB not available) Sex: Male  Female  Others  Place of residence House no: Street name: Village/town: District /province: Contact Mobile: Email: Epidemiological data of contact History of contact Contact of laboratory- confirmed case Yes  No  If yes, write case ID: Close contact with anyone who travelled in the week before the onset of illness Yes  No  If yes, where (give details): Contact with animals Yes  No  Ingestion of unpasteurized dairy products Yes  No  Travel within 10 days prior to illness onset Yes  No  If yes, where (give details): Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 28 Work up of contacts Monitor for 10 days Look for signs and symptoms Pharyngitis  Nasopharyngitis  Tonsillitis  Laryngitis  Adherent pseudomembrane  If yes, describe location: Fever  Systemic disease  If yes, describe Cutaneous lesions  Other nonrespiratory involvement  If yes, describe Outcome of monitoring Meets suspected case definition Yes  No  If yes, classify as case, hospitalize if needed Look for contacts Laboratory tests and results Specimen collected Yes  No  If yes, date: Whether collected before antibiotic provision Yes  No  Type of specimen collected Nasal swab  Pharyngeal swab  Pseudomembrane  Others (specify)  Date when specimen was received in laboratory (dd/mm/yyyy) Processed  Not processed  Culture Positive  Negative  Unknown / intermediate  Not done  Elek test Positive  Negative  Unknown / intermediate  Not done  PCR Positive  Negative  Unknown / intermediate  Test results Positive  Negative  Unknown / intermediate  If positive: categorize as a laboratory – confirmed case and identify contacts If negative: discontinue antibiotics; no further action needed 29 DIPHTHERIA Vaccination status Vaccination status Fully vaccinated  Under- vaccinated  Unvaccinated  If under vaccinated, provide complete series If unvaccinated, provide full course Date of dose 1: Date of dose 2: Date of dose 3: Treatment Antibiotics Penicillin G benzathine  Erythromycin  Dose Duration Classification Final classification Laboratory- confirmed  Epidemiologically linked and clinically compatible  Discarded  Subclassification Classic respiratory  Mild/ asymptomatic  Cutaneous  Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 30 Annex 5: Recommended indicators of surveillance performance Surveillance attributes Indicator Target How to calculate Comments C om pl et en es s of r ep or tin g Proportion of designated sites reporting data, even in the absence of cases (zero reporting) >80% (Total number of reports received/ total number of reporting sites) x 100 (for given time period) Ti m el in es s of re po rt in g Proportion of surveillance units reporting to the national level on time, even in the absence of cases >80% (Number of surveillance units reporting by the deadline / total number of surveillance units) x 100 At each level, reports should be received on or before the requested date. A de qu ac y of in ve st ig at io n Proportion of suspected cases that have been adequately investigated >80% (Number of suspected cases which were adequately investigated / number of suspected cases) x 100 Adequate investigation includes completing a case investigation form, collecting nasal and pharyngeal specimens and line listing close contacts. If any of these is not conducted, the investigation is considered inadequate. Ti m el in es s of in ve st ig at io n Proportion of suspected cases for which investigation was initiated within 48 hours of notification >80% (Number of suspected cases for which investigation was initiated within 48 hours of notification / number of suspected cases) x 100 31 DIPHTHERIA Surveillance attributes Indicator Target How to calculate Comments Sp ec im en c ol le ct io n Proportion of suspected cases with two specimens collected (pharyngeal and nasal) >80% (Number of suspected cases with 2 specimens collected / number of suspected cases) x 100 During outbreak investigations, when epidemiological linkage increases, epidemiologically linked cases should be removed from the denominator. Ti m el in es s of s pe ci m en co lle ct io n Proportion of suspected cases with specimens taken before antibiotic administration >80% (Number of suspected cases with specimen collected before antibiotics/ number of suspected cases with specimen collected) x 100 To xi ge ni ci ty te st in g ra te Proportion of specimens tested for toxigenicity by Elek testing >80% (Number of specimens tested for toxigenicity by Elek testing / number of specimens received) x 100 Indicator applies only to public laboratories. Ti m el in es s of s pe ci m en tr an sp or t Proportion of specimens received by the laboratory within 2 days of collection >80% (Number of specimens received by laboratory within 2 days of collection / number of specimens) x 100 Indicator applies only to public laboratories. Ti m el in es s of r ep or tin g la bo ra to ry r es ul ts Proportion of specimens tested by culture with results reported within 3 days of receipt of specimen >80% (Number of specimens tested by culture with results reported within 3 days of specimen receipt / number of specimens tested by culture) x 100 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 32 Further reading 1. World Health Organization. Diphtheria: Surveillance standards for vaccine- preventable diseases, 2nd ed. World Health Organization; 2018 (https://www.who. int/publications/m/item/vaccine-preventable-diseases-surveillance-standards- diphtheria, accessed 14 July 2022). 2. World Health Organization. Regional Office for South-East Asia. Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region. World Health Organization. Regional Office for South-East Asia; 2017 (https://apps.who.int/iris/ handle/10665/277459, accessed 14 July 2022). License: CCVY-NC-SA3.0IGO. 3. Faulkner A, Bozio CH, Acosta A, Tiwari TSP. Chapter 1: Diphtheria. In: Roush SW, Baldy LM, Hall MAK, eds. Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases: 1999 (https://www.cdc.gov/vaccines/pubs/ surv-manual/chpt01-dip.html, accessed 14 July 2022). 4. Truelove SA, Keegan LT, Moss WJ, Chaisson LH, Macher E, Azman AS et al. Clinical and epidemiological aspects of diphtheria: a systematic review and pooled analysis. Clin Infect Dis. 2020; 71(1): 89–97. doi:10.1093/cid/ciz808. 5. Clarke KEN, MacNeil A, Hadler S, Scott C, Tiwari TSP, Cherian T. Global Epidemiology of Diphtheria, 2000–20171. Emerg Infect Dis. 2019; 25(10): 1834–42. doi:10.3201/ eid2510.190271. 6. Strauss RA, Herrera-Leon L, Guillén AC, Castro JS, Lorenz E, Carvajal A et al. Molecular and epidemiologic characterization of the diphtheria outbreak in Venezuela. Sci Rep. 2021;11(1):6378. doi:10.1038/s41598-021-85957-1. 7. Vitek CR, Wharton M. Diphtheria in the former Soviet Union: reemergence of a pandemic disease. Emerg Infect Dis. 1998:4(4):539–50. doi: 10.3201/eid0404.980404. 8. Sein C, Tiwari T, MacNeil A, Wannemuehler K, Soulaphy C, Souliphone P et al. Diphtheria outbreak in Lao People’s Democratic Republic, 2012–2013. Vaccine. 2016: 34(36):4321–6. doi:10.1016/j.vaccine.2016.06.074. 9. Rahman MR, Islam K. Massive diphtheria outbreak among Rohingya refugees: lessons learnt. J Travel Med. 2019;26(1). doi:10.1093/jtm/tay122. 10. Irish College of General Practitioners. IHR alert: Extensive Outbreak of Diphtheria in Venezuela. Icgp:2016 (https://www.icgp.ie/go/library/public_health_ alerts/4745104B-0F5C-F480-148C74944F931F3D.html, accessed 14 July 2022). 33 DIPHTHERIA 11. Dureab F, Al-Sakkaf M, Ismael O, Kuunibe N, Krisam J, Muller O et al. Diphtheria outbreak in Yemen: the impact of conflict on a fragile health system. Confl Health. 2019;13:19. doi:10.1186/s13031-019-0204-2. 12. Badell E, Alharazi A, Criscuolo A, Almoayed KAA, Lefrancq N, Bouchez V et al. NCPHL diphtheria outbreak group. Ongoing diphtheria outbreak in Yemen: a cross- sectional and genomic epidemiology study. Lancet Microbe. 2021;2(8):e386–e396. doi:10.1016/S2666-5247(21)00094-X. 13. Arguni E, Karyanti MR, Satari HI, Hadinegoro SR. Diphtheria outbreak in Jakarta and Tangerang, Indonesia: epidemiological and clinical predictor factors for death. PLoS One. 2021;16(2): e0246301. doi:10.1371/journal.pone.0246301. 14. Sharma, NC, Efstratiou A, Mokrousov I, Mutraja A, Das B, Ramamurthy T. Diphtheria. Nat Rev Dis Primers. 2019:5(1):81. doi:10.1038/s41572-019-0131-y. 15. Will RC, Ramamurthy T, Sharma NC, Veeraraghavan B, Sangal L, Haldar P et al. Spatiotemporal persistence of multiple, diverse clades and toxins of Corynebacterium diphtheriae. Nat Commun. 2021:12(1):1500. doi:10.1038/s41467-021-21870-5. 16. Polonsky JA, Ivey M, Mazhar MKA, Rahman Z, le Polain de Waroux O, Karo B et al. Epidemiological, clinical, and public health response characteristics of a large outbreak of diphtheria among the Rohingya population in Cox’s Bazar, Bangladesh, 2017 to 2019: A retrospective study. PLoS Med. 2021;18(4):e1003587. doi:10.1371/ journal.pmed.1003587. 17. Nicholson L, Adkins E, Karyanti MR, Ong-Lim A, Shenoy B, Huoi C et al. What is the true burden of diphtheria, tetanus, pertussis and poliovirus in children aged 3–18 years in Asia? A systematic literature review. Int J Infect Dis. 2022;117:116–29. doi:10.1016/j.ijid.2022.01.045. 18. Zendri F, Isgren CM, Sinovich M, Richards-Rios P, Hopkins KL, Russell K et al. Case Report: Toxigenic Corynebacterium ulcerans Diphtheria-Like Infection in a Horse in the United Kingdom. Front Vet Sci. 2021;8:650238. doi:10.3389/fvets.2021.650238. 19. World Health Organization. Diphtheria vaccine: WHO position paper – August 2017. Weekly Epidemiological Record. 2017; 92(31):417–35. World Health Organization: 2017. (https://apps.who.int/iris/handle/10665/258683, accessed 14 July 2022). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 34 CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region MODULE-5 PERTUSSIS September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Pertussis) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO CONTENTS Introduction 5 Objectives 5 Case detection 5 Definition of suspected case 5 Description of terms 6 Other associated signs and symptoms 6 Date of onset 6 Response to suspected case 6 Investigation of suspected case 7 Case investigation form 7 Unique ID 7 Specimen collection 8 Laboratory testing 9 Culture 9 Polymerase chain reaction 10 Serological testing 10 Classification of cases 11 Laboratory-confirmed case 11 Epidemiologically linked case 11 Clinically compatible case 11 Discarded case 11 Contact tracing and management 12 Early treatment and post-exposure prophylaxis 12 Vaccination 13 Active case search 14 Clinical management 15 Antibiotic treatment 15 Isolation 15 Vaccination 15 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Outbreak 15 Definition 15 Interpretation of an outbreak 16 Modifications needed in surveillance 16 Data management 17 Reporting requirements 17 Unique ID 17 Recommended data elements 18 Data analysis 18 Aggregated data 19 Case-based data 19 Indicators for surveillance performance 21 Public health response 21 Annex 1: Disease epidemiology 23 Background 23 Essential epidemiology 23 Vaccines 25 Burden of pertussis 25 Annex 2: Specimen collection 27 Nasopharyngeal swab sample (NPS) 27 Nasopharyngeal aspirate (NPA) 28 Serum sample 28 NOTES 29 Annex 3: Case investigation form 30 Annex 4: Recommended surveillance performance indicators 32 Further reading 34 5PERTUSSIS Pertussis surveillance Introduction The persistence of a high level of transmission of pertussis in several countries indicates that the immunity acquired through the acellular pertussis vaccine has waned and there is a need for additional booster doses for better disease control. Low-income countries (LIC) using the whole-cell pertussis vaccine lack data on the epidemiology of pertussis and this gap must be filled to enable the formulation of policy recommendations on the need for booster doses and the number of these required. Surveillance for pertussis will provide important information on the status of its epidemiology and control. Objectives The objectives of surveillance are to: z monitor the disease burden and the impact of the pertussis vaccination programme, with a special focus on understanding morbidity and mortality among children < 5 years of age; z generate data for deciding on the vaccine schedule and strategy for vaccine delivery to optimize the impact of vaccination; and z guide the public health response to outbreaks of pertussis. Case detection Definition of suspected case A suspected case is a person of any age with a cough lasting ≥ 2 weeks, or of any duration in an infant or any person in an outbreak setting, without a more likely diagnosis and with at least one of the following symptoms, based on observation or parental report: z paroxysms (fits) of coughing; z inspiratory whooping; z post-tussive vomiting, or vomiting without other apparent cause; and z apnoea (only in those < 1 year of age). A physician may suspect pertussis in a patient with cough of any duration. Pertussis in immunized or previously infected individuals can present without the classic signs and, therefore, might not be captured by the above case definition. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 Description of terms Paroxysms of cough: The cough is frequent and spasmodic, with repetitive bursts of 5–10 coughs often within a single expiration. A paroxysm may be marked by bulging eyes, a protruding tongue and cyanosis, and a visible distension of the neck vein (jugular vein). The frequency of paroxysmal episodes varies from several per hour to 5–10 per day. The episodes are often worse at night and interfere with sleep. Whoop: This is the sound produced due to rapid inspiration against the closed glottis at the end of the cough paroxysm. Post-tussive vomiting: This occurs immediately after coughing and occasionally, a mucous plug is expelled at the end of an episode. Without other apparent causes: Other causes of chronic cough, such as tuberculosis, asthmatic episodes and chronic bronchitis, must be excluded. Other associated signs and symptoms The other signs and symptoms frequently associated with pertussis are the clinical features caused by increased intrathoracic pressure generated by paroxysms of cough. These are subconjunctival and intracranial haemorrhages, rectal prolapse, hernias, pneumothorax, petechiae and fracture of the ribs. Date of onset The date of onset of pertussis should be considered as the date of onset of cough. Response to suspected case Within 24 hours: The clinician who first sees a suspected patient should notify the public health authorities within 24 hours. Within 48 hours of report of suspected case: The public health authorities (usually a trained member of the health-care staff) should take the responsibility of investigating the case, preferably within 48 hours of the time when the case was reported. The process of investigation should include the following. z A case investigation form should be filled for every suspected case (see Annex 3). z Try to collect two nasopharyngeal swabs before initiating any treatment and treatment should not be delayed while waiting for the laboratory results. 7PERTUSSIS z The person should undergo laboratory tests. z The case should be confirmed and classified. There is no need to fill the CIF for each contact – it is not practical. The close contacts of the case should be identified and case investigation form should be filled if have symptoms of pertussis. Treatment should be given to the symptomatic contacts with symptoms of pertussis. Treatment should be initiated for the symptomatic cases. z An active case search should be conducted. Investigation of suspected case Suspected cases should be investigated by the trained health staff/clinician designated by the public health authority. Case investigation form A case investigation form should be filled for every suspected case within 48 hours of reporting. (See Annex 3 for a sample case investigation form.) Unique ID A unique case identification number (UID) should be assigned to each suspected case. The case number should begin with one or more three-letter combinations designating the geographical location, followed by the year and the serial number of the case. All communications and forms related to the case should cite the UID. For example: PTS – code for suspected pertussis IND – country code UP – state code BLS – district code 22 – year of onset 001 – serial number of case in the district The UID for first case of 2022 would be PTS IND UP BLS 22 001. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Specimen collection Nasopharyngeal swabs are collected for cases identified within four weeks of the onset of cough. z Ideally, two swabs should be collected: z one for culture; and z one for polymerase chain reaction (PCR). CAUTION: Throat and anterior nasal swabs must not be collected. z Specimens should be obtained using sterile polyester, rayon, or nylon flocked swabs. CAUTION: Cotton swabs must not be used. z Culture z Specimens for culture should be plated directly onto selective culture medium or placed in half-strength Regan–Lowe transport medium. z Regan–Lowe agar or freshly prepared Bordet–Gengou medium is generally used for culture; half-strength Regan–Lowe is generally used as the transport medium. z Specimens should be transported at room temperature and plated in the laboratory within 24 hours. CAUTION: Amies or universal transport media must not be used. Amies transport media with charcoal can be used if Regan-Lowe agar is not available in the country and in this case sample will have to transported at 2-8 degree Celsius. z PCR testing specimens z These should be placed in a sterile tube or universal transport medium for transport to the laboratory. z In case there is only one swab for both the culture and PCR, it should be placed in Regan–Lowe transport medium before being sent to the laboratory. z As an alternative to nasopharyngeal swabs, saline nasopharyngeal aspirate may be collected from suspected cases. Surveillance personnel and other health-care practitioners who are asked to obtain these specimens should receive training and supervision from persons experienced in the collection of nasopharyngeal specimens. Serology is conducted for cases identified 4–12 weeks after the onset of cough. A serum sample can be collected for IgG anti-pertussis toxin antibody testing. 9PERTUSSIS Serology has the following advantages: z It can help in the diagnosis of pertussis in adolescent and adult cases with at least two weeks of cough. z It is useful for confirming diagnoses during outbreaks, when diagnoses are often retrospective and the timing for culture or PCR is not ideal. CAUTION: Do not use serology in children ≤ 10 years of age due to lack of sensitivity, or in patients vaccinated within the preceding one year due to the persistence of IgG antibodies. Annex 2 presents the detailed methodology of specimen collection. Laboratory testing Culture z The isolation of B. pertussis by bacterial culture is the gold standard for confirming the diagnosis of pertussis. z On an average, B. pertussis takes 3–7 days to grow in culture, but it can take up to 10 days. z Culture of the organism is also necessary for testing antimicrobial susceptibility and for molecular typing. z Although bacterial culture is specific for diagnosis, it is relatively insensitive (< 60%). z Positive rates have been found to be the highest among infants. z Success in isolating the organism is less likely if: z the patient has received prior antibiotic therapy that has been effective against B. pertussis; z the collection of the specimen has been delayed beyond the first two weeks of illness; z transport of the specimen to the laboratory is delayed; or z the patient has been vaccinated. z Culture is not optimally sensitive in adolescents and adults. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 Polymerase chain reaction z PCR is more sensitive and rapid than culture. z It can give false-negative or false-positive results. z Cross-contamination of specimens during the collection and testing of specimens can give rise to false-positive results. z False-negative results increase with an increase in the time that has elapsed since the onset of cough (> 4 weeks after onset) or the initiation of antibiotic treatment (> 5 days). z Cross-reaction may occur with other Bordetella species as no single gene target is specific for B. pertussis. z A combination of several PCR targets is needed to differentiate between Bordetella species There are no standardized PCR assays for pertussis across laboratories. z Assay procedures can vary across laboratories. z The sensitivity and specificity of the assay can vary greatly between laboratories. Serological testing z IgG is present in the serum 4–12 weeks after the onset of cough, so the assay should be conducted ≥ 4 weeks from the onset of cough. z Research has shown that measuring the titres of IgG antibody to pertussis toxin is the most specific and sensitive assay, but it needs to be calibrated to the reference standard for single-time point assays, such as the WHO International Standard. Serology based on other pertussis antigens should be avoided. z IgM is not used to diagnose pertussis cases due to inadequate sensitivity and specificity (unlike with other diseases). z The results are unreliable in infants owing to the presence of maternal antibodies. z PCR is insensitive in children ≤ 10 years of age. z Due to the presence of vaccine-induced IgG, serology is inadvisable for persons of all ages if they have received the pertussis vaccination within the past year. z IgG levels sometimes remain elevated for more than a year after infection or vaccination, leading to potential false-positives. z Culture and PCR have higher specificity in the detection of acute pertussis infection and are preferred over serology. 11 PERTUSSIS Classification of cases A case of pertussis may be confirmed by laboratory testing or epidemiological linkage. Laboratory-confirmed case A laboratory-confirmed case is a person who meets the suspected case definition with laboratory confirmation, either through the isolation of B. pertussis OR the detection of genomic sequences of B. pertussis by means of PCR, if PCR meets the performance criteria. Alternatively, the person must be ≥ 11 years of age and must have elevated IgG antibodies to pertussis toxin one year or longer after the last vaccine dose. Epidemiologically linked case An epidemiologically linked case is a person meeting the suspected case definition with close contact to a laboratory-confirmed case (or another epidemiologically linked case in an outbreak setting) in the three weeks prior to onset of cough. Close contact is defined as having face-to-face exposure to a case, which includes household or family contact, people having stayed overnight in the same room with a case, and people having direct contact with respiratory, oral or nasal secretions with a laboratory-confirmed case. Clinically compatible case A suspected case who meets the case definition of pertussis but either sample could not be collected, or lab results are negative for pertussis. Discarded case A suspected case who does not meet the case definition of pertussis. Figure 5.1: Final classification of case Laboratory tests done No Laboratory tests Contact Laboratory Confirmed Contact Epidemiologically linked Epidemiologically linked WITHIN 4 WEEKS OF ONSETDURING 4-12 WEEKS OF ONSET NPS/NPA BLOOD CULTURE PCR Laboratory Confirmed +VE2 +VE3 BLOOD SEROLOGY -VE +VE1 ᴖᴖ 1 - 2 Growth of B pertussis 3 Genome sequence of B pertussis Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 Contact tracing and management Definition of close contact: A close contact is defined as someone who has had face- to-face exposure to a case. This includes household or family, people who have stayed overnight in the same room as a laboratory-confirmed case, and those who have had direct contact with the patient’s respiratory, oral or nasal secretions. Who to track During contact tracing, the focus should be on: z high-risk contacts (at a minimum) z all close contacts (ideally). High-risk contacts are those who have been exposed to a suspected case and: z are themselves at increased risk of complications from pertussis; or z are at risk of transmitting the infection to other persons at risk of severe pertussis disease. A few examples of high-risk contacts are: z infants; z pregnant women in the third trimester of pregnancy; z health-care workers working with infants or pregnant women; and z persons of any age working in or sharing a house with infants. Testing of contacts Only contacts with symptoms consistent with pertussis infection should be tested. Asymptomatic contacts of confirmed cases should not be tested. Testing of contacts should not be a criterion for making decisions on post-exposure prophylaxis. Early treatment and post-exposure prophylaxis z The widespread use of post-exposure antimicrobial prophylaxis (PEP) among contacts need not be an effective way of using limited public health resources. However, if resources permit, the administration of post-exposure therapy to an asymptomatic contact within 21 days of the onset of cough in the index patient can potentially prevent symptomatic infection. z When pertussis is strongly suspected, steps should be initiated to identify close contacts and provide them with preventative treatment without waiting for laboratory confirmation. z A course of antibiotics effective against pertussis should be administered to all close contacts of pertussis cases, regardless of age and vaccination status 13 PERTUSSIS (Table 5.1). While antibiotics may prevent pertussis disease if given prior to the onset of symptoms, there are no data to indicate that the widespread use of PEP among contacts effectively controls or limits the scope of pertussis outbreaks. z Therefore, efforts to provide antibiotic prophylaxis should be focused mainly on women in the third trimester of pregnancy, infants < 1 year of age and their close contacts. Preventative treatment of these groups should not be delayed because pertussis can be severe and life-threatening. z In addition to using PEP for the early treatment of young infants, some countries have chosen to use it for asymptomatic high-risk contacts even when symptoms are not present. Vaccination z Undervaccinated persons who have had contact with pertussis cases should receive pertussis-containing vaccine according to the recommended immunization schedule. z Vaccination might not prevent illness in a person who has already been infected with B. pertussis. z Immunity acquired to pertussis from disease or the vaccine wanes over time and persons who have been vaccinated or had prior infection can become infected. New data on the duration of protection from acellular pertussis vaccines suggest that immunity wanes significantly within 2–3 years of vaccination, particularly in persons who never received any doses of whole cell vaccine. Table 5.1: Recommended treatment and post-exposure prophylaxis for close contacts, by age group Age group Azithromycin Erythromycin* Clarithromycin Alternate agent: TMP-SMX† <1 month Recommended agent for infants <1 month of age; 10 mg/kg per day in a single dose x 5 days§ Not recommended Not recommended Contraindicated in infants <2 months of age (risk for kernicterus). 1–5 months 10 mg/kg per day in a single dose x 5 days 40–50 mg/kg per day in 4 divided doses x 14 days 15 mg/kg per day in 2 divided doses x 7 days Contraindicated in infants <2 months of age. For infants aged >2 months of age, TMP 8 mg/kg per day: SMX 40 mg/kg per day in 2 divided doses x 14 days Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 Age group Azithromycin Erythromycin* Clarithromycin Alternate agent: TMP-SMX† Infants aged >6 months and children 10 mg/kg as a single dose on Day 1 (maximum 500 mg); then 5 mg/kg per day as a single dose on days 2–5 (maxi- mum 250 mg/day) 40 mg/kg per day in 4 divided doses for 7–14 days (maximum 1–2 g per day) See above (maxi- mum 1g/day) See above Adolescents and adults 500 mg as a single dose on Day 1 then 250 mg as a single dose on days 2–5 2g/day in 4 divided doses x 14 days 1g/day in 2 divided doses x 7 days TMP 320 mg/day, SMX 1600mg/ day in 2 divided doses x 14 days *Some experts prefer erythromycin estolate over erythromycin stearate or ethylsuccinate because it achieves higher serum levels with equal doses. †Trimethoprim-sulfamethoxazole (TMP-SMX) can be used as an alternative agent to macrolides in patients >2 months of age and for those who are not pregnant or nursing and are allergic to, cannot tolerate or are infected with a rare macrolide-resistant strain of Bordetella pertussis. §Preferred macrolide for this age because of risk of idiopathic hypertrophic pyloric stenosis associated with erythromycin.. Active case search It is very important to launch an active case search in response to the identification of pertussis cases in the community, as there is a probability of finding additional cases among the contacts of pertussis cases. Not only should the active case search be conducted in the household and neighborhood, but the workplace or school contacts of the case should also be actively assessed for the illness. A thorough active case search in the community will identify any clustering of cases and allow for timely intervention. An assessment of the immunization status of the community should also be conducted during an active case search in the community. Attempts should be made to conduct the search soon after the identification of a suspected case, preferably within 48 hours of the confirmation of the case. 15 PERTUSSIS Clinical management Antibiotic treatment z Macrolide antibiotics, such as erythromycin, are effective. z When given during the incubation period or early catarrhal stage (though it is difficult to make a diagnosis at this point), they are the most effective in preventing or mitigating clinical pertussis. z When given during the paroxysmal phase of the disease, antimicrobial drugs do not change the clinical course, but may eliminate bacteria from the nasopharynx and thus reduce transmission. Isolation z Suspected cases should avoid contact with young children and women in late pregnancy, especially the unimmunized, until they have taken antibiotics for at least five days. z Ideally, untreated cases should avoid contact with high-risk individuals for the entire infectious period. z Hospitalized patients should be placed under respiratory isolation, or at a minimum, they should take precautions related to contact and respiratory droplets (such as wearing a mask when around other patients). Vaccination Natural infection does not confer long-lasting protection against pertussis. Therefore, during convalescence: z patients who have clinical pertussis but have not completed a full primary vaccine series should receive vaccine to complete the series; or z should receive an age-appropriate booster dose, if indicated. Outbreak Definition z An outbreak is an increase in the number of cases or incidence of the disease over the reported baseline in a specific geographical area. This increase is difficult to define exactly and involves some level of local judgment. z Outbreaks can occur in facilities such as schools and hospitals, or in larger geographical areas, e.g. a district. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 z Pertussis outbreaks can be difficult to identify and manage, given the regular periodicity of pertussis (increased rates every 3–5 years) and the existence of other respiratory pathogens causing similar symptoms. z To respond appropriately, it is important to confirm that B. pertussis is circulating in the setting of the outbreak and to determine whether other pathogens are contributing to the outbreak. z Epidemiological investigations of outbreaks can provide useful information on the effectiveness of vaccines and the epidemiology of pertussis. This includes information on the distribution of cases and the case fatality ratio by age group. Interpretation of an outbreak z An outbreak of high severity among infants suggests gaps in the coverage of immunization. z An outbreak in older age groups might signal changing epidemiology (due to waning immunity) or changes in surveillance itself. Modifications needed in surveillance For countries conducting event-based or aggregate surveillance: z Once a cluster of cases has been identified, a case investigation form should be used to investigate cases (individual sporadic cases are not investigated or laboratory-confirmed in an aggregate surveillance system). z In small outbreaks, surveillance should move to line listing individual cases. z In larger outbreaks, information should be collected on a subset of cases to help understand the evolving epidemiology of the outbreak. z Investigations of individual cases and their contacts should aid the implementation of preventive measures to control the outbreak. z If resources are limited, specimens need be collected only from a subset of cases (e.g. the first 5–10 cases) to confirm the outbreak. After this point, epidemiological linking should be conducted to save resources. z After two or three incubation periods (approximately 1–2 months), the process might need to be repeated to confirm whether it is still a pertussis outbreak. For countries conducting case-based surveillance in sentinel sites: z Surveillance can be expanded to encompass more reporting sites or include a wider age range to better understand the epidemiology of the outbreak. 17 PERTUSSIS z Consistency is required for monitoring trends among the sentinel sites over time. z A country may choose to rely more on epidemiologically linking as many cases as possible to limit the burden on the laboratory. Data management Reporting requirements z All reporting sites should immediately notify a suspected case of pertussis to the health authority concerned through any mode of communication available. z The minimum information required to notify a case consists of patient identifiers and contact details. z A mechanism should be established for sending weekly reports to the health authority with basic information on pertussis cases. z If no cases are seen in a week, a weekly report has to be sent nevertheless, specifying that “zero” cases were seen. This is called “zero reporting” or “nil reporting”. Nil reporting establishes the fact that the surveillance system is operational even if no disease is identified. Unique ID A unique identification number (UID) should be assigned to each suspected case. The case number should begin with one or more three-letter combinations to designate the geographical location, followed by the year and the serial number of the case. All communications and forms related to the case should cite the UID. For example: PTS – code for suspected pertussis IND – country code UP – province/ state code BLS – district code 2019 – year of onset 001 – serial number of case in the province Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 Recommended data elements z Demographic information z Reporting information z Clinical information z Hospitalization status z Outcome z Type of treatment z Laboratory investigations and results z Vaccination status z Epidemiological data z Case classification These data elements form part of the case investigation form (see Annex 3). Data analysis Time analysis: Changes in the incidence of the disease can be detected by time analysis. Critical to the analysis is the date of the onset of the symptoms. Basic time analysis can be conducted in the following ways: z comparing the number of cases in the current week with that in the preceding 4 weeks; z comparing the number of cases during the current period (month, quarter) with that reported during the same period in previous years; and z comparing the occurrence of the disease by year to analyse long-term (secular) trends in the disease. Clustering of cases over the specified period (weeks, months) should immediately raise an alarm. The absence of cases during a high-transmission period should trigger an appropriate response in terms of verifying the information. Place analysis: The place where the patient was residing at the time of the onset of the symptoms and during the incubation period must be determined for all cases. It is necessary to simultaneously analyse the occurrence of the disease by time and place. Place analysis is best displayed by plotting the location of cases on a local map over a specified period of time. Any spatial clustering of cases or silent areas will 19 PERTUSSIS immediately become visible and thus help to guide interventions. The repeated occurrence of cases in a particular geographical area over many years helps in the identification of areas with a high risk of disease transmission. Person analysis: Analysing surveillance data by characteristics of affected persons is also helpful. Age, sex and religion are the most basic variables. It is also important to look into other variables, such as vaccination status, hospitalization and associated risk factors for the disease (recent travel, exposure in school or the workplace), to plan targeted interventions. The analysis can take into account just confirmed cases (laboratory-confirmed and epidemiologically linked) or all cases (laboratory-confirmed, epidemiologically linked and possible cases). When interpreting the data, consideration may be given to national or subnational coverage, schedule of vaccination and types of pertussis-containing vaccine. Aggregated data The aggregated data consist of: z the number of cases and incidence rate (where possible) by month, year, age group and geographical area (suggested age groupings depending on local priorities: < 6 months, 6–11 months, 1–4 years, ≥ 5 years); z proportion of cases by number of doses received by district and age group; and z number of cases by pertussis immunization status (0, 1–2, 3+ doses), if available. Case-based data In addition to the data listed under aggregated data, these consist of: z crude and age-specific case fatality ratio overall and by district; z age-specific, sex-specific and district-specific number of cases, or incidence rates by month and year (if able to determine population denominator); z proportion of cases receiving antibiotics after diagnosis; and z proportion of cases by final classification (laboratory-confirmed and epidemiologically linked reported separately). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Table 5.2: Using data for decision-making # Data Decision 1 Monitor disease burden with incidence rates to assess impact of the immunization system and policy (for example, immunization schedule or type of pertussis vaccine in use). 2 Monitor disease burden with incidence rates by geographical area to identify high-risk areas or those with poor immunization system performance (so that corrective actions can be taken). 3 Monitor age distribution of cases (age- specific attack rates) to identify age groups at risk to identify age groups at risk as this could influence the immunization policy 4 Identify outbreaks and conduct investigations to determine the cause and understand the epidemiology of pertussis. 5 Monitor case fatality ratios if they are high, determine the causes (poor/late diagnosis, poor case management, poor/late access to care, underlying conditions). 21 PERTUSSIS Indicators for surveillance performance Regular monitoring of the indicators of surveillance performance might help to identify specific areas of the surveillance and reporting system that need improvement. If the indicators for performance are not being achieved, the reasons should be explored and corrected. Some indicators of surveillance performance that may be monitored are suggested in Annex 4. Public health response Immunization During an outbreak, vaccination efforts should focus on the un- or under-immunized. At the same time, routine immunization should be strengthened in the area of the outbreak. Vaccination campaigns are not a part of the pertussis outbreak response. Post-exposure prophylaxis In some countries, PEP with macrolides is provided to asymptomatic household contacts or other close contacts of pertussis cases who are at the highest risk of developing clinical illness; those at a high risk of developing severe pertussis, such as infants; and persons who will have close contact with those at a high risk of developing severe pertussis. While antibiotics may prevent pertussis disease if given prior to the onset of symptoms, there are no data to indicate that widespread use of PEP among contacts effectively controls or limits the scope of community-wide pertussis outbreaks. The use of PEP may be appropriate in limited closed settings, when the number of identified cases is small and when there is no ongoing community-wide outbreak. However, multiple rounds of antibiotics are not recommended in the case of continued transmission of pertussis. Active case search / contact tracing Given the increasing incidence and widespread community transmission of pertussis, extensive contact tracing and widespread use of PEP among contacts may not be the most effective way of utilizing limited public health resources. Active screening for symptomatic patients with suspected pertussis should be conducted during outbreaks in settings such as schools, day-care centres and hospitals. Active screening for suspected cases potentially reduces exposure to more persons, especially vulnerable infants. The management of contacts has been dealt with in the preceding section. The focus should be on the early treatment of infants who are < 6 months of age and have signs of a respiratory illness. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 Other measures z All public and private health facilities in the affected area and the areas surrounding it must be notified and asked to have a high index of suspicion for pertussis cases. z It is important to conduct health promotion activities and distribute education materials to provide basic information on pertussis and its prevention, particularly vaccination. 23 PERTUSSIS Annex 1: Disease epidemiology Background Pertussis, commonly known as whooping cough, is an acute bacterial disease involving the respiratory tract, caused by Bordetella pertussis. The disease is common among children all over the world. Paroxysms are characterized by repeated violent coughs; each series of paroxysms has many coughs without intervention breathing and may be followed by a characteristic crowing or high-pitched inspiratory whoop. Paroxysms usually end with the expulsion of mucous, often followed by vomiting. Infants < 6 months of age do not have typical paroxysms or the whoop. Pertussis affects mostly infants and children, but can also affect teenagers and adults. Essential epidemiology Infectious agent: Bordetella pertussis Reservoir of infection: Humans Mode of transmission: The disease spreads primarily through direct contact with discharge from the respiratory mucous membrane of an infected person, typically spread through large respiratory droplets generated by coughing or sneezing. Incubation period: 9–10 days (range 6–20 days) Natural history of the disease: Pertussis is not usually associated with fever. Classically, the disease has the following three stages: z Catarrhal stage: The disease has an insidious onset with an irritating cough. The cough gradually becomes paroxysmal, usually between 1 and 2 weeks, and lasts for 1–2 months or longer. z Paroxysmal stage: The cough becomes more frequent and there are repeated violent bursts of 5–10 coughs, often within a single expiration. Visible distension of the neck vein, bulging of the eyes, protrusion of the tongue and cyanosis may occur during a paroxysm. The frequency of paroxysmal episodes varies from several per hour to 5–10 per day. Episodes are often worse at night and interfere with sleep. z There are repeated bouts of cough without intervening inhalation. These may be followed by a characteristic crowing or high-pitched inspiratory Annexes Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24 whooping sound, produced by rapid inspiration against the closed glottis at the end of the paroxysm. Infants < 6 months of age and adults do not have the typical whoop or cough paroxysm. z Paroxysms frequently end with vomiting, occasionally with the expulsion of clear, tenacious mucous. z There are certain clinical features frequently associated with pertussis cases that result from the increased intrathoracic pressure generated by the paroxysms. These are: z subconjunctival and intracranial haemorrhages z rectal prolapse z hernias z pneumothorax z petechiae z rib fracture. z Convalescent stage: The convalescent stage is marked by less frequent and less severe coughing. The presentation of the disease can vary with age and the history of previous exposure or vaccination. For example: z Young infants may have only apnoea and no other symptoms. z Adults and adolescents with some immunity may have only mild symptoms or have the characteristic prolonged paroxysmal cough. z Asymptomatic or mildly symptomatic infections are common, especially among older previously vaccinated persons. Complications: The following are the complications of pertussis. z Commonest: Pneumonia is a complication in all age groups. z Rare: Seizures and encephalopathy generally occur only among very young infants. z Infrequent: Death is the most likely to occur among unvaccinated infants. Period of communicability: This period lasts from the early catarrhal stage to three weeks after the onset of cough in the case of untreated patients. Communicability diminishes rapidly after the catarrhal stage. The initiation of treatment with appropriate antibiotics may reduce it by five days or less. Pertussis is highly contagious in the catarrhal stage, having a secondary attack rate of up to 90% among non-immune household contacts. Case fatality ratio: Below 12 months of age, the average case fatality ratio has been estimated at 4%. Infants too young to be vaccinated are at the highest risk. Among patients who are 1–4 years old, the case fatality ratio is about 1%. 25 PERTUSSIS Vaccines There are currently two types of vaccines available: z whole cell vaccines based on killed B. pertussis organisms (wP); and z acellular pertussis vaccines based on one or more purified pertussis antigens (aP). The whole cell vaccine is in wide use in the low- and middle-income countries (LMIC). It has rare but significant side-effects. In addition to the usual local inflammatory effects and fever associated with many vaccines, it sometimes triggers prolonged crying and febrile convulsions and, very rarely, hypotonic–hyporesponsive episodes. The acellular pertussis vaccine has fewer side-effects and has been shown to be effective, though less than the whole cell vaccine. Many high-income countries (HIC) have replaced the whole cell vaccine with various formulations of the acellular vaccine. Recently, there has been a resurgence of cases of whooping cough in countries using the diphtheria, tetanus and acellular pertussis (DTaP) vaccine, with the characteristic peak occurring every 2–5 years, as observed in the pre-vaccine era. There has also been a resurgence in some countries where the coverage of the acellular pertussis vaccine has been high over a long period. This is so even if changes in diagnostic and surveillance practices are taken into account. Vaccination schedule: WHO recommends that all infants be administered 3 doses of pertussis vaccine and children of 1–6 years of age be given 1 booster dose. One of the strategies used for pertussis vaccination in some countries is the administration of booster doses to adolescents and adults. In addition, the immunization of pregnant women is used as a means of protecting newborns who are too young for direct vaccination, i.e. through the transfer of maternal antibodies. Burden of pertussis Pertussis is endemic worldwide, with epidemic peaks occurring every 2–5 years. The data collected by WHO indicate that in 2020, close to 70 000 cases were recorded from all the WHO Regions. About a third of the cases (about 22 000) was reported from the European Region and almost an equal number from the Region of the Americas (20 000). The South-East Asia Region and the Western Pacific Region contributed 13 000 (19%) and 11 000 (17%) cases, respectively. The remaining 1% came from the Eastern Mediterranean Region and the African Region. The number of reported cases has been gradually falling in the Region, and decreased from 43 000 in 2016 to about 13 000 in 2020. The average annual number of cases has seen a decline from 42 234 in the five-year period of 2001–2005 to 23 883 in 2016–2020. This fall has also been reflected in the annual incidence rate, which declined from 22.2 per 1 million population in 2016 to 6.4 in 2020. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 26 z The smaller number of cases reported from the LMICs should be critically reviewed. However, like the HICs, LMICs may also be experiencing a resurgence of pertussis. Currently, surveillance of pertussis is suboptimal in these countries and as a result, there is a lack of accurate epidemiological data. z A number of hypotheses have been put forward as to why this previously well- controlled disease is now making a resurgence in the HIC. Epidemiological data from HICs show that despite the high coverage of the acellular pertussis (aP) vaccination, the pertussis burden has increased. The reported resurgence has been linked to factors such as the reduced efficacy of aP vaccines and the genetic evolution of the pertussis bacteria. Improved diagnosis and reporting of the disease is another contributing factor. With several HICs recently facing pertussis epidemics due to a reduction in immunity following the use of the aP vaccine, there is a need for additional booster doses for better disease control. In the LICs, the nonavailability of data on the epidemiology of pertussis in the context of using the whole cell pertussis vaccine highlights the need to collect better epidemiological data that can be used to make policy recommendations on the need for booster doses and the number of boosters required. Surveillance for pertussis will provide important information on the status of its epidemiology and control. 27 PERTUSSIS Annex 2: Specimen collection The following is a summary of the biological samples to be collected for the isolation and identification of the agent that causes whooping cough, and the methods of collection. Nasopharyngeal swab sample (NPS) A throat swab sample is not recommended for the confirmation of pertussis. Universal infection prevention precautions should be taken by the person collecting the sample. Preparation before taking the sample z Choose an area for the collection of the NPS that is least used by the family. This is because a family room or kitchen may be more contaminated than the other rooms. z Obtain a thin flexible nasopharyngeal swab made of Dacron or nylon. Do not use cotton and calcium alginate swabs. z Label the specimen tube with the UID, patient’s name and date of collection. z Check the expiry date on the tube and transport media to ensure that the material to be used for sample collection is acceptable. z Place a clean paper towel on the table for holding the equipment. z If the subject is a child and is to be held by a parent, the parent must be masked. z Get the patient to sit with his/her head against a wall or a support, as patients have a tendency to pull away during this procedure. z Explain the procedure to the parents or patient. Collecting the sample z When the subject is positioned properly and ready for the sample collection, wear gloves. z Measure the distance between the anterior nares and the lower lobe of the ear of one side. z Mark the swab with half of the distance that has been measured. z Ask the patient to blow his/her nose forcefully to remove any mucous plug. z Tilt the head slightly upwards and insert the swab along the base of the nose, up to the distance marked. Avoid inserting the swab in the upward direction. z Do not force the swab in if you encounter an obstruction before reaching the nasopharynx. Remove it and try the procedure on the other side. z Try to leave the swab in place for 5–10 seconds to increase sensitivity. z Immediately place the swab in Regan–Lowe transport media/Amies transport media with charcoal and tighten the cap of the specimen collection container. The best would be to wrap tape around the cap to prevent any leakage. z Ship at room temperature. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 28 Nasopharyngeal aspirate (NPA) In neonates and infants, the isolation rate is 15% higher with the use of NPA than with NPS. Preparation before taking the sample z Choose an area for the collection of NPA that is the least used by the family. z Place a clean paper towel on the table for holding the equipment. z If the subject is a child and is to be held by a parent, the parent must be masked. Taking the sample z When the subject is positioned properly and ready for the NPA, put on gloves. Take out the equipment from the bag and place it on the clean paper towel. z Loosen the cap of the sterile container, but do not open it until it is time to insert the catheter tip. z Open the syringe and remove the plastic tip. z Secure the syringe on the end of the catheter. Test the syringe. z Take the catheter out of the wrapper. z Gently and slowly insert the catheter into one of the nostrils, rotating it if necessary, to proceed past the back of the nostril. Insert the catheter until it reaches the back of the throat (approximately 10 cm, depending on the age of the subject). If gagging occurs, you have inserted the catheter too far. z After positioning, withdraw the catheter with suction, placing the thumb over the suction control on the side of the catheter while pulling back on the syringe plunger. z After removing the catheter from the nose, and without touching the tip of the catheter, open the sterile container and place the tip inside. Screw the top on with the catheter and syringe still attached. This protects the part of the tubing containing the specimen. z Label the sterile container, put the container, catheter and syringe in a plastic bag, and seal the bag. Take off the gloves and put them in a plastic bag for disposal. z Transport the NPA specimen. Serum sample It is recommended that one serum sample be obtained. z Obtain a serum collection kit before going to collect the sample. z Remember to take the standard precautions. z Label the blood collection tube properly with the name of the subject, UID and date of collection. 29 PERTUSSIS z Using an acceptable venepuncture technique, collect 2–3 mL whole blood. z Wait for a minimum of 15 minutes to allow a clot to form. z Centrifuge the sample to separate the serum from the clot. Alternatively, store the whole blood sample overnight, in an upright position, in the refrigerator (2–6 °C). z Properly label the 2-mL plastic storage tube in which you will collect the serum. z Store and transport serum samples at 2–8 °C. NOTES Culture: Culture of nasopharyngeal secretions is the most specific diagnostic test for pertussis. Since B. pertussis is highly sensitive to drying, specimens should be inoculated onto the culture medium without delay. Generally, Regan-Lowe agar or freshly prepared Bordet–Gengou medium is used for culture. Fastidious growth requirement makes B. pertussis difficult to isolate. The chances of isolating the organism decrease if: z the collection of the specimen has been delayed beyond the first 2 weeks of illness (catarrhal stage); z the patient has received appropriate antibiotic therapy; or z the patient has been vaccinated. Since the chances of isolating the organism are the maximum during the catarrhal phase, when the aetiology of the infection is not suspected, there is only a small window of opportunity for culture-proven diagnosis. Polymerase chain reaction: PCR is an important tool for the timely diagnosis of pertussis. It detects DNA sequences of the bacterium and does not require the presence of viable bacteria in the specimen. However, PCR may be more prone to yielding false-positive results. The test has optimal sensitivity during the first 3 weeks of the cough as bacterial DNA is present in the nasopharynx during this time. After four weeks of the cough, the amount of bacterial DNA diminishes rapidly. Serological testing: This can be a useful tool for the diagnosis of pertussis after 4 weeks of the onset of cough. Enzyme immunoassays to detect IgA and IgG antibodies to pertussis toxin, filamentous haemagglutinin, pertactin and fimbriae are gaining increasing importance as diagnostic tools. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 30 Annex 3: Case investigation form Demographic information Name Unique case identifier Date of birth (DOB) (dd/mm/\y\y) Age (if DOB not available) Sex M/F/U Place of residence House No: Street name: Village/ town: District /province: Country: Pin/zip code: Contact Mobile number: Email: Reporting information Date of notification to public health department (dd/mm/\y\y) Date of investigation (dd/mm/\y\y) Clinical information Date of onset Cough/apnoea dd/mm/\y\y Comment Signs and symptoms Paroxysms of cough  Inspiratory whoop  Post-tussive vomiting  Apnoea  Sub-conjunctival haemorrhage  Rectal prolapse  Hernia  Pneumothorax  Petechiae  Rib fracture  Any other  If so, describe Hospitalization status Admitted  Not admitted  If so, date of hospital admission: (dd/mm/\y\y) Outcome (we do 60 days follow-up to know the outcome) Survived  Died  If so, date: Unknown  Treatment type Antibiotic  If so, type: Date of first dose: 31 PERTUSSIS Laboratory methods and results Specimen collected Yes  No  If so, date: dd/mm/\yy Whether collected before antibiotic provision Yes  No  Type of specimen sent to laboratory Nasopharyngeal swab  Nasopharyngeal aspirate  Blood  Date specimen sent to laboratory dd/mm/\y\y Date specimen received in laboratory (dd/mm/\y\y) Processed  Not processed  Culture Results Positive  Negative  Unknown / intermediate:  If positive: B. pertussis  Serology IgG Positive  Negative  Unknown  Intermediate  Not done  PCR Positive  Negative  Unknown / Intermediate  Not done  Vaccination status Type of vaccine received DTP  DT(a)P  Dates of vaccine dosage (1) DPT  DT(a)P  Date of vaccine dosage (2) DPT  DT(a)P  Others  Date of vaccine dosage (3) Date of vaccine dosage (4) Date of vaccine dosage (5) Date of vaccine dosage (6) If <1 year Maternal immunization status during pregnancy Yes  No  DPT  DT(a)P  If so, date given dd/mm/\y\y Epidemiological data History of contact Is the person a contact of laboratory-confirmed case? Yes  No  If so, write case ID Close contact with anyone who travelled in the week before the onset of illness Yes  No  If so, where did they travel (give details) Travel within 21 days before illness onset? Yes  No  If so, where (give details) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 32 Classification Final classification Lab-confirmed  Epidemiologically linked  Possible/ clinically compatible  Discarded  Annex 4: Recommended surveillance performance indicators Surveillance attribute Indicator Target How to calculate Comments Completeness of reporting Proportion of designated sites reporting data, even in the absence of cases >80% (Total number of reports received / total number of reporting sites) x 100 Timeliness of reporting Proportion of surveillance units reporting to the national level on time, even in the absence of cases >80% (Number of surveillance units reporting by the deadline / number of surveillance units in the country) x 100 At each level, reports should be received on or before the requested date. Adequacy of investigation (applicable only if conducting case-based surveillance) Proportion of all suspected cases that have been adequately investigated >80% (Number of suspected cases that were adequately investigated / number of suspected cases) x 100 Adequate investigation includes completing a case investigation form, collecting a nasopharyngeal or serum specimen, and line listing close contacts. If any of the above is not conducted, the investigation is considered inadequate. 33 PERTUSSIS Surveillance attribute Indicator Target How to calculate Comments Timeliness of Investigation (applicable only if conducting case-based surveillance) Proportion of suspected cases for which investigation initiated within 48 hours of notification >80% (Number of suspected cases for which investigation was initiated within 48 hours of notification / number of suspected cases) x 100 Adequacy of specimen collection (applicable only if conducting case-based surveillance) Proportion of suspected cases with 2 specimens collected (nasopharyngeal swab or serum) >80% (Number of suspected cases with 2 specimens collected / number of suspected cases) x 100 Timeliness of specimen transport Proportion of specimens received by laboratory within 2 days of collection >80% (Number of specimens received by the laboratory within 2 days of collection / number of specimens) x 100 Indicator applies only to public laboratories Timeliness of reporting PCR results Proportion of PCR specimens with results reported within 2 days of receipt of specimen >80% (Number of specimens tested by PCR with results reported within two days of receipt / number of specimens tested by PCR) x 100 Applies only to public laboratories Timeliness of reporting culture results Proportion of specimens tested by culture with results reported within 7 days of receipt of specimen >80% (Number of specimens tested by culture with results reported within 7 days of specimen receipt / number of specimens tested by culture) x 100 Applies only to public laboratories Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 34 Further reading 1. World Health Organization. Module-5, Pertussis – Surveillance standards Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region. New Delhi: World Health Organization, Regional Office for South-East Asia; 2017. Licence: CC BY-NC- SA 3.0 IGO (https://apps.who.int/iris/bitstream/handle/10665/277459/Module5- Pertussis.pdf?sequence=25&isAllowed=y, accessed 8 August 2022). 2. Blain A, Skoff T, Cassiday P, Tondella MC, Acosta A. Chapter 10: Pertussis. In: Roush SW, Baldy LM, Hall MAK (eds). Manual for the Surveillance of Vaccine-Preventable Diseases. Centres for Disease Control and Prevention, Atlanta, GA (https://www.cdc. gov/vaccines/pubs/surv-manual/chpt10-pertussis.html, accessed 8 August 2022). 3. European Centre for Disease Prevention and Control. Pertussis In: ECDC. Annual epidemiological report for 2018. Stockholm: ECDC; 2020. 4. Yeshanew AG, Lankir D, Wondimu J, Solomon S. Pertussis outbreak investigation in Northwest Ethiopia: A community-based study. PLoS One. 2022; 17(2):e0263708. doi: 10.1371/journal.pone.0263708. 5. Thisyakorn U, Tantawichien T, Thisyakorn C, Buchy P. Pertussis in the Association of Southeast Asian Nations: epidemiology and challenges. Int J Infect Dis. 2019;87:75– 83. doi: 10.1016/j.ijid.2019.07.016. 6. Muloiwa R, Kagina BM, Engel ME, Hussey GD. The burden of laboratory-confirmed pertussis in low- and middle-income countries since the inception of the Expanded Programme on Immunisation (EPI) in 1974: a systematic review and meta- analysis. BMC Med. 2020;18(1):233. doi: 10.1186/s12916-020-01699-3. 7. Stone H, Moa A, MacIntyre CR, Chugtai AA. Using open-source data to estimate the global epidemiology of pertussis. Global Biosecurity. 2020;2(1). DOI: http://doi. org/10.31646/gbio.65. 8. Feng Y, Chiu CH, Heininger U, Hozbor DF, Tan TQ, von König CW. Emerging macrolide resistance in Bordetella pertussis in mainland China: Findings and warning from the global pertussis initiative. Lancet Reg Health West Pac. 2021;8:100098. doi: 10.1016/j.lanwpc.2021.100098. CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region MODULE-6 NEONATAL TETANUS September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Neonatal Tetanus) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO Introduction 5 Objectives 5 Type of surveillance 5 Case detection 6 Definition of suspected case 6 Description of case definition 6 Date of onset of illness 6 Investigation of a suspected case 6 Case investigation form 7 Unique ID 7 How to ascertain protection at birth 7 Diseases which produce similar clinical picture 8 Laboratory testing 8 Classification of cases 8 Confirmed case 8 Discarded case 8 Not investigated 8 Contact tracing 9 Clinical case management of NT 9 Outbreaks 9 Public health response 9 Data management 10 Reporting requirements 10 Unique ID 10 Recommended data elements 11 Data analysis 11 Using data for decision-making 12 CONTENTS Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Indicators for surveillance performance 12 Sustaining maternal and neonatal tetanus elimination 13 Special considerations 13 Annex 1: Disease epidemiology 15 Introduction 15 Essential epidemiology 16 Vaccines 16 Disease burden 17 Annex 2: Case investigation form 17 Annex 3: Reporting form for assessing protection at birth 19 Annex 4: Indicators of surveillance performance 20 Further reading 22 5NEONATAL TETANUS Neonatal tetanus surveillance Introduction “Maternal tetanus is defined as tetanus during pregnancy or with 6 weeks after pregnancy (with birth, miscarriage or abortion) and has the same risk factors and means of prevention as neonatal tetanus. For this reason, neonatal tetanus elimination (<1 case per 1000 live births) is considered a proxy for maternal tetanus elimination. Surveillance for non-neonatal tetanus should detect cases of maternal tetanus but in most countries occurs through aggregated reporting which lacks the required information on age, sex and pregnancy status to distinguish maternal tetanus.” All countries of the WHO South-East Asia Region achieved the status of elimination of maternal and neonatal tetanus (MNT) by May 2016. However, even after a country has been validated for MNT elimination, neonatal tetanus (NT) cases, though rare, can still be found. A sensitive and reliable NT surveillance system is required to detect every case and implement corrective measures to prevent further cases. Thus, NT surveillance should become an integral part of vaccine-preventable diseases (VPD) surveillance. Objectives The main objective of NT surveillance in this context is to detect cases to ensure the maintenance of MNT elimination, defined as less than one NT case per 1000 live births per year in every district. The other objectives are: z to identify areas and subpopulations at high-risk z to guide effective public health response in high-risk subpopulations; z to monitor the impact of interventions at national and subnational levels; and z to identify areas of the health system that need strengthening, as every NT case is an event that indicates the failure of multiple levels of the health system. Type of surveillance The minimal recommended standard is nationwide, case-based surveillance. In other words, each and every suspected case should be investigated and classified as confirmed or discarded. Surveillance, in this case, is population-based and includes all neonates of the age of 0–28 days. Laboratory confirmation is not an aspect of NT surveillance, as the basis of diagnosis is clinical. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 Case detection Definition of suspected case A suspected case should meet either of the following criteria: z could suckle and cry normally during the first two days of life but lost the ability and developed tetanus-like illness or died between 3 and 28 days after birth: or z died of an unknown cause during the first month of life. Description of case definition z suckling well and crying normally for the first few days after birth and subsequently developing progressive difficulty and then inability to feed; z excessive crying; z spasms of facial muscles (trismus or lockjaw); z stiffness of back muscles, leading to backward arching of the back; z generalized convulsions. Date of onset of illness The date of onset of illness is the day the child shows inability to suckle. Investigation of a suspected case The VPD surveillance officer should investigate all suspected cases within 7 days of notification to arrive at a diagnosis. The sooner the mother and the persons who attended the birth are visited, the more likely that they will be available and remember relevant details. At the end of the investigation, the surveillance officer should be able to determine why the infant contracted tetanus. Was it due to: z the lack of maternal vaccination, z birth unattended or attended by unskilled staff; or z the use of unhygienic cutting tools or application of substances to the umbilical stump. In addition, a simplified algorithm can be used to determine if the mother and infant were protected at birth (PAB) against tetanus, based on maternal vaccination history (Annex-3). 7NEONATAL TETANUS Case investigation form A case Investigation form should be filled for every suspected case. (Please see Annex 2 for a sample case investigation form.) The case investigation form must have details of the findings and actions taken or recommended and sent to the next level. A written feedback must be given to the reporting facility and community. Unique ID Each suspected case should be assigned a unique case identification number (UID). The case number should begin with one or more three-letter combinations designating the geographical location, the year, and the serial number of the case. All communications and forms related to the case should cite the UID. For example: Code for NT disease : NNT Country code: NEP Province code: SUP District code: BJR Year of onset: 2022 Serial number of case: 001 The UID would then be NNT-NEP-SUP-BJR-22-001 How to ascertain protection at birth Whether a child was protected against tetanus may be determined on the basis of maternal immunization records and questioning the mother about the number tetanus toxoid-containing vaccine (TTCV) doses she received during the last pregnancy, previous pregnancies, campaigns/outreach before the last pregnancy and during school going age. A birth is protected if the mother received: z two TTCV doses while pregnant with the last child (with second dose at least two weeks before birth); OR z one TTCV dose while pregnant with the last child (at least two weeks before birth) and one or more doses at any time before that pregnancy; or OR Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 z no dose while pregnant with the last child and three or more adolescent/adult doses at any time before that pregnancy. z (A simplified algorithm to determine whether the mother and infant were protected at birth is given in Annex 3). Diseases which produce similar clinical picture Some other diseases which may produce similar clinical features include meningitis, sepsis (including umbilical sepsis) and birth defects. Some differentiating features are: z trismus (lockjaw) is absent in these illnesses; z there is no bulging of the fontanelle in NT; z during tetanus spasms, the child is conscious, while in convulsions from causes such as high fever, the child is unconscious; z tetanus spasms are often brought on by stimuli such as light and sound. Laboratory testing There is no diagnostic test. The diagnosis is based on clinical signs and symptoms. It may be possible to culture the bacteria from the umbilical stump in about a third of the cases. Classification of cases Confirmed case A confirmed case is any suspected case found to have all three of the following: z normal ability to suckle and cry during the first two days of life; AND z progressively lost ability to suckle between 3 and 28 days after birth; and AND z developed stiffness of muscles and/or spasms leading to jerking movement . Discarded case A discarded case is one that has been investigated and does not satisfy the clinical criteria for confirmation or has an alternate diagnosis. Not investigated Any suspected case that was not investigated or about which there was no information on age and symptoms confirming the case should be classified as “not investigated”. 9NEONATAL TETANUS Contact tracing As NT is not contagious, contact tracing is not needed. Clinical case management of NT Neonatal tetanus is a medical emergency requiring hospitalization. Its management consists of the following components. a). Immediate treatment with human tetanus immune globulin (TIG): z A single intramuscular dose of human TIG is recommended as soon as possible to prevent further progression of the disease. z If TIG is not available, equine-derived antitoxin tetanus serum (ATS) may be given in a single intravenous dose, after testing for hypersensitivity. z Alternatively, intravenous immunoglobulin (IVIG) may be used. b). Control of muscle spasm: Benzodiazepines are usually prescribed to control muscle spasms c). Antibiotics: Metronidazole or penicillin G is used as the antibiotic of choice. d). Other supportive treatment: z The patient must be kept in a dark and quiet environment to reduce the risk of reflex spasms. z Nasogastric feeding must be started. z A safe airway must be maintained during muscle spasms. If mechanical ventilation is not available, the patient must be carefully monitored, and efforts must be made to minimize spasm and autonomic dysfunction to avoid respiratory failure. Outbreaks Usually, outbreaks do not occur. However, clusters linked to a single source of substandard clinical care have been observed. Public health response It is good practice to do a rapid community assessment following a case investigation. z The assessment should start from the house where the case occurred and proceed from house to house. z A minimum of seven other mothers who delivered in the preceding two years should be interviewed to record the: Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 z immunization status of the mother; z place of last delivery; z use of traditional substances on the umbilical cord; and z immunization status of the last-born child. If any mother was not immunized, she should be immunized immediately with one dose of Td vaccine and provided with a second dose one month later. She should also be informed about proper cord care. If 90% of the mothers assessed are protected (clean delivery or/and TT2+), only the mother of the NT case need be immunized. Hygienic cord care practices must be promoted. If less than 90% of the mothers are protected, and/or less than 90% of the children are completely immunized: z the cause of non-protection must be determined and addressed; z the community must be included in the microplanning (Reach Every Child) strategy and implementation; z TT vaccination must be made an integral component of upcoming periodic intensification of routine immunization (PIRI) or Child Health Days; and z the community and birth attendants must be informed about proper cord care. If factors that placed the infant at risk of are identified, corrective actions must be taken. Some examples of such actions are including maternal immunization in the training of birth attendants and better coordination with maternal and child health services. Data management Reporting requirements z Designated reporting sites should report cases weekly, monthly or at some other specified frequency, even if there are zero cases (zero reporting). z Copies of case investigation forms or electronic data from these forms should be forwarded to the national level. z Cases should be reported annually to WHO/UNICEF through the Joint Reporting Form. z Reporting of NT is not required under International Health Regulations (IHR). Unique ID A unique case identification number should be assigned to each suspected case, as explained earlier. 11 NEONATAL TETANUS Recommended data elements z Case notification z Geographical information z Demographics z Clinical findings z Neonatal outcome z Maternal and perinatal risk factors z Public health response effort These data elements have been included in the case investigation form (Annex 2). Data analysis z Number and incidence of confirmed cases per 1000 live births, by month, year, sex, and district z Percentage of confirmed cases that were PAB by maternal vaccination z Percentage of confirmed cases whose mother received antenatal care (ANC) z Percentage of mothers not vaccinated among those who received ANC (for analysis of missed opportunities) z Percentage of confirmed cases by z place of birth (health facility/home delivery) z type of birth assistance z type of cord-cutting tools used z type of umbilical cord dressing used z mother’s age z mother’s parity (first birth/multiple births) z Distribution of outcomes (death, left against medical advice, survived, unknown) among confirmed cases z Case fatality ratio among confirmed cases z Percentage of confirmed cases whose mother received a TTCV dose(s) after the case occurred, as a result of case detection/investigation or soon after z Percentage of neonatal deaths attributable to NT (if part of neonatal death surveillance) z Percentage of confirmed cases which triggered an active search in community z Percentage of confirmed cases which triggered an immunization response among women of reproductive age Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 z Number of unreported cases found through active searches z Completeness and/or timeliness of monthly and zero reporting z Risk assessments As with other diseases, surveillance data should be triangulated with data from the immunization programme, such as vaccination coverage and history of supplementary immunization activities (SIAs), as well as ANC coverage, and skilled birth attendance (SBA) coverage to understand the entire picture when drawing conclusions and formulating policies and strategies. Using data for decision-making Surveillance data may be used to draw conclusions, monitor implementation, and identify areas that require special attention. z They may be used to monitor achievement and maintenance of MNTE (< 1 NT case per 1000 live births in every district) and document evidence towards validation of sustained elimination. z They may be fed into annual risk assessments to identify high-risk geographical areas for targeting improvements in antenatal, obstetric, and vaccination services and conducting targeted SIAs for women of reproductive age. z They may be used to identify NT risk factors, such as place/type of delivery, cord care, age and parity of mother, and migrant status and ethnicity, in order to design appropriate messaging and interventions. z They may be used to monitor the impact of interventions, including SIAs. z They may help identify missed opportunities for maternal immunization with TTCV. z They may provide evidence needed to change immunization policy or strategy (for example, the introduction of WHO-recommended booster doses and school-based immunization if first-time mothers are not being reached at ANC visits). z They may help in the rapid identification of cases for appropriate case management. Indicators for surveillance performance Countries should review the performance of each district annually. This should be a joint exercise conducted by the Expanded Programme on Immunization (EPI), maternal, neonatal and child health (MNCH) programme, and surveillance managers at different levels, together with partner representatives. The objectives of the review should be: z to identify and classify districts that could potentially revert to at risk for MNT; z to select and tailor relevant corrective strategies and interventions to sustain MNTE in the short, and longer term; and 13 NEONATAL TETANUS z to use the findings to improve the EPI and MNCH programmes, especially to optimize the ANC and immunization platforms. Districts should be classified into “low risk” and “at risk” for MNT. Then “at risk” districts should be further classified into “high risk” and “medium risk” to enable a more adequate tailoring of corrective strategies. An illustrative list of performance indicators is provided at Annex 4. Sustaining maternal and neonatal tetanus elimination Since countries in the Region have already achieved MNT elimination, regular risk assessments should be performed, triangulating district-level data on NT cases and rates, SBA, TT/PAB coverage from routine and SIAs, and other proxy indicators (details available at: https://www.who.int/publications/i/item/protecting-all-against-tetanus ). Special considerations The following considerations must be kept in mind while conducting surveillance. Ethical and equity issues: Neonatal deaths may be a sensitive topic, especially among some cultures and ethnic groups. Such deaths occur most frequently among marginalized groups, such as migrants, the homeless and residents of urban slums, missed by the immunization programme. Members of these groups may be sensitive to questioning by government officials. Guidance must be taken from the local health staff on how best to address these challenges. Neonatal death surveys: The relative contribution of NT to neonatal mortality can be assessed through audits of neonatal deaths at health facilities or in community settings(for details see: https://www.healthynewbornnetwork.org/hnn-content/uploads/WHO_Audit- Review-of-Stillbirths-and-Neonatal-Deaths-HIghlights_2016-1.pdf). Serological surveys: Where feasible, serosurveys of tetanus IgG among adult women should be considered as a complementary tool for monitoring MNT risk and guiding vaccination strategies. Since immunity does not result from natural infection, tetanus sero- protection reflects population immunity from vaccination. Close attention should be paid to the objective of the survey, sampling strategies and laboratory methods to ensure that the results are valid and interpretable. Serosurveillance should not replace NT surveillance. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 15 NEONATAL TETANUS Annexes Annex 1: Disease epidemiology Introduction Tetanus is a bacterial disease caused by Clostridium tetani. Spores of C. tetani are present in soil contaminated with animal and human faeces. The spores gain entry through breaks in the skin and germinate under anaerobic conditions. The organisms produce a toxin, tetanospasmin, which when it reaches the nervous system, causes painful muscular contractions. Usually, the muscle stiffness begins in the jaw and neck, and later becomes generalized. In 1989, the 42nd World Health Assembly called for the elimination of neonatal tetanus by 1995. The following year, the 1990 World Summit for Children listed neonatal tetanus elimination as one of its goals, and the goal was again endorsed by the 44th World Health Assembly in 199. The Maternal and Neonatal Tetanus Elimination (MNTE) initiative aims to reduce MNT cases to such low levels that the disease is no longer a major public health problem. The eradication of NT is not possible as the bacteria and its spores are found in the environment everywhere in the world. However, it can be eliminated (defined as less than one case of neonatal tetanus per 1000 live births in every district) through the immunization of mothers and other women of reproductive age (WRA), and the promotion of more hygienic deliveries and cord care practices. The South-East Asia Region of WHO was declared to have eliminated MNT in 2016. Indonesia, Nepal, Bangladesh, Myanmar, Timor-Leste, and India reached the elimination goal and were validated in 2005, 2008, 2010, 2012 and 2015, respectively. On the basis of the quality of their longstanding performance in routine immunization and surveillance systems, it was assumed that Bhutan, the Democratic People’s Republic of Korea, Maldives, Sri Lanka, and Thailand had already achieved MNT elimination before 2000. Notwithstanding the fact that MNT has been eliminated in the Region, a small number of cases are likely to occur. Thus, there is a need for an effective and sensitive surveillance system to detect these cases, so that appropriate remedial measures can be taken. Surveillance can be quite challenging, as most neonatal deaths occur at home, and experience has shown that only 1 in 10 NT cases and deaths get reported. However, efforts must be made to ensure that every case gets reported and investigated to understand the reasons why the case occurred. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 Essential epidemiology Infectious agent: Clostridium tetani Reservoir of infection: Spores are present in the environment, especially in the soil and fomites contaminated with animal and human faeces. The organism is a harmless normal inhabitant of the intestines of horses and other animals, including human beings. Mode of transmission: Tetanus spores are introduced into the body of a newborn infant via the umbilical cord following unhygienic deliveries and poor postnatal hygiene and cord care practices. Some examples of unhygienic practices are the use of non-sterile instruments to cut the umbilical cord and the use of contaminated material to cover the umbilical stump. Deliveries carried out by persons with uncleansed hands or on a contaminated surface are also risk factors. Incubation period: The symptoms usually present 3 to 14 days, averaging 7 days, after birth in 90% of cases. Shorter incubation periods are associated with more severe disease and worse prognosis. Period of communicability: The disease is not directly transmitted from person to person. Case fatality ratio: The case fatality ratio is very high, exceeding 80% among cases with a short incubation period and low birth weight. Vaccines The tetanus vaccine is a toxoid vaccine, prepared by the inactivation of the tetanus toxin. It is available as either a single-antigen vaccine or in combinations containing vaccines against diphtheria, pertussis, poliomyelitis, hepatitis B and the Haemophilus influenzae type b (Hib) disease. The pentavalent vaccine, which provides protection against diphtheria, tetanus, pertussis, Hib, and hepatitis B (DTP-Hib-HepB), is the most commonly used childhood vaccine worldwide to complete primary series of vaccination to prevent NT, but other pentavalent (DTaP-IPV/Hib) and hexavalent (DTaP-IPV/Hib-HepB) combinations are also available. A tetanus-diphtheria combination with a lower concentration of the diphtheria antigen is available for booster dosing. The use of combinations containing tetanus toxoid (TT) and diphtheria toxoid vaccines is recommended and single-antigen vaccines should be discontinued whenever feasible to help maintain high immunity to both diphtheria and tetanus throughout the life course. Effectiveness: The effectiveness of ≥2 properly timed doses of TT given to pregnant women or women of reproductive age against NT mortality was 94% [95% CI: 80–98%] 17 NEONATAL TETANUS Disease burden Despite the availability of highly effective TT–containing vaccines, tetanus continues to have a substantial health impact in the world. WHO estimates that in 2018 (the latest year for which estimates are available), 25 000 new-borns died due to NT. Though this was a reduction of 88% from the figure of 200 000 for the year 2000, the MNT elimination initiative still faces numerous challenges. Approximately 47 million women and their infants are not protected against tetanus. In addition to maternal immunization, promotion of clean deliveries and adequate umbilical cord care practices are included in the recommended WHO strategies to eliminate MNT. Annex 2: Case investigation form Case notification Name of child (can be omitted if confidentiality is a concern, provided unique identifier exists) Unique identification number NNT-_______/____________/__________/_____/____________________ Country code/ Province code/District code/ Year/Serial number Date of notification dd/mm/yyyy Date of investigation dd/mm/yyyy Source of notification Health facility location: Name of person: Geographic information Address State: District/ province: City/town: Reporting health facility Demographic information Date of birth dd/mm/yyyy Sex Male  Female  Not known  Clinical information Age of baby in days at onset of symptoms Date of onset (date of inability to suckle or of lockjaw) Date of hospitalization Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 Signs and symptoms Ability to suckle and cry during the first 2 days of life Yes  No  Cannot suckle normally between 3 and 28 days of age * Yes  No  Muscle stiffness Yes  No  Muscle spasms (jerking) Yes  No  Neonatal outcome Final outcome of child’s illness Alive  Dead  Unknown  Final classification Confirmed  Discarded  Not investigated  Unknown  Date of discharge/death Maternal and perinatal risk factors Age of mother Ethnic group Migrant status Number of live births delivered (including the last one) by the mother Number of previous births with similar symptoms and whether children survived Number of ANC contacts the mother had with a trained healthcare worker during this pregnancy Location of ANC (for follow-up regarding missed vaccination opportunity) PAB status of last birth Place of birth: Hospital  Health centre  Home  Others  Specify: Unknown  Assistance during childbirth/ birth attended by Health staff  Traditional birth attendant  Family member  Alone  Others  Unknown  If not health staff, whether clean surface and hands were used for delivery Describe : Yes  No  Tool(s) used to cut umbilical cord Cleaned  Boiled*  Substance put on umbilical cord* Maternal outcome Alive  Dead  If dead, cause of death 19 NEONATAL TETANUS Public health response Mother given TTCV dose(s) at the time of case detection/ investigation; or as soon as possible afterwards Yes  No  Not needed/already protected  Unavailable  Unknown  If protective dose given, date when it was given COMMENTS * Designated core variable that must be recorded Annex 3: Reporting form for assessing protection at birth Health facility information Address Province District Town/city Pin/zip Type Health facility  Community outreach  Date of visit dd/mm/yyyy Mother’s information Name Age in years Gravida (total pregnancies so far) Parity (total number of children so far) Received TTCV vaccination before or during the last pregnancy Yes  No  If yes, total number of vaccinations Source of information Maternal health record  Recall/history  Decision point Was the child protected from tetanus at birth? If mother received 2 or more valid doses of TTCV Yes  If mother received less than 2 doses of TTCV No  Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Annex 4: Indicators of surveillance performance Attribute Indicator Target Formula Notes C om pl et en es s of re po rt in g Percentage of designated sites reporting NT data, even in the absence of cases (zero reporting) ≥ 90% (Number of designated reporting sites sending data/number of designated reporting sites for surveillance) x 100 Ti m el in es s of re po rt in g Percentage of designated sites reporting on time, even in the absence of cases (zero reporting) ≥ 80% (Number of designated reporting sites reporting by deadline /number of designated sites for surveillance) x 100 At each level, reports should be received on or before the requested date. C om pl et en es s of in ve st ig at io n Proportion of suspected cases investigated (only from health facilities) ≥ 90% (Number of case investigations /number of suspected cases reported) x 100 If database only has data on case investigations performed, this indicator can be calculated as: (Number of suspected cases in the case-based dataset/number of suspected cases in the aggregate report) x 100 This indicator will reflect the representativeness of case-based surveillance and efficiency of case investigations. Ti m el in es s of in ve st ig at io n Percentage of all suspected cases investigated within 7 days of notification ≥ 80% (Number of suspected cases investigated within 7 days of notification/ number of suspected cases investigated) x 100 A de qu ac y of in ve st ig at io n Percentage of cases investigated with complete information on all core variables ≥ 80% (Number of suspected cases for which adequate investigation was conducted for all 12 core variables / number of suspected cases investigated)x 100 The core variables are case identification, date of birth, sex, place of residence, date of illness onset, date of notification, date of investigation, symptoms in case definition, outcome, maternal vaccination history, place/ type of delivery, tool for cutting cord, and material applied to cord. If information on any of the core variables is missing, the investigation is considered inadequate. 21 NEONATAL TETANUS Attribute Indicator Target Formula Notes M ai nt en an ce o f M N TE Percentage of districts with < 1 NT case per 1000 live births 100% (Number of districts with < 1 NT case per 1000 live births / total number of districts) x 100 Ideally, this indicator should be calculated using confirmed cases. If the completeness of investigating suspected cases is < 90%, it can be calculated using suspected cases to highlight districts needing targeted interventions and programme strengthening. A de qu at e ca se r es po ns e Percentage of confirmed cases for which the mother received a TTCV dose in conjunction with case detection or investigation 100% (Number of mothers of NT cases who received a TTCV dose in conjunction with case detection or investigation / total number of NT case investigations) x 100 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 Further reading 1. Blain A, Tiwari TSP. Chapter 16: Tetanus. In: Roush SW, Baldy LM, Hall MAK (eds). Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention, Atlanta, GA (https://www.cdc.gov/vaccines/pubs/surv- manual/index.html, accessed 21 July 2022). 2. Dhir SK, Dewan P, Gupta P. Maternal and Neonatal Tetanus Elimination: Where are We Now? Res Rep Trop Med. 2021;12:247–61. doi: 10.2147/RRTM.S201989. 3. Kamath GD, Kukreja S, Mukherjee P, Kolhapure S and Sathyanarayanan S. Maternal immunization: trends in South and Southeast Asian countries. J Matern Fetal Neonatal Med. 2021 Sep 13:1-10. doi. 10.1080/14767058.2021.1974389. 4. World Health Organization‎. Weekly Epidemiological Record, World Health Organization. 2022 97 (11): 97–108 (https://apps.who.int/iris/ handle/10665/352511, accessed 21 July 2022), 5. World Health Organization. Making every baby count: audit and review of stillbirths and neonatal deaths. Geneva: World Health Organization; 2016 (https://www. healthynewbornnetwork.org/hnn-content/uploads/WHO_Audit-Review-of-Stillbirths- and-Neonatal-Deaths-HIghlights_2016-1.pdf, accessed 21 July 2022). 6. World Health Organization. Regional Office for South-East Asia. Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region. World Health Organization. Regional Office for South-East Asia; 2017. License: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/handle/10665/277459, accessed 21 July 2022). 7. World Health Organization. Module-6, Neonatal Tetanus – Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region. New Delhi: World Health Organization, Regional Office for South-East Asia; 2017. Licence: CC BY-NC- SA 3.0 IGO (https://apps.who.int/iris/bitstream/handle/10665/277459/Module6- NT.pdf?sequence=36&isAllowed=y, accessed 21 July 2022). 8. World Health Organization. Regional Office for South-East Asia. Empowered, healthy, free: elimination of maternal and neonatal tetanus in the WHO South-East Asia Region. World Health Organization. Regional Office for South-East Asia; 2014 (https:// apps.who.int/iris/handle/10665/272732, accessed 21 July 2022). 9. Tetanus vaccines: WHO position paper – February 2017. Wkly Epidemiol Rec. 2017;92(6):53–76. 23 NEONATAL TETANUS 10. World Health Organization. Neonatal tetanus: surveillance standards for vaccine- preventable diseases. World Health Organization; 2018 (https://www.who.int/ publications/m/item/vaccine-preventable-diseases-surveillance-standards- neonatal-tetanus, accessed 21 July 2022) 11. World Health Organization. Protecting all against tetanus: guide to sustaining maternal and neonatal tetanus elimination (MNTE) and broadening tetanus protection for all populations. World Health Organization; 2019 (https://www.who.int/publications/i/ item/protecting-all-against-tetanus, accessed 21 July 2022). 12. Yusuf N, Steinglass R, Gasse F, Raza A, Ahmed B, Blanc DC et al. Sustaining Maternal and Neonatal Tetanus Elimination (MNTE) in countries that have been validated for elimination – progress and challenges. BMC Public Health 2022;22(1):691. doi: 10.1186/s12889-022-13110-2. 13. Yususf N, Raza AA, Chang-Blanc D, Ahmed B, Hailegebriel T, Luce RR, et al. Progress and barriers towards maternal and neonatal tetanus elimination in the remaining 12 countries: a systematic review. Lancet Glob Health. 2021; 9(11): e1610–e1617. doi: 10.1016/S2214-109X(21)00338-7. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24 CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region MODULE-7 NON-NEONATAL TETANUS September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Non-Neonatal Tetanus) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO Introduction 5 Objectives 5 Types of surveillance 5 Surveillance procedure 6 Linkages with other surveillance systems 6 Special considerations 6 Case detection 7 Definition of suspected case 7 Case definition 7 Date of onset of illness 7 Investigation of a suspected case 8 Case investigation form 8 Assigning a unique ID 8 Specimen collection 8 Laboratory testing 8 Classification of cases 9 Contact tracing 9 Clinical management 9 Outbreaks 10 Data management 11 Reporting requirements 11 Unique ID 11 Recommended data elements 11 Data analysis 12 CONTENTS Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Evaluation of surveillance performance 13 Annex 1: Disease epidemiology 15 Background 15 Essential epidemiology 16 Vaccine 16 Burden of disease 18 Annex 2: Sample form for aggregate surveillance 19 Annex 3: Case investigation form 20 Further reading 23 5NON-NEONATAL TETANUS Non-neonatal tetanus Introduction Appreciable progress has been made in eliminating maternal and neonatal tetanus (MNT) globally. The South-East Asia Region of WHO eliminated MNT in 2016. However, there is no reliable worldwide data on the number of cases and deaths due to non-neonatal tetanus (non-NT). Tetanus surveillance can provide key epidemiological information about non-NT. The systematic, timely and continuous collection, analysis and interpretation of epidemiological data on tetanus cases and the timely dissemination of the results can facilitate appropriate action for the control and prevention of cases. Objectives The objectives of non-NT surveillance are to: z monitor the disease burden and changing epidemiology over time in order to assess the impact of vaccination; z identify gaps in the immunization programme; z inform targeted strengthening of routine immunization services; z optimize strategies and immunization schedules, including introduction and timing of booster doses; z detect and investigate unusual disease clusters; and z rapidly detect cases to save lives through proper treatment, including antitoxin. Types of surveillance Minimal surveillance: The minimal surveillance recommended is nationwide and population-based. It should include all persons above the age of 28 days. Aggregate surveillance should be conducted with routine reporting from inpatient facilities and any unusual disease cluster must be investigated. Enhanced surveillance: This comprises case-based surveillance to help understand the epidemiology of the disease and the causes of infection. It also entails the monitoring of treatment practices and disease outcomes. Either nationwide or sentinel surveillance may be conducted, depending on: z the burden of disease; z health-seeking behaviours; and z the resources available (sentinel surveillance requires fewer resources). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 Surveillance procedure A formal surveillance network must be created involving hospitals which have facilities to care for tetanus cases or non-NT reporting. Each of these hospitals should nominate a surveillance focal point. The focal point and key clinical staff (such as ICU staff) must be sensitized to recognize and report non-NT cases as per national guidelines. In countries employing aggregate surveillance, designated reporting sites must report the number of inpatients with a final diagnosis of non-NT at a specified frequency (weekly or monthly), even if there are zero cases (referred to as “zero reporting”). The surveillance staff should regularly verify and monitor the health facility reports, especially to detect an unusually high number of cases, which may be either due to errors in data entry (which need to be corrected) or clustering of cases (which needs to be investigated). In countries opting for case-based surveillance, public and private referral hospitals which have intensive care capacity and are located in areas with high non-NT burden should be prioritized as sentinel sites, to begin with. Later, the network can be expanded to include additional sites so that a larger extent of the population may be covered. Linkages with other surveillance systems Surveillance for non-NT may be linked with: z aggregate surveillance systems for other diseases (such as Integrated Disease Surveillance and Response and Early Warning Alert and Response Network); z health management information system reporting for facility-based aggregate reporting of cases; and z maternal death surveillance and response (MDSR) and other maternal and child health surveillance systems. Special considerations Serological surveys: As immunity against tetanus does not result from natural infection, tetanus seroprotection reflects population immunity from vaccination. Serological assessments of tetanus IgG antibody levels may be useful for evaluating protection against tetanus, and identify immunity gaps in different age groups for launching an intervention. Immunity gaps: Investigations have documented immunity gaps and a higher burden of disease in children of the schoolgoing age and adult men in countries that do not provide 7NON-NEONATAL TETANUS the WHO-recommended six doses of tetanus toxoid-containing vaccine (TTCV) to both sexes. All immunization programmes should review programme data and adjust routine immunization schedules to ensure tetanus protection over the life course (three primary doses in infancy and three booster doses in childhood/adolescence). Humanitarian emergencies: Whenever surveillance systems are set up during humanitarian emergencies, non-NT should be considered for inclusion because of the documented outbreaks after earthquakes and tsunamis. Case detection Definition of suspected case A suspected case is any person of age > 28 days with acute onset of at least one of the following: z trismus (lockjaw) z risus sardonicus (sustained spasm of the facial muscles) z generalized muscle spasms (contractions). Case definition The disease is characterized by painful muscular contractions, primarily of the muscle for chewing (masseter) and neck muscles. The muscle stiffness usually begins in the jaw and neck and then becomes generalized, also involving the trunk muscles. There may be difficulty in swallowing, the body temperature may be raised, the pulse rate fast, and there may be sweating. Generalized spasms induced by sensory stimuli (light/sound) occur frequently. These spasms may last for several minutes, and continue for 3–4 weeks. Complete recovery may take months. A typical feature is a fixed grin with raised eyebrows, known as risus sardonicus. This is caused by sustained spasm of the facial muscles. During tetanus spasms, the patient is usually conscious. A history of an injury or portal of entry of the infection may be lacking. Three different forms of tetanus may be diagnosed on the basis of clinical findings – generalized is the most common, localized is uncommon, and cephalic is rare. Date of onset of illness The date of onset should be considered as the date of onset of at least one of the following (whichever comes first): lockjaw/ facial muscle spasm/any generalized muscle contraction. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Investigation of a suspected case Case investigation form In countries conducting aggregate surveillance, information should be collected at designated health facilities from inpatient records for cases with a final diagnosis of non- NT, and reported to the next higher level, based on national surveillance guidelines. No further investigation is needed except in the case of unusual disease clusters. A sample data collection form is given at Annex 2. In countries conducting case-based surveillance, each suspected case should be investigated using a standard case investigation form, ideally within seven days of notification, to confirm the diagnosis and determine the cause of infection. The completed case investigation forms detailing findings and actions taken or recommended must be sent to the next level and written feedback must be given to the reporting facility and community. A sample data collection form is given at Annex 3. Assigning a unique ID In countries conducting case-based surveillance, each suspected case should be assigned a unique case identification number (UID). The UID should begin with one or more three- letter combinations to designate the geographic location, followed by the year and the case number. All communications and forms related to the case should cite the UID. For example: TET– code for suspected tetanus (non-neonatal) BHU – country code PRO – province code DIS – district code 2022 – year of onset 001 – serial number of case in the province The UID would then be TET-BHU-PRO-DIS-22-001. Specimen collection Specimens are not collected for non-NT cases, as there is no laboratory diagnosis. Laboratory testing The organism is recovered from the site of infection in only about 30% of cases, and usually there is no antibody response. Besides, because of its ubiquitous nature, the bacteria may occasionally be grown from patients who do not have tetanus. Hence, laboratory 9NON-NEONATAL TETANUS conformation of the disease is not recommended. The diagnosis is based entirely on the clinical features. The clinician should rule out conditions that display a similar clinical presentation (like hypocalcemic tetany, drug-induced dystonias (from drugs such as phenothiazines), meningoencephalitis, strychnine poisoning and trismus due to dental infections). Classification of cases Classification is based entirely on the clinical features and does not depend on laboratory confirmation. Confirmed: A case that meets the definition of a suspected case and is clinically confirmed by a physician/trained clinician. Probable: A case that meets the definition of a suspected case without clinical confirmation by a physician/trained clinician. Discarded: A case that has been investigated and does not satisfy the clinical criteria for confirmation or has an alternative diagnosis. Contact tracing As tetanus is not contagious, no contract tracing is needed. Clinical management Non-NT is a medical emergency requiring hospitalization and immediate treatment. Tetanus immune globulin (TIG) is recommended. A single intramuscular dose of 500 units is generally recommended for children and adults, with part of the dose infiltrated around the wound, if it can be identified. Note that TIG can only help remove unbound tetanus toxin. It cannot affect toxin bound to nerve endings. If TIG is not available, equine- derived ATS can be given in a single intravenous dose after testing for hypersensitivity. Alternatively, intravenous immune globulin (IVIG), which contains tetanus antitoxin, may be used. The patient must also be given drugs to control muscle spasms (preferred: benzodiazepines), and antibiotics (preferred: metronidazole or penicillin G). All wounds should be cleaned. Necrotic tissue and foreign material should be removed. Supportive care should also be provided. The patient must be kept in a dark and quiet environment to reduce the risk of reflex spasms. If muscle spasms are occurring, it is critical to maintain a safe airway. If Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 mechanical ventilation is not available, the patient must be carefully monitored in order to minimize spasms and autonomic dysfunction, while avoiding respiratory failure. Because of the extreme potency of the toxin, tetanus disease does not result in tetanus immunity. Active immunization with tetanus toxoid should be considered as soon as the person’s condition has stabilized. The need for active immunization, with or without passive immunization, depends on the condition of the wound and the patient’s immunization history. Rarely have cases of tetanus been reported in persons with a documented history of primary series of tetanus toxoid. A patient whose wounds are neither clean nor minor and who has had fewer than three prior doses of tetanus toxoid or has an unknown history of prior doses, should receive TIG as well as tetanus toxoid vaccine. This is because early doses of toxoid may prime the immune system but not induce immunity. TIG provides temporary immunity by directly providing antitoxin. This ensures that protective levels of antitoxin are achieved even if an immune response has not yet occurred. Finally, before discharge, age-appropriate TTCV should be administered to prevent future disease. Outbreaks There is no person-to-person transmission in non-NT infection, therefore the conventional outbreak of infectious diseases does not occur. However, cases may cluster together in time and space as a result of the same exposure, for example, clusters of cases have been documented after natural disasters, after male circumcision and from injection drug use. Any significant increase compared with previous reports from the same area within a comparable time frame should be investigated, though there is no threshold number beyond which investigation should be conducted. In all countries conducting any type of non-NT surveillance, data should be regularly monitored to identify potential clustering of cases. When such clustering occurs: z the cases must be investigated for a common environmental exposure risk factor (nosocomial, occupational, accident); z all cases with all possible essential variables must be line listed so that a more detailed analysis can be conducted (by age, sex, vaccination status, risk factors, treatment, etc.); z the results of the detailed analysis must be used to formulate risk mitigation efforts for individuals and health-care settings, including vaccination and promotion of improved hygiene practices. 11 NON-NEONATAL TETANUS Data management Reporting requirements z The number of non-NT cases should be reported separately from NT cases by designated reporting sites weekly, monthly or at another specified frequency, even if there are zero cases (zero reporting). Only confirmed inpatient cases should be counted for national reporting. Including outpatients could result in overestimation because of problems such as misdiagnosis, reporting errors from smaller facilities or double counting of outpatients referred for inpatient admission. z Case investigation forms or electronic data related to the cases should be reported to the national level. z Cases of non-NT must be reported annually (separately from NT) to WHO–UNICEF through the Joint Reporting Form. z Reporting of tetanus is not a requirement under International Health Regulations. Unique ID In countries conducting case-based surveillance, a UID should be generated for each case. Recommended data elements For aggregate surveillance, the data needed are: z age group (recommended: 29 days–4 years, 5–14 years, 15–44 years, 45– 64 years and 65+ years, but can be adjusted according to the needs of the surveillance system) z sex z date z geographical area z immunization status (if possible). (For more information, see Annex 2.) The following are required for case-based surveillance: z case notification z demographic information z clinical data z vaccination status z risk factors z treatment z outcome. (For more information, see Annex3.) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 Data analysis z Number of cases and incidence rate by month, year and geographical area z Incidence rate by sex and age group z Trends in the sex ratio of cases over time z Proportion of cases protected against tetanus z Proportion of cases by risk factor z Proportion of cases who received TIG/ATS/IVIG z Case-fatality ratio (number of non-NT deaths / number of non-NT cases x 100) z Proportion of maternal tetanus cases As with other diseases, surveillance data should be triangulated with data from the immunization programme, such as coverage and history of vaccination schedules, to understand the entire picture when drawing conclusions and formulating new policy. Table 7.1: Using data for decision-making Data Decision Disease burden impact of vaccination, including TTCV campaigns targeting women of reproductive age or wide- range campaigns targeting both sexes with TT- conjugate vaccines such as MenA. Identify and investigate non-NT disease clusters to determine risk factors and design appropriate risk mitigation strategies such as provision of vaccine and improved hygiene practices. Identify gaps in the immunization programme (areas with low coverage, cold chain issues resulting in frozen TTCV, etc.) to inform targeted strengthening of routine immunization services or need for catch-up vaccination. Identify groups at higher risk for tetanus infection (women of reproductive age, children of schoolgoing age, male adults, elderly) to inform changes in policy or strategy such as introduction of booster doses or optimization of schedule. Assess tetanus risk factors (occupation, road accidents, unclean deliveries/surgeries, migrant status, ethnicity) periodically to design and implement messaging and interventions appropriately. 13 NON-NEONATAL TETANUS Data Decision Identify cases rapidly for appropriate case management, including provision of TIG/ATS/IVIG. Monitor surveillance reporting to identify areas that need targeted surveillance reviews or strengthening. Evaluation of surveillance performance z Non-NT surveillance should be evaluated through periodic national reviews approximately every five years. This should be integrated with the evaluation of other VPDs and include triangulation of aggregate and case-based NT reports as well as a review of facility records for missed cases. z Targeted subnational reviews and data quality assessments can be conducted more frequently. z Surveillance, coverage and programme performance data may be reviewed at the national and subnational levels as part of the quarterly data review meetings of the Expanded Programme on Immunization. This could help identify potential areas of surveillance gaps or areas where surveillance needs to be strengthened. z The regular monitoring of surveillance indicators could help identify specific areas of the surveillance system and reporting network that should be targeted for improvement. Table 7.2 lists some indicators that could be used. Table 7.2: Key performance indicators Surveillance attribute Indicator Target How to calculate Comments Completeness of reporting Proportion of designated reporting sites reporting data, even in the absence of cases ≥ 90% (Number of designated sites reporting in absence of cases/ number of designated sites) x 100 Designated reporting sites for non-NT surveillance might only include hospitals or referral hospitals, rather than all health facilities. Timeliness of reporting Proportion of designated sites reporting non- NT data on time ≥ 80% (Number of designated sites reporting non-NT on time /number of designated reporting sites) x 100 At each level, reports should be received on or before the requested date. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 Surveillance attribute Indicator Target How to calculate Comments For case-based surveillance only Completeness of investigation Proportion of suspected cases investigated (among cases included in surveillance) ≥ 90% (Number of cases investigated / number of suspected cases reported) x 100 If database includes only data on case investigations performed, this indicator can be calculated as: (Number of suspected cases in the dataset / number of suspected cases in the aggregate report) x 100. This will reflect the representativeness of case-based surveillance and efficiency of case investigations. Timeliness of investigation Proportion of suspected cases investigated within 7 days of notification ≥ 80% (Number of suspected cases investigated within 7 days of notification / number of suspected cases investigated) x 100 15 NON-NEONATAL TETANUS Annex 1: Disease epidemiology Background Tetanus is a potentially fatal disease that is caused by the spore-forming bacterium Clostridium tetani. Spores – the dormant form of the organism – are found in soil contaminated with animal and human excreta in all parts of the world. Tetanus occurs when wounds or injured tissues are contaminated with these spores. The spores enter the body through breaks in the skin and germinate under anaerobic conditions. Puncture wounds and wounds with a significant amount of tissue injury are more likely to promote germination. In some cases, the site of entry is unknown or no longer visible when symptoms start. The organism produces a potent toxin, tetanospasmin, which binds to gangliosides at neuromuscular junctions and proceeds along the neuron to the ventral horns of the spinal cord or motor horns of the cranial nerves in 2–14 days. The toxin can also be absorbed through the blood stream and lymphatic system. Once the toxin reaches the nervous system, it causes painful and often violent muscular contractions. Most often, the muscle stiffness initially involves the jaw (lockjaw) and neck, and later becomes generalized. Tetanus is not transmitted from one person to another. It may occur at any age and the case fatality rates are high even where intensive care is available. The disease remains an important public health problem in many parts of the world where immunization programmes are suboptimal, particularly in the least developed districts of low-income countries. In many countries, tetanus disease surveillance is not well established, and its incidence is not known accurately. Historically, surveillance systems have focused on the detection of neonatal tetanus cases in health facilities. However, many cases occur outside the reach of the health system and are not reported. Tetanus is preventable through immunization with TTCVs, which are included in routine childhood immunization programmes globally, and administered during antenatal care contacts in many countries. Clean medical practices can also prevent tetanus disease including clean delivery and cord care for childbirth and proper wound care for surgical and dental procedures. In countries where national programmes have maintained high coverage of TTCVs for several decades, tetanus incidence rates are very low. In these settings, tetanus cases tend to occur in unimmunized or insufficiently immunized individuals. Annexes Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 Essential epidemiology Infectious agent: Clostridium tetani Reservoir of infection: The intestines of horses and other animals including humans comprise the normal habitat of the bacteria, which resides there harmlessly. Soil and fomites contaminated with animal and human faeces contain the spores of the organism. Mode of transmission: Tetanus spores are usually introduced into the body through a wound (lacerations, burns, or trivial or unnoticed wounds) contaminated with soil, street dust or animal or human faeces. They may also be introduced by injected contaminated street drugs. Tetanus occasionally follows surgical procedures. The presence of necrotic tissue and/or foreign bodies favours the growth of the anaerobic bacteria. Incubation period: The incubation period is usually 3–21 days, though it can range from 1 day to several months, depending upon the character, extent and location of the wound. In general, the farther the site of injury is from the central nervous system, the longer is the incubation period. The average incubation period is 10 days, the median is 7 days. In general, the shorter the incubation period, the more severe is the disease. Period of communicability: Not directly transmitted from person to person. Case fatality ratio: Among patients in the youngest and oldest age groups without intensive care, the case fatality rate approaches 100%. With intensive care, the rate can be reduced to 10–20%, varying inversely with the length of the incubation period. Vaccine Tetanus toxoid, one of the earliest vaccines to be developed (in the 1920s), was widely used in World War II. The vaccine is available as a standalone single antigen vaccine and in combination with other antigens (TTCVs), for example diphtheria, pertussis, poliomyelitis, hepatitis B and the illness caused by Haemophilus influenzae type b (Hib). WHO recommends shifting from the use of single-antigen TT to combinations containing diphtheria toxoid, i.e. DT or Td vaccines. The administration of TTCVs is the most cost-effective measure for preventing tetanus. These vaccines are safe and affordable. WHO recommends 6 doses (3 primary plus 3 booster doses) of TTCV for lifelong protection. The primary series should begin as early as at the age of 6 weeks, with the subsequent doses being given at a minimum interval of 4 weeks. The 3 booster doses should preferably be given during the second year of life (12–23 months), at 4–7 years of age, and at 9–15 years of age. Ideally, there should be an interval of at least 4 years 17 NON-NEONATAL TETANUS between booster doses. Different national schedules are in use for the 3-dose primary series. Some vaccines containing TT are: z Diphtheria and tetanus (DT) vaccines z Diphtheria, tetanus, and pertussis (DTaP) vaccines z Tetanus and diphtheria (Td) vaccines z Tetanus, diphtheria, and pertussis (Tdap) vaccines. The pentavalent vaccine which provides protection against diphtheria, tetanus, pertussis, Hib and hepatitis B (DTP-Hib-HepB) is the most commonly used childhood vaccine worldwide. Other pentavalent (DTaP-IPV/Hib) and hexavalent (DTaP-IPV/Hib-HepB) combinations are also available. For booster dosing, a tetanus–diphtheria combination with a lower concentration of the diphtheria antigen (Td) is available. TT used alone or in combinations is considered very safe. Mild local reactions are common, but more serious reactions are rare. A complete vaccine series has a clinical efficacy of virtually 100% for tetanus. The following table shows the duration of protection provided Table 7. A1: Expected duration of protection provided by valid TTCV doses Cumulative no. of doses if vaccination began in infancy Cumulative no. of doses if vaccination began ≥1 year of age Minimum interval between doses to be considered valid Duration of protection from receipt of last dose TTCV1 TTCV1 -- None TTCV2/TTCV3 TTCV2 4 weeks 3 years TTCV4 TTCV3 6 months 5 years TTCV5 TTCV4 1 year 10 years TTCV6 TTCV5 1 year 20–30 years by TTCV doses. If vaccination begins in infancy, 6 TTCV doses are required; if vaccination begins after the first year of life, five appropriately spaced doses of TTCV are sufficient. A “valid dose” is a dose administered after the minimum time interval required. TTCV doses received during childhood are considered only if verified by written records, such as infant or school vaccination records. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 Burden of disease In 2020, approximately 11 763 tetanus cases were reported globally through the WHO/ UNICEF Joint Reporting Form. This number is likely to be an underestimate because in general, there is low reporting sensitivity for tetanus cases. Besides, surveillance systems have historically focused on the detection of neonatal tetanus cases in health facilities. In many countries tetanus disease surveillance is not well established, and its incidence is not known accurately. Moreover, many cases occur outside the reach of the health system and are not reported. In 2019, the Global Burden of Disease Study estimated over 73 000 total tetanus cases, including over 27 000 neonatal tetanus infections. Of the 11 763 cases reported in 2020, about two thirds (7737) were from the African Region, and about 15% (1783), from the South-East Asia Region. Almost all the cases in the South-East Asia Region were reported by India, Nepal and Bangladesh, with India accounting for three fourths of the total. There was a decline of a little over 50% in the number of tetanus cases reported globally in 2020 as compared to that reported in 2000. In the same period, the South-East Asia Region documented a decline of about 85% in the number of cases reported, from a total of 11,554 cases in 2000 to 1783 in 2020. 19 NON-NEONATAL TETANUS Annex 2: Sample form for aggregate surveillance Source of notification (Name of health facility) Village/ town/ city District Province/ state Diagnosis Confirmed  Probable  Age group 29 days–4yrs  5–14 yrs  15–44 yrs  45–64 yrs  65+ yrs  Sex Male  Female  Unknown  Vaccination history Dose 1 Yes  No  Unknown  If yes, date: Dose 2 Yes  No  Unknown  If yes, date: Dose 3 Yes  No  Unknown  If yes, date: Dose 4 Yes  No  Unknown  If yes, date: Dose 5 Yes  No  Unknown  If yes, date: Dose 6 Yes  No  Unknown  If yes, date: Boosters given after 6th dose Yes  No  Unknown  If yes, date: Comment(s) Name of person reporting: Designation: Institution: Telephone (mobile): Email: Date: Signatures: Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Annex 3: Case investigation form Case identification number: Non-NT_____/____________/__________/____/_____ Country code/ Province code/District code/ Year/serial number Patient information Name and address of health facility Patient’s name Age in years / months 29 days–4yrs  5–14 yrs  15–44 yrs  45–64 yrs  65+ yrs  Date of birth dd/mm/yyyy Sex Male  Female  Unknown  Residential address City / District / Province / State Contact number (mobile) Educational status Migrant status Clinical data Date of admission dd/mm/yyyy Date of investigation dd/mm/yyyy Date of onset of symptoms dd/mm/yyyy Fever: Yes  No  Unknown  Trismus Yes  No  Unknown  Duration (in days) Risus sardonicus Yes  No  Unknown  Muscle spasm Yes  No  Unknown  Duration (in days) Vaccination history TTCV received Yes  No  If yes, specify Hib  Men A  Men C  Pneumo  Typhoid  TT  21 NON-NEONATAL TETANUS Vaccination history Source of vaccination information Vaccination card  Medical records  Maternal recall  Others  specify: TTCV doses received Dose 1 Yes  No  Unknown  If yes, date Dose 2 Yes  No  Unknown  If yes, date Dose 3 Yes  No  Unknown  If yes, date Dose 4 Yes  No  Unknown  If yes, date Dose 5 Yes  No  Unknown  If yes, date Dose 6 Yes  No  Unknown  If yes, date Boosters given after 6th dose Yes  No  Unknown  If yes, date Risk factors O cc up at io n Please specify History of wound/injury (including chigger/jigger infestation and IV drug use) Yes  No  Unknown  History of surgery or medical procedure (e.g. male circumcision) Yes  No  Unknown  History of dental infection Yes  No  Unknown  History of ear infection Yes  No  Unknown  Maternal tetanus Yes  No  Unknown  Maternal tetanus Current pregnancy ( within the last 6 weeks ) Number of antenatal care visits Pregnancy outcome Live birth/ healthy child  Live birth/NT case  Still birth  Miscarriage/ abortion  Information on birth / termination Date of birth/ termination dd/mm/yyyy Place of birth Hospital  Health centre  Home  Others  Specify Not known  Delivery attended by Health staff  Traditional birth attendant  Family member  Alone  Others  Specify Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 Treatment given Te ta nu s im m un og lo bu lin Yes  No  Unknown  If yes, date Antitoxin tetanus serum Yes  No  Unknown  If yes, date Intravenous immune globulin Yes  No  Unknown  If yes, date A nt ib io tic s Yes  No  Unknown  If yes, specify: Date of starting dd/mm/yyyy Duration Classification Final classification Confirmed  Probable  Discarded  Outcome Follow-up Discharged alive  Lost to follow- up  Died  Left against medical advice  Date of death/ discharge dd/mm/yyyy Comments Investigator’s name: Designation: Institution: Telephone (mobile): Email: Date: Signature: 23 NON-NEONATAL TETANUS Further reading 1. Behrens H, Ochmann S, Dadonaite B and Roser M. Tetanus [website]. Published online at OurWorldInData.org; 2019 (https://ourworldindata.org/tetanus[Online Resource], accessed 13 August 2022). 2. Causey K, Fullman N, Sorensen RJD, Galles NC, Zheng P, Aravkin A, et al. Estimating global and regional disruptions to routine childhood vaccine coverage during the COVID-19 pandemic in 2020: a modelling study. Lancet. 2021;398 (10299):522–34. doi: 10.1016/S0140-6736(21)01337-4. 3. Blain A, Tiwari TSP. Chapter 16: Tetanus. In: Roush SW, Baldy LM, Hall MAK (eds). Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention, Atlanta, GA (https://www.cdc.gov/vaccines/pubs/ surv-manual/index.html, accessed 21 July 2022). 4. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020; 396 (10258):1204–22. doi: 10.1016/S0140-6736(20)30925- 9. 5. Tetanus vaccines: WHO position paper – February 2017. Wkly Epidemiol Rec. 2017;92(6):53–76. 6. World Health Organization. Non-neonatal Tetanus: surveillance standards for vaccine-preventable diseases. World Health Organization; 2018. (https:// www.who.int/publications/m/item/vaccine-preventable-diseases-surveillance- standards-non-neonatal-tetanus, accessed 13 August 2022). 7. World Health Organization. Protecting all against tetanus: guide to sustaining maternal and neonatal tetanus elimination (‎MNTE)‎ and broadening tetanus protection for all populations. World Health Organization; 2019 (https://www. who.int/publications/i/item/protecting-all-against-tetanus, accessed 13 August 2022). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24 25 NON-NEONATAL TETANUS Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 26 CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region MODULE-8 HEPATITIS B September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Hepatitis B) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO CONTENTS Introduction 5 Objectives 5 Types of surveillance 6 Minimal syndromic surveillance 6 Enhanced case reporting 6 Special considerations 7 Case detection 7 Definition of presumptive case 7 Chronic infection 7 Date of onset of illness 8 Response to presumptive case 8 Case investigation 8 Unique ID 8 Specimen collection 8 Laboratory testing 9 Classification of cases 10 Contact management 10 Clinical case management 10 Outbreak 10 Definition 10 Modifications in surveillance 10 Public health response 10 Data management 11 Reporting requirements 11 Unique ID 11 Recommend data elements 11 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Data analysis 12 Using data for decision-making 12 Surveillance performance indicators 13 Annex 1: Disease epidemiology 15 Background 15 Essential epidemiology 15 Vaccines 16 Disease burden 16 Annex 2: Case investigation form 17 Further reading 20 5HEPATITIS B Hepatitis B Introduction An infection with the hepatitis B virus (HBV) may evolve in three phases: z A new infection is most often asymptomatic, but may sometimes be symptomatic in the form of acute hepatitis. z This may evolve into chronic infection, which too is usually asymptomatic. z Finally, it may evolve into cirrhosis and hepatocellular carcinoma (HCC) that lead to morbidity and mortality. Surveillance can be conducted for any or all of these phases. However, acute and chronic infections are frequently asymptomatic in children. Besides, surveillance for chronic hepatitis cannot inform a vaccine programme or evaluate its impact in a timely manner due to the long gap between an infection and its chronic sequalae. As there can be an interval of more than 20–30 years between infection and mortality, ideally viral hepatitis surveillance must capture all three phases to describe the epidemiological situation fully (Table 8.1). Table 8.1: Usefulness of surveillance for the three phases of infection Phase Usefulness New infection Guides prevention activities Chronic infection Guides testing and treatment Cirrhosis and HCC Quantifies the baseline burden and evaluates the impact of past interventions Objectives The objectives of surveillance are to: z detect outbreaks of viral hepatitis (local) z monitor trends in incidence among high-risk adult populations and identify risk factors for new infections (local, national) z estimate the prevalence of chronic infections and monitor trends in sentinel groups, including the impact of vaccination programmes on these groups (local, national, regional/global) z estimate the burden of sequelae of chronic hepatitis, including cirrhosis, liver failure and carcinoma, and mortality due to these (national, regional/global); and Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 z provide data to inform vaccine introduction among high-risk populations (national). Types of surveillance Most new infections are asymptomatic, hence undiagnosed. However, capturing a constant fraction of new infections that are detected because they are symptomatic provides information on trends in acute hepatitis. Minimal syndromic surveillance This uses presumptive case definitions based on presentation and clinical examination at health-care facilities. It captures undifferentiated, acute viral hepatitis, and is a baseline surveillance that is not resource intensive. The detection of acute hepatitis outbreaks should lead to laboratory testing to confirm the aetiology of the outbreak. However, the usefulness of this type of surveillance is limited to detecting large outbreaks, which are usually of hepatitis A or E. Enhanced case reporting Syndromic surveillance supplemented by case-based surveillance (including laboratory confirmation and collection of more data elements on all suspect cases) is known as enhanced case reporting. It uses confirmed case definitions based on a combination of clinical and biomarker criteria, usually in fixed sentinel sites. It captures cases of acute hepatitis by type (A, B, C, D or E), following diagnosis (i.e. immunoglobulin tests), and collects information on possible exposure. Enhanced case reporting of acute hepatitis is particularly important in places where the incidence of new HBV infection is high. If the national system for acute hepatitis surveillance is based on syndromic case definitions, enhanced case reporting can be established in a small number of sentinel facilities which have diagnostic facilities and staff who can collect information on potential risk factors. Building on universal syndromic surveillance and adding enhanced case reporting allows for a description of trends in type-specific acute hepatitis and contributes to the generation of hypotheses regarding the predominant modes of transmission. Enhanced case reporting may be implemented: z during outbreaks of acute hepatitis; and z in sentinel sites, which could be extended nationwide, depending on resources and the objectives of surveillance. 7HEPATITIS B Special considerations z Some behaviours (for example, injection drug use or men having sex with men) that put a person at increased risk for hepatitis B can be considered sensitive, stigmatized or illegal in a country. Hence, confidentiality of all collected data is of the utmost importance, and the term “presumptive case” should be used instead of “suspected case”. z Laboratory test results should be returned to the patient. This is more important in the case of positive results, as infected patients should be counselled on appropriate clinical follow-up and ways of reducing the risk of transmission to contacts. z Surveillance is not considered an effective tool to measure the impact of childhood vaccination in a timely manner. However, conducting serosurveys of hepatitis B biomarkers provides a useful measure of the impact of vaccination. Details on how to conduct such surveys are described in other WHO documents. Case detection Definition of presumptive case A presumptive case of acute hepatitis B is a person with either or both of the following: z discrete onset of an acute illness with symptoms of acute infectious illness (fever, malaise, fatigue) along with signs of liver damage: z anorexia, z nausea, z jaundice, z dark urine, z tenderness in right upper quadrant of abdomen z raised alanine aminotransferase (ALT) levels more than ten times the upper limit of normal (400 IU/L). Please note that “ten times the upper limit of normal (400 IU/L)” is the threshold used by the United States’ State and Territorial Epidemiologists (CSTE). Countries may select lower (more sensitive) or higher (more specific) thresholds. Chronic infection Most people with chronic hepatitis B do not have any symptoms, do not feel ill, and remain symptom free for decades. When and if symptoms appear, they are similar to the symptoms of new infection. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Date of onset of illness The date of onset of illness is the date of onset of key symptoms consistent with acute viral hepatitis as determined by the examining physician based on the clinical judgement. Response to presumptive case Case investigation Syndromic surveillance for acute hepatitis: All outbreaks should be investigated immediately and confirmed serologically. Enhanced surveillance: Case investigation forms should be filled for each individual case of acute hepatitis and appropriate specimens should be collected for confirmatory testing. See Annex 2 for a sample case investigation form. Unique ID A unique case identification number (UID) should be assigned to each suspected case. This number should begin with one or more three-letter combinations to denote the geographical location, followed by the year and case number. All communications and forms related to the case should cite the UID. For example: HBV – code for presumptive hepatitis B PRK – country code PRO – province code DIS – district code 2022 – year of onset 001 – serial number of case in the province The UID would then be HBV-PRK-PRO-DIS-22-001. Specimen collection If biomarker testing is available, a blood sample should be collected through venepuncture and sent to the laboratory for testing by ELISA. Blood should be drawn from acutely ill patients. Collection tubes for serum or plasma may be used. Serum and plasma samples may be stored for up to five days at 2–8°C or for four weeks at -20°C. IgM can persist up to six months after onset. 9HEPATITIS B Laboratory testing ELISA testing for the presence of antigen or antibody is the recommended testing methodology. Acute hepatitis: The recommended methodology is ELISA testing for immunoglobulin M antibodies to core antigen of hepatitis B virus (IgM-anti HBc). Chronic hepatitis: ELISA or rapid diagnostic test may be conducted for the hepatitis B surface antigen (HBsAg). Table 8.1: Interpretation of serological test results Biomarkers Acute phase Chronic phase Cleared Vaccination HBcAb IgM + - - - HBcAb IgG + + + - HBsAg + + - - Anti-HBs - - + + HBeAg + +/- - - Anti-HBe - +/- +/- - HBV DNA High/low Low/high - - HBcAb IgG: hepatitis B core antibody immunoglobulin G; HBcAb IgM: hepatitis B core antibody immunoglobulin M; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen. Source: Pattyn J, Hendrickx G, Vorsters A, Damme PV (3) z In limited resources settings, a serial approach might be considered. Initially, testing may be conducted for the most common type of hepatitis. If the result is negative, the sample may be tested for the next common type, and so on. z If resources are adequate, a standard panel of serological assays for all the hepatitis viruses may be used for all presumptive cases. z The ALT level might also be tested to determine whether a patient falls under the presumptive case definition. z Genotype testing may also be undertaken, though this is of limited utility in routine surveillance. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 Classification of cases Laboratory-confirmed case: A laboratory-confirmed case meets the presumptive case Discarded case : a case that does not meet the laboratory confirmation criteria and/or the presumptive case Contact management Contact investigations are not usually conducted in acute hepatitis B surveillance. In settings with enhanced case reporting (such as health-care facilities), individuals known to have been exposed to hepatitis B through percutaneous or mucus-membrane contact should receive post-exposure prophylaxis with the hepatitis B vaccine, hepatitis B immunoglobulin (HBIG) or both, depending on their history of vaccination and the serostatus of the source of exposure. Clinical case management Clinical care for hepatitis B should be in line with the country’s guidelines. Outbreak Definition An outbreak of acute hepatitis B is an increase of incidence over the reported baseline. Most outbreaks of hepatitis B are healthcare related (for example, haemodialysis or unsafe injections). Modifications in surveillance If a country is conducting syndromic surveillance for acute hepatitis, the detection of an outbreak should trigger an investigation, which should include the laboratory testing of acute cases to determine the aetiology. Case report forms should include new data elements pertaining to the mode of transmission. Public health response The contacts of cases should be offered testing, post-exposure prophylaxis and prevention services, where feasible. 11 HEPATITIS B Data management Reporting requirements Health-care workers should report cases of acute viral hepatitis to the local public health authority. Case reporting can be syndromic (where no testing is done and cases are reported on the basis of signs and symptoms) or type-specific, based on biomarker testing. There should be routine monthly reporting of aggregated data on presumptive cases. If available, the number of confirmed cases of each type of hepatitis should be reported from the peripheral level to the intermediate and central levels. HBV is currently not required to be reported under International Health Regulations (2005) or as part of the WHO/UNICEF Joint Reporting Form. Designated reporting sites at all levels should report at a specified frequency (such as weekly or monthly) even if there are zero cases (“zero reporting”). Unique ID A unique case identification number should be assigned to each suspected case, as explained earlier. Recommend data elements For aggregated data collection z Number of total acute hepatitis cases by age group, month and geographical area For case-based data collection z Name (if confidentiality is a concern, only UID) z UID z Date of birth (or age) z Sex z Place of residence (city, district and province) z Date of onset z Signs and symptoms: Fever, malaise, fatigue, anorexia, nausea, jaundice, dark urine, right upper quadrant tenderness z Acute liver failure z Contact of a laboratory-confirmed case Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 z Number of hepatitis B vaccine doses received z Dates of all hepatitis B vaccine doses (if card available) z Laboratory z Specimen collected z Date of specimen collection z Date specimen sent to laboratory z Date specimen received in laboratory z Results of serology tests (IgM-anti HBc, HBsAg, others) z Results of testing for other viral hepatitis z ALT result z Date of notification to public health department z Date of investigation z Final case classification (Please see Annex 2 for further details.) Data analysis Data analysis for acute hepatitis surveillance with enhanced case reporting should include: z number of acute hepatitis B cases and incidence rate by month, year and geographical area; and z age-specific, gender-specific and district-specific incidence rates by month/ year. Using data for decision-making Acute hepatitis surveillance data may be used to: z identify risk factors z prevent infections in populations at higher risk by implementing prevention strategies, including vaccination z describe trends z identify breakthrough infections among vaccine recipients z estimate vaccine efficacy among children, using the screening method. The following considerations must be kept in mind while interpreting surveillance data: 13 HEPATITIS B Children are frequently asymptomatic, so routine surveillance information is not useful in determining the introduction or impact of paediatric vaccination. Surveillance data related to chronically infected patients may be problematic since patients might be serially tested and there may be duplicate reporting. Risk groups might be under-represented or missed in population-based surveillance or surveys of the general population. Surveillance performance indicators z There are no formal performance indicators for acute hepatitis surveillance. z Countries might choose to monitor surveillance regularly to identify specific areas of surveillance and the reporting system that need improvement. z At the minimum, syndromic surveillance should be evaluated to determine if it is detecting outbreaks as designed. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 15 HEPATITIS B Annex 1: Disease epidemiology Background The term “hepatitis” is used to describe inflammation of the liver. Viruses are the most common cause of hepatitis. The commonest types of viral hepatitis are denoted by the letters A, B, C, D, and E. Table 8. A1 shows the routes of transmission of these viruses. Type Transmission A (HAV) E (HEV) Hepatitis A and E are typically caused by the intake of food or water contaminated by the faeces of someone with the infection. B (HBV), C (HCV), D(HDV) Hepatitis B, C and D usually occur as a result of parenteral contact with infected body fluids. They are commonly transmitted through contaminated blood or blood products and invasive medical procedures using contaminated equipment. Hepatitis B is also transmitted from mother to baby at birth, from family member to child, and through sexual contact. Essential epidemiology Infectious agent: The hepatitis B virus is a hepadnavirus. It is relatively heat stable, remains infectious for at least one week in the environment, and is highly infectious. Reservoir of infection: Humans are the only known reservoir for human HBV genotypes, but closely related HBV genotypes exist in higher primates. Mode of transmission: Hepatitis B can be transmitted vertically, from mother to infant; and horizontally, through parenteral contact with infected body fluids. Incubation period: The incubation period ranges from 30 to 180 days. On an average, it is about 75 days. The virus may be detected within 30–60 days after infection and can persist and lead to chronic hepatitis B, especially when transmitted in infancy or childhood. Period of communicability: An infected person is potentially infective 2–3 weeks before the onset of symptoms, during the clinical disease and for 2–3 months after acute infection or as long as HBsAg continues to be present in the blood. All persons who are HBsAg- positive are potentially infectious, and those with detectable HBV DNA in the blood are highly infectious. Annexes Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 Case fatality rate: Fulminant disease develops rarely in infants and children, but occurs in 0.5–1% of adult cases of acute hepatitis B, with a case fatality rate of 20–33%. About 1 in 4 people who become chronically infected during childhood and about 15% of those who become chronically infected after childhood will eventually die from serious liver conditions such as cirrhosis or liver cancer. Vaccines There is a large number of WHO pre-qualified vaccines for hepatitis B. These are available as monovalent formulations to be administered at birth or for the vaccination of adults who are at risk, and in combination with other vaccines for infants, including diphtheria– tetanus–pertussis (DTP), Haemophilus influenzae type b (Hib), and inactivated polio vaccine (IPV). The Global Advisory Committee on Vaccine Safety (GACVS) has confirmed the excellent safety profile of hepatitis B vaccines. In general, there are mild adverse reactions, such as local pain, myalgia and transient fever, mostly within 24 hours of vaccination. The reactions tend to be less common in children than in adults (<10% vs 30%). WHO recommends that all infants receive the first dose of the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours, followed by 2 or 3 doses at least 4 weeks apart, to complete the vaccination series. A primary 3- or 4-dose series induces protective antibody concentrations in >95% of healthy infants, children and young adults, and offers 98% to 100% protection against hepatitis B which lasts at least 20 years and is probably lifelong. WHO does not recommend booster vaccinations for persons who have completed the 3-dose vaccination series. Disease burden Globally, 1.5 million [1.1 million–2.6 million] people had new chronic hepatitis B infection and almost an equal number were infected with chronic hepatitis C in 2019, despite the existence of safe and effective vaccines that can prevent hepatitis B and antiviral drugs that can manage chronic hepatitis B and cure most cases of hepatitis C. In the same year, 820 000 [450 000–950 000] people died from causes related to hepatitis B infection and 290 000 [230 000–580 000] people died from hepatitis C infection. Much of the disease and death due to hepatitis B is preventable. An estimated 60 million people in the WHO South-East Asia Region live with chronic hepatitis B and around 10.5 million live with chronic hepatitis C. In 2019, around 180 000 people in the Region died of hepatitis B and about 38 000 died of hepatitis C. 17 HEPATITIS B Annex 2: Case investigation form Case identification number: HBV ______/____________/__________/____/_____ Country code/ Province code/District code/ Year/serial number Patient information Name of sentinel site Sentinel site code Patient’s name Age in years / months completed Date of birth dd/mm/yyyy Sex Male  Female  Unknown  Residential address City / District /Province / State Contact number (mobile) Clinical data Date of admission dd/mm/yyyy Date of onset dd/mm/yyyy Date of investigation dd/mm/yyyy Date of notification dd/mm/yyyy Fever: Yes  No  Unknown  Malaise Yes  No  Unknown  Fatigue Yes  No  Unknown  Anorexia Yes  No  Unknown  Nausea Yes  No  Unknown  Jaundice Yes  No  Unknown  Dark urine Yes  No  Unknown  Eyes/skin discolouration Yes  No  Unknown  Abdomen tenderness (rt upper side) Yes  No  Unknown  Any other Yes  No  Unknown  If yes, specify Contact of a laboratory- confirmed HBV case Yes  No  Unknown  Vaccination history Hep B Yes  No  Unknown  Birth dose dd/mm/yyyy 1st dose dd/mm/yyyy 2nd dose 3rd dose dd/mm/yyyy 4th dose dd/mm/yyyy Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 Source of information Birth dose card  Register  Memory  Unknown  1st dose card  Register  Memory  Unknown  2nd dose card  Register  Memory  Unknown  3rd dose card  Register  Memory  Unknown  4th dose card  Register  Memory  Unknown  Risk factors Alcohol and drug use Yes  No  Unknown  Unsafe sex Yes  No  Unknown  Family history of hepatitis Yes  No  Unknown  Recent gatherings/ festivals Yes  No  Unknown  History of jaundice in last 6 months Yes  No  Unknown  History of sharing razors/ needles/ toothbrush Yes  No  Unknown  History of getting tattoos Yes  No  Unknown  History of injections in last 6 months Yes  No  Unknown  History of surgical or dental intervention in last 6 months Yes  No  Unknown  Any other Samples collected Blood sample collected Yes  No  Unknown  If yes, date when collected dd/mm/yyyy Date specimen sent to laboratory dd/mm/yyyy Date specimen received in laboratory dd/mm/yyyy Laboratory results Hepatitis A Total antibody, HAV +ve  -ve  Unknown  IgM antibody to hepatitis A +ve  -ve  Unknown  Hepatitis B Hepatitis B surface antigen +ve  -ve  Unknown  Total antibody, hepatitis B core antigen +ve  -ve  Unknown  IgM antibody to hepatitis B core antigen +ve  -ve  Unknown  Antibody to hepatitis B surface antigen +ve  -ve  Unknown  Hepatitis B e antigen +ve  -ve  Unknown  Antibody to hepatitis B e antigen +ve  -ve  Unknown  Hepatitis B virus genotype others Hepatitis C Antibody to hepatitis C virus +ve  -ve  Unknown  Anti-HCV signal to cut-off ratio +ve  -ve  Unknown  19 HEPATITIS B Supplemental anti- HCV assay [e.g. RIBA] Quantitative Hepatitis C RT- PCR Qualitative Hepatitis C RT- PCR Hepatitis C Virus Genotype Others Hepatitis D Antibody to hepatitis D virus +ve  -ve  Unknown  Hepatitis E Antibody to hepatitis E virus +ve  -ve  Unknown  IgG hepatitis E antibody +ve  -ve  Unknown  Liver enzymes ALT (SGPT) AST (SGOT) Others Diagnosis (check all that apply) Acute hep A  Acute hep B  Acute hep C  Acute hep E  Hepatitis D (co- or super infection)  Perinatal HBV infection  Chronic HBV  Hep C (chronic or resolved)  Final laboratory results Hepatitis A  Hepatitis B  Hepatitis C  Hepatitis D  Hepatitis E  Final case classification Final classification Laboratory- confirmed  Presumptive  Discarded  Others  Outcome Follow-up Discharged  Left against medical advice  Lost to follow-up  Died  Date of death/ discharge dd/mm/yyyy Comments Investigator’s name: Designation: Institution: Telephone (mobile): Email: Date: Signature: Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Further reading 1. Akbar SMF, Al Mahtab M, Begum F, Hossain SAS, Sarker S, Shrestha A et al. Implications of birth-dose vaccination against hepatitis B virus in South-East Asia. Vaccines (Basel). 2021;9(4):374. doi: 10.3390/vaccines9040374. 2. Kodani M, Schillie SF. Chapter 4: Hepatitis B. In: Roush SW, Baldy LM, Hall MAK, editors. Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases, Atlanta, GA (https://www.cdc.gov/ vaccines/pubs/surv-manual/chpt04-hepb.html, accessed 27 August 2022). 3. Pattyn J, Hendrickx G, Vorsters A, Van Damme P. Hepatitis B Vaccines. J Infect Dis. 2021;224(12 Suppl 2):S343–S351. doi: 10.1093/infdis/jiaa668. 4. Sandhu H S, Roesel S, Sharifuzzaman M, Chunsuttiwat S, Tohme R A. Progress toward hepatitis B control – South-East Asia Region, 2016–2019. MMWR Morb Mortal Wkly Rep. 2020;69(30):988–92. doi: 10.15585/mmwr. mm6930a2. 5. WHO. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016–2021: actions for impact. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO (https://www.who.int/publications/i/ item/9789240027077, accessed 28 August 2022). 6. Hepatitis B vaccines: WHO position paper – July 2017. Wkly Epidemiol Rec. 2017;92(27):369–92. 92 (‎27):369–92. 7. WHO guidelines on hepatitis B and C testing. Geneva: WHO; 2017. Licence: CC BY-NC-SA 3.0 IGO. (https://apps.who.int/iris/bitstream/hand le/10665/254621/9789241549981-eng.pdf, accessed 28 August 2022). 8. World Health Organization. Global health sector strategy on viral hepatitis 2016–2021. Towards ending viral hepatitis. World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/246177, accessed 28 August 2022). 9. World Health Organization. Hepatitis B – Surveillance standards for vaccine- preventable diseases, 2nd ed. Geneva: World Health Organization; 2018. (https://www.who.int/publications/m/item/vaccine-preventable-diseases- surveillance-standards-hepb, accessed 28 August 2022). 10. World health Organization. Consolidated strategic information guidelines for viral hepatitis: planning and tracking progress towards elimination. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO (https:// apps.who.int/iris/bitstream/handle/10665/310912/9789241515191-eng. pdf, accessed 28 August 2022). 21 HEPATITIS B 11. Web Annex 1. Standard operating procedures (SOPs) for enhanced reporting of cases of acute hepatitis. In: Consolidated strategic information guidelines for viral hepatitis planning and tracking progress towards elimination. Geneva: World Health Organization; 2019 (WHO/CDS/HIV/19.2). Licence: CC BY- NC-SA 3.0 IGO (https://apps.who.int/iris/bitstream/handle/10665/280098/ WHO-CDS-HIV-19.2-eng.pdf?ua=1, accessed 28 August 2022.) 12. Web Annex 3. Protocol for surveillance of the fraction of cirrhosis and hepatocellular carcinoma attributable to viral hepatitis in clinical centres of excellence. In: Consolidated strategic information guidelines for viral hepatitis planning and tracking progress towards elimination. Geneva: World Health Organization; 2019 (WHO/CDS/HIV/19.4). Licence: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/bitstream/handle/10665/280097/WHO-CDS- HIV-19.4-eng.pdf?ua=1, accessed 28 August 2022). 13. World Health Organization. Interim guidance for country validation of viral hepatitis elimination. Geneva: World Health Organization; 2021 (https:// www.who.int/publications/i/item/9789240028395, accessed 28 August 2022). 14. Childs L, Roesel S, Tohme RA. Status and progress of hepatitis B control through vaccination in the South-East Asia Region, 1992– 2015. Vaccine. 2018;36(1):6–14. doi: 10.1016/j.vaccine.2017.11.027. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region MODULE-9 ROTAVIRUS GASTROENTERITIS September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Rotavirus gastroenteritis) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO Introduction 5 Objectives 5 Types of surveillance 5 Selection criteria for sentinel surveillance sites 6 Types of surveillance 6 Linkage to other surveillance platforms 7 Case detection 7 Definition of suspected case 7 Signs and symptoms 7 Other associated signs and symptoms 8 Date of onset of illness 8 Response to suspected case 8 Within 48 hours 8 Investigation of suspected case 8 Case investigation form 9 Unique ID 9 Specimen collection 9 Preferred specimen 9 Amount 9 Storage 10 Laboratory testing 10 Classification of cases 11 Contact tracing 11 Clinical management 11 Outbreak 11 Special considerations 12 CONTENTS Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Data management 12 Reporting requirements 12 Unique ID 12 Recommended data elements 13 Data analysis 13 Using data for decision-making 14 Supporting vaccination strategies 14 Evaluating impact of vaccines 14 Evaluating vaccine effectiveness 15 Indicators for surveillance performance 16 Public health intervention 17 Annex 1: Disease epidemiology 19 Background 19 Essential epidemiology 19 Vaccines 20 Vaccine safety and precautions 20 Disease burden in South-East Asia 20 Annex 2: Responsibilities of a surveillance officer 21 Data and specimen collection 21 Data management 21 Monitoring quality of data 21 Annex 3: Case investigation form 22 Further reading 25 5ROTAVIRUS GASTROENTERITIS Rotavirus gastroenteritis surveillance Introduction Globally, rotavirus is the leading cause of severe gastroenteritis among infants and young children. In temperate climates, outbreaks of rotavirus diarrhoea occur during the winter months every year. In the tropics and subtropics, too, outbreaks occur during the cool dry months, but in general, rotaviruses are prevalent throughout the year. Since in low-income countries, children below 5 years of age get recurrent rotavirus infections and confirming the diagnosis requires special laboratory testing of faecal specimens, the identification of every case of rotavirus diarrhoea is neither necessary, nor practical. Yet, surveillance, together with laboratory support for the diagnosis of rotavirus, is necessary as rotavirus vaccination has been recommended in the Expanded Programme on Immunization in all countries. Objectives Surveillance for rotavirus gastroenteritis can have different objectives, depending on the stage of the roll-out of the rotavirus vaccine in the country. However, there are general objectives which are common to all. For countries planning to introduce the rotavirus vaccine, the main objective is to generate information to facilitate and support the introduction of the vaccine. For countries that have introduced the vaccine, the objectives are to: z determine the epidemiology and burden of rotavirus hospitalizations; z monitor the impact of vaccination on the reduction of morbidity and mortality from rotavirus disease over time; z evaluate the effectiveness of the vaccine in field use; z monitor the possible emergence of rotavirus strains; and z identify population groups that might not be adequately covered by vaccination. Types of surveillance It is recommended that surveillance of rotavirus gastroenteritis be conducted through sentinel hospital units which have the capacity for providing laboratory confirmation. The global minimum standard for rotavirus surveillance is one sentinel site per country. Depending on the availability of personnel and laboratory resources, some countries may choose to have additional sentinel sites. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 Selection criteria for sentinel surveillance sites z The hospital should have demographically and geographically defined catchment populations. z The hospital (in public or private sector) should be accessible and affordable to general public. z It is widely used for the care of children under 5 years of age (hence likely to be representative of the target population). z It should admit, on an average, a minimum of 100 children who are under 5 years of age and have diarrhoea (preferably about 250–500 before RVV introduction and 100 cases after RVV introduction) every year. z The hospital should have the capacity to collect and store faecal samples. z It should either have or is willing to build the capacity to conduct rotavirus screening through methods of rapid antigen detection (e.g., enzyme immune assay [EIA]), or should have a reliable system for transporting samples to a reference laboratory. z The hospital should have the human and logistical resources necessary for establishing and sustaining the sentinel surveillance system. z The hospital should be willing to make an institutional commitment to the conduct of rotavirus surveillance. Types of surveillance Minimal surveillance: The global minimum standard for rotavirus surveillance is one sentinel hospital per country that has the capacity for laboratory confirmation of cases. The sentinel site should conduct active, case-based surveillance. Enhanced surveillance: Other than the minimum recommended requirements for active, case-based surveillance at sentinel hospitals, the following types of surveillance can be conducted to meet some of the surveillance objectives in certain settings. z Laboratory-based surveillance: This can be initiated in countries where samples from cases of acute gastroenteritis are already collected and tested routinely for rotavirus. The rotavirus cases thus identified are reported to the public health authorities. Laboratory-based surveillance provides additional information on circulating strains of rotavirus and the general trends in the disease. z Population-based surveillance: This involves the use of the sentinel surveillance protocol for all facilities within a defined geographical area with a known population. It allows for the calculation of the incidence of the disease in settings with one or multiple facilities in an area with a defined population. z Household-based surveillance/community clinics: Using an adapted version of the hospital-based surveillance methodology (e.g., modifying the case definition 7ROTAVIRUS GASTROENTERITIS to include patients who are not hospitalized), the surveillance can be expanded to outpatient and non-hospital settings. This kind of surveillance will provide a more complete picture of the clinical spectrum of rotavirus disease in the community. Linkage to other surveillance platforms Rotavirus surveillance can be linked with other types of surveillance, as described below. z Integrated Disease Surveillance and Response (IDSR) collects aggregate numbers of cases of diarrhoea with dehydration among children < 5 years of age. With the addition of laboratory testing, IDSR surveillance could meet some of the objectives of rotavirus surveillance. z When stool samples are already being collected in a facility for surveillance of other diseases (such as polio), the existing systems for the collection, transport and virological laboratory testing of stool specimens could be leveraged for rotavirus surveillance. z Rotavirus surveillance can be used to conduct global pediatric diarrhoea (GPD) surveillance. GPD surveillance (GPDS) monitors the burden of other enteric pathogens, such as enterotoxigenic Escherichia coli (ETEC), Shigella and norovirus, after modifying some components of the definitions of suspected and confirmed case, e.g., bloody diarrhoea might be included. In that case, these symptoms should be included in the CIF. Case detection Definition of suspected case A suspected case refers to a child who is below 5 years of age and is admitted (to a hospital ward or emergency unit at a participating surveillance facility) for the treatment of acute (< 14 days) watery diarrhoea, defined as 3 or more loose or watery stools in a 24-hour period. Children with bloody diarrhoea and nosocomial infections are excluded. Signs and symptoms In a typical case, the onset of disease is abrupt and marked by: z fever (up to one-third of infected children may have a temperature greater than 39°C (102°F). z vomiting; followed by z watery diarrhoea Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Other associated signs and symptoms The clinical spectrum of rotavirus disease is wide and the disease may: z be asymptomatic z cause self-limiting watery diarrhoea; or z result in severe dehydrating diarrhoea with a fever and vomiting, causing electrolyte disturbances, shock, and death if rehydration is not provided. Gastrointestinal symptoms normally resolve within 3–7 days but may last for up to 2–3 weeks. Although most patients recover completely, fatalities may occur in settings where timely access to rehydration is not available, mainly among children ≤ 1 year of age. Infants below 3 months of age: The rates of rotavirus infection are relatively low in this group, probably because of passive maternal antibodies and possibly because of breastfeeding. Infants above 3 months of age: The first infection after 3 months of age is generally the most severe. The gastrointestinal symptoms usually resolve in 3–7 days. Date of onset of illness The date of onset of rotavirus should be considered to be the date of the onset of diarrhoea. Response to suspected case A suspected case should be Investigated by a surveillance officer. The responsibilities of the officer are described in Annex 2. Within 48 hours Surveillance staff in sentinel hospitals should screen cases of diarrhoea and identify those that meet the criteria of suspected cases. The staff should fill in case investigation forms for all cases meeting the definition of a suspected case. A stool specimen should be collected from the suspected cases within 48 hours of admission to avoid the detection of hospital-acquired pathogens. The detection of individual rotavirus cases does not require immediate notification to the public health authorities. Investigation of suspected case The investigation of suspected cases should be done by the trained health staff/clinician designated by the public health authority. 9ROTAVIRUS GASTROENTERITIS Case investigation form A case investigation form should be filled in for every suspected case within 48 hours of reporting. (See Annex 3 for a sample case investigation form.) Unique ID A unique case identification (UID) number should be assigned to each suspected case. The number should begin with one or more three-letter combinations to designate the geographical location of the case, followed by the year and the case number. All communications and forms related to the case should cite the UID. For example: RVG – code for suspected rotavirus gastroenteritis THA – country code BKK – province code BBN – district code 2022 – year of onset 001 – serial number of diphtheria case of the province The UID would thus be RVG-THA-BKK-BBN-22-001. Specimen collection The collection and shipping of specimens are important steps in obtaining a diagnosis or confirmation of the disease from a laboratory. Preferred specimen The preferred specimen is whole stool, which should be collected within 48 hours of hospital admission (to avoid the detection of hospital-acquired infections). Amount About 5–10 mL should be collected in a sterile screw capped container with proper labels. A minimum of around 2–3 mL is required for basic confirmatory testing, and 3–4 mL or more may be needed for genotyping and additional testing. [It is advisable to avoid the use of rectal swabs or swabs placed in bacterial media, since these are not optimal for the detection or characterization of rotavirus.] Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 Storage Stool specimens should be placed in sterile screw-top containers that are properly labelled. At sentinel sites where EIA is not performed: The specimen should be stored at 2–8 oC till it is transferred to a laboratory for testing. At sentinel sites / national laboratories performing EIA: z For up to 1 month, samples should be stored at 4-8 oC for up to one month. z For more than 1 month but under a year, samples should be stored at -20 oC. Freeze–thaw cycles should be avoided, where possible. If not possible, glycerol should be added to make a final concentration of 1–3% as this will minimize the harmful effects of repeated thawing and freezing. z For prolonged storage for more than 1 year, samples should be stored at -70oC (the ability to characterize rotaviruses declines if a sample is stored at -20 oC for years). If stool samples are to be tested for bacterial or parasitic pathogens by conventional methods, the specimens should be transported to the laboratory within 2 hours of collection and placed on appropriate media. They should then be stored at -20 oC or less until testing. Laboratory testing An aetiological diagnosis of rotavirus gastroenteritis requires laboratory confirmation. A range of diagnostic tests are commercially available. z Enzyme Immunoassays (EIA): EIA for the detection of rotavirus antigen directly in stool specimens are in wide use. Some EIA kits are: Premier™ Rotaclone®, ProSpecT™ and RIDASCREEN®. The sensitivity of EIAs has been found to be 75–82% and their specificity, 100%. Thus, occasional false negatives are possible, particularly at lower viral loads, though the clinical significance of rotavirus at concentrations below the threshold of EIA detection is unclear. z Latex agglutination assay: Rapid tests such as latex agglutination assays are simple-to-use immunochromatographic test strips but are less sensitive and often less specific than EIAs. z Reverse transcription-polymerase chain reaction (RT-PCR): RT-PCR is used to characterize rotavirus strains and can identify both the G and P types. A subset of rotavirus-positive stools obtained from routine surveillance should be chosen for the characterization of strains. It is recommended that a minimum of 50–60 randomly selected specimens be genotyped from each country per 11 ROTAVIRUS GASTROENTERITIS year. The randomly selected samples should be proportional to the age and seasonal distribution of the cases. If resources permit, the strains of all EIA- positive samples should be characterized. Only specimens >3 mL should be chosen to avoid running out of material. All non-typeable isolates should be sent to an appropriate reference laboratory for sequencing. Classification of cases Suspected case: This refers to a child who is below 5 years of age and is admitted (to a hospital ward or emergency unit at a participating surveillance facility) for the treatment of acute (< 14 days) watery diarrhoea, defined as 3 or more loose or watery stools in a 24-hour period. Children with bloody diarrhoea and nosocomial infections are excluded. Confirmed case: This is a suspected case in whose stool the presence of rotavirus is demonstrated by means of an EIA or PCR-based methods. Contact tracing Contact tracing is not conducted routinely for rotavirus. Clinical management z Currently, no specific antiviral therapy is available against rotaviruses. z Fluid replacement is important for preventing or treating dehydration. z Solutions of low-osmolarity oral rehydration salts (ORS) are more effective at replacing fluids than conventional ORS formulations. z If ORS are not available, appropriate fluids that are available in the home can be used. z Zinc treatment reduces the duration and severity of diarrhoea episodes, the volume of stools, and the need for advanced medical care. z Due importance should be given to continued feeding, including breastfeeding. Country-specific guidelines or Integrated Management of Childhood Illness guidelines can be followed for the management of rotavirus. Outbreak Rotavirus is an endemic disease that does not usually occur in large-scale outbreaks that require intervention. Diarrhoea due to other causes, such as norovirus, cholera and ETEC, Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 can occur during outbreaks. These outbreaks might be detected by syndromic surveillance for diarrhoea, though sentinel surveillance is not an adequate way to detect outbreaks. Laboratory capacity developed for rotavirus surveillance can possibly be expanded to identify outbreaks of diarrhoea due to other causes. Special considerations z A previously available rotavirus vaccine was associated with an increased risk of intussusception. It will be important to conduct surveillance of intussusception in some countries to monitor the safety of rotavirus vaccines after they have been introduced, as described elsewhere (10). However, the lack of such surveillance should not be an impediment to the introduction of rotavirus vaccines. z Sentinel surveillance sites used for rotavirus surveillance can also be considered for: z intussusception surveillance; and z surveillance for other enteric pathogens, including ETEC, Shigella and norovirus (vaccines for all of which are in the pipeline). These special considerations would require modifications in the surveillance approach, including case definitions, the tests to be performed and case investigation forms. Data management Reporting requirements z The number of rotavirus cases occurring each month should be reported to the ministry of health. z If no cases of diarrhoea are identified at the sentinel site, this should be indicated specifically in the report (“zero reporting”). z Aggregate reporting (numbers only) is sufficient for routine reporting even if case- based surveillance is conducted. z There are no global reporting requirements for rotavirus. Unique ID A unique case identification number should be assigned to each suspected case, as explained earlier. 13 ROTAVIRUS GASTROENTERITIS Recommended data elements z Geographical information z Demographics z Clinical data z Treatment z Vaccination history z Specimen collection details z Laboratory data z Outcome of case z Date of discharge or death z Additional elements for case-based data z Clinical characteristics z Type of treatment z Laboratory investigations results The sample case investigation form (Annex 3) provides details of the data elements. Data analysis The data should be periodically analysed to understand the characteristics of the disease and monitor the surveillance system. Since age distribution and seasonality are important in the epidemiology of rotavirus gastroenteritis, suspected and confirmed cases should be described according to the epidemiological week of the onset of diarrhoea and data must be consolidated monthly by the age of the affected children and the place where the cases occurred. It should also be established whether the case is an isolated occurrence, or an outbreak has occurred in a day-care centre, another institution, or the community. z Minimal data analysis should comprise: z Number of hospitalizations z Number and percentages of diarrhoea-associated hospitalizations z numbers and percentages of diarrhoea-associated hospitalizations caused by rotavirus by age group (suggested: 0–2 months, 3–5 months, 6–8 months, 9–11 months, 12–17 months, 18–23 months, 24–59 months, and < 5 years). z numbers and percentages of hospitalizations due to diarrhoea and rotavirus diarrhoea by month of year. z number of deaths associated with rotavirus diarrhoea and in-hospital case fatality rate; and Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 z Some surveillance settings require enhanced analyses, which should include the following. z The clinical and epidemiological characteristics of cases must be described. z The distribution of genotypes must be analysed. z The seasonal trends must be examined, using weekly (if number of cases is sufficient) or monthly detection rates. z The peak of rotavirus activity should be defined as the 2 consecutive weeks (for weekly data) or the month (for monthly data) in which the greatest number of rotavirus cases was detected. z The onset of the rotavirus season is the week in which the number of rotavirus cases detected first exceeds the mean number of rotavirus cases detected per week for the entire year. z The duration of the rotavirus season is the number of weeks during which the number of cases detected exceeds the weekly mean. z For population-based surveillance, the rates of hospitalization and deaths associated with diarrhoea and rotavirus per 1000 children < 5 years of age per year, in the surveillance population overall and by age group, must be recorded. z The number of hospitalizations for all diarrhoea cases among children < 5 years of age may be gathered through logbooks or a review of hospitals’ administrative data. z The percentage of total hospitalizations due to diarrhoea among children < 5 years of age may be gathered through logbooks or a review of hospitals’ administrative data. z The distribution of hospitalizations due to diarrhoea by aetiology, including rotavirus diarrhoea may be noted if testing for other etiologist is conducted routinely. Using data for decision-making Supporting vaccination strategies Rotavirus surveillance data are used primarily to support national vaccination strategies. Rotavirus is not targeted for global elimination or eradication. Evaluating impact of vaccines There are two principal ways of analysing surveillance data following the introduction of a rotavirus vaccine. The first is to measure the impact of the vaccine in terms of the reduction 15 ROTAVIRUS GASTROENTERITIS in disease and evaluate the trends of the disease burden before and after the introduction of the vaccine. This is done by comparing the annual rates of rotavirus disease before and after the introduction of the vaccine, ideally when population-based surveillance data are available. If the surveillance population is relatively stable, counts of rotavirus cases or the proportion of rotavirus-positive cases by year can show a reduction in disease after the introduction of the vaccine. Second, it is possible to estimate the indirect effects of the introduction of the vaccine by monitoring for reductions in the rates of diarrhoea and rotavirus among unvaccinated children before and after the introduction of the vaccine. Evaluating vaccine effectiveness The effectiveness of a rotavirus vaccine can be estimated through test-negative, case– control studies. In these studies, which are often carried out in the setting of diarrhoea or rotavirus surveillance, confirmed cases of rotavirus gastroenteritis serve as the cases and confirmed rotavirus-negative gastroenteritis cases serve as the controls. This design is possible because of the high specificity of the rotavirus EIA test. It decreases the potential for selection biases since all children are prospectively enrolled prior to the confirmation of rotavirus infection or their vaccination status. However, considerable effort is needed to appropriately document the vaccination status of the enrolled children. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 Indicators for surveillance performance Table 9.1 gives the attributes that could be included in an evaluation of surveillance performance. It also shows the indicators, targets, and the formulas for calculation. Table 9.1: Indicators for surveillance performance Attribute Indicator Target How to calculate Comments Completeness of reporting Consistent reporting throughout the year At least 10 months of reporting (including zero reporting) Number of months of reporting per year The ideal is 12 months; and confirmed zero reporting if no cases. Enrolment of suspected cases Proportion of eligible cases enrolled during the calendar year 80% (Total number of children who met the case definition and were enrolled with a completed case report form and specimen collected total number of hospitalizations for acute watery diarrhoea among under-5 children eligible for enrolment)x 100 Case ascertainment Minimum number of cases reported annually ≥ 80 cases of suspected diarrhoea /year Number of diarrhoea cases reported per site per year The ideal is ≥ 100 diarrhoea cases/year. Specimen collection Proportion of suspected cases with specimens collected within 2 days of admission ≥ 80% (Number of suspected cases with specimen collected within 2 days of admission / number of suspected cases) x 100 The specimen is stool. ≥ 90% is ideal. Completeness of laboratory testing Proportion of specimens tested for rotavirus by EIA ≥ 80% (Number of cases with specimens tested for rotavirus by EIA / number of cases with specimens collected) x 100 The ideal is ≥ 90%. * There is no minimum number that should test positive since the number varies widely among countries and depends on the use of rotavirus vaccine. 17 ROTAVIRUS GASTROENTERITIS Public health intervention It is well established that to reduce diarrhoea in a community, one must improve hygiene and the water supply and ensure the safe disposal of wastewater. However, it has also become increasingly clear that measures being taken in these respects are not enough to reduce severe rotavirus gastroenteritis. The fact that the incidences of rotavirus disease are comparable in the developed and developing countries, which have widely different sanitation standards, is a definite indication that the disease cannot be controlled exclusively by such measures. The routine immunization of infants with a rotavirus vaccine is now considered the most effective public health intervention for population-wide rotavirus control. Post-exposure vaccine prophylaxis is not recommended in response to an outbreak of rotavirus gastroenteritis. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 19 ROTAVIRUS GASTROENTERITIS Annex 1: Disease epidemiology Background Rotavirus is an RNA virus, of which 7 groups (labelled A to G) are known. Of these, group A causes most of the illness in humans, and has been classified into the G and P genotypes. G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] and G12, in combination with P[6] or P[8], account for 90% of the genotypes that infect humans. The disease affects mostly infants between the ages of 3 months and a year. Rotavirus gastroenteritis is the most common cause of severe diarrhoeal disease in infants and young children worldwide. A major reason for the occurrence of nearly all rotavirus deaths in the less developed countries – despite the fact that the disease is common in rich and poor countries alike – is the lack of timely access to health care. In addition, rotavirus can be more severe in low-income countries due to frequent concurrent infections, malnutrition and other factors. Year-round transmission due to climatic factors may also contribute to the much higher toll of the disease among children in low-income countries. In high-income countries/ low-mortality countries, rotavirus accounted for 40–50% of hospital admissions due to diarrhoeal disease in the pre-rotavirus vaccine period. Essential epidemiology Infectious agent: Rotavirus belongs to the Reoviridae family. Reservoir: The reservoir is the gastrointestinal tract and stool of infected humans. Although rotavirus infection occurs in many other mammals, the transmission of animal rotaviruses to humans is believed to be uncommon and probably does not lead to clinical illness. Mode of transmission: Transmission is by the faecal–oral route, primarily through close person-to-person contact or indirectly via fomites (such as toys and other environmental surfaces contaminated by stool). The transmission of rotavirus through contaminated water or food appears to be uncommon. Rotavirus is highly communicable, its infectious dose being as small as < 100 virus particles. Incubation period: The incubation period is short, usually less than 48 hours (range: 24–72 hours). Duration of illness: The illness usually lasts for 3–7 days but may go on for 2–3 weeks. Annexes Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Period of communicability: The disease is communicable from 2 days before the onset of diarrhoea to several days after the onset of symptoms, during the acute phase of the disease and later while virus shedding continues. Case fatality ratio: In developing countries, rotavirus has a case fatality rate of approximately 2.5% among children who present to health facilities. It is difficult to estimate a case fatality ratio as it depends primarily on access to health services for rehydration. Vaccines The currently available rotavirus vaccines are live, oral, attenuated rotavirus strains of human and/or animal origin that replicate in the human intestine to elicit an immune response. WHO has prequalified four vaccines: Rotarix, RotaTeq, Rotavac and Rotasiil. Vaccine safety and precautions Each of the vaccines prequalified by WHO has a good safety profile. While rotavirus vaccines have been associated with intussusception, no other serious adverse event has been identified. Risk of intussusception One of the earliest vaccines, RotaShield (Wyeth-Lederle), was associated with intussusception. The recent Cochrane review of the four WHO prequalified rotavirus vaccines showed that in randomized controlled trials for each vaccine, there was no increase in the risk of intussusception after any dose. Disease burden in South-East Asia Building on the findings of the Global Burden of Disease Study 2016, models were used to estimate the burden of the disease in locations with sparse data. In 2016, rotavirus infection was responsible for an estimated 128 500 deaths (95% uncertainty interval [UI], 104 500–155 600) among children younger than 5 years of age throughout the world. South-East Asia accounted for 3765 of these deaths (95% UI, 2895–4789). Rotavirus infection was responsible for more than 29 million episodes of diarrhoea among children under 5 years of age in 2016 (95% UI, 21.19–41.49 million) in the Region, an incidence of 508 cases per 1000 population (95% UI, 21–41 million) (13). In 2008, WHO launched the Global Rotavirus Surveillance Network. Its objectives are to generate local data for decision-making on the introduction and sustained use of rotavirus vaccines; assess and monitor the trends in the disease and the genotype distribution over time; develop a platform for studies on the effectiveness of vaccines; and highlight the value of surveillance data in general and in fund-raising and advocacy. 21 ROTAVIRUS GASTROENTERITIS Annex 2: Responsibilities of a surveillance officer The sentinel site surveillance officer’s responsibilities include the following. Data and specimen collection z Conduct a daily survey of the wards and maintain a diarrhoea log. This would help to identify children eligible for surveillance and facilitate their enrolment. z Enroll eligible patients for surveillance. Ensure that a unique case ID is assigned to each enrolled patient, and a case investigation form filled (see Annex 3 for a sample case investigation form.) The unique IDs should be entered in the surveillance logbook. z Ensure that the appropriate specimen is collected and sent to the laboratory for investigation. z Track all cases whose samples are sent to the national or regional reference laboratory for genotyping and follow up to obtain results in a timely manner. z Share the results with the sentinel surveillance hospital and with the Central data team so that they may be recorded in the database. z Update the data logbook regularly to record follow-up visits, interactions with clinicians, nursing staff and laboratory personnel, etc. Data management The surveillance officer has the following functions related to data management: z cleaning and validation of data; z maintaining a back-up of the surveillance database; and z analyzing core data variables epidemiologically, and sharing the results with the relevant stakeholders, including clinicians and staff at the sentinel hospital. Monitoring quality of data The surveillance officer should make a periodic review of the data collected to identify problems in the collection of data, enrolment of patients, or collection and handling of specimens. The following are a few useful examples of monitoring activities. z If the number of children enrolled for surveillance from the sentinel surveillance hospital is less than 75% of the expected number for 2 consecutive months, it may indicate that the procedures for case-finding are inadequate. z If < 15% of the children enrolled for surveillance test positive for rotavirus, it should raise a red flag. The following aspects need to be reviewed: z Is the surveillance system missing the youngest age groups? Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 z Is the quality of the stool collected poor and its volume insufficient to detect rotavirus? Are the handling procedures for stool specimens not optimal? z Are the staff facing problems in using the enzyme immunoassay test kits? z Are stools being tested in a timely manner? Annex 3: Case investigation form Case identification number: RVGE ______/____________/__________/____/_____ Country code/ Province code/District code/ Year/Serial number Patient information Name of health facility Patient’s name Age in years / months Date of birth dd/mm/yyyy Sex Male  Female  Unknown  Residential address House no: Street name: Village/ town/ city: District/ province: State: Zip code: Contact number (mobile) Clinical data Date of admission dd/mm/yyyy Date of investigation dd/mm/yyyy Date of onset of diarrhoea dd/mm/yyyy Number of days of diarrhoea Maximum number of diarrhoea episodes in a 24-hour period at peak of illness Fever: acute onset Yes  No  Unknown  Maximum temperature recorded: Vomiting Yes  No  Unknown  Duration (in days) Maximum number of vomiting episodes in a 24-hour period at peak of illness (number) Dehydration Yes  No  If yes, specify Unknown  Mild  Moderate  Severe  Unknown  23 ROTAVIRUS GASTROENTERITIS Treatment Rehydration therapy provided Yes  No  Not known  Type of rehydration therapy provided ORS  ORT  Intravenous fluids  Others  (Specify) Unknown  Vaccination history Was rotavirus vaccine administered? Yes  No  Unknown  Source of vaccination information Vaccination card  Medical records  Maternal recall  Others  (Specify) Rota vaccine (type) Number of doses received 1  2  3  Unknown  Date of 1st dose dd/mm/yyyy Date of 2nd dose dd/mm/yyyy Date of 3rd dose dd/mm/yyyy Investigations Type of specimen collected Stool  None  If stool collected, specimen ID Type(s) of testing methodology EIA  Rapid tests  Specify: Latex agglutination test  Immuno- chromatographic test  RT-PCR  Date of specimen collection dd/mm/yyyy Type of laboratory where EIA was performed Hospital laboratory  Private laboratory  National laboratory  Regional laboratory  Not known  Type of laboratory where GP was performed Hospital laboratory  Private laboratory  National laboratory  Regional laboratory  Not known  Laboratory results Dates on which specimen(s) were received dd/mm/yyyy Dates on which specimen(s) were tested dd/mm/yyyy Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24 Date(s) on which results were reported dd/mm/yyyy Laboratory results for each specimen EIA +ve  -ve  Indeterminate  Rapid test +ve  -ve  Indeterminate  RT-PCR genotyping G type: P type: Classification of cases Final classification Laboratory- confirmed  Suspected  Discarded  Outcome Follow-up Discharged alive  Discharged alive with sequelae  Lost to follow- up  Died  Left against medical advice  Referred / Transferred Date of death/ discharge dd/mm/yyyy Comments Investigator’s name: Designation: Institution: Telephone (mobile): Email: Date: Signature: 25 ROTAVIRUS GASTROENTERITIS Further reading 1. Agócs MM, Serhan F, Yen C, Mwenda JM, de Oliveira LH, Teleb N et al. Department of Immunization, Vaccines, and Biologicals, World Health Organization (WHO), Geneva, Switzerland; Centers for Disease Control and Prevention (CDC). WHO global rotavirus surveillance network: a strategic review of the first 5 years, 2008–2012. MMWR Morb Mortal Wkly Rep. 2014;63(29):634–7. 2. Aliabadi N, Antoni S, Mwenda JM, Weldegebriel G, Biey J, Cheikh D et al. Global impact of rotavirus vaccine introduction on rotavirus hospitalisations among children under 5 years of age, 2008–16: findings from the Global Rotavirus Surveillance Network. Lancet Glob Health. 2019;7(7):e893–e903. doi: 10.1016/S2214-109X(19)30207-4. 3. Ardura-Garcia C, Kreis C, Rakic M, Jaboyedoff M, Mallet MC, Low N et al. Rotavirus disease and health care utilisation among children under 5 years of age in highly developed countries: A systematic review and meta-analysis, Vaccine. 2021; 39(22): 2917–28. doi: 10.1016/j.vaccine.2021.04.039 . 4. Behera DK, Mishra S. The burden of diarrhea, etiologies, and risk factors in India from 1990 to 2019: evidence from the global burden of disease study. BMC Public Health 2022;22(1):92. doi: 10.1186/s12889-022-12515-3. 5. Bennett A, Pollock L, Bar-Zeev N, Lewnard JA, Jere KC, Lopman B et al. Community transmission of rotavirus infection in a vaccinated population in Blantyre, Malawi: a prospective household cohort study. Lancet Infect Dis. 2021;21(5):731–40. doi: 10.1016/ S1473-3099(20)30597-1. 6. Bergman H, Henschke N, Hungerford D, Pitan F, Ndwandwe D, Cunliffe N et al. Vaccines for preventing rotavirus diarrhoea: vaccines in use. Cochrane Database Syst Rev. 2021 Nov 17;11(11):CD008521. doi: 10.1002/14651858. CD008521.pub6 . 7. Payne DC, Parashar UD. Chapter 13: Rotavirus. In Roush SW, Baldy LM, Hall MAK, editors. Manual for the Surveillance of Vaccine-preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases, Atlanta, GA (https://www.cdc.gov/vaccines/pubs/surv- manual/chpt13-rotavirus.pdf, accessed 28 August 2022). 8. Chissaque A, Cassocera M, Gasparinho C, Langa JS, Bauhofer AFL, Chilaúle JJ et al. Rotavirus A infection in children under five years old with a double health problem: undernutrition and diarrhoea – a cross-sectional study in four provinces of Mozambique. BMC Infect Dis. 2021; 21(1):18. doi: 10.1186/s12879-020- 05718-9. 9. Crawford S, Ramani S, Tate J, Parashar UD, Svensson L, Hagbom M et al. Rotavirus infection. Nat Rev Dis Primers. 2017 Nov 9;3:17083. doi:10.1038/ nrdp.2017.83. 10. Das MK, Arora NK, Bonhoeffer J, Zuber PLF, Maure CG. Intussusception in young children: protocol for multisite hospital sentinel surveillance in India. Methods Protoc. 2018; 1(2):11. doi: 10.3390/mps1020011. 11. Hasso-Agopsowicz M, Ladva CN, Lopman B, Sanderson C, Cohen AL, Tate JE et al. Global rotavirus surveillance network and rotavirus age study collaborators. Global review of the age distribution of rotavirus disease in children aged <5 years before the introduction of rotavirus vaccination. Clin Infect Dis. 2019;69(6):1071– 8. doi:10.1093/cid/ciz060. 12. Lestari FB, Vongpunsawad S, Wanlapakorn N, Poovorawan Y. Rotavirus infection in children in Southeast Asia 2008–2018: disease burden, genotype distribution, seasonality, and vaccination. J Biomed Sci. 2020;27(1):66. doi:10.1186/ s12929-020-00649-8. 13. Troeger C, Khalil IA, Rao PC, Cao S, Blacker BF, Ahmed T et al. Rotavirus vaccination and the global burden of rotavirus diarrhea among children younger than 5 years. JAMA Pediatr. 2018;172(10):958–965. doi:10.1001/ jamapediatrics.2018.1960. 14. World Health Organization. Rotavirus vaccines: WHO position paper on Rotavirus. Wkly Epidemiol Rec. 2021;96(28):301–20 (https://www.who.int/publications/i/ item/weekly-epidemiological-record-vol.-28-2021-96-301-320, accessed 28August 2022). 15. World health Organization. Surveillance guide for vaccine-preventable diseases in the WHO South-East Asia Region. New Delhi: World Health Organization, Regional Office for South-East Asia; 2017. Licence: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/bitstream/handle/10665/277459/Module8-Rotavirus. pdf?sequence=64&isAllowed=y, accessed 28 August 2022). 16. World Health Organization. Rotavirus – Surveillance standards for vaccine- preventable diseases. WHO; 2018 (https://cdn.who.int/media/docs/default- source/immunization/vpd_surveillance/vpd-surveillance-standards-publication/ who-surveillancevaccinepreventable-19-rotavirus-r2.pdf?sfvrsn=2c43bf06_10 &download=true, accessed 28 August 2022). 17. World Health Organization. Building rotavirus laboratory capacity to support the global rotavirus surveillance network : Introduction. Wkly Epidemiol Rec. 2013;88(21):217–23 (https://apps.who.int/iris/handle/10665/242071, accessed 28 August 2022). CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region MODULE-10 JAPANESE ENCEPHALITIS September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Japanese Encephalitis) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO Introduction 5 Objectives 5 Types of surveillance 5 Case detection 6 Definition of suspected case 6 Sensitivity and specificity of definition 7 Case description 7 Differential diagnosis 7 Date of onset of illness 7 Response to suspected case 8 Investigation of suspected case 8 Case investigation form 8 Unique ID 8 Specimen collection 8 Types of specimens 8 How much to collect 9 Storage and transport 9 Indications for a second blood sample 9 Laboratory testing 10 Recommended method of laboratory confirmation 10 Interpretation of IgM antibodies test 10 Classification of cases 12 Laboratory-confirmed case 12 Probable JE 12 AES – other agent 12 AES – unknown 12 Caveats 13 CONTENTS Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Contact tracing 13 Clinical management 14 Outbreak 14 Definition 14 Modifications needed in surveillance 14 Data management 15 Reporting requirements 15 Unique ID 15 Recommended data elements 15 Data analysis 16 Using data for decision-making 16 Surveillance performance 17 Public health response 18 Annex 1: Disease epidemiology 19 Background 19 Essential epidemiology 19 Vaccines 20 Disease burden 20 Annex 2: Case investigation form 21 Further reading 23 5JAPANESE ENCEPHALITIS Japanese encephalitis surveillance Introduction Japanese encephalitis (JE) is caused by the JE virus. In temperate and tropical regions of Asia, the virus is maintained through a transmission cycle between vertebrate amplifying hosts (e.g. pigs, herons, egrets) and several Culex mosquito species. JE virus is the leading cause of encephalitis in Asia. Human vaccination has proven to be the single most effective preventive intervention against JE. JE surveillance is essential for monitoring the effectiveness of the vaccine and measuring the degree of control achieved by the local immunization programme. Since clinical grounds alone do not suffice to distinguish JE from encephalitis due to other causes, a syndromic approach is used for the identification of cases. Acute encephalitis syndrome (AES) surveillance is conducted to characterize the epidemiology and burden of the disease, identify high-risk areas requiring an appropriate public health response and document the impact of control measures. For several reasons, sentinel hospital- based surveillance is more practical than general passive surveillance. First of all, in many countries, especially large ones, JE may be confined to certain geographical regions. Second, laboratory confirmation is necessary to confirm the aetiology of the virus, but the required facilities may not be widely available. Objectives The objectives of JE surveillance are to: z understand the epidemiology of JE, including the definition of the populations at risk and estimation of the disease burden in the country; z determine the geographical distribution of JE in the country; z provide information for the formulation of a vaccination policy; and z evaluate the impact and effectiveness of the vaccine after its introduction. Types of surveillance Sentinel hospital-based surveillance: This type of surveillance is indicated in areas where JE is suspected to be a health issue. The sentinel sites in a geographical area should initially consist of the hospitals with the largest input of suspected cases, and the sites can be increased when feasible. The criteria for the strategic selection of sentinel sites should be based on their representativeness within the geographical region(s), and should also include the following: Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 z the risk profile for JE, e.g. if it is located in a JE-endemic area and if it serves as a referral centre for encephalitis patients; z the size of the health facility and the access of the catchment population; and z the capability of the health facility staff to carry out active encephalitis case detection and the feasibility of specimen collection and testing. When a country has achieved a high level of control of JE, surveillance should be case- based throughout the country and should include laboratory confirmation of all reported cases. Nationwide case-based surveillance: Nationwide, case-based surveillance for JE and AES might be useful in the following ways, though it requires extensive resources: z Data from nationwide surveillance of AES, with laboratory confirmation, constitute the best source of information on the complete disease burden of JE. z Nationwide surveillance in all hospitals, with laboratory confirmation of all suspected cases, can capture the maximum cases in countries where a high level of control of JE has been achieved. Age group for surveillance: Surveillance for JE is recommended for all age groups for the following reasons: z Though JE is commonly found to affect children younger than 15 years of age in Asia, cases can occur among the older age groups too, especially when the virus enters a new area. z In areas with a JE vaccination programme, the proportion of cases frequently rises among older, unvaccinated age groups. While it is recommended that surveillance should include all age groups, in countries that are in the early stage of implementing a JE vaccination programme, it is cost-effective to conduct surveillance among children < 15 years of age, or in the group with the preponderance of cases. Case detection Definition of suspected case z A suspected JE case is a person whose condition matches the definition of AES. The clinical case definition of AES refers to a person of any age who, at any time of the year, develops a fever of acute onset and at least one of the following: 7JAPANESE ENCEPHALITIS z a change in mental status (including symptoms such as confusion, disorientation, coma or inability to talk); or z new onset of seizures, excluding simple febrile seizures. A simple febrile seizure is defined as a seizure among children who are between 6 months and 6 years of age, in whom the only findings are fever and a single generalized convulsion lasting less than 15 minutes, and who recover consciousness within 60 minutes of the seizure. Sensitivity and specificity of definition The definition of a suspected AES case has high sensitivity but low specificity. It might have reduced sensitivity for JE among children in some settings. Overall, the AES case definition has been seen to capture two-thirds of children with JE; it had 100% sensitivity among adults, though the numbers were small. Case description The illness usually begins with fever of sudden onset, headache and vomiting. Among children, gastrointestinal pain and vomiting may be the dominant initial symptoms. Changes in mental status, focal neurological deficits, generalized weakness and movement disorders may develop over the next few days. The classical description of JE includes a mask-like face, tremor, muscular stiffness and involuntary (choreoathetoid) movements. Acute flaccid paralysis, with clinical features similar to those of poliomyelitis, has also been associated with JE. Seizures are common, especially among children. Differential diagnosis Acute disease with impaired brain function may have other causes as well, such as: z meningitis (viral and bacterial, including tuberculosis); z encephalopathy due to toxins; z cerebral malaria; z viral encephalitis due to herpes simplex virus, mumps virus or neurovirulent enteroviruses (e.g. enterovirus 68 or enterovirus 71 with hand, foot and mouth syndrome); and z or post-infectious meningoencephalitis (e.g. post-measles or post-varicella). Date of onset of illness The date of onset of JE should be considered as the date of onset of the first sign/symptom of AES. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Response to suspected case Case reporting The sites most likely to report cases are sentinel hospitals where AES cases are expected to be seen and admitted. All suspected JE cases must be reported to the district surveillance officer. The on-site staff is responsible for collecting specimens for laboratory tests. Investigation of suspected case Once the health-care staff has identified a case according to the criteria of AES, it must fill in a case investigation form and draw specimens for laboratory testing. Case investigation form A case investigation form should be filled for every suspected case within 48 hours of reporting. (See Annex 2 for a sample case investigation form.) Unique ID A unique case identification number (UID) should be assigned to each suspected case. The number should begin with one or more three-letter combinations that designate the geographical location, followed by the year and the serial number of the case. All communications and forms related to the case should cite the UID. For example: AES – suspected AES code THA – country code BKK – province code BBN – district code 2022 – year of onset 001 – serial number of JE case in the province The UID would then be AES-THA-BKK-BBN-22-001. Specimen collection Types of specimens The preferred specimen for laboratory confirmation is cerebrospinal fluid (CSF), obtained through a lumbar puncture, to test for JE virus-specific IgM antibody. JE virus-specific IgM 9JAPANESE ENCEPHALITIS can be measured in the CSF of most patients by 4 days of the onset of symptoms If facilities for a lumbar puncture are not available, blood samples should be collected soon after admission to test for JE virus-specific IgM. The antibody can be measured in the serum by 7 days of the onset of symptoms. How much to collect z Cerebrospinal fluid: z At least two tubes should be sent to the hospital laboratory for microbiology (Gram stain and bacterial culture), and the estimation of CSF glucose, protein and cell count. The results of these tests will assist with the diagnosis and clinical management of the patient. z If facilities for JE testing are not available at the sentinel hospital, another tube of CSF should be sent to the national or regional reference laboratories for JE-specific testing. z Amount of blood sample to be sent to the laboratory: z 3–5 mL of blood for older children and adults; and z 1–2 mL of blood for infants and younger children. Storage and transport z If the specimens can be transported within 1–3 days, the CSF and serum samples should be stored at 2–8 °C in a refrigerator. z For longer term storage, specimens should be stored at or below -20 °C. z As a general rule, repeated freezing and thawing of samples should be avoided. Therefore, it is important to store them at the appropriate temperature. Indications for a second blood sample If the first CSF or blood sample is positive for JE IgM, it is not necessary to test a second sample. However, the IgM ELISA test is more often than not conducted at a location that is different from where the sample was collected (such as a national laboratory or provincial laboratory). This means a prolonged specimen transport and testing time, and the results are often not available till the patient’s discharge or death. Therefore, it is good clinical practice to collect a second sample of blood as well. If JE-specific IgM antibodies are not be present when the first blood sample is taken, a second blood sample must be obtained: z on day 10 of the illness (usually on the seventh day of hospitalization); z at the time of discharge; or z at the time of death. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 Laboratory testing Recommended method of laboratory confirmation For laboratory confirmation, the JE virus IgM antibody test needs to be conducted. An IgM capture ELISA specifically for JE virus may be used to detect the presence of the JE virus- specific IgM in a single sample of CSF or serum. The sensitivity to the antibodies increases to > 95% in 10 days after the onset of the initial symptoms. It is important to differentiate true JE virus infections from other infections that yield false-positive JE results because of cross-reactive epitopes among flaviviruses. To cite an example, a patient with a dengue virus infection might have a positive JE IgM result because of flavivirus cross-reactivity. The current commercial assays for the detection of JE IgM have low specificity for JE. Therefore, to rule out false-positive results, a validated dengue-specific assay has to be carried out on all JE-positive specimens. In addition, JE can be confirmed by any of the following: z detection of JE virus antigens in brain tissue by immunohistochemistry or immunofluorescence assay; z detection of the JE virus genome in CSF, serum, plasma, blood or brain tissue by reverse transcription polymerase chain reaction (RT-PCR) or an equally sensitive and specific nucleic acid detection assay, such as loop-mediated isothermal amplification or whole genome sequencing; z isolation of the JE virus in CSF, serum, plasma, blood or brain tissue; z detection of a fourfold or greater rise in JE virus-specific IgG antibody as measured by the plaque reduction neutralization test (PRNT) in serum collected during the acute and convalescent phases of the illness (the two specimens should be collected at least 14 days apart). Interpretation of IgM antibodies test z Positive: z IgM antibodies usually persist for 30–90 days and in a few cases, for longer periods as well. Therefore, a positive result for IgM antibodies occasionally reflects a past infection or vaccination. z In areas highly endemic for JE, it is possible for a patient to have AES due to other causes, but to have JE virus-specific IgM antibody present in the 11 JAPANESE ENCEPHALITIS serum from a recent, possibly subclinical infection. Therefore, all persons with encephalitis are advised to have a CSF sample tested, if feasible. Even in the presence of a positive CSF specimen, further confirmatory tests should be carried out (such as looking for cross-reactivity with other flaviviruses circulating in the geographical area) in any of these situations: z if there is an ongoing dengue or other flavivirus outbreak; z if the coverage of JE vaccination is very high; and z if the area does not have epidemiological and entomological data supportive of JE transmission. z For persons vaccinated with the JE vaccine within 6 months prior to the onset of illness, testing a single serum sample for JE IgM may not be diagnostic because any IgM detected may be vaccine-related. In such cases, a diagnosis can be confirmed only by: z detection of JE IgM in the CSF; z isolation of the JE virus; z a positive nucleic acid amplification test; z immunohistochemistry; or z a fourfold or greater rise in antibody titre between acute- and convalescent-phase serum samples. z Negative: Serum collected in the initial days of the illness (before 7 days of onset) may not have detectable IgM. In such cases, the test should be repeated on a convalescent-phase serum sample. A fourfold or greater rise in JE virus-specific antibodies between acute- and convalescent- phase serum specimens may be used to confirm recent infection. When interpreting results, it is necessary to consider the person’s vaccination history, the date of onset of the symptoms, and information regarding other flaviviruses known to circulate in the geographical area that may cross-react in serological assays. Virus isolation and nucleic acid amplification tests should not be used for ruling out a diagnosis of JE as they are insensitive in detecting JE virus or viral RNA in blood or CSF, since humans have a low level of viraemia. An examination of the CSF, including the cell count, cell morphology and standard biochemistry, can distinguish between encephalitis and encephalopathy and between encephalitis and meningitis, as shown in Table 10.1. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 Table 10.1: CSF examination results and conditions indicated Result Indicative of CSF cell count < 10 cells/mm3, and especially < 6 cells/mm3 Encephalopathy or early bacterial infection CSF cell count of 10–100 cells/mm3, predominantly lymphocytic Encephalitis or viral meningitis CSF cell count > 100 cells/mm3 with predominantly polymorphs Bacterial meningitis CSF cell count > 100 cells/mm3 with predominantly lymphocytes Viral meningitis A high protein concentration (> 100 mg/dL) and low glucose (< 40 mg/dL) may indicate tuberculous meningitis or another bacterial cause. Classification of cases Laboratory-confirmed case A laboratory-confirmed case is a suspected case that has been confirmed in the laboratory as being one of JE. Probable JE This is a suspected case that occurs in close geographical and temporal relationship to a laboratory-confirmed case of JE, in the context of an outbreak. AES – other agent This refers to a suspected case in which diagnostic testing was performed and an aetiological agent other than JE virus was identified. AES – unknown This refers to a suspected case in which no diagnostic testing was performed or in which testing was performed but no aetiological agent was identified, or in which the test results were indeterminate. 13 JAPANESE ENCEPHALITIS Caveats z JE cannot be ruled out in cases with IgM-negative results if the sample was collected less than seven days after the onset of illness because the IgM may not have risen to detectable levels, and a second sample should be collected. z The detection of the virus genome or isolation of the virus in serum, plasma or blood is very specific for the diagnosis of JE; however, it is not sensitive, as virus levels are usually undetectable in clinically ill JE cases. Therefore, a negative result by these methods should not be used to rule out JE in a suspected case. z It is usually in fatal cases that the virus genome is detected or the virus isolated in CSF. Therefore, these methods are not very sensitive and should not be used for ruling out a diagnosis of JE. Fig. 10.1: Classification of AES cases Contact tracing Contact investigations are not carried out for JE as the disease is vector-borne. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 Clinical management z No specific antiviral treatment has been found to benefit patients with JE. z As in other AES cases, the patient generally requires hospitalization for supportive care and close observation. z Special supportive care should be provided if any of the following potentially life-threatening, preventable complications is detected: z raised intracranial pressure z status epilepticus z hypoglycaemia z aspiration pneumonia z secondary infections. z Normal supportive care includes rest, intake of fluids and pain relievers and medication to reduce fever. The administration of intravenous fluids and vasopressors might be needed in severe cases. Outbreak Definition An outbreak is an occurrence of the disease in excess of the expected frequency in a given area among a specific group of people over a particular period of time, or of two or more epidemiologically linked cases in a short period. Major outbreaks occur every 2–15 years in endemic areas, especially those where the use of the JE vaccine is not widespread. The transmission of the virus usually intensifies during the rainy season, when vector populations increase. Studies have shown a strong association between agricultural practices, including rice cultivation, and the density of the vector mosquitoes. Therefore, an increase in the abundance of rice fields or the establishment of rice cultivation in new areas is likely to increase the risk of JE. Modifications needed in surveillance z Only the first 5–10 cases of an outbreak need to be confirmed through laboratory testing. z If an outbreak continues over a protracted period of time, another 5–10 samples should be collected every 2–3 months to ascertain whether it is still JE that is causing the outbreak. z If the outbreak is not an expected seasonal one, or there are unusual epidemiological features (such as the age distribution of cases not being consistent with the pattern of JE infection or the absence of typical vectors or hosts), it is especially important to test CSF samples, as an encephalitis outbreak can have other causes. 15 JAPANESE ENCEPHALITIS Data management Reporting requirements Aggregate case counts (confirmed and probable) to track the disease burden are sufficient to identify clusters and monitor trends. z Aggregate case counts should be reported to the public health authorities at least once a month. z In countries where a high level of JE control has been achieved, case-based data should be reported. Reporting should be weekly or monthly, and must include “zero reporting” (i.e. a zero should be written when no cases have been detected, leaving no blanks in the reporting forms). z Although the International Health Regulations do not require the reporting of JE cases, JE is included in the World Health Organization (WHO)/United Nations Children’s Fund Joint Reporting Form, which should be submitted annually. Unique ID A unique case identification number should be assigned to each suspected case, as explained earlier. Recommended data elements z Unique case identifier z Date of birth (or age, if date of birth is not available) z Sex z Place of residence (city, district and province) z Travel history over the past two weeks z If ever immunized against JE z Number of vaccine doses received z Dates of vaccine doses (if available) z If vaccinated, type of vaccine received most recently z Symptoms (fever, change in mental status, seizure) z Date of onset of first symptoms z Type of specimen collected (CSF, serum, autopsy) z Type(s) of testing methodology (IgM, PRNT, PCR, virus isolation, etc.) z Date(s) of specimen collection (including serum samples 1 and 2) z Date(s) of receipt of specimen(s) in laboratory z Date(s) of testing of specimen(s) (for each type of test) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 z Date(s) on which laboratory reported results z Laboratory results for each specimen z Final classification: laboratory-confirmed JE, probable JE, AES-unknown, AES- other agent z Status at discharge: alive, dead, unknown z Date of death or discharge These data elements have been put together in the sample case investigation form (Annex 2). Data analysis z Number of suspected cases by week, month, year, age group and geographical area z Number of confirmed cases by week, month, year, age group and geographical area z Number of deaths due to JE z Coverage of JE vaccine by year and geographical area z Percentages of vaccinated and unvaccinated cases, and completeness/timeliness of monthly reporting by geographical area z Suspected and confirmed cases – incidence specific to age, gender, geographical area and immunization status z Percentage of suspected cases whose CSF and/or serum specimens were collected z Percentage of cases whose serum sample was collected 10 or more days after the onset of illness (when testing methodology was IgM-capture ELISA) z Case fatality ratio z Final classification of all suspected cases z Proportion of AES attributed to JE Using data for decision-making Surveillance data on JE may be used to: z guide policy and strategies on the control of JE; z assess the impact of vaccination; z identify geographical areas or populations at high risk to provide further guidance on where the coverage of immunization should be improved; z monitor the performance of surveillance; z monitor the performance of laboratories; and z monitor the effectiveness of vaccines. 17 JAPANESE ENCEPHALITIS Surveillance performance Table 10.2 shows the indicators and targets for evaluating the performance of a surveillance system. The targets are for countries with a well-established AES surveillance system. Table 10.2: Indicators for surveillance performance Attribute Indicator Target How to calculate Comments Completeness of reporting Proportion of surveillance units reporting to the national level, even in the absence of cases ≥ 80% (Number of surveillance units reporting / number of surveillance units in the country) x 100 Timeliness of reporting Proportion of surveillance units reporting to the national level on time, even in the absence of cases ≥ 80% (Number of surveillance units reporting by the deadline / number of surveillance units in the country) x 100 Note 1 Specimen collection Proportion of all suspected cases for which at least 1 specimen was collected ≥ 90% (Number of AES cases with specimen collected / number of AES cases) x 100 None Proportion of suspected AES cases who had a lumbar puncture performed ≥ 90% (Number of suspected AES cases who had a lumbar puncture performed / number of suspected AES cases) x 100 None Proportion of serum samples taken a minimum of 10 days after onset of illness ≥ 80% (Number of serum samples obtained at least 10 days after onset of illness / number of serum samples received by laboratory) x 100 Note 2 Specimen adequacy Proportion of CSF and serum samples reaching laboratory in adequate condition ≥ 80% (Number of CSF and serum samples reaching laboratory in adequate condition / all CSF and serum samples received by laboratory) x 100 Note 3 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 Attribute Indicator Target How to calculate Comments Timeliness of reporting laboratory results Proportion of laboratory results reported to national public health authorities 7 days after receipt of specimen ≥ 80% (Number of laboratory test results reported < 7days after receipt of specimen / number of specimens received by laboratory) x 100 Note 4 . Sensitivity Minimal AES rate per 100 000 population >2/100 000 (Number of AES cases captured by surveillance / number of target population in the country) x 100 000 Note 5 Notes The reporting should be at least quarterly. At each level, reports should be received on or before the requested date. This applies to laboratories where the testing methodology is IgM capture ELISA. To be “adequate”: (a) the specimen should be transported using reverse cold chain, and (b) the sample volume must be greater than 100 µL. This indicator applies only to public laboratories. This applies to enhanced (nationwide) surveillance and not minimal (sentinel) surveillance. Public health response The public health response to JE should include the following. Vaccination JE vaccination should be integrated into national immunization schedules in all areas where the illness is recognized as a public health priority. Health education and community involvement Community awareness helps to shorten the delay between the onset of symptoms and the time of seeking medical care. Immediate supportive management of cases helps to cut down deaths. Interruption of transmission Vaccination of humans is the only proven method for reducing JE disease. There is little evidence to support the vaccination of pigs, environmental management for vector control, and chemical control of vectors. 19 JAPANESE ENCEPHALITIS Annex 1: Disease epidemiology Background Japanese encephalitis is an infection of the brain/central nervous system, caused by a flavivirus. JE virus (JEV) is transmitted to humans through the bite of infected mosquitoes of the Culex species, particularly Culex tritaeniorhynchus. The virus is maintained in nature via a cycle between mosquitoes and vertebrate hosts, primarily pigs and water birds. Humans are infected incidentally and are dead-end hosts as they are unable to pass on the infection. This is because they usually do not develop high enough concentrations of the virus in their bloodstream to infect mosquitoes feeding on them. The virus has five genotypes. Most infected people are asymptomatic. Therefore, it is difficult to determine the accurate incidence of JE and the disease burden may be underestimated. It is estimated that less than 1% of humans infected by JEV develop disease. Japanese encephalitis is a disease of great public health concern due to its severe morbidity and mortality and the continuing increase in its global distribution. It is the leading cause of tropical viral diseases. At present, most cases are being reported from the WHO South- East Asia Region (almost 60%) and Western Pacific Region (about 40%). Though most JEV infections either have no symptoms or mild (fever and headache) or short-lived ones, approximately 1 in 250 infections results in severe clinical illness. Severe disease is characterized by the rapid onset of a high fever, headache, stiffness of the neck, change in mental status /disorientation, coma, fits/convulsions (common among children), weakness in the limbs, spastic paralysis and ultimately, death. The case fatality rate can be as high as 30% among those with symptoms, the number of deaths amounting to approximately 13 600–20 400 annually. Of those who survive, 20–30% suffer permanent intellectual, behavioural or neurological sequelae, such as paralysis, recurrent seizures and the inability to speak. Essential epidemiology Infectious agent: The Japanese encephalitis virus is a flavivirus. Reservoir of infection: The virus is maintained in a cycle between mosquitoes and pigs and water birds. Annexes Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Mode of transmission: JE is transmitted through the bite of an infected mosquito belonging to the Culex species. Incubation period: 5–15 days Period of communicability: Humans are generally a dead-end host and do not infect mosquitoes. Case fatality ratio: Up to 30% among those with severe clinical symptoms Vaccines The four main types of JE vaccines currently in use are shown in Table 10. A1. Table 10. A1: JE vaccines and doses Type of vaccine Number of doses Age at which to be administered Inactivated mouse brain-derived vaccines Production halted in 2006, remaining supplies limited Inactivated Vero cell-derived vaccines* 2 doses 4 weeks apart > 6 months of age in endemic settings Live attenuated vaccines (primary hamster kidney cell-derived)* Single dose > 8 months of age Live recombinant (chimeric) vaccines* Single dose > 9 months of age * WHO prequalified Although all current JE vaccines are derived from genotype III strains, they elicit protective levels of neutralizing antibodies against heterologous strains of other genotypes. Disease burden The JE virus is the most important cause of viral encephalitis in many Asian countries, the number of estimated clinical cases being 68 000 every year. The transmission of JEV is endemic in 24 countries in the WHO South-East Asia and Western Pacific regions, which means that more than 3 billion people are exposed to the risk of infection. The annual incidence of clinical disease varies both across and within endemic countries, ranging from <1 to >10 or higher per 100 000 population during outbreaks. The virus primarily affects children as most adults in endemic countries develop natural immunity after childhood infection. However, individuals of any age may be affected. 21 JAPANESE ENCEPHALITIS Annex 2: Case investigation form Case Identification Number: JE- _______/____________/__________/____/_____ Country code/ Province code/District code/ Year/ Serial number Patient information Name of health facility Patient’s name Age in years / months Date of birth dd/mm/yyyy Sex Male  Female  Unknown  Residential address House no. Village/ town/ city: Street name: District/ province: Country: Pin/ zip code: Contact number (mobile) Clinical history Date of notification to public health system dd/mm/yyyy Date of investigation dd/mm/yyyy Date of onset of first symptom dd/mm/yyyy Fever: acute onset Yes  No  Unknown  Altered mental status Yes  No  Unknown  Seizures Yes  No  Unknown  Vaccination history JE vaccine (type) Number of doses received 1  2  Unknown  Others  Date of first dose dd/mm/yyyy Date of second dose dd/mm/yyyy Date of other doses dd/mm/yyyy Comments Investigations done Type of specimen collected CSF  Serum  Autopsy  Type(s) of testing methodology IgM  PRNT  PCR  Virus isolation  Others (describe) Date of collection of specimen dd/mm/yyyy Number of specimen(s) collected One  Two  Date of collection of second sample dd/mm/yyyy Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 Laboratory results Dates of receipt of specimen(s) dd/mm/yyyy Dates of testing of specimens dd/mm/yyyy Date(s) of reporting of results dd/mm/yyyy Laboratory results for each specimen Classification of case Final classification Laboratory- confirmed  Epidemiologially linked  Compatible  AES unknown  AES other agent  Outcome Follow-up Death  Survived  Lost to follow- up  Date of death/ discharge dd/mm/yyyy Comments Investigator’s name: Designation: Institution: Telephone (mobile): Email: Date: Signature: 23 JAPANESE ENCEPHALITIS Further reading 1. Bharucha T, Shearer FM, Vongsouvath M, Mayxay M, Lamballerie X, Newton PN, et al. A need to raise the bar – a systematic review of temporal trends in diagnostics for Japanese encephalitis virus infection, and perspectives for future research. Int J Infect Dis. 2020 Jun; 95:444–56. doi: 10.1016/j. ijid.2020.03.039. 2. Simon LV, Sandhu DS, Goyal A, Kruse B. Japanese Encephalitis. 2022 Jun 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. 3. Vannice KS, Hills SL, Schwartz LM, Barrett AD, Heffelfinger J, Hombach J et al.; Japanese encephalitis vaccination experts panel. The future of Japanese encephalitis vaccination: expert recommendations for achieving and maintaining optimal JE control. NPJ Vaccines. 2021;6(1):82. doi: 10.1038/ s41541-021-00338-z. 4. World Health Organization. Japanese Encephalitis vaccines: WHO position paper. Wkly Epidemiol Rec. 2015 Feb 27; 90(9): 69–87. (https://www.who. int/publications/i/item/japanese-encephalitis-vaccines-who-position-paper, accessed 20 August 2022). 5. Surveillance guide for vaccine-preventable diseases in the WHO South- East Asia Region. New Delhi: World Health Organization, Regional Office for South-East Asia; 2017. Licence: CC BY-NC-SA 3.0 IGO (https:// apps.who.int/iris/bitstream/handle/10665/277459/Module9-JE. pdf?sequence=81&isAllowed=y, accessed 20 August 2022). 6. World Health Organization. Regional Office for South-East Asia. Regional workshop on strengthening the capacity of Japanese Encephalitis (‎JE)‎ laboratory network in the WHO South-East Asia Region. World Health Organization. Regional Office for South-East Asia; 2019. (https://apps.who. int/iris/handle/10665/332738, accessed 20 August 2022). 7. World Health Organization. Manual for the Laboratory Diagnosis of Japanese Encephalitis Virus Infection. World Health Organization; 2007 (https://cdn. who.int/media/docs/default-source/immunization/vpd_surveillance/lab_ networks/manual-lab-diagnosis-je.pdf?sfvrsn=e2b62a35_4, accessed 20 August 2022). 8. World Health Organization. Japanese encephalitis: surveillance standards for vaccine-preventable diseases, 2nd ed. World Health Organization; 2018. (https://www.who.int/publications/m/item/vaccine-preventable-diseases- surveillance-standards-je, accessed 20 August 2022). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24 9. Xu C, Zhang W, Pan Y, Wang G, Yin Q, Fu S et al. A bibliometric analysis of global research on Japanese encephalitis from 1934 to 2020. Front. Cell. Infect. Microbiol. 2022 Jan 27; 12:833701. doi: 10.3389/fcimb.2022.833701. 10. Hu YL, Lee PI. Safety of Japanese encephalitis vaccines. Hum Vaccin Immunother. 2021; 17:11, 4259–64. doi: 10.1080/21645515.2021.1969852.

CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

MODULE-11 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region September 2023 Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region (Invasive bacterial vaccine-preventable diseases) ISBN 978-92-9021-009-2 © World Health Organization 2023 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BYNC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Printed in India Cover and inside photo credit: WHO Introduction 5 Objectives 5 Surveillance 6 Nation-wide, sentinel, case-based and prospective surveillance including all ages 6 Special considerations 6 Case detection 7 Investigation of suspected case 8 Case investigation form 8 Assigning a unique ID 8 Specimen collection 8 Laboratory testing 11 Cerebrospinal fluid 11 Blood 12 Pleural fluid 13 Strain characterization 13 Laboratory Network 14 Antimicrobial resistance testing 14 Classification of cases 15 Probable case 15 Confirmed case 16 Managing contacts 17 Invasive meningococcal disease 17 Invasive pneumococcal disease 17 Invasive H. influenzae disease 17 Clinical management 17 Outbreaks 18 CONTENTS Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 4 Definition 18 Pneumococcal cluster/outbreak 18 Invasive meningococcal disease cluster/outbreak 18 H. influenzae cluster/outbreak 19 Modifications needed in surveillance 19 Data management 19 Reporting requirements 19 Unique ID 20 Recommended data elements 20 Data analysis 20 Sentinel hospital IPD surveillance 20 Population-based IPD surveillance 21 Using data for decision-making 21 Indicators of surveillance performance 21 Public health response 24 Reactive vaccination 25 Chemoprophylaxis 25 Annex 1: Disease epidemiology 27 Background 27 Vaccines 29 Annex 2: The global IB-VPD surveillance network 33 Annex 3: Responsibilities of surveillance officers at sentinel IB-VPD sites 33 Key points to consider: 34 Annex 4: Case investigation form 35 Further reading 40 5INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Invasive bacterial vaccine-preventable diseases Introduction Invasive bacteria are pathogens that can invade parts of the body where bacteria are not normally present (sterile sites), such as the bloodstream, soft tissues like muscle or fat, and the meninges (the tissues covering the brain and spinal cord). Four major agents – Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae and Streptococcus agalactiae (group B streptococcus or GBS) – are responsible for severe invasive infections in children >1 month of age. These bacteria cause more than half of the deaths from meningitis globally. Although meningitis affects all ages, newborn babies are at the greatest risk from group B streptococcus, young children are at a high risk from meningococcus, pneumococcus and Haemophilus influenzae. Adolescents and young adults are at particular risk of meningococcal disease while the elderly are at specific risk of pneumococcal disease. Surveillance for invasive bacterial vaccine-preventable diseases (IB-VPD) contributes significantly to the goal of “Defeating meningitis by 2030”. To standardize the monitoring of the global burden and etiology of IB-VPD, WHO has been coordinating and monitoring a global IB-VPD surveillance network since 2009. Objectives The objectives of surveillance for IB-VPD are to: z quantify disease burden and epidemiology, including disease trend; z evaluate the impact of vaccines on epidemiology and disease burden; z describe locally circulating serotypes/serogroups to generate evidence for identifying the right type of vaccine(s); z identify gaps in the implementation of the immunization programme and provide data to determine if changes are needed in the vaccine policy; z monitor antimicrobial resistance (AMR) to guide treatment choices and improve health-care outcomes; z detect, confirm and respond rapidly to cases, clusters and outbreaks; and z identify geographical areas and populations at risk in order to implement and adapt adequate control measures. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 6 Surveillance Nation-wide, sentinel, case-based and prospective surveillance including all ages Surveillance for IB-VPD requires skilled health staff to perform procedures such as lumbar- puncture and collection of blood for culture, while minimizing contamination of specimens. In addition, there is a need to transport specimens very quickly to a high-quality laboratory to ensure a high yield of the targeted pathogens. Care should be taken to choose sentinel sites that attract a large number of patients of the target diseases. Special considerations z Surveillance for IB-VPD is not pathogen-specific. It covers N. meningitidis, S. pneumoniae, H. influenzae and GBS, and laboratory capacity is required to identify these organisms. The surveillance can be nationwide or regional and is typically aggregate passive surveillance. If a meningitis outbreak due to N. meningitidis is detected, a rapid public health response is warranted. This includes reactive vaccination. Mass gatherings have been settings for meningococcal disease outbreaks. Cases related to mass gatherings must be reported under International Health Regulations (IHR). z Surveillance for GBS needs particular attention as it is virtually nonexistent in most countries. Quantifying the burden of neonatal GBS disease remains a challenge even in high income countries. The task is even more difficult in low- and middle-income countries because: a portion of births may occur outside hospital settings; facility-born infants may be discharged quickly after birth; care- seeking, particularly early in life, may be limited; access to care, particularly in rural areas, may pose challenges; and health facilities may lack access to diagnostic tests, laboratory capacity or resources to diagnose GBS infection. As a result, particularly for early-onset disease, most of which occurs within the first 24–48 hours of life, GBS disease is likely to be under-represented in studies from these settings. z Sentinel surveillance is not adequate for measuring the impact of vaccines in all settings. The most appropriate method should be chosen in accordance with the setting, and multiple methods may be needed. z Serosurveys and carriage studies are not recommended for surveillance. They should be limited to research activity. z The ability of the surveillance system to detect and report all IB-VPDs should be evaluated through capture–recapture studies. 7INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Case detection Table 11.1: Definition of suspected case Disease Definition Meningitis Any child of the age of 0–59 months admitted to hospital with sudden onset fever (> 38.5°C rectal or 38°C axillary) and one of the following signs: neck stiffness, altered consciousness with no other alternative diagnosis, or other meningeal signs; or hospitalized with a clinical diagnosis of meningitis Sepsis Any child of the age of 0–59 months admitted to hospital with at least two of the following signs and without meningitis or pneumonia clinical syndrome: z inability to drink or breastfeed z vomiting everything z convulsions (except in malaria endemic areas) z prostration/lethargy z severe malnutrition z hypothermia (≤ 36°C). Pneumonia Any child of the age of 0–59 months demonstrating cough or difficulty in breathing and displaying fast breathing when calm, as defined by age: 0 to < 2 months: 60 breaths/minute or more 2 to < 12 months: 50 breaths/minute or more 12 to ≤ 59 months: 40 breaths/minute or more. Severe pneumonia Any child of the age of 0–59 months with a cough or difficulty in breathing and displaying one or more of the following: z inability to drink or breastfeed z vomiting everything z convulsions z prostration/lethargy z chest indrawing z stridor when calm. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 8 Investigation of suspected case Suspected cases should be investigated by the designated surveillance officer. Case investigation form Case investigation forms should be filled for all suspected cases for sentinel surveillance and population-based surveillance. (See Annex 4 for a sample case investigation form.) Assigning a unique ID A unique case identification number (UID) should be assigned to each suspected case. This case number should begin with one or more three-letter combinations to designate the geographical location, followed by the year and the case number. All communications and forms related to the case should cite the unique case identification number. For example: IBD – code for suspected IB-VPD case THA – country code BKK – province code BBN – district code 2022 – year of onset 001 – serial number of case in the province The UID would then be: IBD-THA-BKK-BBN-22-001. Specimen collection For sentinel hospital surveillance, all children of the age of 0–59 months who meet the suspected case definition should undergo a lumbar puncture for the collection of cerebrospinal fluid (CSF) unless the procedure is clinically contraindicated. The fluid should be collected before the administration of antibiotics, otherwise the laboratory may be unable to culture the pathogen and provide information on antimicrobial susceptibility. However, a specimen should be obtained from all suspected cases even if antimicrobial therapy has begun because bacterial pathogens can still be detected. For expanded surveillance approaches, appropriate specimens should also be collected from patients with suspected pneumonia and sepsis. Treatment should not be delayed while awaiting results from the laboratory. 9INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Table 11.2: Collection, storage and transport of specimens Cerebrospinal fluid Volume z 3 mL, divided equally into three test tubes: z tube 1: chemical analysis – protein and glucose tests z tube 2: microbiological tests z tube 3: overall appearance; white blood cell count z If only one tube of CSF is available, it should be given to the microbiology laboratory for culture/reverse transcription-polymerase chain reaction (RT- PCR)/antigen testing. However, an aliquot of 50–100 μL should be spared for molecular testing. z The presence of blood in the CSF can affect cultures, since antibiotics in blood can inhibit bacterial growth. If more than one tube is being collected, the first tube may contain contaminated blood from lumbar puncture and should not be sent to the microbiology laboratory. Timing of collection z CSF should be collected as soon as possible after admission, preferably before antibiotic therapy is started. z The laboratory must be informed about the lumbar puncture so that the technician can be ready to process the sample as soon as possible. z The collection of specimens should never delay the administration of antibiotics. Storage and transport z The CSF specimen should be sent to the laboratory immediately, and processed within two hours of collection. z If it cannot be processed in one or two hours, 0.5–1.0 mL of the specimen should be inoculated into trans-isolate (T-I) medium and the incubate vented at 35–37°C with 5% CO2 overnight, or until transport is possible (up to four days). z If transport is delayed beyond four days, the specimen should be stored at room temperature (unvented). z CSF specimens should not be refrigerated. They should be stored at room temperature. z If there is no access to a microbiology laboratory, the inoculated T-I media should be sent to the district or reference laboratory as soon as possible. z Districts should send the inoculated T-I media to the reference laboratory at least twice a week. Long-term storage z Isolates should ideally be stored at -70°C. z They may be stored at -20°C for further testing (serotyping and antimicrobial susceptibility) in the future, or if the local facility lacks culture capacity and processing needs to be done at the national or regional reference laboratory. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 10 Blood Volume z 1–3 mL is considered adequate for a child, and 5–10 mL for an adult. z For culture, the blood collected should be diluted in blood culture broth in the appropriate ratio for optimal bacterial growth. The recommendations of the culture broth manufacturer should be followed closely. The blood-to-blood culture broth ratio should be: z 1–3 mL blood to 20 mL of broth for children; and z 5–10 mL blood to 50 mL of broth for adults. Timing of collection z The specimen should be collected prior to the administration of antibiotics, if possible. However, the collection of specimens should never delay the administration of antibiotics. z The laboratory should be informed so that the technician can be ready to process the specimen as soon as possible. Storage and transport z Blood and pleural fluid should be inoculated into a blood culture bottle within one minute and transported to a microbiology laboratory as soon as possible for overnight incubation and growth of bacteria. z All inoculated blood culture media should be protected from extremes of temperature (< 18°C or > 37°C) with a transport carrier and thermal insulator (such as extruded polystyrene foam). z Inoculated blood culture bottles should not be placed in the refrigerator. z Blood cannot be transported in syringes because these do not contain any anticoagulant, so the blood will coagulate within a few minutes. Long-term storage z It is preferable to store isolates at -70°C . z Isolates should be frozen at -20°C for further testing (serotyping and antimicrobial susceptibility), or if the local hospital lacks culture capacity and the specimen needs to be processed at a reference laboratory. 11 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Pleural fluid Volume z Approximately 20–40 mL of aspirated fluid should be placed immediately in tubes coated with the appropriate anticoagulant (EDTA or heparin) for z biochemistry (5 mL) z microbiology (5–10 mL) z cytology (10–25 mL) z PCR testing (200 μL–1mL). z A heparin-coated syringe must be used to measure pH. Timing of collection z Though it is preferable to collect specimens prior to the administration of antibiotics, the collection of specimens should not delay the administration of antibiotics. z The laboratory must be informed in advance so that the technician can process the specimen as soon as possible. Storage and transport z Pleural fluid should be immediately inoculated (within one minute) into a blood culture bottle and transported to a microbiology laboratory as soon as possible for overnight incubation and growth of bacteria. All inoculated blood culture media should be protected from temperature extremes (< 18°C or > 37°C) with a transport carrier and thermal insulator (such as extruded polystyrene foam). Long-term storage z Isolates should preferably be stored at -70°C. z They should be frozen at -20°C for further testing (serotyping and antimicrobial susceptibility), or if the local hospital lacks culture capacity and processing needs to be done at a reference laboratory. Laboratory testing Cerebrospinal fluid Since meningitis syndrome may be caused by various pathogens, clinical syndromic surveillance must be complemented by a strong laboratory component. Laboratory confirmation of pneumococcal meningitis is carried out by culture, PCR or antigen detection. Bacterial culture is the first priority for confirmation and isolation of the pathogen. Culture: Culture is considered the gold standard, but has low sensitivity due to potential antibiotic use by the patient before sample collection. Besides, local hospitals often do not have adequate capacity for culture, and frozen samples need to be sent to reference laboratories. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 12 CSF samples should be cultured on blood agar plates and supplemented chocolate agar plates that are prepared with 5–10% sheep or horse blood. The optimal medium for the growth of pneumococcus is BAP, but it can also grow on a CAP, which is the optimal medium for H. influenzae culture. For the maximum yield of isolates from blood culture, all negative cultures from probable invasive meningococcal disease (IMD) cases should be subcultured after five days of incubation before they are discarded. PCR: This is recommended for all suspected cases because bacterial culture might be inhibited if the case has already received antibiotics. As PCR capacity is not always available at the district or local level, the residual volume of the original non-manipulated CSF can be frozen and sent to a national or regional reference laboratory for further testing. Rapid diagnostic test kits: These increase yield and provide results quickly, so they may be used for clinical care and outbreak identification. Rapid diagnostic tests (RDTs) identify the three primary causative pathogens of bacterial meningitis within hours. In general, RDTs only identify the species and not the serotype or serogroup. There are two commonly used RDTs. Latex agglutination testing (LAT) should be performed according to the manufacturer’s instruction with quality control strains. Kits for LAT often have a short shelf life, so care must be taken to ensure that expired kits are not used. The BinaxNOW kit can be used to test CSF and pleural fluid for the detection and limited characterization of pneumococcus. It identifies only S. pneumoniae and not H. influenzae and is recommended for use in cases of suspected meningitis to identify bacterial aetiology. Gram stain: Gram stain should not be used to confirm cases, but it is reliable and relatively inexpensive if the staff is well trained, and reagents are of the requisite quality. On Gram stain: S. pneumoniae appear as a Gram-positive lance-shaped diplococci, sometimes occurring in short chains, intracellularly or extracellularly. N. meningitidis appear as Gram-negative bean-shaped diplococci. H. influenzae are small, pleomorphic Gram-negative rods or coccobacilli with random arrangement. Blood Blood culture can be used to diagnose pneumococcal meningitis, pneumonia and sepsis. The laboratory methods for blood culture are the same for all the syndromes. However, the sensitivity for pneumococcal pneumonia is lower than that for the other syndromes because only approximately 10–15% of pneumococcal pneumonia cases are bacteraemic. The same is the case for pneumonia caused H. influenzae. 13 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES z To get the maximum yield of isolates, all negative cultures must be subcultured after five days of incubation before they are discarded. z PCR and RDTs are not used routinely to detect pneumococcus/H. influenzae due to low sensitivity and specificity. z All RDT results must be reported within one to two hours of testing. z CSF and blood culture results must be reported to the clinicians daily if cultures are done in the hospital laboratory. Pleural fluid The presence of microbes on Gram staining and/or culture of pleural fluid indicates pleural infection, but such investigations have a poor yield of <50% in most studies. The absence of microbes, therefore, does not exclude infection. The use of PCR to amplify and detect RNA gene from pleural fluid samples has shown confusing results. Strain characterization All confirmed cases should have the serogroup designated to guide vaccination efforts and help to understand the local epidemiology. Serogrouping can be carried out on a bacterial isolate (if available from culture) or on PCR-positive clinical specimens. Specimens or isolates from confirmed or probable cases should be stored for further strain characterization. Strain characterization or whole genome sequencing (WGS) should be performed at national, regional or global reference laboratories (such as a WHO collaborating centre for meningococcal meningitis). Fig. 11.1: Algorithm for laboratory diagnosis of IBD for hospital-based sentinel surveillance Source: Rajkumar P, Bharathy S, Girish Kumar CP, Veeraraghavan B, Verghese V, Gupta N et al (7) Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 14 Laboratory Network The Global Invasive Bacterial Vaccine-Preventable Diseases Laboratory Network is a network of more than 100 laboratories that support surveillance for invasive bacterial disease, including IMD. It is coordinated by WHO and Public Health England. The Network has developed standardized laboratory procedures and guidelines for data collection and implemented quality assurance and quality control systems (see Annex 2 for details). Antimicrobial resistance testing Antimicrobial resistance testing should be performed to monitor emerging resistance during outbreaks as well as for sporadic cases, in accordance with laboratory capacity. The choice of antimicrobials used for AMR testing should be based upon those used in the treatment and chemoprophylaxis of IMD as per national or regional guidelines. z If WGS is performed, AMR-related genes should be characterized. z National and regional reference laboratories and WHO collaborating centres can be utilized for gene characterization. z To the greatest extent possible, sites should perform antimicrobial sensitivity testing for all H. influenzae, N. meningitidis and S. pneumoniae isolates and evaluate the result by: z antibiotic type and route; z time between antibiotic administration and culture; z volume of fluid cultured; z geographical area; and z serotype z The recommended methods are disk diffusion (modification of the Kirby–Bauer technique) and antimicrobial gradient strip diffusion. z It is recommended that antimicrobial susceptibility testing be routinely done and reported to the national authorities and international networks such as the Global Antimicrobial Resistance Surveillance System (www.who.int/glass/en/). Pneumococcus should be tested for susceptibility to penicillins, sulfonamides and trimethoprim, and third generation cephalosporins. 15 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Classification of cases Table 11.3: Case classification for IBDs Probable case Disease Definition Bacterial meningitis A suspected meningitis case with CSF examination showing at least one of the following: z turbid appearance z leukocytosis (> 100 cells/mm3) z Leukocytosis (10–100 cells/mm3), with z elevated protein (> 100 mg/dL) z decreased glucose (< 40 mg/dL). Note: The first two may be used to diagnose if protein and glucose results are not available. IMD Clinical diagnosis of meningitis or septicaemia and at least one of the following: z purpuric rash where IMD is considered the most likely cause (linked to confirmed cases and other causes of haemorrhagic rash excluded or considered less likely); z Gram-negative diplococci identified from any normally sterile site (blood, CSF) or from a purpuric skin lesion; or z N. meningitidis antigen detection (for example, by LAT) from any normally sterile site or from a purpuric skin lesion. Note: Since IMD surveillance is based on laboratory findings or a characteristic haemorrhagic rash, there is no suspected case definition. GBS Clinically compatible signs and symptoms with a clinical diagnosis of GBS disease in a newborn (up to 28 days of age), and one of the following: z laboratory confirmation of GBS in a lower vaginal or anorectal specimen or a normally sterile site (e.g. blood) of the mother; or z laboratory confirmation of GBS isolated from the placenta or amniotic fluid. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 16 Confirmed case Disease Definition Meningitis H. influenzae meningitis A suspected or probable meningitis case that is laboratory-confirmed by culture or identification of H. influenzae (by antigen detection, immunochromatography, RT-PCR or other methods) in the CSF or blood Pneumococcal meningitis A suspected or probable meningitis case that is laboratory-confirmed by culture or identification of pneumococcus (by antigen detection, immunochromatography, RT-PCR or other methods) in the CSF or blood Sepsis H. influenzae sepsis A case that meets the definition of sepsis and has a positive culture of H. influenzae from a normally sterile site Pneumococcal sepsis A case that meets the definition of sepsis and has a positive culture of S. pneumoniae from a normally sterile site Pneumonia H. influenzae pneumonia A person meeting the definition of pneumonia or severe pneumonia with a positive culture of H. influenzae from blood or pleural fluid Pneumococcal pneumonia A person meeting the definition of pneumonia or severe pneumonia with a positive culture of S. pneumoniae from blood or pleural fluid GBS Laboratory confirmation of GBS from a normally sterile site (e.g. CSF) in a newborn (up to 28 days of age) with clinically compatible signs and symptoms of invasive disease Disease Definition Invasive disease Invasive H. influenzae (Hib) disease H. influenzae identified through culture of specimen from any normally sterile site (e.g. blood, CSF, pleural fluid, joint fluid) of a symptomatic person; or in CSF or pleural fluid by antigen detection, immunochromatography or PCR Note: In the case of a blood sample, only culture is confirmatory, as other detection methods do not have enough specificity to diagnosis Hib, particularly in children. Invasive meningococcal disease N. meningitidis identified through culture or PCR of sample from a purpuric skin lesion or any normally sterile site (blood, CSF or other fluids such as synovial fluid) 17 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Invasive pneumococcal disease (IPD) S. pneumoniae identified by culture of specimen from any normally sterile site (blood, CSF, pleural fluid, joint fluid); or by antigen detection, immunochromatography or PCR of CSF or pleural fluid of a symptomatic person Note: In the case of blood, only culture can confirm IPD, as other detection methods do not have enough specificity to diagnose IPD, particularly in children. Invasive GBS Laboratory confirmation of GBS in a sample from a normally sterile site (e.g. CSF) in a newborn (up 28 days of age) with clinically compatible signs and symptoms of invasive disease Managing contacts Invasive meningococcal disease Close contacts of IMD cases are at increased risk of IMD disease. Close contacts include those living in the same household or who have an equivalent level of contact, for example, those in the same childcare or preschool setting, travel contacts on a long flight and anyone directly exposed to the respiratory or oral secretions of a case in the 7 days before the onset of disease. Vaccination and chemoprophylaxis of close contacts should follow national guidelines. If chemoprophylaxis with antibiotics is given, it should be done as soon as possible, preferably within < 24 hours of the identification of the index case, as most secondary disease occurs within 72 hours of the presentation of the index case. Specific antibiotics that clear pharyngeal carriage of meningococci are recommended for chemoprophylaxis. Invasive pneumococcal disease Contact tracing is not routinely done for pneumococcal surveillance. Invasive H. influenzae disease Contact tracing is not routinely done for H. influenzae surveillance. Clinical management Laboratory diagnosis is important in distinguishing between these diseases. All cases of should be hospitalized and promptly treated with presumptive antibiotics, given parentally (intravenous or intramuscular). It might be necessary to provide supportive care, including fluids, oxygen and possibly mechanical ventilation. Blood and CSF samples should be taken before initiating antibiotic treatment, if possible. However, treatment Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 18 should not be delayed until the laboratory results arrive. All cases of IB-VPD should be treated as quickly as possible, using appropriate antibiotics and isolation procedures, in accordance with national treatment protocols. Outbreaks Sentinel site surveillance is not designed to identify all outbreaks since it is geographically limited, so other types of surveillance with greater geographical coverage are required to identify outbreaks. Except for N. meningitidis and S. pneumoniae which cause meningitis, none of the other organisms included in IB-VPD generally cause outbreaks. Although most pneumococcal disease is sporadic, outbreaks may occur in crowded institutions, such as military barracks, shelters for the homeless and prisons. Hib, too, can cause outbreaks in settings such as day-care centres, while large-scale outbreaks of pneumococcal meningitis have been reported in the African meningitis belt. Definition Pneumococcal cluster/outbreak There is no accepted definition. z Some consider a cluster of serious pneumococcal disease to be two or more temporally linked cases that occur in a closed setting. z If the serotype is the same among IPD cases, the evidence for an epidemiologically linked cluster is strengthened. z In the African meningitis belt, some consider a significant rise above baseline rates to be an outbreak, while others apply the epidemic threshold of 10 suspected meningitis cases/100 000 population that was developed for meningococcal meningitis outbreak responses. Invasive meningococcal disease cluster/outbreak The occurrence of a minimal number of cases (of the same serogroup/strain, if possible to identify) within a defined time period, or of a minimal attack rate above a defined threshold, usually expressed as the number of cases per 100 000 population, is considered to be an outbreak. These thresholds are specific to each setting. The occurrence of a number of cases close in time and within a defined geographical area or population (in the community or in institutional settings, such as schools or prisons), but not meeting the definition of an outbreak is called a cluster. A cluster may comprise two or three cases. 19 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Hyperendemic situation: This is defined as persistently high levels of occurrence of the disease. Typically, this happens between epidemics in the African meningitis belt. Should this happen: z All cases must be treated with the appropriate antibiotics as quickly as possible, and patients should be isolated in accordance with national treatment protocols. z Taking a pharyngeal swab of each case is not recommended. z Specimens for laboratory confirmation should be obtained before antibiotic treatment, if possible. However, patients should be treated presumptively with antibiotics without waiting for laboratory results. z In some areas with a higher prevalence of IMD, patients may suffer from rashes due to endemic haemorrhagic viruses, which might be confused clinically with the haemorrhagic rash of IMD. Laboratory diagnosis is important for distinguishing these diseases from IMD. H. influenzae cluster/outbreak There is no accepted definition of an outbreak or cluster of H. influenzae or Hib. Some consider a cluster of serious H. influenzae disease to be two or more temporally linked cases occurring in a closed setting. The evidence for an epidemiologically linked cluster is strengthened if the serotype is the same in the cases. Modifications needed in surveillance Surveillance should be intensified during outbreaks. It should be extended to all area hospitals and clinics that might see meningitis cases and potential cases of pneumonia and sepsis. To improve detection and enhance case finding, a suspected case may be defined on the basis of the main symptoms encountered. Community-based and active surveillance may be considered. Weekly reporting, including zero reporting, should be instituted in all area clinics. Data management Reporting requirements Confirmed cases must be reported to the ministry of health on a monthly basis. Sentinel surveillance sites must follow the “zero reporting” protocol. Aggregate reporting (numbers only) is sufficient for routine reporting, even if case-based surveillance is conducted. There are no global reporting requirements for pneumococcus (International Health Regulations or WHO/UNICEF Joint Reporting Form). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 20 Unique ID A unique case identification number should be assigned to each suspected case, as explained earlier. Recommended data elements The core data elements for sentinel hospital surveillance of meningitis are: z sentinel site information – name or code z demographic information z clinical data z vaccination history z laboratory data z CSF collection date and results z blood collection date and results z pleural fluid collection date and results z epidemiological information z date of investigation z date of notification to public health department z final case classification. (For details of data elements, see Annex 4.) For population based IPD surveillance: z The number of cases in the catchment area population by age group (0–5 months, 6–11 months, 12–23 months, 24–59 months, 5–17 years, 18–64 years, > 64 years) Data analysis Sentinel hospital IPD surveillance z Confirmed case counts, stratified by onset date (week, month, year), age group, sex and syndrome z Suspected meningitis, pneumonia and sepsis case counts, stratified by the same groupings as confirmed cases z Confirmed death counts and case fatality ratios z Suspected meningitis, pneumonia and sepsis death counts and case fatality ratios z Vaccination status of cases and proportion of cases vaccinated 21 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Population-based IPD surveillance z Incidence of confirmed IPD, stratified by onset date (week, month, year), age group, sex and syndrome Using data for decision-making z Determine the local disease burden (cases, deaths, disability). z Monitor trends in disease epidemiology. z Prioritize IB-VPD among other diseases of public health importance. z Advocate for and implement proper control strategies such as immunization, and targeted strategies for populations determined to be at increased risk. z Evaluate the impact of immunization services and identify areas with weak performance. z Evaluate the impact and effectiveness of vaccines, and identify areas with weak performance. Indicators of surveillance performance The IB-VPD Surveillance Network recommends the indicators listed in Table11.4. Table 11.4: Indicators of surveillance performance for pneumococcus and Haemophilus influenzae Attribute Indicator Target How to calculate Comments Completeness of reporting Consistent reporting throughout year At least 10 months of reporting (including zero reporting) Number of months of reporting per year The ideal is 12 months and confirmed zero reporting if there are no cases. Case ascertainment Minimum number of cases reported annually ≥ 80 suspected meningitis cases per year; ≥ 400 suspected cases of meningitis plus pneumonia or sepsis per year (Sentinel hospital). Number of cases reported per year ≥ 500 suspected cases of meningitis plus pneumonia or sepsis, per year is the ideal (Sentinel hospital). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 22 Attribute Indicator Target How to calculate Comments Specimen collection Proportion of suspected cases with specimens collected ≥ 80% (yellow zone[1]) ≥ 90% (green zone1) (Number of suspected cases with specimens collected / number of suspected cases) x 100 Specimen is CSF for meningitis and CSF, blood or pleural fluid for pneumonia and sepsis; ideal is ≥ 90% Specimen collection (CSF) Proportion of suspected meningitis cases with lumbar puncture performed (Number of suspected cases of meningitis with lumbar puncture performed/ number of suspected meningitis cases) x 100 The ideal is 90%. Specimen collection (Blood) Proportion of suspected pneumonia/ sepsis cases with blood culture performed (Number of suspected cases of pneumonia/ sepsis with blood culture performed/ number of suspected pneumonia / sepsis cases) x 100 Laboratory confirmation with serotype determination Proportion of laboratory- confirmed cases classified according to serotype/ group ≥ 60% (yellow zone) ≥ 80% (green zone) (Number of laboratory- confirmed cases classified according to serotype/number of laboratory- confirmed cases) x 100 For sentinel hospitals that perform serotyping or send isolates for serotyping; ideal is ≥ 80% 1 Yellow and green zones are based on performance, red being the worst and green the best. 23 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Table 11.5: Indicators of surveillance performance at country level for meningococcus disease Attribute Indicator Suggested target How to calculate Surveillance and laboratory performance Laboratory confirmation with serogroup determination Proportion of confirmed cases with serotype/ group confirmed > 80% (Number of laboratory- confirmed cases with serogroup determined / number of laboratory- confirmed cases) x 100 Specimen transport to reference laboratory Proportion of specimens received at national reference laboratory in appropriate media ≥ 80% (Number of specimens received at national reference laboratory in appropriate media /number of specimens collected ) x 100 Time taken for specimen transport to first-level laboratory Proportion of specimens received at first-level laboratory < 24 hours after collection ≥ 80% (Number of specimens received < 24 hours after collection / total number of specimens) x 100 Time taken for specimen transport to national laboratory Proportion of specimens received at national reference laboratory < 4 days after collection ≥ 80% (Number of specimens delivered to national reference laboratory < 4 days after collection / total number of specimens) x 100 Time taken for result to be made available by reference laboratory Proportion of specimens for which result was given < 7 days after collection ≥ 80% (Number of specimens for which result was delivered < 7 days after collection / total number of specimens) x 100 Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 24 Attribute Indicator Suggested target How to calculate Data management Timeliness of case reporting Proportion of cases reported in < 24 hours (or per national or regional guidelines) ≥ 80% (Number of cases reported in < 24 hours/total number of cases reported) x 100 Completeness of recording outcome Proportion of enrolled cases with outcome recorded ≥ 80% (Number of enrolled cases with outcome recorded / number of enrolled cases) x 100 Completeness of vaccine status information Proportion of cases with vaccine status reported ≥ 80% (Number of enrolled cases with vaccine status reported /number of enrolled cases) x 100 Completeness of all core information Proportion of case-based records with complete core information ≥ 80% (Number of case-based records with complete core information /number of case-based records) x100 Public health response All cases of IB-VPD should be hospitalized and promptly treated with intravenous (or intramuscular) antibiotics to which the bacteria are susceptible. Supportive care, including fluids, oxygen and mechanical ventilation, might be necessary. Samples of CSF, blood and pleural fluid (if applicable) must be taken before initiating antibiotic treatment, if possible. However, patients must be treated with presumptive antibiotics without waiting for laboratory results. Each country should define specific actions that need to be undertaken during clusters or outbreaks, including further investigation, active case finding and outbreak control measures. Control measures may include the organization of case management structures, vaccination of the population at risk and antibiotic prophylaxis to contacts. These differ in accordance with factors such as the organism responsible for the outbreak, the extent of the outbreak and the serogroup type. To ensure a robust and efficient public health response to an outbreak, the implementation of an operational threshold strategy may be considered. 25 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES In some settings, operational thresholds have been defined by modelling historical disease data to help identify populations at risk. For example, a predictive “alert” threshold might trigger the reinforcement of surveillance, while crossing a predictive “epidemic” threshold might trigger mass control measures. Reactive vaccination Reactive vaccination is used as a public health response to outbreaks due to N. meningitidis. It is not an established strategy for S. pneumoniae or H. influenzae outbreaks. However, some argue that it could be considered in very large outbreaks due to S. pneumoniae, especially in Africa, because of the high rate of sequelae with pneumococcal meningitis. In an outbreak associated with H. influenzae, non-immunized or incompletely immunized contacts under the age of 12 months should complete the vaccination schedule (3 primary doses or 2 primary doses plus a booster). When a first dose is given to a child under the age of 12 months, only one dose is recommended. Hib vaccine is usually not required for healthy children above the age of 5 years. Chemoprophylaxis Meningococcal disease: The public health response to meningococcal disease includes identifying close contacts and arranging for the appropriate chemoprophylaxis for those in close contact with a case in the 7 days preceding the onset of illness. The use of antibiotics should be guided by the national policy. Rifampicin is the antibiotic of choice except in the following cases: z for women taking hormonal contraceptives, ciprofloxacin is a preferred option as rifampicin can affect the efficacy of these contraceptives; and z for pregnant women, ceftriaxone is the preferred chemoprophylaxis agent. Table 11.6: Chemoprophylaxis agents for meningococcal disease Age group Dose Rifampicin 0–12 months 5 mg/kg twice daily for 2 days 1–12 years 10 mg/kg twice daily for 2 days (max. 600 mg) > 12 years 600 mg twice daily for 2 days Ciprofloxacin 2–4 years a single dose of 125mg 5–12 years a single dose of 250mg >12 years a single dose of 500mg Ceftriaxone < 12 years a single dose of 125mg IM >12 years a single dose of 250mg IM Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 26 Hib disease: Chemoprophylaxis is recommended for household contacts only if they are at risk, that is, unvaccinated children below the age of 10 years, partially vaccinated children below the age of 4 years and adults with asplenia, hyposplenism, etc. It is not recommended for contacts of a single case in preschool but recommended if two or more cases occur within two months. Ciprofloxacin is the drug of choice, and ceftriaxone is an alternative. Table 11.7: Chemoprophylaxis agents for Hib disease # Age group Dosage Rifampicin for Hib prophylaxis 1. < 1 year 10 mg/kg once daily for 4 days 2. > 1 year 20 mg/kg once daily for 4 days, max. 600 mg/day Pneumococcal disease: Chemoprophylaxis is not normally recommended for contacts of cases of sporadic pneumococcal meningitis. S. pneumoniae may cause clusters of serious disease on rare occasions. Clusters have been described in settings such as hospitals, long-term care facilities, prisons, military settings, hostels and day-care centres. In such cases, infection control measures, antibiotic chemoprophylaxis and vaccination of close contacts may need to be undertaken. The choice of antibiotic should be guided by the in vitro susceptibility of the bacteria, the target population, and the national policies. Amoxicillin (7-day course) is generally used as the first-line antibiotic and azithromycin (3-day course) or rifampicin (4 days) where resistance to amoxicillin is reported. Group B streptococcus: Identifying mothers whose babies are at risk of getting GBS disease is recommended in many countries. One way to do this is by universal screening for carriage of GBS during pregnancy. Mothers at risk are offered intravenous penicillin during labour to protect their babies from GBS infection. 27 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Annex 1: Disease epidemiology Background Meningitis is the most known disease caused by invasive bacteria, the other clinical forms reported being septicaemia, pneumonia and septic arthritis. Diagnosis is commonly made on basis of microbiological tests. However, culture may not be possible in all cases because of several reasons. These reasons include the lack of expertise and infrastructure, the fragility of the organisms and the early initiation of antibiotic treatment. Thus, molecular and nucleotide sequence-based diagnostic typing methods are becoming preferred alternatives. Many cases of and deaths from meningitis, septicaemia, and pneumonia are vaccine- preventable. Effective vaccines are available against three of the four causative organisms – N. meningitidis, S. pneumoniae and H. influenzae. Vaccines against S. agalactiae are under various stages of development. Table 11.A1: Essential epidemiology Infectious agent Neisseria meningitidis Streptococcus pneumoniae Haemophilus influenzae Streptococcus agalactiae Classification 12 serogroups; A, B, C, W, X, Y cause most cases of meningitis due to N. meningitidis At least 97 serotypes; predominant disease-causing serotypes vary by region Serotype b causes most Hi meningitis (Hib), with occasional cases due to type a Of the 10 serotypes, Ia, Ib, II, III, IV, V are predominant in causing disease Reservoir of infection Humans Humans Humans Humans Mode of transmission Peron-to-person – via direct contact, and respiratory droplets from nose and throat Person-to-person – via droplet infection, direct oral contact, and through articles freshly soiled with respiratory discharges Person-to-person – via droplet infection and discharges from nose and throat Person-to-person – from mother to child around birth, through contact, or nosocomial Annexes 28 Infectious agent Neisseria meningitidis Streptococcus pneumoniae Haemophilus influenzae Streptococcus agalactiae Incubation period 2–10 days; commonly 3 or 4 days 1–3 days 2–4 days 1–7 days (early onset); 7days to several months (late onset); typically 3–4 weeks Period of communicability Until meningococci are no longer present in discharges from nose and mouth Until virulent pneumococci are no longer present in discharges from nose and mouth As long as organisms are present in body discharges which may be prolonged periods even without nasal discharge The period of communicability is unknown, but can extend throughout the duration of colonization or disease. Infants can remain colonized for several months after birth and after treatment for systemic infections. Carrier stage; carriage site Yes; pharynx Yes; pharynx Yes; pharynx Yes; gastrointestinal and genitourinary tracts Disease caused Meningitis, sepsis Pneumonia, sepsis, meningitis Meningitis, pneumonia, sepsis, epiglottitis Sepsis, pneumonia, meningitis Case fatality ratio 5–20% (substantial variations between countries, depending on access to and quality of care) 20–90% (children in the age group 1–59 months) (substantial variations between countries, depending on access to and quality of care) 7–30% (children 1-59 months) (substantial variations between countries, depending on access to and quality of care; up to 20% for septicaemia and 50% for meningitis in LMICs) 5–20% (babies of the age of 0–89 days) (substantial variations between countries, depending on access to and quality of care) Epidemic potential High Moderate Low Very low Adapted from: World Health Organization (16) 29 Vaccines Several vaccines are available against S. pneumoniae, H. influenzae b and N. meningitidis. Details of the vaccines pre-qualified by WHO are given in Table 11.A2. Also included are the vaccines under development for S. agalactiae (GBS). The biggest challenges for GBS vaccines are the demonstration of effectiveness and regulatory pathways to licensure and WHO prequalification. Recent interactions with regulators suggest that there may be a pathway for initial licensure based on a correlate of protection and demonstration of effectiveness in post- licensure studies (to be defined). Table 11.A2: Vaccines against invasive bacterial diseases Manufacturer Commercial name (WHO PD status) Active constituents Vaccination schedule Pneumococcal conjugate vaccines (PCV)* Pfizer Prevnar 13 (WHO PQ) 13 valent: serotypes (PCV 13) 1,3,4,5,6A,6B,7F,9V,14,18C,1 9A,19F,23F polysaccharides – conjugated to CRM197 Infants: 3 doses – either 3+0 (at 6,10,14 weeks) or 2+1 (at 6,14 weeks and booster at 9–12 months) GSK Synflorix (WHO PQ) 10 valent: serotypes (PCV 10) 1,4,5,6B,7F,9V,14,18C,19F,23F polysaccharides – conjugated to protein D from non-typable H. influenzae except 18C (TT) and 23F (DT) Infants: 3 doses – either 3+0 (at 6,10,14 weeks) or 2+1 (at 6,14 weeks and booster at 9–12 months) Serum Institute of India Pneumosil (WHO PQ) 10 valent: serotypes (PCV 10) 1,4,5,6A,6B, 7F,9V,14,19A, 19F,23F polysaccharides – conjugated to CRM197 Infants: 3 doses (at 6,10,14 weeks) 30 Manufacturer Commercial name (WHO PD status) Active constituents Vaccination schedule Note: Both PCV10 and PCV13 have substantial impacts against pneumonia, vaccine type (VT) invasive pneumococcal disease (IPD), and nasopharyngeal (NP) carriage in a variety of settings. Both products show high levels of immunogenicity, reduction in VT IPD, all cause pneumonia, chest x-ray (CXR) confirmed pneumonia, and VT colonization (the effector of herd effect). The choice of product should be based on programmatic characteristics, vaccine supply, vaccine price, the local and regional prevalence of vaccine serotypes and antimicrobial resistance patterns. PCV13 may have an additional benefit [over PCV-10GSK] in settings where disease attributable to serotype (ST) 19A or ST 6C is significant. Though the efficacy data for PCV-10SII are not available, its efficacy is expected to be equivalent to PCV-13 and PCV-10 (GSK) based on immunogenicity data showing non-inferiority. Quadrivalent/pentavalent meningococcal conjugate vaccines** Sanofi Pasteur Menactra (WHO PQ) ACWY polysaccharide – conjugated to CRM197 (detoxified diphtheria toxin) 2 doses at 9–23 months, 1 dose at 2–55 years GSK (ex-Novartis) Arabio* (same product, different manufacturers) Menveo (WHO PQ) Aramen** (same product, different commercial names) ACWY polysaccharide – conjugated to CRM197 (detoxified diphtheria toxin) 2 doses at 7–23 months, 1 dose at 2–55 yea Pfizer (ex GSK) Nimenrix (WHO PQ) ACWY polysaccharide – conjugated to tetanus toxoid (TT) 1 dose at ≥ 12 months Meningococcal B vaccine, 2018** GSK Bexsero Protein-based vaccine (B NHBA fusion protein, B NadA protein, B fHbp fusion protein and OMV B strain NZ98/254 PorA B:4:P1.7–2,4) 3 doses at 2–5 months 2 doses at 6 months–50 years 31 Manufacturer Commercial name (WHO PD status) Active constituents Vaccination schedule Pfizer Trumenba Protein-based vaccine (B fHbp subfamily A and B fHbp subfamily B) 2 or 3 doses at ≥ 10 years Finlay Institute of Cuba VA-MENGOC-BC Bivalent C polysaccharide and OMVs B strain CU385 B:4:P1.19,15:L3,7,9 2 doses at 3 months–24 years Hib vaccines, 2021† Monovalent Hib Centro de Ingenieria Genetica y Biotecnologia, Sanofi Pasteur, Serum Institute of India Quimi-Hib (WHO PQ) (Hib) Sanofi-Pasteur Act-Hib (WHO PQ) Hib Quadrivalent Hib vaccines Serum Institute of India Diphtheria, Tetanus, Pertussis and Haemophilus influenzae type b Conjugate Vaccine and Diphtheria, Tetanus, Pertussis, Hepatitis B and Haemophilus influenzae type b Conjugate Vaccine Adsorbed (DTP, Hib) 3 doses, 4 weeks apart, after the age of 6 weeks 32 Manufacturer Commercial name (WHO PD status) Active constituents Vaccination schedule Pentavalent Hib vaccine Serum Institute, PT BioFarma (Pentabio) (All WHO PQ) Haemophilus influenzae type b (DTP, Hep B, Hib) 3 doses, 4 weeks apart, starting at age of 6 weeks Biological E LG Chem Panacea Sanofi b Conjugate Vaccine ComBE Five Eupenta Easyfive-TT Shan-5 6-valent Hib vaccines Sanofi Pasteur (All WHO PQ) Shant6 Hexaxim (DTP, Hep B, polio, Hib) 3 doses, 4 weeks apart, starting at age of 6 weeks Vaccines in the pipeline Pfizer 6-valent conjugate vaccine: serotypes Ia,Ib,II,III,IV,V – conjugated to CRM197 Phase1/2 Minervax Protein vaccine (Alpha C and Rib) Phase1/2 Biovac 5–6 valent conjugate vaccine Pre-clinical The GSK trivalent conjugate vaccine candidate is on hold due to competitive products with higher valency, and lower than expected immunogenicity in Phase 2 trials in pregnant women. Minervax is reformulating its protein vaccine candidate to provide better coverage against global strains. The 6-valent vaccine from Pfizer is therefore the most advanced candidate. Sources: WHO (15); WHO (16); Alderson MR et al (1) 33 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Annex 2: The global IB-VPD surveillance network The global IB-VPD Surveillance Network has been coordinated by WHO since 2009. It was established to standardize the monitoring of the global burden and etiology of IB-VPD and to support the introduction of PCVs, as well as monitor their impact, primarily in low- and middle-income countries (LMICs). The laboratory network of the Global Influenza Surveillance Network (GISN) provides technical assistance and guidance to country-level surveillance activities related to meningitis and other IBDs. Its operational modalities are similar to other WHO-coordinated laboratory networks for VPDs, which extend technical support from global and regional laboratories to national and sentinel site laboratories. Sentinel hospitals report cases of children under the age of 5 years hospitalized for suspected meningitis. The laboratories report results of confirmatory tests and strains of S. pneumoniae, H. influenzae, and N. meningitidis characterized by PCR testing. As of 2019, the laboratory network of GISN included 88 sentinel site laboratories, 26 national laboratories, 8 regional reference laboratories, and 1 global reference laboratory (total of 123) that follow validated, standardized testing and reporting strategies. Annex 3: Responsibilities of surveillance officers at sentinel IB-VPD sites z Assign a UID to all selected cases for enrolment during registration. Use the same UID to link clinical/epidemiological information with laboratory information. z Fill a case investigation form/case reporting form (CIF/CRF) for each case selected for enrolment. Gather all core data variables to complete CRF/CIFs. Use the UID on CRF/CIFs, sample labels, sample collection and reporting forms, laboratory logbook and surveillance logbook. Track cases for which additional data are expected, and update CRF/CIF records. z Update records every week. When submitting the CRF/CIF to the unit responsible for surveillance, ensure that all the required core variables have been recorded for all enrolled cases. z Identify cases with missing discharge data, and review ward registries, medical records and work with doctors and nurses to gather the data. z Maintain a data logbook, which should have entries on missing data and notes on suspected errors. Gather missing data and verify/correct suspected errors by going back to the source documents. z Update data logbook by making follow-up visits to the wards and laboratories and interacting with clinicians, nurses and laboratory staff. Review the CRF/CIF entries and data logbook to see if there are data fields that have the same problems consistently. Such problems generally indicate that some part of the data flow is not functioning properly and there is a need for data quality improvement. Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 34 z If the sentinel site uses hospital sample ID, or patient’s name in clinical specimens instead of a UID, the officer collecting data should enter the case ID and the ID used for laboratory specimens in the logbook, follow up with the laboratory and update the laboratory information in the CRF/CIF. Key points to consider: z The central data team should work with officers collecting data to identify issues with the data quality and to find ways to improve the data quality. The central unit should track all cases with samples sent to the national or regional reference laboratory for testing and follow up to obtain results in a timely manner. z The results received from the reference laboratory should be shared with doctors, nurses and hospital laboratory staff, as well as with the central data team. z The core data variables should be analysed epidemiologically and the results shared with the relevant stakeholders, including the clinicians and staff at the sentinel hospital. 35 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Annex 4: Case investigation form UID: IB-VPD______/____________/__________/____/_____ Country code/ Province code/District code/ Year/serial number Patient information Name of sentinel site Sentinel site code Patient’s name Age in years / months completed Date of birth dd/mm/yyyy Sex Male ; Female ; Unknown  Residential address City / District / Province / State Contact number (mobile) Epidemiological link to another case Yes ; No ; Unknown  If yes, UID: Name and address: History of travel/ attendance at a mass gathering Yes ; No ; Unknown  If yes, give details Clinical data Date of admission dd/mm/yyyy Date of notification dd/mm/yyyy Date of investigation dd/mm/yyyy Date of onset dd/mm/yyyy Fever: Yes ; No ; Unknown  Seizures/ convulsions Yes ; No ; Unknown  Altered consciousness Yes ; No ; Unknown  Neck stiffness Yes ; No ; Unknown  Purpura Yes ; No ; Unknown  Petechial/ purpural rash Yes ; No ; Unknown  Bulging fontanelle Yes ; No ; Unknown  Prostration/ lethargy Yes ; No ; Unknown  Difficulty in breathing Yes ; No ; Unknown  Cough Yes ; No ; Unknown  In-drawing of chest Yes ; No ; Unknown  Vomiting Yes ; No ; Unknown  Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 36 Central cynosis Yes ; No ; Unknown  Hypothermia Yes ; No ; Unknown  Respiratory rate Number/ minute Severe malnutrition Yes ; No ; Unknown  Yes ; No ; Unknown  Yes ; No ; If yes, specify Present status of case Alive  Dead  Unknown  Vaccination history Hib Yes ; No ; Unknown  If yes, type Date of 1st dose dd/mm/yyyy Date of 2nd dose dd/mm/yyyy Date of 3rd dose dd/mm/yyyy Source of information Card  Register  Memory  Unknown  PCV Yes ; No ; Unknown  If yes, type Date of 1st dose dd/mm/yyyy Date of 2nd dose dd/mm/yyyy Date of 3rd dose dd/mm/yyyy Source of information Card  Register  Memory  Unknown  Meningococcal Yes ; No ; Unknown  If yes, type Date of 1st dose dd/mm/yyyy Date of 2nd dose dd/mm/yyyy Date of 3rd dose dd/mm/yyyy Source of information Card  Register  Memory  Unknown  Samples collected Specimen collected CSF  Date collected dd/mm/yyyy Blood  Date collected dd/mm/yyyy Pleural fluid  Date collected dd/mm/yyyy No specimen collected  Whether specimen collected before antibiotic provision Yes ; No ; Yes ; No ; Yes ; No ; Date specimen sent CSF dd/mm/yyyy Blood dd/mm/yyyy Pleural fluid dd/mm/yyyy Date specimen received at laboratory CSF dd/mm/yyyy Blood dd/mm/yyyy Pleural fluid dd/mm/yyyy 37 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES Laboratory results Appearance of CSF Clear  Turbid  Hematic  Cloudy  Purulent  Others  Specify Appearance of pleural fluid Clear  Turbid  Hematic  Cloudy  Purulent  Others  Specify Cytology Leucocytes / mm3 Poly…. % Lympho …% Biochemistry CSF Glucose Protein Biochemistry Pleural fluid Glucose Protein pH Gram stain CSF H. influenzae  N. meningitidis  S. pneumoniae  GBS  CSF culture Positive  Negative  Inconclusive  Pending  Not tested  Not required  Organism identified S. pneumoniae  H. influenzae  N. meningitidis  GBS  None  Gram stain Blood H. influenzae  N. meningitidis  S. pneumoniae  GBS  Blood culture Positive  Negative  Inconclusive  Pending  Not tested  Not required  Organism identified S. pneumoniae  H. influenzae  N. meningitidis  GBS  None  LAT  H. influenzae  N. meningitidis  S. pneumoniae  GBS  Others  Immunochro- matographic test  H. influenzae  N. meningitidis  S. pneumoniae  GBS  Others  Culture H. influenzae  N. meningitidis  S. pneumoniae  GBS  Others  RT-PCR 38 Serotypes H. influenzae N. meningitidis S. pneumoniae GBS Strain characterization Antibiogram results: Disk diffusion  (modified Kirby– Bauer technique) Antimicrobial gradient strip diffusion  Sensitive to: Resistant to: Intermediate Not done Treatment given Final laboratory results H. influenzae  N. meningitidis  S. pneumoniae  GBS  None/negative  Not done Final laboratory case classification Final classification Laboratory- confirmed  Suspected  Discarded  39 Outcome Follow-up Discharged alive , without sequelae  Discharged alive with sequelae  Lost to follow-up  Died  Left against medical advice  Transferred/ Referred Unknown Date of death/ discharge dd/mm/yyyy Diagnosis at time of discharge Bacterial Meningitis  Other Meningitis  Bacterial Pneumonia  Other Pneumonia  Sepsis  Unknown  Multiple (i.e., Meningitis and/ or Pneumonia and/or Sepsis)  Other diagnosis  Final Case Classification Lab-confirmed for HI  Lab-confirmed for Spn  Lab-confirmed for Nm  Lab-confirmed for another organism  Probable  Suspect  Incomplete investigation  Discarded case  Unknown  Comments Investigator’s name: Designation: Institution: Telephone (mobile): Email: Date: Signature: Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 40 Further reading 1. Alderson MR, Welsch JA, Regan K, Newhouse L, Bhat N, Marfin AA. Vaccines to prevent meningitis: historical perspectives and future directions. Microorganisms. 2021;9(4):771. doi: 10.3390/ microorganisms9040771. 2. Oliver SE. Chapter 2: Haemophilus influenzae invasive disease. In: Roush SW, Baldy LM, Hall MAK, editors. Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases, Atlanta, GA (https://www.cdc.gov/ vaccines/pubs/surv-manual/chpt02-hib.html, accessed 28 August 2022). 3. McNamara LA, Blain A. Chapter 8: Meningococcal Disease. In Roush SW, Baldy LM, Hall MAK, editors. Manual for the Surveillance of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases, Atlanta, GA (https://www.cdc.gov/ vaccines/pubs/surv-manual/chpt08-mening.html, accessed 28 August 2022). 4. Gierke R, Lesley McGee L, Beall B, Pilishivili T. Chapter 11: Pneumococcal. In Roush SW, Baldy LM, Hall MAK, editors. Manual for the Surveillance of Vaccine- Preventable Diseases. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases, Atlanta, GA (https://www. cdc.gov/vaccines/pubs/surv-manual/chpt11-pneumo.html, accessed 28 August 2022). 5. Nakamura T, Cohen AL, Schwartz S, Mwenda JM, Weldegebriel G, Biey JNM et al. The global landscape of pediatric bacterial meningitis data reported to the World Health Organization-coordinated invasive bacterial vaccine-preventable disease surveillance network, 2014–2019. J Infect Dis. 2021;224 (12 Suppl 2):S161–S173. doi: 10.1093/infdis/jiab217. 6. Peck ME, Hampton LM, Antoni S, Ogbuanu I, Fatima S, Nakamura T et al. Global rotavirus and pneumococcal conjugate vaccine introductions and the association with country disease surveillance, 2006–2018. J Infect Dis. 2021;224 (12 Suppl 2): S185–193. doi: 10.1093/infdis/jiab069. 7. Rajkumar P, Bharathy S, Girish Kumar CP, Veeraraghavan B, Verghese V, Gupta N et al. HBSSPIBD network team. Hospital-based sentinel surveillance for Streptococcus pneumoniae and other invasive bacterial diseases in India (HBSSPIBD): design and methodology. BMJ Open. 2020 Apr 8;10(4):e034663. doi.org:10.1136/ bmjopen-2019-034663. 8. Saha S, Saha SK. Invasive bacterial vaccine-preventable disease surveillance: successes and lessons learned in Bangladesh for a sustainable path forward. J Infect Dis. 2021;224(12 Suppl 2):S293–S298. doi: 10.1093/infdis/jiab129. 41 INVASIVE BACTERIAL VACCINE- PREVENTABLE DISEASES 9. Stuart J, editor. Meningitis Epidemiology and Vaccines. MDPI; 2021 (https://doi. org/10.3390/books978-3-0365-1808-4, accessed 28 August 2022). 10. WHO Global Invasive Bacterial Vaccine-Preventable Disease and Rotavirus and Pediatric Diarrhoea Surveillance Network Bulletin. October 2020. (https://us13. campaign-archive.com/?u=920b793663d2f2d5f22813b38&id=88eeadb 6a5, accessed 28 August 2022). 11. World Health Organization. Meningococcus: Surveillance Standards. For Vaccine Preventable Diseases. World Health Organization, 2018 (https://www.who.int/ publications/m/item/vaccine-preventable-diseases-surveillance-standards- meningococcus, accessed 28 August 2022). 12. World Health Organization. Meningococcal A conjugate vaccine: Updated guidance, February 2015. Wkly Epidemiol Rec. 2015;90(8):57–68 (https:// www.who.int/publications/i/item/WHO-WER9008-57-62, accessed 28 August 2022). 13. World Health Organization. Haemophilus influenzae: Surveillance Standards for Vaccine-Preventable Diseases. World Health Organization; 2018 (https:// www.who.int/publications/m/item/vaccine-preventable-diseases-surveillance- standards-haemophilus-influenzae, accessed 28 August 2022). 14. World Health Organization, Centers for Disease Control and Prevention‎. Laboratory methods for the diagnosis of meningitis caused by Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae : WHO manual, 2nd ed. World Health Organization, Centers for Disease Control and Prevention; 2011 (https://www.who.int/publications/i/item/laboratory-methods-for-the- diagnosis-of-meningitis-caused-by-neisseria-meningitidis-streptococcus- pneumoniae-and-haemophilus-influenzae, accessed 28 August 2022). 15. World Health Organization. Considerations for Pneumococcal Conjugate Vaccine (PCV) Product Choice. World Health Organization; 2021 (https://www.who.int/ publications/i/item/considerations-for-pneumococcal-conjugate-vaccine-(pcv)- product-choice, accessed 28 August 2022). 16. World Health Organization. Defeating meningitis 2030: baseline situation analysis. Geneva: World Health Organization; 2019 (https://www.who.int/publications/m/ item/defeating-meningitis-2030-baseline-situation-analysis, accessed 28 August 2022). 17. World Health Organization. Defeating meningitis by 2030: a global road map. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO (https://www.who.int/publications/i/item/9789240026407, accessed 28 August 2022). Surveillance Guide for vaccine-Preventable diSeaSeS in the Who South-eaSt aSia reGion 42 18. World Health Organization. Group B streptococcus vaccine: full value of vaccine assessment. Geneva: World Health Organization; 2021 (https://www.who.int/ publications/i/item/9789240037526, accessed 28 August 2022). 19. World Health Organization. Haemophilus influenzae type b (‎Hib)‎ Vaccination Position Paper — July 2013: Introduction Wkly Epidemiol Rec. 2013;88(‎39):413– 26 (https://apps.who.int/iris/handle/10665/242126, accessed 28 August 2022). 20. Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region. New Delhi: World Health Organization, Regional Office for South-East Asia; 2017. Licence: CC BY-NC-SA 3.0 IGO (https://apps.who.int/iris/bitstream/ handle/10665/277459/Module7-IBD.pdf?sequence=49&isAllowed=y, accessed 28 August 2022). 21. World Health Organization. Regional Office for South-East Asia. Sentinel surveillance of invasive bacterial vaccine-preventable diseases and rotavirus gastroenteritis. WHO Regional Office for South-East Asia; 2013 (https://apps. who.int/iris/handle/10665/206355, accessed 28 August 2022). 22. World Health Organization. Standard operating procedures for surveillance of meningitis preparedness and response to epidemics in Africa. WHO Regional Office for Africa, Brazzaville; 2019 (https://www.who.int/publications/i/item/ standard-operating-procedures-for-surveillance-of-meningitis-preparedness- and-response-to-epidemics-in-africa, accessed 28 August 2022). 23. World Health Organization. Pneumococcus. Surveillance standards for vaccine- preventable diseases, 2nd ed. World Health Organization; 2018 (https://www. who.int/publications/m/item/vaccine-preventable-diseases-surveillance- standards-pneumococcus , accessed 28 August 2022). CONTRIBUTION The document was produced under the strategic guidance of the Regional Director, Dr. Poonam Khetrapal Singh; Director, Programme Management Dr. Pem Namgyal, and Director CDS Dr. Suman Rijal WHO SEARO. The entire process was overseen by Dr. Sunil Bahl, Coordinator, COVAX, Immunization and Vaccines Development. Dr. Sudhir Khanal, IVD/CDS WHO SEARO, lead the coordination and development of the technical document together with Dr. Sudhir Joshi, IVD/CDS WHO SEARO. WHO Consultant Dr. Lalit Kant played a crucial role in the updating the technical content of the document. This document also benefited from the expert input of all the participants of the Regional workshop to review progress towards measles-rubella and other priority VPD surveillance and outbreak preparedness and response in WHO South-East Asia Region from 13-16 June 2022 in Dhaka, which included National EPI Programme Managers and VPD Surveillance Officers from Member States , as well as a number of WHO country office staff, UNICEF, and other external collaborators. WHO HQ staff: Dr. Anindya Bose and Dr. Heidi Soeters reviewed the draft surveillance standard document and provided technical inputs. WHO-SEARO: Dr. Jayantha Liyanage, Dr. Sigrun Roesel, Dr. Emmanuel Njambe, Dr. Lucky Sangal, Dr. Pankaj Bhatnagar, Ms. Uttara Aggarwal, Mr. Sharifuzzaman , Dr. Rajendra Bohara, Dr. Ariful Islam, Dr. Tanbir Islam, Dr. Subramanya Balakuntlam Pattabhiramaiah, Dr. Ratnesh Murugan, Dr. Stephen Chacko, Dr. Paba Palihawadana, Dr. Aishath Thimna Latheef, Dr. Balwinder Chawla, Dr. Khaing Khaing Gyi, Dr. Vinod Bura, Dr. Rahul Pradhan, Dr. Pasang Rai, Dr. Preshila Samaraweera, Ms Aree Moungsookjareoun, Dr. Sudath Peiries UNICEF: Christopher Gregory provided inputs as well as coordinated inputs from UNICEF team to the various sections of the document. US CDC: Dr. Ahmed Kassem, Dr. Michelle Morales provided inputs to the various sections of the document and coordinated inputs from various teams within US CDC. WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int

WHO-SEARO IP Estate, MG Marg, New Delhi 110002, India Tel: +91 11 23370804, Fax: +91 11 23370251 Email: SearEpidata@who.int www.searo.who.int Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region 2023 MO DUL E-1: ME ASL ES & RU BEL LA MO DUL E-5: PER TUS IS MO DUL E-2: CO NGE NITA L RU BEL LA S YND ROM E (C RS) MO DUL E-6: NE ONA TAL TET ANU S MO DUL E-3: PO LIO MYE LITI S MO DUL E-7: NO N-N EON ATA L TE TAN US MO DUL E-8: HE PAT ITIS B MO DUL E-4: DIP HTH ERIA MO DUL E-9: RO TAV IRU S G AST ROE NTE RITI S MO DUL E-10 : JA PAN ESE EN CEP HAL ITIS MO DUL E-11 : INV ASI VE B ACT ERIA L VA CCI NE PRE VEN TAB LE D ISEA SES OVE RVI EW MO DUL E: S TRA TEG IC G UID ANC E O N V PD SUR VEIL LAN CE I N TH E W HO SOU TH- EAS T AS IA R EGI ON MODULE-1 MEASLES & RUBELLA OVERVIEW MODULE: STRATEGIC GUIDANCE ON VPD SURVEILLANCE IN THE WHO SOUTH-EAST ASIA REGION MODULE-2 CONGENITAL RUBELLA SYNDROME (CRS) MODULE-3 POLIOMYELITIS MODULE-4 DIPHTHERIA MODULE-5 PERTUSIS MODULE-6 NEONATAL TETANUS MODULE-7: NON- NEONATAL TETANUS MODULE-8 HEPATITIS B MODULE-9 ROTAVIRUS GASTRO- ENTERITIS MODULE-10 JAPANESE ENCEPHALITIS MODULE-11 INVASIVE BACTERIAL VACCINE PREVENTABLE DISEASES