Eastern Mediterranean Health Journal [2022; Vol.28, Issue 9]

La Revue de Santé de la Méditerranée orientale Eastern Mediterranean Health Journal Volume 28 No. 09 September/Septembre 9 ددع / نوشرعلاو نماثلا دلجلما لوليأ/ربمتبس 2022 Women always function as the gatekeepers to the formal/informal health sector. Despite global and regional progress in advancing women’s health, the COVID-19 pandemic forced governments and development partners in the EMR and beyond to re-set their priorities. A renewed commitment to women’s health is inescapable to expedite progress towards the SDGs in an integrated manner. Eastern Mediterranean Health Journal IS the official health journal published by the Eastern Mediterranean Regional Office of the World Health Organization. It is a forum for the presentation and promotion of new policies and initiatives in public health and health services; and for the exchange of ideas, concepts, epidemiological data, research findings and other information, with special reference to the Eastern Mediterranean Region. It addresses all members of the health profession, medical and other health educational institutes, interested NGOs, WHO Collaborating Centres and individuals within and outside the Region. طسوتلما قشرل ةيحصلا ةلجلما ةماعلا ةحصلا في ةديدلجا تاردابلماو تاسايسلا ميدقتل برنم ىهو .ةيلماعلا ةحصلا ةمظنمب طسوتلما قشرل ىميلقلإا بتكلما نع ردصت ىتلا ةيمسرلا ةلجلما ىه قشر ميلقإب اهنم قلعتي ام ةصاخو ،تامولعلما نم كلذ يرغو ثاحبلأا جئاتنو ةيئابولا تايطعلماو ميهافلماو ءارلآا لدابتلو ،اله جيوترلاو ةيحصلا تامدلخاو ةمظنم عم ةنواعتلما زكارلماو ،ةينعلما ةيموكلحا يرغ تماظنلما اذكو ،ةيميلعتلا دهاعلما رئاسو ةيبطلا تايلكلاو ،ةيحصلا نهلما ءاضعأ لك لىإ ةهجوم ىهو .طسوتلما .هجراخو ميلقلإا فى ةحصلاب ينمتهلما دارفلأاو ةيلماعلا ةحصلا La Revue de Santé de la Méditerranée Orientale EST une revue de santé officielle publiée par le Bureau régional de l’Organisation mondiale de la Santé pour la Méditerranée orientale. Elle offre une tribune pour la présentation et la promotion de nouvelles politiques et initiatives dans le domaine de la santé publique et des services de santé ainsi qu’à l’échange d’idées, de concepts, de données épidémiologiques, de résultats de recherches et d’autres informa- tions, se rapportant plus particulièrement à la Région de la Méditerranée orientale. Elle s’adresse à tous les professionnels de la santé, aux membres des instituts médicaux et autres instituts de formation médico-sanitaire, aux ONG, Centres collaborateurs de l’OMS et personnes concernés au sein et hors de la Région. Correspondence Editor-in-chief Eastern Mediterranean Health Journal WHO Regional Office for the Eastern Mediterranean P.O. Box 7608 Nasr City, Cairo 11371 Egypt Tel: (+202) 2276 5000 Fax: (+202) 2670 2492/(+202) 2670 2494 Email: emrgoemhj@who.int Members of the WHO Regional Committee for the Eastern Mediterranean Afghanistan . Bahrain . Djibouti . Egypt . Islamic Republic of Iran . Iraq . Jordan . Kuwait . Lebanon Libya . Morocco . Oman . Pakistan . Palestine . Qatar . Saudi Arabia . Somalia . Sudan . Syrian Arab Republic Tunisia . United Arab Emirates . Yemen طسوتلما قشرل ةيلماعلا ةحصلا ةمظنلم ةيميلقلإا ةنجللا ءاضعأ نادلبلا ةيملاسلإا ناريإ ةيروهجم . ايبيل . سنوت . نيرحبلا . ناتسكاب . ةدحتلما ةيبرعلا تاراملإا . ناتسناغفأ . ندرلأا برغلما . صرم . نانبل . تيوكلا . رطق . ينطسلف . نماُع . قارعلا . لاموصلا . نادوسلا . تيوبيج . ةيروسلا ةيبرعلا ةيروهملجا نميلا . ةيدوعسلا ةيبرعلا ةكلملما Membres du Comité régional de l’OMS pour la Méditerranée orientale Afghanistan . Arabie saoudite . Bahreïn . Djibouti . Égypte . Émirats arabes unis . République islamique d’Iran Iraq . Libye . Jordanie . Koweït . Liban . Maroc . Oman . Pakistan . Palestine . Qatar . République arabe syrienne Somalie . Soudan . Tunisie . 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EMHJ is a trilingual, peer reviewed, open access journal and the full contents are freely available at its website: http://www/emro.who.int/emhj.htm EMHJ information for authors is available at its website: http://www.emro.who.int/emh-journal/authors/ EMHJ is abstracted/indexed in the Index Medicus and MEDLINE (Medical Literature Analysis and Retrieval Systems on Line), ISI Web of knowledge, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Lexis Nexis, Scopus and the Index Medicus for the WHO Eastern Mediterranean Region (IMEMR). © World Health Organization (WHO) 2022. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO licence (https://creativecommons.org/licenses/by-nc-sa/3.0/igo). 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ISSN 1020-3397 Cover image © WHO Cover 28-08.indd 4,6 14/09/2022 12:25 PM Vol. 28 . 09 – 2022 La Revue de Santé de la Méditerranée orientale Eastern Mediterranean Health Journal Editorial Women’s health in the Eastern Mediterranean Region: time for a paradigm shift Mohamed Afifi, Maha El-Adawy and Rana Hajjeh ...........................................................................................................................................................635 Research articles Engagement of private healthcare sector in reproductive, maternal, newborn, child and adolescent health in selected Eastern Mediterranean countries Meesha Iqbal, Anam Shahil Feroz, Khalid Siddeeg, Karima Gholbzouri, Jamela Al-Raiby, Nilmini Hemachandra, Sarah Saleem and Sameen Siddiqi ..........................................................................................................................................................................................638 Translation and cultural adaptation of the WHO generic tuberculosis patient cost survey to an Egyptian context Ramy Ghazy, Rasha Ashmawy,Omar Reyad, Samar Abd ElHafeez, Mai El-Shishtawy, Heba Khedr, Ehab El-Rewiny, Haider El-Saeh, Mohamed Yacoub, Nancy Ali and Rasha Mosallam .........................................................................................649 Pilot study of safety and efficacy of topical liposomal amphotericin B for cutaneous leishmaniasis caused by Leishmania major in Islamic Republic of Iran Ali Khamesipour, Akram Mohammadi, Mahmoud Jaafari, Seyed Eskandari, Minoo Tasbihi, Amir Javadi, Farzaneh Afshari, Hossein Mortazavi and Alireza Firooz ...............................................................................................................................................658 Could self-reported symptoms be predictors of RT-PCR positivity in suspected COVID-19 cases? The Libya experience Amira El Ghiadi, Omnia Eddali, Sana Ashur and Laila Sabei .........................................................................................................................................664 Evaluation and comparison of vitamin A supplementation with standard therapies in the treatment of patients with COVID-19 Mohamad Rohani, Hasan Mozaffar, Mehdi Mesri, Mehdi Shokri, Daniel Delaney and Mahmood Karimy ...............................................673 Diagnostıc and treatment outcomes of patients with pulmonary tuberculosis in the first year of COVID-19 pandemic Yusuf Yakupogullari, Hilal Ermis, Zeynep Kazgan, Baris Otlu, Yasar Bayindir, Gazi Gulbas, Elif Tanriverdi and Emek Guldogan .....................................................................................................................................................................................................................682 Short research communication Mental health and driving behaviour of students and alumni of a university in the United Arab Emirates: a cross-sectional study Gabriel Andrade, Dalia Bedawi and Ibrahim Bani ............................................................................................................................................................ 690 Review Risk assessment of road traffic accidents related to sleepiness during driving: a systematic review Shehzad Saleem .............................................................................................................................................................................................................................695 WHO event addressing public health priorities Workshop for sharing best practices in sexual and reproductive health in the Eastern Mediterranean Region .............701 Book 28-09.indb 633 09/10/2022 11:07 AM Ahmed Al-Mandhari Editor-in-Chief Arash Rashidian Executive Editor Ahmed Mandil Deputy Executive Editor James Ayodele Managing Editor Editorial Board Mahmoud Fahmy Fathalla Akbar Fotouhi Rita Giacaman Rana Hajjeh Ahmed Mandil Ziad Memish Arash Rashidian Abla Mehio Sibai Sameen Siddiqi Huda Zurayk International Advisory Panel Mansour M. Al-Nozha Fereidoun Azizi Rafik Boukhris Zulfiqar Bhutta Majid Ezzati Hans V. Hogerzeil Mohamed A. Ghoneim Alan Lopez Hossein Malekafzali El-Sheikh Mahgoub Hooman Momen Sania Nishtar Hikmat Shaarbaf Salman Rawaf Editorial assistants Nadia Abu-Saleh, Suhaib Al Asbahi (graphics), Diana Tawadros (graphics) Editorial support Guy Penet (French editor) Eva Abdin, Fiona Curlet, Cathel Kerr, Marie-France Roux (Technical editors) Abbas Rahimiforoushani, Manar El Sheikh Abdelrahman (Statistics editors) Administration Iman Fawzy, Marwa Madi Web publishing Nahed El Shazly, Ihab Fouad, Hazem Sakr Library and printing support Gehane Al Garraya, Mariam Zaki, Fouad Abdelghaffar Ahmed Magdy, Amin El Sayed Cover and internal layout designed by Diana Tawadros and Suhaib Al Asbahi Printed by WHO Regional Office for the Eastern Mediterranean, Cairo, Egypt Book 28-09.indb 634 09/10/2022 11:07 AM 635 Editorial EMHJ – Vol. 28 No. 9 – 2022 Women’s health in the Eastern Mediterranean Region: time for a paradigm shift Mohamed Afifi,1 Maha El-Adawy 2 and Rana Hajjeh 3 1Regional Adviser, Women Health, World Health Organization Regional Office for the Eastern Mediterranean, Cairo, Egypt. 2Director, Healthier Populations, World Health Organization Regional Office for the Eastern Mediterranean, Cairo, Egypt. 3Director, Programme Management, World Health Organization, Regional Office for the Eastern Mediterranean, Cairo, Egypt. Citation: Afifi M; El-Adawy M; Hajjeh R. Women’s health in the Eastern Mediterranean Region: time for a paradigm shift. East Mediterr Health J. 2022;28(9):635–637. https://doi.org/10.26719/2022.28.9.635 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Investing in the health of women and girls has been shown to produce good returns not only for women and girls, but also for the society as a whole (1-9). It yields high returns on investment through improved productivity, reduced absenteeism, and reduced health care costs (10-13). Over the past decades the terms women’s health and reproductive health were used interchangeably to refer to conditions related to pre-conception, pregnancy, childbirth, and postnatal care only. However, with the improvement in life expectancy, reduction in maternal mortality ratios and the constant reduction in fertility rates, women now enjoy more years and are exposed to risk factors and diseases that are not always related to the reproductive function. Women in the post-menopausal period undergo physiological and psychological changes that may cause discomfort or change their response to several risk factors, and some diseases may present differently in women than in men. With this in mind, and in an attempt to better understand and respond to women’s comprehensive health needs, the WHO Office for the Eastern Mediterranean Region (WHO/EMRO) launched a programme on women’s health to generate and analyze evidence related to women’s overall health beyond the reproductive component and propose relevant solutions. We need to act now to ensure that health services for women are available, acceptable, and accessible, to ensure that women’s health needs are well-covered in the hope of achieving Universal Health Coverage by 2030. A proposed definition of women’s health therefore should include all health conditions that affect women, especially if they are among the leading causes of death and disability for women or if they affect women and men differently. Attending to and prioritizing women’s health is a strategic contributor to a healthier society because healthier women are essential gatekeepers to healthier families and healthier communities and contribute to socioeconomic development (11). The Eastern Mediterranean Region (EMR) is home to a mix of high-, middle- and low-income countries, with resident populations ranging from around 1 million to more than 200 million. Women in the EMR, including those in fragile and emergency contexts, are not a homogeneous group, therefore, their health needs and socioeconomic circumstances vary significantly (16). The average life expectancy for women in the EMR varies widely as well (from 55 to 83 years), as do maternal mortality ratios (from 3 to 829 per 100 000 live births). Anaemia among women of reproductive age presents another stark diversity in the region, ranging from 24% to around 70% (17). The EMR is currently experiencing a situation known as the “demographic dividend”. As the younger population cohort enters the workforce, they will age eventually and, therefore, require special attention to, and preventive investment in, their future health needs (18). Such ageing presents a phenomenal challenge for women because they comprise the greater proportion of the elderly population in the world (411 million compared to 336 million male population above 65 years of age in 2021) (19). Women are major providers of health care; sufficiently skilled and empowered women are key to the success of the formal and informal healthcare delivery systems. The EMR is home to high-scale natural and human-made crises that jeopardize health care delivery. Adopting a women’s health lens would help minimize missed opportunities where competent workforce may play a role in addressing non-reproductive health issues such as breast cancer, which is estimated to constitute 37% of all female cancers in the region. Just as adopting an integrated model of care has the potential to reduce missed opportunities especially in emergency and low- resource settings. UNHCR estimates that there are 16 million people in need in the EMR, of which 72% are women and children (20). It is therefore important to strike a balance between women’s health and an enabling environment, in terms of empowering laws, policies, and systems (21). Understanding and acknowledging the different roles that women play, as paid and/or unpaid caregivers, especially in emergency and fragile settings, is crucial to improving women’s health in a comprehensive manner. Women and health interact in multi-faceted pathways that contribute to healthier societies. For example, nurses and midwives in the EMR, who are mostly women, require dedicated attention by policy- and decision- Book 28-09.indb 635 09/10/2022 11:07 AM 636 Editorial EMHJ – Vol. 28 No. 9 – 2022 Figure 1 The role of women in healthcare provision 2 Women are major providers of healthcare; equitably empowered women are key to the success of the formal and informal healthcare delivery system. The EMR is home to high-scale natural and human-made crises that jeopardize healthcare delivery. Adopting a women’s health lens would help minimize missed opportunities where competent workforce may play a role in addressing non- reproductive health emergencies such as breast cancer, which is estimated to constitute 37% of all female cancers in the region. Just as adopting an integrated model of care has the potential to reduce missed opportunities especially in emergency and low-resource settings. UNHCR estimates that there are 16 million people in need in the EMR, of which 72% are women and children (19). It is therefore important to strike a balance between women’s health and an enabling environment, in terms of empowering laws, policies, and systems (20). Understanding and acknowledging the different roles that women play, as paid and/or unpaid caregivers, in healthcare provision, especially in emergency and fragile settings, is crucial to improving women’s health in a comprehensive manner (Figure 1). Figure 1: The role of women in healthcare provision It is imperative for governments in the EMR to embrace a women-inclusive, whole-of-society and whole-of-government approach that involves, and builds on, the strengths of all relevant stakeholders. Investing in women’s health is a highly profitable investment for the health, wealth (economy) and wellbeing of the whole society. It is time for the United Nations with its entities such as the WHO, UNFPA, UN Women, UNICEF, UNDP, and others to partner with Member States in comprehensively addressing women’s health using the thrust created by the Sustainable Development Goals (SDGs) and accelerate progress towards the relevant targets. An all-inclusive attention to women’s health cannot be timelier. The momentum around the SDGs offers a unique opportunity that the WHO Regional Office for the Eastern Mediterranean should capitalize on to References 1. Remme M, Vassall A, Fernando G, Bloom D. Investing in the health of girls and women: a best buy for sustainable development. BMJ 2020;369:m1175 doi: https://doi.org/10.1136/bmj.m1175. 2. World Health Organization. Delivered by women, led by men: A gender and equity analysis of the global health and social workforce. Geneva: World Health Organization, 2019: Human Resources for Health Observer Series No. 24. https://cdn.who.int/ media/docs/default-source/health-workforce/delivered-by-women-led-by-men.pdf. 3. Dabla-Norris E, Kochhar K. Closing the gender gap. Finance & Development 2019: March. file:///C:/Users/james/Downloads/closh- ing-the-gender-gap-dabla.pdf. 4. Weber AM, Cislaghi B, Meausoone V, et al., Gender norms and health: insights from global survey data. Lancet, 2019;393(10189):2455-2468. DOI: 10.1016/S0140-6736(19)30765-2. 5. Taukobong HF, Kincaid MM, Levy JK, Bloom SS, Platt JL, Henry SK, Darmstadt GL. Does addressing gender inequalities and empowering women and girls improve health and development programme outcomes? Health Policy Plan, 2016;31(10):1492-1514. DOI: 10.1093/heapol/czw074. 6. Downe S, Lawrie TA, Finlayson K, Oladapo OT. Effectiveness of respectful care policies for women using routine intrapartum services: a systematic review. Reprod Health, 2018;15(1):23. DOI: 10.1186/s12978-018-0466-y. 7. Diebolt C, Perrin F. Diebolt, Claude, and Faustine Perrin. 2013. From Stagnation to Sustained Growth: The Role of Female Em- powerment. American Economic Review, 103 (3): 545-49. DOI: 10.1257/aer.103.3.545 makers. Investing in nursing and midwifery workforces, which constitute up to 60% of the health workforce in some par s o the region, is vital to women’s health. They play the roles of service providers, patrons, and beneficiaries at the same time. Efficient and effective training, as well as efficient and effective recruitment and retention strategies are prerequisites to facilitating an enabling environment for healthier women and societies (Figure 1). It is imperative for governments in the EMR to embrace a women-inclusive, whole-of-society and whole-of-government approach that involves, and builds on, the strengths of all relevant stakeholders. Investing in women’s health is a highly profitable investment for the health, wealth (economy), and wellbeing of the whole society. It is time for the United Nations with its entities such as the WHO, UNFPA, UN Wome , UNICEF, UNDP, and others to partner with Member States in comprehensively addressing women’s health using the thrust created by the Sustainable Development Goals (SDGs). Healthier women contribute, not only to SDG 3 and SDG 5, but to most of the SDGs. The momentum around the SDGs offers a unique opportunity that WHO/EMRO should capitalize on to develop an analytical framework for women’s health that will inform the development of a regional roadmap for healthier women by 2030 (22). Book 28-09.indb 636 09/10/2022 11:07 AM 637 Editorial EMHJ – Vol. 28 No. 9 – 2022 8. Langer A, Meleis A, Knaul FM, Atun R, Aran M, Arreola-Ornelas H, Bhutta ZA, Binagwaho A, Bonita R, Caglia JM, et al: Women and health: the key for sustainable development. Lancet, 2015; 386:1165-1210. DOI: https://doi.org/10.1016/S0140-6736(15)60497-4. 9. UNFPA. Investing in family planning is a best buy. New York: UNFPA, https://www.unfpa.org/sites/default/files/resource-pdf/ FINAL_UNFPA_infographic_080817.pdf. 10. IFU and DFPA. Companies’ Return on Investment (ROI) on investments in women’s health in the workplace - an overview of evidence and cases. https://csr.dk/sites/default/files/IFU_DFPA_ROIReport%20%281%29.pdf. 11. Peters SAE, Woodward M, Jha V, Kennedy S, Norton R: Women’s health: a new global agenda. BMJ Glob Health 2016, 1:e000080. 12. Starrs AM, Ezeh AC, Barker G, Basu A, Bertrand JT, Blum R, Coll-Seck AM, Grover A, Laski L, Roa M. Accelerate progress—sex- ual and reproductive health and rights for all: report of the Guttmacher–Lancet Commission. The Lancet, 2018; 391:2642-2692. DOI:https://doi.org/10.1016/S0140-6736(18)30293-9 13. Khani S; Moghaddam-Banaem L; Mohamadi E; Vedadhir AA; Hajizadeh E. Women’s sexual and reproductive health care needs assessment: an Iranian perspective. East Mediterr Health J. 2018;24(7):637–643. https://doi.org/10.26719/2018.24.7.637 14. OHCHR. Women’s rights are human rights. New York: OHCHR, 2014. https://www.ohchr.org/sites/default/files/Documents/ Publications/HR-PUB-14-2.pdf. 15. Peterson NA, Hughey J. Social cohesion and intrapersonal empowerment: gender as moderator. Health Education Research, 2004;19(5): 2004, 533–542. DOI: https://doi.org/10.1093/her/cyg057. 16. Egli-Gany D, Aftab W, Hawkes S, Abu-Raddad L, Buse K, Rabbani F, et al. The social and structural determinants of sexual and re- productive health and rights in migrants and refugees: a systematic review of reviews. East Mediterr Health J. 2021;27(12):1203– 1213. DOI: https://doi.org/10.26719/ emhj.20.101. 17. World Health Organization. Monitoring health and health system performance in the Eastern Mediterranean Region: core in- dicators and indicators on the health-related Sustainable Development Goals 2020. Cairo: WHO Regional Office for the Eastern Mediterranean, 2021. https://apps.who.int/iris/handle/10665/346297. 18. UNFPA. Development challenges and population dynamics in a changing Arab world – Cairo declaration 2013. New York: UNF- PA, 2013. https://www.unfpa.org/sites/default/files/event-pdf/Cairo_Declaration_English.pdf. 19. United Nations. World Population Prospects 2019: Highlights (ST/ESA/SER.A/423). New York: United Nations Department of Economic and Social Affairs, Population Division, 2019. https://population.un.org/wpp/publications/files/wpp2019_highlights. pdf. 20. UNHCR. Middle East and North Africa. Global report 2021. New Yourk: UNHCR, 16 June 2022. https://reporting.unhcr.org/ globalreport2021/mena. 21. World Health Organization. Women and health: today’s evidence tomorrow’s agenda. Geneva: World Health Organization, 2009). https://apps.who.int/iris/handle/10665/44168. 22. Integrating sexual and reproductive health and rights package in national health policies, programmes and practices in the East- ern Mediterranean Region. East Mediterr Health J. 2019;25(10):763-764 https://doi.org/10.26719/2019.25.10.763. Book 28-09.indb 637 09/10/2022 11:07 AM 638 Research article EMHJ – Vol. 28 No. 9 – 2022 Engagement of private healthcare sector in reproductive, maternal, newborn, child and adolescent health in selected Eastern Mediterranean countries Meesha Iqbal,1 Anam Shahil Feroz,2,3 Khalid Siddeeg,4 Karima Gholbzouri,4 Jamela Al-Raiby,4 Nilmini Hemachandra,4 Sarah Saleem2 and Sameen Siddiqi2 1UTHealth School of Public Health Houston, United States of America (Correspondence to: M. Iqbal: meesha.iqbal@uth.tmc.edu; meesha_jazz@hotmail. com) 2Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan. 3Institute of Health Policy, Management and Evaluation, University of Toronto, Ontario, Canada. 4World Health Organization Regional Office for the Eastern Mediterranean, Cairo, Egypt Introduction The World Health Organization (WHO) for the Eastern Mediterranean Region (EMR) comprises a diverse group of 22 countries, and presents a varied picture of reproductive, maternal, neonatal, child and adolescent health (RMNCAH). The EMR has an average maternal mortality ratio (MMR) of 164 per 100 000 and under-5 mortality rate (U5MR) of 46 per 1000 live births (second to the region of Africa) (1). The MMR improved by 50% from 1990 to 2013, and U5MR by 46% (2). Despite the downward trend, the EMR missed the United Nation’s Millennium Development Goals (2000–2015) to decrease MMR by three quarters and U5MR by two thirds (3,4). It is estimated that 26 000 maternal and 845 000 under-5 child deaths occur each year in the region (2). The EMR countries have been implementing the Sustainable Development Goals (SDGs) and aim to reduce U5MR to < 25 per 1000 and MMR to 70 per 100 000 live births by 2030 (5). There is wide disparity in progress across the region: as of 2019, 13 countries had met the MMR target and 15 the U5MR target (6). Meeting the RMNCAH-related targets across the rest of the region remains a public health challenge. Several initiatives have been adopted to improve RMNCAH services including: The global strategy for women’s and children’s health (7); Global action plan for prevention and control of pneumonia and diarrhea (8); Every newborn action plan (9); Survive and thrive: transforming care for every small and sick newborn (10); and the Regional initiative on saving the lives of mothers and children (11). The public sector has a mandate to provide health services and improve RMNCAH. However, with the Abstract Background: The private healthcare sector in the Eastern Mediterranean Region (EMR) is active and growing, provid- ing curative, preventive, and promotive services related to reproductive, maternal, newborn, child, and adolescent health (RMNCAH). Aims: To understand the contribution of formal for-profit private health-care sector in delivering RMNCAH services and explore best practices for improvement. Methods: Desk review of available literature from Saudi Arabia, Oman, Iraq, Egypt, Sudan, Yemen, Pakistan, and Islamic Republic of Iran, followed by stakeholder interviews in Iraq, Pakistan, and Oman were carried out. Directed content analy- sis using Maxqda 2020 was performed, and information was triangulated according to a priori themes: governance, health information systems, financing, and service delivery related to RMNCAH. Results: Formal and informal public–private partnerships exist in RMNCAH but lack a strategic roadmap to guide col- laboration. The private healthcare sector is minimally represented in the main policy stream at national and subnational levels due to resistance from the private and public sectors. They are weak in collecting, maintaining, and sharing health information. Data on abortion and postabortion complications are scarce. Various models of supply and demand financ- ing (voucher schemes, private and social health insurance) related to antenatal care and contraception have been imple- mented in the EMR. Despite the higher cost of care in the private sector, limited training of providers, ill-defined service delivery packages, and lack of continuity-of-care and team-based approaches, the private sector remains the predominant sector providing RMNCAH services in the EMR. Conclusion: Partnering with the private sector has huge untapped potential that should be harnessed by national govern- ments for expanding RMNCAH services and progressing towards Universal Health Coverage. Keywords: private healthcare, reproductive health, maternal health, newborn health, child and adolescent health Citation: Iqbal M; Shahil Feroz A; Siddeeg K; Gholbzouri K; Al-Raiby J; Hemachandra N; et al. Engagement of private healthcare sector in reproductive, maternal, newborn, child and adolescent health in selected Eastern Mediterranean countries. East Mediterr Health J. 2022;28(9):638–648. https://doi.org/10.26719/emhj.22.057 Received: 26/10/21; accepted: 11/05/22 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo) Book 28-09.indb 638 09/10/2022 11:07 AM 639 Research article EMHJ – Vol. 28 No. 9 – 2022 whole of society and whole of government approach, the vital role of the private sector is increasingly highlighted and its engagement advocated for (12). The private sector includes private healthcare providers, pharmaceutical and health technology industries, media and advertisements, information technology, private insurance, associations of private sector industries, services provided by religious institutions, trade unions and philanthropic organizations. In the context of service provision, the private healthcare sector is defined as “the individuals and organizations that are neither owned nor directly controlled by governments and are involved in provision of health services. They can be classified as for profit and not-for-profit, formal and informal, domestic and international.” (13). The private healthcare sector is an active provider in the EMR, providing ambulatory, hospital, and medical educational services in many countries (14). It is estimated that the private healthcare sector delivers 11–81% of services to the poorest quintile and 33–86% of outpatient services, and owns more than 60% of pharmacies in the region. The WHO Regional Committee for the Eastern Mediterranean Region endorsed the Framework for Action on Effective Engagement with the Private Sector in 2018, to expand service coverage for achieving Universal Health Coverage (UHC) (15). The private healthcare sector is now increasingly recognized as a major stakeholder in healthcare provision and is considered an untapped resource in the context of RMNCAH services and UHC. It is acknowledged that contracting with private healthcare sector providers for the delivery of essential health service packages can help countries achieve UHC (16). Engagement of the private healthcare sector to deliver agreed quality essential healthcare services for RMNCAH, using strategic purchasing and financial protection arrangements is no longer an option but a necessity (17). There is dearth of data regarding the role, contri- bution and engagement of the private healthcare sector in RMNCAH services in the EMR. We designed this study to: (1) elaborate the contribution of the private healthcare sector in governance, health information systems, financing, and service delivery related to RMNCAH services at primary, insert space here secondary and tertiary care levels; (2) explore the best practices of engagement with the private healthcare sector and identify potential areas for improvement; and (3) formulate recommendations to improve and leverage private healthcare sector engagement in RMNCAH services at policy, programme and service delivery levels in the EMR. Methods The private healthcare sector includes for-profit and not-for-profit, formal and informal, domestic and international individuals and organizations that are neither owned nor directly controlled by governments and are involved in provision of health services (13). We only explored the private formal, for-profit healthcare providers in this study. An analytical framework was developed to guide the study, based on field experts’ opinions, literature review and WHO health systems framework (Table 1). The study was based on a desk review followed by stakeholder interviews and data synthesis (Figure 1). The desk review was based on 1) systematic search using PubMed and Google Scholar; 2) solicitation of documents from WHO Regional Office for the Eastern Mediterranean; and 3) manual search for relevant reports. The countries selected for the desk review included Saudi Arabia, Oman, Iraq, Egypt, Sudan, Yemen, Pakistan and Islamic Republic of Iran. The search was carried out in August 2020 and no time filters were applied. The review helped identify gaps in evidence that were bridged through the stakeholder interviews. Based on the recommendations of the regional office, Pakistan, Iraq and Oman were selected for interviews. The WHO focal person for RMNCAH in each country served as the starting point for the interviews. Subsequently, a snowball technique was used to reach other relevant stakeholders from the public and private healthcare sectors and academia. The interviews were semistructured and based on the analytical framework and a priori themes and gaps identified by the literature review. Each key informant interview was web-based, conducted in English language and lasted for about 45–70 minutes. Verbal consent was obtained before the start of the interview, which was audio/video recorded and subsequently transcribed. An effort was made to include interviewees from the public, private and academic sectors of each country. The interviewees were key informants representing the RMNCAH section of the public sector or Ministry of Health, WHO country office, or noteworthy representatives of private healthcare organizations and academia, working directly or indirectly with the government. Gaining access to key informants was cumbersome and the maximum number of interviews from each country was conducted. Directed content analysis using Maxqda 2020 was performed, and information was triangulated with the findings of the desk review. SWOT analysis (strengths, weaknesses, opportunities, threats) based on study findings was performed to yield meaningful insights. The Ethical Review Committee, Aga Khan University (ERC No. 2020-5383-14096) and National Bioethics Committee, Pakistan provided ethical clearance for conduct of the study. Results A total of 36 documents were eligible for inclusion in the desk review (14 peer reviewed articles, 4 dissertations, 18 reports; Figure 2) (16,18–52). Thirty-three documents addressed the EMR: 13 from Pakistan, 8 from Egypt, 6 from Iraq, 2 each from Jordan and Saudi Arabia, and 1 each from the Islamic Republic of Iran and Yemen. Sixteen stakeholder interviews were conducted from Iraq (n = 3), Book 28-09.indb 639 09/10/2022 11:07 AM 640 Research article EMHJ – Vol. 28 No. 9 – 2022 Table 1 Analytical framework for RMNCAH in the EMR Governance Health information systems with data on RMNCAH indicators Financing modalities for RMNCAH RMNCAH service delivery Involvement of private healthcare sector in development of national legislation, health plans, policies, guidelines, and strategies related to RMNCAH at all levels Routine data collection and maintenance by private healthcare sector (patient records, scorecards, routine surveillance system, registries) Supply-side financing and sources of financing: -Public sector -Insurance (Social & private) -Out of pocket payments -Community -Donors Compliance of private healthcare sector to evidence-based guidelines for RMNCAH service delivery Trends of private healthcare sector engagement in primary healthcare versus hospital level PPPs and contracting to cater for RMNCAH services Capacity of Ministry of Health to engage private healthcare sector Data sharing (mortality & morbidity data) -Mechanisms of incorporating information from private healthcare sector into national HIS -Role of surveys to capture information from the private sector - Triangulation of information (from surveys and HIS) Demand-side financing: -Voucher schemes -Cards -Conditional cash transfers (introduce exemption schemes for priority target groups including pregnant mothers, newborn, children aged < 5 years) Package of services for improving RMNCAH along the continuum of care to be delivered at all levels of care Regulation, monitoring, and accreditation: -Private healthcare sector providers -Practice and quality of private healthcare services at all levels Mechanisms of processing, analysing and using data and information for decision-making and policy-planning Financial risk protection measures for interventions pertaining to RMNCAH services Availability of RMNCAH essential drugs as well as commodities to the private sector Establishing of RMNCAH essential service packages, and clinical practice guidelines Key Indicators: 1. Proportion of family planning demand met with modern contraception 2. Proportion of women who have received the recommended number of doses of HPV vaccine before age 15 years 3. Antenatal coverage rate (≥ 4 times during pregnancy) 4. Number of stillbirths per 1000 births 5. 3 doses of combined DTP3 immunization coverage (12–23 months) 6. Antibiotic treatment for suspected pneumonia Subsidize marketing of products with a public health benefit through retail networks Capacity building: training supports or incentives to PHS providers to conform to service delivery standards Key indicators: 1. Availability of frameworks, national strategic plans, and technical policy documents to govern the private healthcare sector 2. Existence of platforms for effective public–private collaboration 3. Number of PPPs facilitated, strengthened, or established in RMNCAH 4. Assessing the technical supervisory role of PHS to maintain quality of RMNCAH services Key Indicators: 1. Private contribution (by households and other private entities) as % of THERH 2. Out-of-pocket spending as % of THERH 3. Out-of-pocket spending per woman of reproductive age 4. Out-of-pocket spending on reproductive health as % of overall out-of-pocket spending on healt. 5. Percentage of RH funds managed by Ministry of Health and other public entities, nongovernmental organizations and donors, and households (through out-of-pocket payments) - Role of PHS in community education campaigns and awareness raising related to RMNCAH - Perceptions of the community regarding service delivery of private healthcare sector related to RMNCAH Key indicators: 1. Proportion/number of antenatal clients with haemoglobin level measured 2. Proportion/number of ANC attendees or number of facility-based deliveries 3. Proportion/number of women received postnatal care 4. Proportion/number of children with pneumonia who received amoxicillin 5. Proportion/number of children who received treatment for diarrhoea 6. Proportion/number of antenatal clients with 4th ANC visit 7. Proportion/number of women of reproductive age who were screed for cervical cancer RMNCAH = Reproductive, maternal, neonatal, child and adolescent health; EMR = Eastern Mediterranean Region; HPV = Human papillomavirus; THERH = Total health expenditure on reproductive health; PPP = Public–private partnership; HIS = Health information system; ANC = Antenatal care. Book 28-09.indb 640 09/10/2022 11:07 AM 641 Research article EMHJ – Vol. 28 No. 9 – 2022 Pakistan (n =7 ) and Oman (n = 6) (Table 2). The results of the desk review and interviews were organized according to the a priori themes of the analytical framework. RMNCAH governance The study results indicated a minimal role of the private healthcare sector in national and subnational policy- making related to RMNCAH in the EMR. Involvement of the private healthcare sector in decision-making was not well received by public sector professionals in Pakistan and Iraq. The private sector also lacked interest due to negligible incentives and high opportunity costs. On the contrary, in Oman, the private healthcare sector was represented in policy-making at the national and subnational levels. The private partners participated in the formation of strategies/policies on maternal health and infectious diseases, with the final authority resting with the government. Public–private partnerships (PPPs)1 are prevalent in the EMR in the field of RMNCAH. A WHO background paper on private sector engagement for advancing UHC mentioned the dominant role of PPPs in the quality, costs and use of services (antenatal, postnatal and newborn care, and birth facilities) in Pakistan and the Islamic Republic of Iran (16,52). The national policies of Oman and Pakistan recognize the importance of PPPs for improving healthcare and achieving global targets related to RMNCAH. The not-for-profit private sector has been more active in partnerships with the government, than the for-profit sector. Apart from formal partnerships, many informal collaborations exist between the public and private sectors. However, a major gap is the lack of planning and a clear direction for rolling out PPPs. One of the academic participants in Pakistan stated: “PPPs are implemented on an ad hoc basis…and to place a burden on the private sector. They collaborate just to avoid their responsibilities. The government needs to wake up. ” 1 ‘A long-term contractual arrangement between public (national, state, provincial, or local) and private entities through which the skills, assets, and/or financial resources of each of the public and private sectors are allocated in a complementary manner—thereby sharing the risks and rewards, to seek to provide optimal service delivery and good value to citizens.’ Definition taken from Asian Development Bank. PPP Guidance Note on Procurement. 2018. https://www.adb.org/sites/default/files/ppp- procurement.pdf. The available literature reiterates regulation of the private healthcare sector as a universal challenge. There are almost 50 000 private clinics in Egypt and 75 000 private general practitioners in Pakistan that cannot be classified under any proper regulatory system (16). The Ministry of Health has a mandate and responsibility for regulation, and regulatory policies exist on paper (Iraq and Pakistan); however, there was no evidence of regulation (16,35). High-income countries such as Oman had a healthier situation: licensing of private providers and establishments was strict and inspection teams were operational to monitor quality. Health information systems with data on RMNCAH indicators The available literature indicates that the private healthcare sector is lagging in collecting, maintaining and sharing health-related data with the government across the EMR. Data regarding abortion and postabortion complications are limited in low- and middle-income countries (38,44). The interviewees from Iraq stated that secondary and tertiary care hospitals shared monthly data related to spontaneous vaginal deliveries and caesarean sections with the Ministry of Health; however, data flow from private clinics remained limited. One of the public sector respondents in Iraq stated: “The private sector information only comes indirectly via the population- based surveys.” Similarly, the private healthcare sector of Pakistan is obliged to notify about child and maternal death, but other indicators of RMNCAH are not routinely shared with the government. Oman presented an encouraging scenario of continuous recording of number of pregnancies, maternal and child births, and deaths. The public sector offered a central health information system that kept track of patients; however, data in the public and private sectors were not comprehensive and many vital indicators of RMNCAH were missing. A public sector Figure 1 Phases of the study to assess the role of formal, for-profit private healthcare sector in some Eastern Mediterranean countries Phase I Framework of Analysis Phase II Desk review (country focus: Egypt, Islamic Republic of Iran, Pakistan, Sudan, Oman, Saudi Arabia, Iraq and Yemen) Phase III Stakeholders’ interviews (country focus: Oman, Pakistan and Iraq) Phase IV Triangulation of findings & SWOT analysis Book 28-09.indb 641 09/10/2022 11:07 AM 642 Research article EMHJ – Vol. 28 No. 9 – 2022 interviewee from Oman stated: “We feel our patients get lost in the private sector.” Our findings suggest that a centralized health information system was being developed in Oman through which “the public and private sectors would be able to tap into each other’s systems” (private sector interviewee). Financing modalities for RMNCAH There was a large variation in out-of-pocket payments as proportion of total health expenditure across the EMR, ranging from 10% in Oman to 70% in Yemen (53). Catastrophic payments were common for the private healthcare sector, including caesarean sections and postnatal complications (52). As a response to high out-of- pocket payments in Egypt (62%), the government rolled out a new insurance scheme to achieve UHC, based on a family physician model that separates financing from service provision; however, the impact of the model remains inconclusive (22). Private and social health insurance in Iraq was minimal. A health insurance law was drafted in 2014, but is yet to be endorsed. Public healthcare services (including RMNCAH) were free for Omani citizens and the insured population. The private sector was generally used by expatriates or people without insurance. However, there were no standard insurance packages for antenatal care. Various models of supply- and demand-side financing have been tested in the EMR, with varied results. Financing vouchers complemented by social franchising in the form of demand-side financing have been rolled out in Pakistan for over a decade to improve family planning practices (29). Supply-side financing has been improved through social health insurance and private health insurance, which are generally available for residents of urban areas (31). Task sharing by building PPPs via the community midwives model, and community health workers connecting clients with local facilities, have been instrumental in improving family planning practices in Pakistan (31). Organizations such as Green Star, Marie Stopes, and Suruj Network have worked with mid-level private sector providers to increase the uptake of long- acting contraceptives (29). Their effectiveness is well documented in increasing family planning; however, the geographical coverage is too small to create an impact at the national or subnational levels. Figure 2 Analytical framework to assess engagement of private healthcare sector in addressing RMNCAH in EMR Id en tifi ca tio n Sc re en in g El ig ib ili ty In cl us io n Records identified through PubMed n= 35 Records identified through Google scholar n=818 Records screened by title n=35 Records screened by title n=818 Records selected for abstract review n=18 No duplicates identified Records selected for abstract review n=65 Abstracts selected for full text review n=16 Abstracts selected for full text review n=10 (full text found for all) Full text not found n=3 Articles reviewed n= 13 Documents manually selected or retrieved from WHO-EMRO to be included in desk review full text review n=22Articles selected to be included in desk review full text review n=7 Articles selected to be included in desk review n=7 Total records included in desk review n=36 Book 28-09.indb 642 09/10/2022 11:07 AM 643 Research article EMHJ – Vol. 28 No. 9 – 2022 In Oman, some vouchers for antenatal and postnatal care were commonly distributed during campaigns to commemorate Mother’s Day, Breast Feeding Week, Birth Spacing Week etc. Community financing was common in Najaf and Karbala (holy shrines), as stated by one of the public sector interviewees in Iraq: “Free mobile clinics are provided during holy events by the community. These services are however, not constant throughout the year”. RMNCAH service delivery Types and use of private healthcare sector services The private healthcare sector remained the sector of choice for RMNCAH-related services in most of the developing countries in the EMR (31,37,38,40,45,46,49). Anecdotal evidence suggested that around 50% and 80% of RMNCAH-related healthcare services in Iraq and Pakistan were provided by the private healthcare sector (38). The role of the private healthcare sector was particularly prominent in providing postabortion care in Pakistan, given that it treated about 50% more postabortion cases (62% vs 38%) than public health facilities treated (44). The caesarean section rates tended to be higher in the private healthcare sector. In 2002, the caesarean section rate for public hospitals in Baghdad (Iraq) was 30% of all births (compared to an acceptable standard of 5–10% in most countries) and the recorded rate was much higher, at 48% in private hospitals (25). Availability of drugs such as misoprostol was better in the private healthcare sector in Pakistan (89% vs 54% in the public sector) (44). The stakeholder interviews elaborated that the service delivery packages of RMNCAH care were not well defined in the private healthcare sector. In high- income countries such as Saudi Arabia and Oman, the public sector remained the predominant provider of care (23% child health services in Saudi Arabia are provided by the private healthcare sector) (40). Quality of services In low- and middle-income countries of the EMR, the private healthcare sector was perceived by the public to offer higher quality of services than the public sector (45,49). However, this perception was not supported by scientific evidence. People preferred the private healthcare sector for reasons such as hospitality, short waiting time, and better laboratory and diagnostic facilities, nursing care and infrastructure. Although the communities preferred the private sector, one of the key informants from Pakistan stated: “The public and private sectors are equally incompetent.” Other concerns were raised regarding the private healthcare sector of Pakistan. Some respondents said it was a “money-making machine”, with poor quality of services. The providers were accused of using “quick relief formulas” for treating the patients. They said providers in private clinics often use steroids, antibiotics and intravenous analgesics that provided instant relief to patients. One of the academic respondents in Pakistan stated: “Everyone in the private sector gives clomid (clomiphene) for management of infertility….which can increase the risk of polycystic ovarian disease”. In Oman, the public sector was said to be better than providers in private clinics in the provision of RMNCAH services, because of its team-based approach, skill mix and continuity of care. Public healthcare providers had better training opportunities in Oman while continuous capacity building for private providers was limited. In contrast, data from 6 private clinics in Sudan suggested that private healthcare providers had limited to no training in the diagnosis and management of sexually transmitted diseases (54). Dual practice was commonly reported in the developing countries, leaving providers with little time and interest to provide quality care for patients in the public healthcare sector. SWOT analysis A SWOT analysis for the engagement of private healthcare sector in RMNCAH in the EMR was conducted, based on the results of desk review and interviews. Major strengths of private healthcare sector included its vast spread, diversity of services, trust of the masses, high- quality laboratory and diagnostic support and specialized care (e.g. in vitro fertilization and neonatal care) in some countries. The sector suffered from the weaknesses of being focused on curative care for enhanced monetary benefits, uneven geographical distribution, urban bias, and poor record keeping and continuity of care. However, the sector offered opportunities such as indirect referral linkages between public and private sectors, higher technical capacity in some countries, and a drive at national and subnational levels to incorporate private healthcare sector into the mainstream. At the same time, stakeholders needed to be mindful of the accompanying threats: there was no clear roadmap for incorporating the private healthcare sector and old legislation remained incompatible with PPPs; corruption in the public sector affected regulation and accountability of the private healthcare sector; and dual practice by healthcare providers raised conflict of interest. Discussion Private healthcare sector is a vital stakeholder in the provision of RMNCAH care in the EMR. It has grown greatly over the past few decades and is now widespread. A general trend of a predominant private sector was reported in developing countries where the public sector was lagging, whereas its role was less prominent in high-income countries that had strong health systems, such as Oman. The international and national platforms acknowledge the need to incorporate the private healthcare sector into related activities of the public sector. Its representation, though minimal, is seen in the formation of clinical guidelines, standards and policies pertaining to RMNCAH in some countries. PPPs have been popular in the EMR, being tested for family planning, antenatal care, immunization and child nutrition, etc. However, there is lack of vision and Book 28-09.indb 643 09/10/2022 11:07 AM 644 Research article EMHJ – Vol. 28 No. 9 – 2022 framework to guide the PPPs. Regulation of the private healthcare sector remains a challenge in developing countries, where corruption and lack of accountability and transparency in the public sector hamper regulation. Private healthcare sector remains an unexplored domain due to lack of information flow to the public sector. Private tertiary care hospitals collect, maintain and share records with the public sector regarding number of deliveries and caesarean sections. The lower tiers seldom share patient records. Private healthcare sector is the preferred option due to shorter waiting time, better perceived quality, laboratory and diagnostic support, hospitality of staff and clean environment; although the technical capacity is questionable. In countries such as Pakistan and Islamic Republic of Iran, there is over- reliance on the private sector, which culminates in a potentially negative impact such as high out-of-pocket payments, caesarean section rate, and overuse and misuse of drugs. Thus, streamlining the private healthcare sector in a public-led system is critical to ensure its proper use in advancing UHC. A similar scenario of widespread private healthcare sector and limited engagement with the government has been reported across the WHO African Region (55). It is believed that the private healthcare sector can be a valuable contributor to improving population health and moving towards UHC in the WHO Region of the Americas (56). The alignment of the private healthcare sector with the public sector is similar worldwide, with limited engagement but a huge untapped potential that needs to be efficiently used by the government. Based on our study findings, we present the following suggestions for strengthening engagement of the private healthcare sector with the public sector. We believe that a clearly stated policy needs to be formulated to engage the private healthcare sector in all health domains including RMNCAH, at the regional and national levels. The countries need to develop a guiding framework to engage the private healthcare sector in RMNCAH for all service delivery tiers of healthcare. Planning for PPPs needs improvement by building the technical capacity of the government. A separate department of private healthcare establishments (with allocated budget) should be established in the public sector for PPPs, contracting out services, ensuring accountability, licensing, regulation and accreditation of the private healthcare sector. If a separate department is not feasible, the function inside the ministry of health should be strengthened. The allocated health budget to the ministry of health should be increased, with separate allocation for PPPs. The range of services should be clearly stated with designation of responsibilities of both parties such that the collaboration is mutually beneficial. We suggest that the PPPs should typically address abortion and postabortion services, family planning, neonatal care and community awareness raising. The private healthcare sector professionals need to be represented at the policy level for formulation of clinical standards, guidelines and strategies related to RMNCAH. The licensing of practitioners should be renewed every 5 years with strict requirements for continuous medical education to maintain standards of care. A separate directorate/commission should be established to ensure registration of all private facilities and licensing of providers. Similarly, the private facilities should be accredited and only those clearly eligible should be engaged by the public sector. Capacity building related to antenatal and postnatal care, family planning, weaning practices, integrated management of newborn and childhood illnesses guidelines, and syndromic management of sexually transmitted diseases should be offered to private healthcare providers at a minimal cost, and participation encouraged through certification and recognition. Health information systems should transit to electronic databases with standardized comprehensive data forms capturing number of antenatal visits, immunizations, postnatal and neonatal care, uptake of contraception and child mortality. The private sector should be incentivized to share data with government and such information should be incorporated in the formulation of RMNCAH-related strategic and operational plans. A legal claims department should be established in the ministries of health to address the concerns of patients, indirectly ensuring accountability of private providers. Demand-side financing in the form of voucher schemes could be implemented to improve contraceptive uptake. Regulatory mechanisms should be established to implement updated clinical guidelines and protocols related to RMNCAH in the private healthcare sector. This study has highlighted engagement of the private healthcare sector in RMNCAH in some countries of the WHO EMR, with particular focus on Oman, Pakistan and Iraq. It captures insights of stakeholders from WHO, public and private sectors, and academia across all tiers of service delivery. The study has some limitations. Interviews were conducted in only three countries, and findings cannot be generalized to the Eastern Mediterranean Region. There was no representation from the low-income countries, which would have added robustness and balance to the results. The point of saturation for the interviews was not reached and we believe additional interviews could have helped strengthen the findings. However, this study provides a foundation for further research and identifies areas of action for engagement with the private healthcare sector. Conclusion The private healthcare sector offers a huge untapped potential for improving RMNCAH-related services across EMR. The public sector needs to incorporate and align services of the private sector to the national and subnational health agendas, to improve RMNCAH towards achieving UHC Funding: This study was funded by the World Health Organization - Regional Office of the Eastern Mediterranean Region. Competing interests: None declared. Book 28-09.indb 644 09/10/2022 11:07 AM 645 Research article EMHJ – Vol. 28 No. 9 – 2022 لافطلأاو ةدلاولا يثيدلحاو تاهملأا ةياعرو ةيباجنلإا ةيحصلا ةياعرلا في صالخا ةيحصلا ةياعرلا عاطق ةكراشم طسوتلما قشر ميلقإ في ينقهارلماو يقيدص ينمث ،ميلس ةراس ،اردنشاهم ينيملين ،يبعرلا ةليجم ،ىروزبلغ ةميرك ،قيدص دلاخ ،زويرف لهاش مانأ ،لابقإ اشيم ةصلالخا قلعتت ةيزيزعتو ةيئاقوو ةيجلاع تامدخ مدقيو ،ومنلاو طاشنلا نم ةلاحب طسوتلما قشر ميلقإ في ةصالخا ةيحصلا ةياعرلا عاطق رمي :ةيفللخا .ينقهارلماو لافطلأاو ةدلاولا يثيدلحاو تاهملأا ةحصو ةيباجنلإا ةحصلاب ةحصو ةيباجنلإا ةحصلا تامدخ ميدقت في حبرلا لىإ فديه يذلا يمسرلا صالخا يحصلا عاطقلا ةهماسم مهف لىا ةساردلا هذه تفده :فادهلأا .ينسحتلل تاسرمالما لضفأ في ثحبلاو ينقهارلماو لافطلأاو ةدلاولا يثيدلحاو تاهملأا ناريإ ةيروهجمو ناتسكابو نميلاو نادوسلاو صرمو قارعلاو نماُعو ةيدوعسلا ةيبرعلا ةكلملما( ةحاتلما تاساردلل يبتكم ضارعتسا :ثحبلا قرط Maxqda ماظن مادختساب اًه َّجوم ىوتمح ليلتح نوثحابلا ىرجأ دقو .نماُعو ناتسكابو قارعلا في ةينعلما فارطلأا عم تلاباقم هتبقعأ ،)ةيملاسلإا تامدلخا ميدقتو ،ليومتلاو ،ةيحصلا تامولعلما مظنو ،ةمكولحا :اًمدقم ةددمح عيضاولم اًقفو ثيلثتلا ةقيرطب تامولعملل اًحسم اورجأ مث ،2020 .ينقهارلماو لافطلأاو ةدلاولا يثيدلحاو تاهملأا ةحصو ةيباجنلإا ةحصلاب ةقلعتلما لافطلأاو ةدلأولا يثيدحو تاهملأا ةحصو ةيباجنلإا ةحصلا لامج في صالخاو ماعلا ينعاطقلا ينب ةيمسر يرغو ةيمسر تاكاشر دجوت :جئاتنلا تاسايسلا في ٌفيعض صالخا ةيحصلا ةياعرلا عاطق ليثتمو .نواعتلا هيجوتل ةيجيتاترسا قيرط ةطيرخ تاكاشرلا هذله دجوت لا نكلو ،ينقهارلماو تامولعلما عجم في اهمدوهج فعضب نماستي نيذللا ،ماعلاو صالخا ينعاطقلا نم ةمواقلما ببسب ،ينطولا نودو ينطولا نيديعصلا لىع ةيسيئرلا ةفلتمخ جذمان طسوتلما قشر ميلقإ في تذ ِّفُن دقو .رفوتت ام اًردان ضاهجلإا دعب ام تافعاضمو ضاهجلإاب ةقلعتلما تانايبلاو .الهدابتو ابه ظافتحلااو لىعو .لملحا عنم لئاسوو ةدلاولل ةقباسلا ةياعرلاب قلعتي مايف )يعماتجلااو صالخا يحصلا ينمأتلاو ،مئاسقلا ةمظنأ( بلطلاو ضرعلا ليومتل Participation du secteur privé de la santé aux soins de santé reproductive, maternelle, néonatale, infantile et des adolescents dans la Région de la Méditerranée orientale Résumé Contexte : Le secteur privé des soins de santé dans la Région de la Méditerranée orientale est actif et en pleine évolution, fournissant des services curatifs, préventifs et promotionnels liés à la santé reproductive et à la santé de la mère, du nouveau-né, de l'enfant et de l'adolescent. Objectifs : Comprendre la contribution du secteur privé des soins de santé formel à but lucratif dans la prestation des services de santé reproductive et de santé de la mère, du nouveau-né, de l'enfant et de l'adolescent ainsi qu'examiner les meilleures pratiques pour les améliorer. Méthodes : Revue documentaire de la littérature disponible (Arabie saoudite, Égypte, République islamique d’Iran, Iraq, Oman, Pakistan, Soudan, Yémen), suivie d'entretiens avec les parties prenantes en Iraq, au Pakistan et à Oman. Une analyse de contenu dirigée a été réalisée à l'aide du programme Maxqda 2020, et les informations ont été triangulées en fonction de thèmes a priori : gouvernance, systèmes d'information sanitaire, financement et prestation des services liés à la santé reproductive et à la santé de la mère, du nouveau-né, de l'enfant et de l'adolescent. Résultats : Des partenariats public-privé formels et informels existent dans le domaine de la santé reproductive et de la santé de la mère, du nouveau-né, de l'enfant et de l'adolescent, mais aucune feuille de route stratégique n'est disponible pour orienter la collaboration. La représentation du secteur privé des soins de santé dans le courant politique principal aux niveaux national et infranational est faible en raison de la résistance des secteurs privé et public. Ils sont faibles dans la collecte, la conservation et le partage des informations sanitaires. Les données sur les complications liées à l'avortement et au post-avortement sont rares. Divers modèles de financement de l'offre et de la demande (systèmes de bons, assurance-maladie privée et sociale) liés aux soins prénatals et à la contraception ont été mis en œuvre dans la Région de la Méditerranée orientale. Malgré le coût plus élevé des soins dans le secteur privé, la formation limitée des prestataires, les ensembles de prestations de services mal définis et le manque de continuité des soins et d'approches d'équipe, le secteur privé reste le secteur prédominant qui fournit des services de santé reproductive et de santé de la mère, du nouveau-né, de l'enfant et de l'adolescent dans la Région de la Méditerranée orientale. Conclusion : Le partenariat avec le secteur privé présente un énorme potentiel inexploité dont les gouvernements nationaux devraient tirer parti pour étendre les services de santé reproductive et de santé de la mère, du nouveau-né, de l'enfant et de l'adolescent et progresser vers la couverture sanitaire universelle. Book 28-09.indb 645 09/10/2022 11:07 AM 646 Research article EMHJ – Vol. 28 No. 9 – 2022 References 1. World Health Organization. Global Health Observatory data repository [website]. 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Book 28-09.indb 648 09/10/2022 11:07 AM 649 Research article EMHJ – Vol. 28 No. 9 – 2022 Translation and cultural adaptation of the WHO generic tuberculosis patient cost survey to an Egyptian context Ramy Ghazy,1 Rasha Ashmawy,2 Omar Reyad,3 Samar Abd ElHafeez,4 Mai El-Shishtawy,5 Heba Khedr,6 Ehab El-Rewiny,1 Haider El-Saeh,7 Mohamed Yacoub,8 Nancy Ali9 and Rasha Mosallam5 1Tropical Health Department, High Institute of Public Health, Alexandria University, Alexandria, Egypt. 2Department of Clinical Research, Maamora Chest Hospital, Alexandria, Egypt. 3Internal Medicine and Cardiology Department, Alexandria Main University Hospital, Alexandria, Egypt. 4Epidemiology Department, High Institute of Public Health, Alexandria University, Alexandria, Egypt. 5Department of Health Administration and Behavioral Sciences, High Institute of Public Health, Alexandria University, Alexandria, Egypt (Correspondence to: R. Mosallam: hiph.rmosallm@alexu. edu.eg). 6MDR-TB Center, Maamora Chest Hospital, Alexandria, Egypt. 7Community Medicine Department, Faculty of Medicine, University of Tripoli, Tripoli, Libya. 8Department of English, Florida International University, Miami, United States of America. 9Department of Communications Media, Indiana University of Pennsylvania, Indiana, United States of America. Introduction Tuberculosis (TB) represents a major public health problem worldwide (1). In 2019, there were an estimated 10 million new cases of TB and 1.4 million deaths and more than 90% of these cases and deaths occurred in developing countries (2). The incidence of TB in Egypt was 12 per 100 000 people according to the World Health Organization (WHO) global tuberculosis report in 2020 (1). TB is estimated to have cost the world economy US$616 billion from 2000 to 2015 (3). A considerable proportion of the economic burden is shouldered by patients within the low-income quartiles. Three studies conducted in South Africa and Malawi stratified TB costs by income status and revealed that poorer patients incurred higher costs for treating TB than those who were richer (4–6). Accordingly, WHO set a target of zero TB-affected families facing catastrophic costs as 1 of 3 aims of the End TB Strategy (7). Catastrophic costs are defined as those that account for ≥ 20% of patients’ annual household income (including direct medical expenses, nonmedical expenses, and overall indirect costs, which include lost wages and time off work due to symptoms and treatment seeking) (8,9). In a meta-analysis of 29 studies, the aggregated proportion of catastrophic costs at a cutoff point of 20% for the 29 studies was 43% (10). To reduce the risk of TB-related poverty, it is critical to have a valid tool to measure TB-related patient and household expenditure so that relevant policies can be implemented (11). A tool for measuring the direct and indirect costs for TB patients and their households was developed in 2015. This tool measures the proportion of patients who experience catastrophic payments due to TB. This generic tool was expanded into a handbook in 2017 after field testing in 9 countries and consultation with a WHO-led TB patient cost task force (12). By March 2020, 17 countries had completed the survey, with another 30 planning to do so by the end of 2020. According to the countries that have completed the survey evaluations, 27–83% of people with any kind of TB faced catastrophic expenditures. Those with drug-resistant TB had a substantially higher rate, ranging from 67% to 100% (13). The tool has been cross-culturally adapted in many countries, including Indonesia (14), Ethiopia, Kazakhstan (15), South Africa, Mozambique, United Republic of Tanzania, and Gambia (11). Cross-cultural adaptation is Abstract Background: Tuberculosis (TB) represents a major health problem having serious financial impact on a substantial pro- portion of patients. This has necessitated the development of a valid tool for measuring TB-related expenditure by patients and their households so that appropriate measures can be taken to reduce the financial burden. Aims: To translate and culturally validate the generic WHO tuberculosis patient cost survey within the Egyptian context. Methods: The instrument was translated and culturally adapted using forward-translation, back-translation, expert pan- el assessment, pretesting, cognitive interviewing, and appraisal by the developer. Results: A final Arabic version with modifications to 35 descriptors of the original tool was produced after review by an expert committee and cognitive interviews with patients. Twelve questions were modified, 13 response options were changed, 6 questions were added, and 4 questions were removed. Pretesting of the tool ensured that the final version is culturally sensitive and fit for assessing the costs incurred by TB patients in an Egyptian context. Conclusion: Policymakers are encouraged to use the WHO tuberculosis patient cost survey tool for assessing the expend- iture of TB patients with a view to developing appropriate policies to reduce the financial burden of patients. Keywords: Tuberculosis, Egypt, catastrophic health expenditure, WHO, cost survey, cultural adaptation. Citation: Ghazy R; Ashmawy R; Reyad O; Abd ElHafeez S; El-Shishtawy M; Khedr H; et al. Translation and cultural adaptation of the WHO generic tuberculosis patient cost survey to an Egyptian context. East Mediterr Health J. 2022;28(9):649–657. https://doi.org/10.26719/emhj.22.058 Received: 11/10/21; accepted: 12/05/22 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo) Book 28-09.indb 649 09/10/2022 11:07 AM 650 Research article EMHJ – Vol. 28 No. 9 – 2022 a process in which a questionnaire is translated into a language other than that with which it was developed and adapted to the local context where it will be applied (16). Based on the measurements of catastrophic costs, several countries have applied TB-specific strategies such as cash transfer to TB patients in India and Nigeria, and medical insurance coverage, food support and cash transfer in Kenya (17). Other countries have applied TB- sensitive strategies such as conditional cash transfers based on income in Brazil and Universal Health Coverage (UHC) in Indonesia (18,19). In Egypt, the national TB control programme offers free treatment; however, there is no social support to help patients cope with indirect and out-of-pocket payments. Few studies have been conducted to measure the financial burden on TB patients. In a recent study in Cairo Governorate, 33% of patients encountered catastrophic payment with the highest proportion during the prediagnostic stage (20). In Egypt a UHC law was approved in 2017 and will be applied gradually between 2018 and 2032. The law will extend insurance to 30% of the population who are not currently covered by any form of insurance (21). UHC is a social solidarity-based compulsory system that exempts individuals who cannot afford to pay contributions. In the new system, the family is the primary insurance coverage unit, as opposed to the current system, which provides separate coverage to each family member, leaving some uninsured (22). The law aims to reduce catastrophic payments due to medical care and it is considered a TB-sensitive strategy. The current study aimed to adapt the WHO cost tool to an Egyptian context. It assessed the catastrophic payments due to TB before and after applying UHC; thus enabling policy- makers to determine whether this strategy is sufficient to protect TB patients against improvisation, or whether additional social protection measures are needed. Methods Original WHO survey The WHO generic TB patient cost survey gathers data from patients about their current treatment and the costs incurred during the treatment phase in which they are interviewed (12). Translation adaptation Guidelines for translation and cross-cultural adaptation were followed (16,23). The tool was translated through the following 5 stages: Stage 1: forward translation Two bilingual translators whose mother tongue is Arabic translated the WHO tool. The translators were health professionals who were aware of the concepts examined by the questionnaire. The translation aimed at conceptual equivalence between the generic and translated tools rather than literal translation. The tool was translated into the written Arabic language with the goal of ensuring that the terms in the target language conveyed the same or similar meanings as the source language. Stage 2: back translation Two bilingual, native English-speaking translators translated the tool backwards to English. The translators were unaware of the concepts being explored in order to avoid information bias and to point out unexpected meanings of terms in the translated tool (24). Back- translation provided validity checks and uncovered inconsistencies in the translation process. Discrepancies between the original and the back-translated versions were discussed. The forward-translated tool was iterated as many times as needed by the bilingual expert panel until a satisfactory version was achieved. Stage 3: expert committee (content validity and cross-cultural adaptation) Content validity is defined as the extent to which the element of an assessment instrument is relevant and representative of the targeted structure for a particular assessment goal (25). Content validity was achieved in several steps. First, the content validation form was prepared to ensure that the review panel had clear expectations and understanding of the task. Second, the group responsible for reviewing the questionnaire was selected based on individual expertise on catastrophic costs incurred by TB patients. The panel consisted of 8 reviewers with specialties in tropical and infectious diseases, TB and pulmonary diseases, health economics, clinical pharmacy, and epidemiology . In a face-to-face discussion, the experts critically reviewed the field and its components before assigning a score to each. They provided verbal feedback to improve the relevance of each item to the focus area. All comments were taken into consideration to refine the domain and its items. Upon completing the review of the domain and items, the experts were requested to provide a score on each item independently based on the relevant scale (26). The conceptualized equivalence between the generic and translated tools was evaluated. The content validity index was 0.8. As recommended by the WHO task force (11), questions on income and household assets were adapted for the local context using the same wording as in the Demographic Health Survey and the Household Income and Expenditure Survey available in Egypt (27,28). Stage 4: pretesting and cognitive interviewing Cognitive interviewing is a research-based qualitative method for determining whether a survey question fulfils its intended purpose (29,30). The lead investigator trained a physician and a pharmacist to conduct the cognitive interview through role play. Fifteen participants were recruited for the interview (5 physicians and 10 TB patients aged > 18 years at the TB Department of El Mamora Chest Hospital, Alexandria at least 2 weeks after initiation of the intensive phase, and after signing informed consent). Recruitment of subjects for cognitive interviewing aimed to include variation of subjects rather than statistical representation. The interview was conducted in a quiet place and notes were taken Book 28-09.indb 650 09/10/2022 11:07 AM 651 Research article EMHJ – Vol. 28 No. 9 – 2022 by trained cognitive interviewers. The interviewers prepared the draft form of the questionnaire together with probe questions to be asked (30). The interviewer used concurrent probing, which is a verbal probing approach in which the interviewer asked the probe question just after the respondent had read aloud and answered each survey item (29). The following types of cognitive probes were used: (1) comprehension/ interpretation: respondents were asked what they thought was meant by each questionnaire item and the chosen response; (2) paraphrasing: respondents were asked whether they could repeat the question in their own words; (3) recall: respondents were asked to explain how they came up with their answer; and (4) general: respondents were asked about any word they did not understand and any word or expression that they found unacceptable or offensive. Stage 5: submission of the final version to the developer for appraisal of the adaptation process All forms, reports and the final culturally adapted and pretested questionnaire were sent to the WHO expert panel, which audited the process of translation and adaptation and assessed whether the constructs measured the catastrophic costs. Analysis The raw data were coded and entered using Microsoft Excel software an the data were described using frequency distribution tables. Qualitative data were described using number and percentage and the variable “age” was described using arithmetic mean and standard deviation. Analysis of the cognitive interviews was based on text summarization (30); the interviewers’ written notes were summarized and the consistent themes were identified, and the questions modified based on results of the analysis. Results A total of 35 modifications were made to the original WHO cost survey. Twelve questions were modified, 13 response options were changed, 6 questions were added and 4 questions were removed. Examples of the changes in questions were replacing “patient registration number” with “patient ID number” and “province” with “governorate” (Table 1). Thirteen sociodemographic questions had their response options altered, including education, employment and occupation, so that the answers represented the local categories. Other examples of alterations were questions on health insurance and social protection schemes, to reflect the schemes in Egypt (e.g. government insurance, private insurance and donors), and types of facilities for diagnosis and treatment, to reflect the health facilities in Egypt (e.g. chest hospital and chest clinics) (Table 2). Six questions were added, including questions about savings in the cost of TB treatment; cost of accommodation because sometimes patients received treatment in remote facilities that required an overnight stay in a governorate other than their home governorate; and nonessential jobs in the informal sector for additional income (Table 3). Four questions were removed, such as “Was a fee paid to pick up medications?” TB medications are subsidized by the National Tuberculosis Control Program and dispensed free to patients. Questions on vouchers were Table 1 World Health Organization TB patient cost survey questions and their adaptation to the Egyptian context Original item Item after adaptation 1. Patient registration number in the TB register Patient ID number 2. Name of province Name of governorate 3. Name of district Name of administrative region 4. Supplements during healthcare visit or hospital stay Divided into separate questions for nutritional supplements, vitamins and food 5. Cost of travel (total for the stay) Total cost of transportation for patient and relatives throughout the stay in addition to ambulance costs 6. Cost of food (total for the stay) Cost of food during stay and travel for patient and relatives 7. Other (payment for furniture, soap and other administrative and services) 8. (total for the stay) Other costs (payment for furniture, soap, cloths and other administrative and services and personal supplies for patients and relatives) 9. Are fees charged to obtain drugs? Did you pay for medications? 10. What fees did you pay during your last outpatient follow-up visit for X-rays and other imaging scans? What fees did you pay during your last outpatient medical follow-up visit for radiology and other imaging scans? 11. What is your primary job, regular work, or other regular major activity now? What is your job after getting TB? (the choices are the same as the question “what is your main job?”) 12. How many rooms are in the house except the bathroom? How many rooms are in the house except the bathroom and kitchen? 13. What is your household’s weekly expenditure in the following items? – Oil? What is your household’s weekly expenditure in the following items? transportation? TB = tuberculosis. Book 28-09.indb 651 09/10/2022 11:07 AM 652 Research article EMHJ – Vol. 28 No. 9 – 2022 Table 2 World Health Organization TB patient cost survey questions and their adaptation to the Egyptian context Questions Original options Options after adaptation 1. Type of health facility 2. Diagnostic place – Primary health care facility – Public hospital – Nongovernmental organization / health centre or charitable hospital – Hospital or private clinic – Other – Chest hospital – Chest clinic – Other 3. Type of TB – Pulmonary, bacteriologically confirmed – Pulmonary, bacteriologically unconfirmed – Extrapulmonary – Lung, confirmed by bacteriological analysis – Lung, not confirmed by bacteriological analysis – Outside the lung 4. Is the patient currently in the stage of intensive or complementary treatment? – Intensive treatment stage, ----- weeks completed – Complementary treatment phase, ----- weeks completed – Intensive treatment stage, ----- weeks completed – Continuation treatment phase, ----- weeks completed 5. Before your TB treatment began in this facility, from which of the following facilities did you seek care or advice for symptoms of current illness (including hospitalization; several types of facilities can be mentioned)? 6. Where did you go first? – Dispensary – Health centre – Public hospital – Pharmacy – Herbalist/traditional practitioner – Private clinic – Private hospital – Community health worker – Other facility – Family health centre – Central / public hospitals – Private clinic / hospital – District health department – Chest clinic – Primary health centre – Health insurance hospital/ clinic 7. On a daily basis, are you currently taking your medications on your own without supervision or support [self-administered or do you have a supervising or supportive therapy (DOT)]? 8. Did you take your medications in the intensive phase on your own without supervision or support (self-administering) or did you have a supervising or supportive therapy (DOT)? – Self-managed – Point – DOT intensive – DOT continuation – Self-managed – Point 9. Where do you or a family member get your TB medicines? – Dispensary – Health centre – Public hospital – Pharmacy – Herbalist/traditional practitioner – Private clinic – Private hospital – Community health worker – Other facility – Chest hospital – Chest clinic – Health insurance – Others, specify 10. Do you have any of the following types of health insurance? – Payment scheme – Medical allowance – Health insurance from NGOs in the form of donations – Family / community fund – Private health insurance – Other – Government insurance – Private insurance – Donors (e.g., charities) 11. What is your level of education (for the patient)? – No education – Elementary education (up to grade 3) – Incomplete high school (up to grade 9) – Completion of high school (up to grade 12) – Professional – Vocational high school – Higher education (university) – Below education age – Illiterate does not read or write – Read and write – Elementary – Preparatory – Secondary – Higher education (university) 12. What is your main job? – School student – Technical – Service – Factory worker – Farmer – Government employee – Teacher – Retired – Housewife – Unemployed – other – Student – Employee – Professional – Manual worker – Merchant – Housewife – Not working – Retired 13. Who did you borrow / receive from? (Multiple answers) – the last option “other” – the respondent was asked to specify “others” DOT = directly observed therapy; TB = tuberculosis. Book 28-09.indb 652 09/10/2022 11:07 AM 653 Research article EMHJ – Vol. 28 No. 9 – 2022 removed because such a system does not exist in Egypt (Table 4). For cognitive interviews, 10 patients and 5 physicians were interviewed [10 male, 5 female, mean age 34.56 (12.32) years]. All patients were living in Alexandria and recruited from Mamora Chest Hospital. All patients were drug sensitive, and 8 of them were in the continuation phase (Table 5). After the interviews, subjects declared that questions were clear and understandable and suggested minor changes. The date of presentation of symptoms and initiation of treatment could not be recalled precisely, especially for patients in the continuation phase. One of the confusing items was the cost of drugs other than anti-TB treatment (nutritional supplementation and vitamins) because these 2 items were inseparable in the prescription. Therefore, a question was added about the total cost of other medication if the patient could not report the cost of each item; patients usually receive a hospital bill with the total cost of hospitalization without itemization. Thus, we added an item that reported the total cost of hospitalization if the patient did not know the cost of each subcategory. Some words were confusing, such as ambulatory treatment, consultation fee, and biopsy. These words were adapted to suit the local context; for example, energy drinks were replaced with milk and consultation fee with examination fee. We added a question that asked for other national forms of transportation, such as toktok (in Egypt, a 2-wheeled pulled rickshaw with a seat for 1 or 2 people). A question was added about household monthly expenditure on rent. We also asked about the cost of utilities, the estimated monthly net income from work- related activities, the methods of rubbish and municipal waste disposal, and other fixed sources of income. Discussion A final Arabic version of the original WHO tuberculosis patient cost survey was developed with modifications to 35 descriptors. Twelve questions were modified, 13 response options were changed, 6 questions were added and 4 questions were removed. We encountered some challenges during translation. First, the Arabic language has a rich vocabulary, with many terms used to convey the same meaning. One description in English may have multiple Arabic equivalents, necessitating a lengthy translation procedure to select the most acceptable and accurate equivalent word for the Arabic version (31). The disparity between the spoken (colloquial) and written (classical) versions of the language was another challenge. It is worth mentioning that, while written Arabic is the same across the 22 countries of the Middle East, spoken Arabic varies (31). Thus, a decision was taken to translate the tool into written Arabic. This resulted in a translated version that could be valid for use in all Arab- speaking countries with some cultural adaptation. The research team made the following changes to adapt the generic WHO survey to the Egyptian context: changing wording of the questions, changing the response options, and adding and omitting questions. For example, we omitted questions about transportation or accommodation vouchers for TB patients because the voucher system does not exist in Egypt. Similarly, we omitted a question about fees paid to collect TB medications because patients receive TB medications at no charge under the National Tuberculosis Control Program. We added 6 questions. For example, the accommodation costs for the patients and their caregivers because some patients receive treatment in a governorate other than the one they resided. We added a question about nonessential jobs because it is common for Egyptians to take up informal private employment in addition to their main employment as a means to increase their income (32). We changed questions about type of healthcare facilities, education, employment, facilities for dispensing TB medications…etc. to make them appropriate for the Egyptian context. The WHO patient cost survey adapted in our study has a cross-sectional design in which the patient is interviewed only once. Expenditure incurred after treatment completion is not included, and costs cannot be linked to treatment outcomes, which are sometimes unavailable at the time of the survey. This is likely to underestimate the economic impact of TB because costs incurred after treatment for TB sequelae or loss of job or income due to disability would be overlooked (11). Accordingly, several TB cost studies have drawn attention to the necessity for longitudinal studies, including the costs incurred by patients after recovery, including economic recovery (e.g. ability to repay debts or regain production), and the ability to build resilience against future shocks after completion of TB treatment (11). In one study, the WHO generic cost survey was adapted for longitudinal use in African countries: at enrolment Table 3 Questions added to the World Health Organization TB patient cost survey after adaptation to the Egyptian context Cost of dietary supplements 1. What is the accommodation cost for you and the accompanying person during direct observation? 2. How many TB follow-up visits have you had so far during this phase of treatment (to see a doctor or nurse, have follow-up checks, etc.)? 3. How much did you spend on food and drinks on the last follow-up visit (on the road, while waiting, lunch, etc.), in total, for you and any accompanying person? 4. What is your non-essential job? (the choice options are the same as the question "What is your main job?" 5. How much savings did you spend? TB = tuberculosis. Book 28-09.indb 653 09/10/2022 11:07 AM 654 Research article EMHJ – Vol. 28 No. 9 – 2022 Acknowledgement We are grateful for the assistance with the cognitive interviewing provided by Dr. Nesma Abbas Mohamed, Clinical Pharmacist at the Egyptian Ministry of Health, and Dr. Heba Hassan, National Institute of Chest Diseases, Imbaba. Funding: None Competing interests: None declared. (start of TB therapy at day 0), and at 2, 6, 12 and 24 months after enrolment. The periods were designed to determine expenditure for diagnosis, treatment and long-term follow-up once treatment was concluded. Repeated measurements allowed for comparison of costs over time, measuring the economic impact after concluding TB treatment, and linking the cost survey to treatment outcomes. Thus, further studies adapting the current tool for use in longitudinal studies is recommended. The income provided by patients in the generic WHO survey is self-reported income. This can be challenging in an informal economy setting (4,33). For example, it would not be possible to measure lost income due to illness for patients who report a zero income (11). A report by the World Bank estimated that income from informal private employment accounted for 62% of the overall income (32). In the current study, questions about the monetary value of all items consumed by households were added, using the Demographic Health Survey and the Household Income and Expenditure Survey available in Egypt (27,28). Estimating the income based on possession of assets, such as televisions, refrigerators and mobile phones, is more accurate than self-reported income. This was illustrated in a study in South Africa that used 6 different approaches for estimating catastrophic expenditure. Depending on the estimation method, the total proportion of households experiencing catastrophic costs ranged from 0% to 36%, with the self- reported income significantly lower than the estimated income based on asset linking (34). The South African study highlighted the difficulty of accurate assessment of income when estimating disease-specific catastrophic costs. A consumer expenditure questionnaire is the gold standard for estimating permanent income. The current study had some limitations. The Demographic Health Survey and Household Income and Expenditure Survey provided accurate estimates of the respondents’ income. However, these surveys are specific to the Egyptian context and will be difficult to use in other countries. If the survey is to be replicated in an Arab country, the local context should be taken into consideration when estimating income. Another limitation was that the tool did not account for expenditure incurred after treatment completion. Further adaptation of the tool for use in longitudinal studies is recommended. Conclusion This study has resulted in the availability of an Arabic version of the WHO TB patient cost survey that could be used to estimate the catastrophic health expenditure among TB patients in Arab countries. With the use of the adapted tool, focused interventions could be applied to reduce the financial burden on TB patients. Table 4 Questions removed from the World Health Organization TB patient cost survey after adaptation to the Egyptian context 1. What was your primary job, regular job, or other normal major activity before you got the TB? 2. Was a fee paid to pick up medications? 3. Do you currently receive vouchers or items for TB? (travel, nutritional and others) 4. Who do you receive the voucher/merchandise from? TB = tuberculosis. Table 5 Demographic characteristics of respondents Characteristics No. % Gender (male) 10 60% Mean age 34.56 (12.32) years Urban residence 15 100% Occupation Unemployed/housewife 2 13.30% Employee 6 40% Student 2 13.30% Physician 5 33.40% Patients with MDR-TB 10 100% Patients in treatment phase (continuation phase) 8 80% Negative HIV status 10 100% Patient currently hospitalized 10 100% MDR-TB = multidrug-resistant tuberculosis. Book 28-09.indb 654 09/10/2022 11:07 AM 655 Research article EMHJ – Vol. 28 No. 9 – 2022 References 1. Chakaya J, Khan M, Ntoumi F, Aklillu E, Fatima R, Mwaba P, et al. Global Tuberculosis Report 2020 - Reflections on the Global TB burden, treatment and prevention efforts. Int J Infect Dis. 2021 Dec;113 (Suppl 1):S7–12. https://doi.org/10.1016/j.ijid.2021.02.107 PMID:33716195 2. Global Tuberculosis Report. Geneva: World Health Organization; 2020 (https://apps.who.int/iris/bitstream/hand le/10665/336069/9789240013131-eng.pdf, accessed 12 July 2022). 3. Burki TK. The global cost of tuberculosis. Lancet Respir Med. 2018 Jan;6(1):13. https://doi.org/10.1016/S2213-2600(17)30468-X PMID:29239796 Traduction et adaptation culturelle de l'enquête générique de l'OMS sur les coûts de la tuberculose pour les patients dans un contexte égyptien Résumé Contexte : La tuberculose représente un problème de santé majeur qui a de graves répercussions financières sur une proportion importante des patients. Il a donc été nécessaire de mettre au point un outil valable pour mesurer les dépenses liées à la tuberculose par les patients et les membres de leur foyer afin de prendre les mesures appropriées pour réduire la charge financière. Objectifs : Traduire et valider culturellement l'enquête générique de l'OMS sur les coûts de la tuberculose pour les patients dans le contexte égyptien. Méthodes : L'instrument a été traduit et adapté culturellement à l'aide de la traduction initiale, de la rétrotraduction, de l'évaluation par un groupe d'experts, du prétest, de l'entretien cognitif et de l'évaluation par le développeur. Résultats : Après avoir été examinée par un comité d'experts et après des entretiens cognitifs avec les patients, une version finale en arabe a été produite avec des modifications apportées à 35 descripteurs de l'outil original. Douze questions ont été modifiées, 13 options de réponse ont été changées, six questions ont été ajoutées et quatre questions ont été supprimées. Le prétest de l'outil a permis de s'assurer que la version finale tient compte des différences culturelles et qu’elle est adaptée pour l'évaluation des coûts supportés par les patients tuberculeux dans un contexte égyptien. Conclusion : Les responsables politiques sont incités à utiliser l'outil d'enquête de l'OMS sur les coûts de la tuberculose pour les patients afin d'évaluer les dépenses de ces derniers en vue d'élaborer des politiques appropriées pour réduire leur charge financière. قاطنلا في همادختسلا اًّيفاقث هفييكتو لسلا ضىرم اهدبكتي يتلا ةفلكتلا نع ةيلماعلا ةحصلا ةمظنلم ماعلا حسملل ةجمرت يصرلما ،ليع سينان ،بوقعي دممح ،حلاصلا رديح ،ينيورلا بايهإ ،ضرخ ةبه ،يواتششلا يم ،ظفالحا دبع رمس ،ضاير رمع ،يوماشع اشر ،يزاغ يمار ملسم اشر ةصلالخا سايقل قدصلاب زيمتت ةادأ دادعإ كلذ مزلتسا دقو .هب ينباصلما نم ابه ناهتسُي لا ةبسن لىع يربك ليام رثأ اله ةيربك ةيحص ةلكشم لسلا لثمي :ةيفللخا .ليالما ءبعلا فيفختل ةبسانلما يربادتلا ذاتخا نكمي ىتح مهسرأو ضىرلما اهدبكتي يتلا لسلاب ةلصلا تاذ تاقفنلا ا ًّيفاقث هتمءلام نم ققحتلاو لسلا ضىرم اهدبكتي يتلا فيلاكتلل ماعلا ةيلماعلا ةحصلا ةمظنم حسم ةجمرت لىا ةساردلا هذه تفده :فادهلأا .يصرلما قاطنلا في مادختسلال رابتخلاا ءارجإو ،ءابرخ قيرف ةفرعمب اهمييقتو ةيزيلجنلإا لىإ ةيسكعلا ةجمترلا مث ،ةيبرعلا لىإ اهتجمترب ا ًّيفاقث اهفييكتو ةادلأا ةجمرت تتم :ثحبلا قرط .روطلما ةفرعمب اهمييقت مث مهفلا سايقل تلاباقم ءارجإو ،قبسلما عم تلاباقم ءارجإو ءابرخ ةنلج نم ةعجارم دعب كلذو ،ةيلصلأا ةادلأا نم اًفِصاو 35 لىع تلايدعت تنمضت ةيئانه ةيبرع ةخسن تدعُأ :جئاتنلا ،ةلئسأ 6 ةفاضإو ،تاباجلإا تارايخ نم اًرايخ 13 يريغتو ،ًلااؤس شرع يتنثا ليدعت ةيئاهنلا ةخسنلا دادعإ نمضت دقو .اله مهمهف سايقل ضىرم فيلاكتلا مييقتل ةبسانمو ةيفاقثلا تارابتعلاا يعارت ةيئاهنلا ةخسنلا نأ نم ،ةادلأل قبسلما رابتخلاا للاخ نم ،نوثحابلا ققتح دقو .ةلئسأ 4 فذحو .ةيصرلما ةئيبلا في لسلا ضىرم اهلمحتي يتلا ،لسلا ضىرم تاقفن مييقتل لسلا ضىرم اهدبكتي يتلا فيلاكتلل ةيلماعلا ةحصلا ةمظنم حسم مادختساب تاسايسلا وعضاو صىوُي :تاجاتنتسلاا .ضىرلما هلمحتي يذلا ليالما ءبعلا فيفختل ةمئلام تاسايس عضو فدبه Book 28-09.indb 655 09/10/2022 11:07 AM 656 Research article EMHJ – Vol. 28 No. 9 – 2022 4. Erlinger S, Stracker N, Hanrahan C, Nonyane S, Mmolawa L, Tampi R, et al. Tuberculosis patients with higher levels of pov- erty face equal or greater costs of illness. Int J Tuberc Lung Dis. 2019 Nov 1;23(11):1205–12. https://doi.org/10.5588/ijtld.18.0814 PMID:31718757 5. Foster N, Vassall A, Cleary S, Cunnama L, Churchyard G, Sinanovic E. The economic burden of TB diagnosis and treatment in South Africa. Soc Sci Med. 2015 Apr;130:42–50. https://doi.org/10.1016/j.socscimed.2015.01.046 PMID:25681713 6. Kemp JR, Mann G, Simwaka BN, Salaniponi FM, Squire SB. Can Malawi’s poor afford free tuberculosis services? Patient and household costs associated with a tuberculosis diagnosis in Lilongwe. Bull World Health Organ. 2007 Aug;85(8):580–5. https:// doi.org/10.2471/blt.06.033167 PMID:17768515 7. End TB strategy. Geneva: World Health Organization; 2018 (https://reliefweb.int/attachments/f41571f8-e203-3804-b647- 906b4072f91e/post2015_TBstrategy.pdf, accessed 12 July 2022). 8. Global tuberculosis report. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/bitstream/hand le/10665/329368/9789241565714-eng.pdf, accessed 12 July 2022). 9. Pedrazzoli D, Borghi J, Viney K, Houben RMGJ, Lönnroth K. Measuring the economic burden for TB patients in the End TB Strategy and Universal Health Coverage frameworks. Int J Tuberc Lung Dis. 2019 Jan 1;23(1):5–11. https://doi.org/10.5588/ ijtld.18.0318 PMID:30674374 10. Ghazy RM, El Saeh HM, Abdulaziz S, et al. A systematic review and meta-analysis of the catastrophic costs incurred by tubercu- losis patients. Sci Rep. 2022;12:558. https://doi.org/10.1038/s41598-021-04345-x 11. Evans D, van Rensburg C, Govathson C, Ivanova O, Rieß F, Siroka A, et al. Adaptation of WHO’s generic tuberculosis patient cost instrument for a longitudinal study in Africa. Glob Health Action. 2021 Jan 1;14(1):1865625. https://doi.org/10.1080/16549716.2020.1 865625 PMID:33491593 12. Tuberculosis patient cost surveys: a handbook. 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Guidelines for the process of cross-cultural adaptation of self-report meas- ures. Spine (Phila Pa 1976). 2000 Dec 15;25(24):3186–91. https://doi.org/10.1097/00007632-200012150-00014 PMID:11124735 17. Shete PB, Reid M, Goosby E. Message to world leaders: we cannot end tuberculosis without addressing the social and economic burden of the disease. Lancet Glob Health. 2018 Dec;6(12):e1272–3. https://doi.org/10.1016/S2214-109X(18)30378-4 PMID:30224288 18. Torrens AW, Rasella D, Boccia D, Maciel EL, Nery JS, Olson ZD, et al. Effectiveness of a conditional cash transfer programme on TB cure rate: a retrospective cohort study in Brazil. Trans R Soc Trop Med Hyg. 2016 Mar;110:199–206. https://doi.org/10.1093/ trstmh/trw011 PMID:26884501 19. Fuady A, Houweling TAJ, Mansyur M, Richardus JH. Catastrophic total costs in tuberculosis-affected households and their determinants since Indonesia’s implementation of universal health coverage. Infect Dis Poverty. 2018 Jan 12;7(1):3. https://doi. org/10.1186/s40249-017-0382-3 PMID:29325589 20. Ellaban MM, Basyoni NI, Boulos D, Rady M, Gadallah M. Assessment of household catastrophic total cost of tuberculosis and its determinants in Cairo: prospective cohort study. Tuberc Respir Dis. 2022 Apr;85(2):165–74. https://doi.org/10.4046/trd.2021.0028 PMID:34814238 21. Devi S. Universal health coverage law approved in Egypt. Lancet. 2018 Jan 20;391(10117):194. https://doi.org/10.1016/S0140- 6736(18)30091-6. PMID:30277878 22. Eleiba Z. Universal health insurance in Egypt: informal workers’ perspective [website]. Cairo: Alternative Policy Solutions; 2020 (https://aps.aucegypt.edu/en/articles/452/universal-health-insurance-in-egypt-informal-workers-perspective, accessed 12 July 2022). 23. Sousa VD, Rojjanasrirat W. Translation, adaptation and validation of instruments or scales for use in cross-cultural health care research: a clear and user-friendly guideline. J Eval Clin Pract. 2011 Apr;17(2):268–74. https://doi.org/10.1111/j.1365- 2753.2010.01434.x PMID:20874835 24. Guillemin F, Bombardier C, Beaton D. Cross-cultural adaptation of health-related quality of life measures: literature review and proposed guidelines. J Clin Epidemiol. 1993 Dec;46(12):1417–32. https://doi.org/10.1016/0895-4356(93)90142-n PMID:8263569 25. Haynes SN, Richard D, Kubany ES. Content validity in psychological assessment: a functional approach to concepts and meth- ods. Psychol Assess 1995;7(3):238–47. https://doi.org/10.1037/1040-3590.7.3.238 26. Yusoff MSB. ABC of content validation and content validity index calculation. Resource. 2019;11(2):49–54. https://doi. org/10.21315/eimj2019.11.2.6 Book 28-09.indb 656 09/10/2022 11:07 AM 657 Research article EMHJ – Vol. 28 No. 9 – 2022 27. Willis GB, Artino AR Jr. What do our respondents think we’re asking? Using cognitive interviewing to improve medical educa- tion surveys. J Grad Med Educ. 2013 Sep;5(3):353–6. https://doi.org/10.4300/JGME-D-13-00154.1 PMID:24404294 28. Egypt. Health issues survey 2015. Cairo: Ministry of Health and Population/Egypt and ICF International; 2015 (https://dhsproi- gram.com/publications/publication-FR313-DHS-Final-Reports.cfm, accessed 12 July 2022). 29. Household income, expenditure, and consumption survey, HIECS 2015 [website]. Economic Research Forum (http://www.erfdat - aportal.com/index.php/catalog/129#metadata-questionnaires, accessed 12 July 2022). 30. Willis GB. Analysis of the cognitive interview in questionnaire design. Oxford University Press; 2015 31. Madi D, Badr LK. Translation, cross-cultural adaptation, and validation of the adolescent Pediatric Pain Tool (APPT) for multidi- mensional measurement of pain in children and adolescents. Pain Manag Nurs. 2019 Dec;20(6):549–55. https://doi.org/10.1016/j. pmn.2019.06.004 PMID:31447300 32. Krafft C, Assaad R, Rahman KW, Cumanzala M. How do small formal and informal firms in the Arab Republic of Egypt com- pare? World Bank Equitable Growth, Finance and Institutions Practice Group; 2020 (https://openknowledge.worldbank.org/ bitstream/handle/10986/34594/How-Do-Small-Formal-and-Informal-Firms-in-the-Arab-Republic-of-Egypt-Compare.pdf?se- quence=1&isAllowed=y, accessed 12 July 2022). 33. Stracker N, Hanrahan C, Mmolawa L, Nonyane B, Tampi R, Tucker A, et al. Risk factors for catastrophic costs associated with tuberculosis in rural South Africa. Int J Tuberc Lung Dis. 2019 Jun 1;23(6):756–63. https://doi.org/10.5588/ijtld.18.0519. PMID:31315710 34. Sweeney S, Mukora R, Candfield S, Guinness L, Grant AD, Vassall A. Measuring income for catastrophic cost estimates: limitations and policy implications of current approaches. Soc Sci Med. 2018 Oct;215:7–15. https://doi.org/10.1016/j. socscimed.2018.08.041 PMID:30196149 Book 28-09.indb 657 09/10/2022 11:07 AM 658 Research article EMHJ – Vol. 28 No. 9 – 2022 Pilot study of safety and efficacy of topical liposomal amphotericin B for cutaneous leishmaniasis caused by Leishmania major in Islamic Republic of Iran Ali Khamesipour,1 Akram Mohammadi,1 Mahmoud Jaafari,2,3 Seyed Eskandari,1 Minoo Tasbihi,1 Amir Javadi,1,4 Farzaneh Afshari,5 Hossein Mortazavi6 and Alireza Firooz1 1Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran (Correspondence to: A. Khamesipour: Ali.Khamesipour@gmail.com). 2Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran. 3Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran. 4Department of Social Medicines, Qazvin University of Medical Sciences, Qazvin, Islamic Republic of Iran. 5ExirNanoSina Co., Tehran, Islamic Republic of Iran. 6Department of Dermatology, Tehran University of Medical Sciences, Razi Hospital, Tehran, Islamic Republic of Iran. Introduction Cutaneous leishmaniasis is the most common form of leishmaniasis and it is endemic in about 90 countries, with 600 000 to 1 million new cases annually. According to the World Health Organization (WHO), more than 90% of cutaneous leishmaniasis cases reported in 2019 were from Afghanistan, Algeria, Brazil, Colombia, Islamic Republic of Iran, Iraq, Libya, Morocco, Pakistan, Peru, Syrian Arab Republic and Tunisia (1). Cutaneous leishmaniasis is a vector-borne parasitic disease caused by different Leishmania species and transmitted through sand fly bites, specifically in uncovered parts of the body. The most common species of the parasite include Leishmania major, Leishmania tropica, Leishmania infantum and Leishmania donovani, which are found in many geographical areas such as North Africa, Mediterranean, Middle East, Indian Subcontinent and Central Asia (1,2). Cutaneous leishmaniasis causes skin lesions with various clinical features from slow-healing lesions to permanent scars (3), resulting in social stigma and psychological disorders that negatively affect the quality of life (4). Standard treatment for cutaneous leishmaniasis currently depends on multiple injections of antimoniate derivatives. However, several alternative therapies are under investigation because of the challenges of antimoniate derivatives, including injection site pain, high cost, severe adverse effects, variable efficacy and drug resistance. Oral treatments such as azole antifungal drugs, dapsone, azithromycin, miltefosine and zinc sulfate have been evaluated for treatment of cutaneous leishmaniasis but are associated with adverse effects and Abstract Background: Topical nanoliposomes containing 0.4% amphotericin B (Lip-AmB 0.4%) have shown promising safety re- sults in preclinical and phase 1 clinical trials in healthy volunteers. Aims: To evaluate safety and efficacy of Lip-AmB 0.4% in cutaneous leishmaniasis patients. Methods: Fourteen patients with a total of 84 lesions received national standard treatment of weekly intralesional meglu- mine antimoniate with biweekly cryotherapy, or daily intramuscular meglumine antimoniate (20 mg/kg/day for 14 days), and topical Lip-AmB 0.4% twice daily for 28 days. Twenty-two patients with a total of 46 lesions (7 at most) were treated with topical Lip-AmB 0.4% alone twice daily for 28 days. Thirty patients with a total of 68 lesions received national stand- ard treatment of weekly intralesional meglumine antimoniate (to blanch around the lesion) and biweekly cryotherapy. Results: Sixty-six patients with cutaneous leishmaniasis lesions completed the study. In the safety evaluation, 2 of the 36 patients evaluated reported a tolerable burning sensation and they preferred to continue treatment. Twelve (92%) of 14 patients with 84 lesions who received national standard treatment combined with Lip-AmB 0.4% completed the study with complete cure. In 1 of the patients with 4 lesions, 1 lesion showed complete cure and 3 showed partial cure. Among 22 patients with 46 lesions who received only topical LipAmB 0.4%, 19 completed the study and 18 showed complete cure (95% efficacy). In the 30 patients who received national standard treatment alone, 33 lesions in 15 patients showed complete cure (48.5%) on day 42 follow-up. Conclusion: Lip-AmB 0.4% alone or in combination with national standard treatment is safe with high-efficacy rate and warrants further investigation during phase 3 clinical trials. Keywords: nano, liposomal, amphotericin B, cutaneous, leishmaniasis, Glucantime, Iran Citation: Khamesipour A; Mohammadi A; Jaafari M; Eskandari S; Tasbihi M; Javadi A; et al. Pilot study of safety and efficacy of topical liposomal amphotericin B for cutaneous leishmaniasis caused by Leishmania major in Islamic Republic of Iran. East Mediterr Health J. 2022;28(9):658–663. https://doi.org/10.26719/emhj.22.070 Received: 30/11/21; accepted: 11/05/22 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo) Book 28-09.indb 658 09/10/2022 11:07 AM 659 Research article EMHJ – Vol. 28 No. 9 – 2022 variable efficacy (2–7). Topical formulations have been developed against cutaneous leishmaniasis and tested in clinical trials but they are not yet available in the market (8–10). Amphotericin B (AmB) is a polyene antifungal agent that kills pathogens by binding to ergosterol and causing subsequent pore formation in the cell membrane and oxidative damage. Despite the effectiveness of AmB against fungal infections and visceral leishmaniasis, its use is limited because of the significant toxicity, especially nephrotoxicity and infusion-related reactions (11). To reduce the adverse effects and increase tolerance to AmB, 3 lipid-based formulations have been developed (Amphotec, Abelcet and AmBisome) to treat visceral leishmaniasis but their efficacy for cutaneous leishmaniasis is not high (11–13). Therefore, novel formulations with optimal skin penetration are needed to improve cutaneous leishmaniasis treatment. Liposomes are spherical biodegradable vesicles that are extensively used because of their safety and improved delivery. Numerous studies have revealed that topical liposomal formulations reduce adverse effects and improve skin penetration and on-site drug accumulation (13,14). Nanoliposomes containing 0.4% amphotericin B (Lip-AmB 0.4%) have been developed under good manufacturing practice guidelines using phosphatidylcholine and cholesterol for treatment of cutaneous leishmaniasis. The formulation demonstrated promising results against L. tropica and L. major in vitro and L. major in vivo (15) and shown to be safe in animal models (16). The safety of Lip-AmB 0.4% has been evaluated in healthy volunteers in a phase I clinical trial. The skin before and after topical application of Lip-AmB 0.4% twice daily showed no significant difference in hydration, transepidermal water loss, melanin, erythema, temperature, sebum and pH (17). Another clinical study showed no significant difference in the safety and efficacy of Lip-AmB 0.4% compared to intralesional injection of meglumine antimoniate in cutaneous leishmaniasis patients (18). In the current study, we compared the safety and efficacy of topical Lip-AmB 0.4% alone, topical Lip- AmB 0.4% combined with meglumine antimonate, and meglumine antimonate plus cryotherapy for treatment of cutaneous leishmaniasis lesions. Methods Study design This was an open, pilot clinical trial, registered at the Center for Research and Training in Skin Diseases and Leprosy (CRTSDL), conducted in accordance with guidelines for good clinical practice. Ethical approval was obtained from the institutional ethics committees at CRTSDL, and informed consent was obtained from all candidates before enrolment. The study objectives and procedures were explained to the patients and the treatment option was selected based on the patient’s wishes and physician’s decision. The study evaluated the safety and efficacy of the following treatments for cutaneous leishmaniasis lesions caused by L. major: topical Lip-AmB 0.4% alone, topical Lip-AmB 0.4% combined with meglumine antimonate, and meglumine antimonate plus cryotherapy. Study patients The inclusion criteria were: (1) age 14–60 years; (2) parasitologically confirmed cutaneous leishmaniasis lesions caused by L. major using direct smear, culture and polymerase chain reaction (PCR); and (3) clinical diagnosis of up to 5 cutaneous leishmaniasis lesions with a diameter < 5 cm. Patients who were eligible to receive national standard treatment and willing to apply Lip- AmB 0.4% were included and received both treatments. Patients who were not willing or eligible to receive meglumine antimonate but were willing to receive Lip- AmB 0.4% were treated with Lip-AmB 0.4% alone. Exclusion criteria were: (1) pregnancy or patients not willing or unable to use contraceptives during and 3 months after the end of therapy; (2) lactation; and (3) using any other treatment for cutaneous leishmaniasis. Initially 46 patients were enrolled to receive Lip-AmB 0.4% based on the inclusion/exclusion criteria. Ten patients were excluded for the following reasons: (1) 2 patients’ lesions were not confirmed parasitologically using direct smear, culture and PCR; (2) lesions in 6 patients were caused by L. tropica; and (3) 2 patients developed sporotrichoid lesions. Thirty-six patients completed the study. Drug administration Lip-AmB 0.4% was produced under good manufacturing practice conditions at Razaak Arak Pharmaceutical Company (Tehran, Islamic Republic of Iran). The production was supported by DNDi (Geneva, Switzerland). Glucantime (meglumine antimonate) was produced by Sanofi Aventis (France). Fourteen patients with a total of 84 lesions received national standard treatment of weekly intralesional meglumine antimonate (7 IL injections) plus biweekly cryotherapy (3 or 4 sessions), or daily intramuscular meglumine antimonate (20 mg/ kg) per day for 14 days plus topical Lip-AmB 0.4% twice daily for 28 days. Twenty-two patients with a total of 46 lesions (7 each at most) were treated with topical Lip-AmB 0.4% alone twice daily for 28 days. Thirty patients aged 14–60 years with a total of 68 lesions received national standard treatment of weekly intralesional meglumine antimonate (7 IL injections) plus biweekly cryotherapy (3 or 4 sessions). Study procedures At baseline before treatment initiation and at each of the weekly visits up to day 28 of follow-up, patients were given a written instruction to rub each of their lesions with Lip-AmB 0.4%, twice daily in the morning and at night. During each weekly visit, the Lip-AmB 0.4% tubes were replaced with new ones and the old ones were collected and kept till the end of the study. Book 28-09.indb 659 09/10/2022 11:07 AM 660 Research article EMHJ – Vol. 28 No. 9 – 2022 Measurement of lesions At baseline, each patient was interviewed for demographic and health backgrounds. The number, location and type of each lesion were recorded and the lesions were measured in 2 dimensions using a digital calliper. The details were entered into a computer and after double entry, the data were cleaned and analysed by the data management team. The lesion specifications were recorded during each visit and a standardized digital photograph was taken. Results Treatment safety Safety evaluation in 36 patients, aged 19–60 years (20 female and 16 male) showed no adverse events such as itching, burning, inflammation, or pain at the lesion site. In 2 other patients with lesions > 15 cm, topical treatment with Lip-AmB 0.4% induced a burning sensation that was tolerable and the patients preferred to continue treatment. Treatment efficacy Fourteen patients, aged 24–51 years (8 female and 6 male) with 84 lesions received national standard treatment (weekly intralesional meglumine antimonate and biweekly cryotherapy, or daily intramuscular meglumine antimonate plus topical Lip-AmB 0.4% twice daily for 4 weeks). Follow-up was conducted on 12 of the patients, and on day 42 after treatment initiation, 11 showed complete cure (91.7% efficacy). In 1 of the patients with 4 lesions, 1 lesion showed complete cure and 3 showed partial cure at 42 days after initiation of treatment. Twenty-two patients, aged 28–51 years (13 female and 9 male) with 46 lesions (7 lesions each at most) were treated with topical Lip-AmB 0.4% alone twice daily for 4 weeks. One patient did not take the treatment and 2 were not available for follow-up visits. Thus, 19 patients completed the study according to the protocol. On day 42 after treatment initiation, 18 patients with 36 lesions showed complete cure (94.7% efficacy). Among the 30 patients who received standard treatment alone, 15 (50% efficacy) showed complete cure on day 42 after treatment initiation. On day 42, in the patients who received standard treatment plus Lip-AmB 0.4%, 70 of 77 lesions showed complete cure (90.9% efficacy). In the patients who received Lip-AmB 0.4% alone, 36 of 39 lesions showed complete cure (92.3% efficacy). In the patients who received standard treatment alone, 33 of 68 lesions showed complete cure (48.5% efficacy). Discussion The current study was completed during the period that antimoniate derivatives (Glucantime/Pentostam) were not easily available in the Islamic Republic of Iran, partly due to the economic sanctions. Generous support from DNDi enabled formulation and production of Lip-AmB under good manufacturing practice conditions, and the topical formulation was tested first in animal models and then its safety was checked in healthy volunteers (15–17). The results of current study showed an acceptable efficacy and tolerable safety profile for Lip-AmB 0.4% alone and in combination with meglumine antimonate for treatment of cutaneous leishmaniasis lesions caused by L. major. Cutaneous leishmaniasis is a major public health threat in some endemic areas, with 600 000 to 1 million new cases worldwide annually (1, 2). Various treatments have been used for cutaneous leishmaniasis. Antimoniate derivatives, the costly WHO-recommended treatment for cutaneous leishmaniasis, require multiple long- term injections, are accompanied by adverse effects and are not always effective, making treatment of cutaneous leishmaniasis a challenge in developing and developed regions (5,6,19,23). Accordingly, alternative treatments, especially topical formulations, are desired by patients, physicians and governments. Different topical formulations, mainly paromomycin formulations, have shown promising results in preclinical and clinical studies and are marketed (21–24). Amphotericin B is an antifungal agent and second- line treatment for cutaneous leishmaniasis, visceral leishmaniasis and mucocutaneous leishmaniasis, but is associated with severe toxicity (25). Although Lip-AmB (Ambisome) has limited toxicity and has improved the efficacy of amphotericin B for treatment of visceral leishmaniasis, its application in treatment of cutaneous leishmaniasis is limited due to variable efficacy in different geographical areas, high cost and limited access (26–28). Conventional topical formulations of amphotericin did not show acceptable efficacy, mainly due to the high molecular weight and amphipathic nature of amphotericin, which limits skin penetration (29, 30). The epidermis is the outer layer of the skin and the main barrier to cutaneous absorption of drugs (31, 32). An ideal topical drug delivery system for the treatment of cutaneous leishmaniasis should have enough penetration to reach the dermis, where Leishmania parasites reside (33). The advantages of nanocarriers for cutaneous drug delivery are under investigation (34). The advantages of using liposomes as nanodelivery systems include greater skin penetration, controlled drug release, drug deposition and targeting in skin layers, lower systemic absorption, and limited adverse effects in transdermal delivery (35). Previously, the same group have developed several topical liposomal drugs, including amphotericin B. The characteristics of these topical liposomal formulations, including stability, diffusion and efficacy have been investigated in vitro and in vivo. Different concentrations of topical Lip-AmB (0.1, 0.2 and 0.4%) were checked in vitro and in vivo against a few Leishmania species in comparison with Fungizone (micellar formulation) in vitro [15]. Accordingly, it seems that Lip-AmB 0.4% is a promising formulation for treatment of cutaneous leishmaniasis. Lip-AmB 0.4%, with a size ~100 nm, has Book 28-09.indb 660 09/10/2022 11:07 AM 661 Research article EMHJ – Vol. 28 No. 9 – 2022 received a US patent and is produced according to good manufacturing practice guidelines. An irritancy potential test (Draize test) revealed that Lip-AmB 0.4% is safe in animal models (16). In a double-blind, randomized, phase 1 clinical trial, the safety of Lip-AmB 0.4% and its vehicle was evaluated in 27 healthy human volunteers. The healthy volunteers applied Lip-AmB 0.4% and its vehicle twice a day for 1 week or 3 times a day for 2 weeks. In 7 of the volunteers, no skin reactions (including pruritus, burning, skin redness, oedema and scaling) were seen and no significant differences in biophysical characteristics of the skin were observed between Lip-AmB 0.4% and its vehicle. Local skin reactions were observed in some of the remaining 20 volunteers that resulted in withdrawal of 2 of the volunteers (17). Conclusion Lip-AmB 0.4% alone or combination with national standard treatment showed acceptable efficacy and safety for treatment of cutaneous leishmaniasis lesions caused by L. major and warrants further investigation in phase 3 clinical trials. Finding: None. Competing interests: None declared. يدللجا تاينماشيللا ءاد جلاعل B ينسيرتوفملأا لاموسوبيلل يعضولما مادختسلاا ةيلعافو ةملاسل ةيدايترا ةسارد ناريإ في ةيربكلا ةينماشيللا نع مجانلا زويرف اضر ليع ،یوضترم ينسح ،يراشفأ هنازرف ،یداوج يرمأ ،يحيبست ونيم ،يردنكسإ ديس ،يرفعج دوممح ،يدممح مرکا ،روپ یسماخ ليع ةصلالخا ةدعاو ةملاس جئاتن )Lip-AmB 0.4 %( % 0.4 زيکترب B ينسيرتوفملأا لىع يوتيح يذلا لاموسوبيل ونانل يعضولما مادختسلاا رهظأ :ةيفللخا .ءاحصلأا ينعوطتلما لىع لىولأا ةلحرلماو ةيريسرلا لبق ةلحرلما في ةيريسرلا براجتلا في )Lip-AmB 0.4 %( % 0.4 زيکترب B ينسيرتوفملأا لىع يوتيح يذلا لاموسوبيل ونان ةيلعافو ةملاس مييقت لىا ةساردلا هذه تفده :فادهلأا .يدللجا تاينماشيللا ءاد ضىرم عم همادختسا دنع Étude pilote sur l'innocuité et l'efficacité de l'amphotéricine B liposomale topique pour le traitement de la leishmaniose cutanée causée par Leishmania major en République islamique d'Iran Résumé Contexte : Les nanoliposomes topiques contenant 0,4 % d'amphotéricine B ont montré des résultats prometteurs en termes d'innocuité lors d'essais précliniques et cliniques de phase 1 chez des volontaires en bonne santé. Objectifs : Évaluer l'innocuité et l'efficacité de l'amphotéricine B à 0,4 % chez les patients atteints de leishmaniose cutanée. Méthodes : Quatorze patients présentant un total de 84 lésions se sont vu administrer le traitement standard national constitué d'injections intralésionnelles d'antimoniate de méglumine hebdomadaire avec cryothérapie bihebdomadaire, ou d'antimoniate de méglumine intramusculaire de manière quotidienne (20 mg/kg/jour pendant 14 jours), et d'amphotéricine B topique à 0,4 % deux fois par jour pendant 28 jours. Vingt-deux patients présentant un total de 46 lésions (sept au maximum) ont été traités seulement par amphotéricine B topique à 0,4 % deux fois par jour pendant 28 jours. Trente patients présentant au total 68 lésions ont reçu le traitement standard national d'antimoniate de méglumine intralésionnel chaque semaine (pour blanchir le pourtour de la lésion) et de cryothérapie bihebdomadaire. Résultats : Soixante-six patients présentant des lésions de leishmaniose cutanée ont terminé l'étude. Dans l'évaluation de l'innocuité, deux des 36 patients évalués ont signalé une sensation de brûlure tolérable et ont préféré poursuivre le traitement. Douze (92 %) des 14 patients présentant 84 lésions qui ont reçu le traitement standard national associé à l'amphotéricine B à 0,4 % ont terminé l'étude avec une guérison complète. Chez l'un des patients présentant quatre lésions, on a observé une guérison complète pour une lésion et une guérison partielle pour trois lésions. Parmi les 22 patients présentant 46 lésions qui ont reçu uniquement de l'amphotéricine B topique à 0,4 %, 19 ont terminé l'étude et 18 ont montré une guérison complète (efficacité à 95 %). Chez les 30 patients ayant reçu le traitement standard national seul, 33 lésions chez 15 patients ont présenté une guérison complète (48,5 %) au 42ème jour de suivi. Conclusion : L'amphotéricine B à 0,4 % seule ou en association avec le traitement standard national est sans risque et présente un taux d'efficacité élevé. Elle mérite donc d'être étudiée de manière plus approfondie lors des essais cliniques de phase 3. Book 28-09.indb 661 09/10/2022 11:07 AM 662 Research article EMHJ – Vol. 28 No. 9 – 2022 References 1. The Global Health Observatory. Explore a world of health data. Leishmaniasis [website]. Geneva: World Health Organization (https://www.who.int/data/gho/data/themes/topics/topic-details/GHO/leishmaniasis#:~:text=The%20disease%20mainly%20 affects%20poor,endemic%20for%20leishmaniasis%20in%202019, accessed 18 June 2022). 2. Reithinger R, Dujardin J-C, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis. 2007 Sep;7(9):581–96. https://doi.org/10.1016/S1473-3099(07)70209-8 3. Gonzalez U, Pinart M, Reveiz L, Alvar J. Interventions for Old World cutaneous leishmaniasis. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD005067. https://doi.org/10.1002/14651858.CD005067.pub3 PMID:18843677 4. Khatami A, Emmelin M, Talaee R, Miramin-Mohammadi A, Aghazadeh N, Firooz A, et al. Lived experiences of patients suffering from acute Old World cutaneous Leishmaniasis: a qualitative content analysis study from Iran. J Arthropod Borne Dis. 2018 Jun 13;12(2):180–95. PMID:30123812 5. Kashani MN, Firooz A, Eskandari SE, Ghoorchi MH, Khamesipour A, Khatami A, et al. Evaluation of meglumine antimoniate effects on liver, kidney and pancreas function tests in patients with cutaneous leishmaniasis. Eur J Dermat. 2007. Nov–Dec 2007;17(6):513–5. https://doi.org/10.1684/ejd.2007.0266 PMID:17951131 6. Khatami A, Firooz A, Gorouhi F, Dowlati Y. Treatment of acute Old World cutaneous leishmaniasis: a systematic review of the randomized controlled trials. J Am Acad Dermatol. 2007 Aug;57(2):335.e1–29. https://doi.org/10.1016/j.jaad.2007.01.016 PMID:17337090 7. Nassiri-Kashani M, Firooz A, Khamesipour A, Mojtahed F, Nilforoushzadeh M, Hejazi H, et al. A randomized, double-blind, placebo-controlled clinical trial of itraconazole in the treatment of cutaneous leishmaniasis. J Eur Acad Dermatol Venereol. 2005 Jan;19(1):80–3. https://doi.org/10.1111/j.1468-3083.2004.01133.x PMID:15649196 8. Jaafari MR, Bavarsad N, Bazzaz BSF, Samiei A, Soroush D, Ghorbani S, et al. Effect of topical liposomes containing paromo- mycin sulfate in the course of Leishmania major infection in susceptible BALB/c mice. Antimicrob Agents Chemother. 2009 Jun;53(6):2259–65. https://doi.org/10.1128/AAC.01319-08 PMID:19223613 9. Shazad B, Abbaszadeh B, Khamesipour A. Comparison of topical paromomycin sulfate (twice/day) with intralesional meglu- mine antimoniate for the treatment of cutaneous leishmaniasis caused by L. major. Eur J Dermatol. Mar–Apr 2005;15(2):85–7. PMID:15757817 10. Firooz A, Khamesipour A, Ghoorchi MH, Nassiri-Kashani M, Eskandari SE, Khatami A, et al. Imiquimod in combination with meglumine antimoniate for cutaneous leishmaniasis: a randomized assessor-blind controlled trial. Arch Dermatol. 2006 Dec;142(12):1575–9. https://doi.org/10.1001/archderm.142.12.1575 PMID:17178983 11. Laniado-Laborín R, Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Rev Iberoam Micol. 2009 Dec 31;26(4):223–7. https://doi.org/10.1016/j.riam.2009.06.003 PMID:19836985 12. Wortmann G, Zapor M, Ressner R, Fraser S, Hartzell J, Pierson J, et al. Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis. Am J Trop Med Hyg. 2010 Nov;83(5):1028–33. https://doi.org/10.4269/ajtmh.2010.10-0171 PMID:21036832 13. Zylberberg C, Matosevic S. Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulato- ry landscape. Drug Deliv. 2016;23(9):3319–29. https://doi.org/10.1080/10717544.2016.1177136 ةفلآا في تاينوميتنأ ينمولجيم ءاطعإ في لثمتي يذلا ،يرايعلما ينطولا َجلاعلا ًةفآ 84 نم ًلااجمإ نوناعي اًضيرم شرع ةعبرأ ىقلت :ثحبلا قرط ،)اًموي 14 ةدلم ا ًّيموي/مجک /مجلم 20( لضعلا في تاينوميتنأ ينمولجيمب نقلحاب ا ًّيموي اًجلاع وأ ،ا ًّيعوبسأ ينترم ديبرتلاب جلاعلا عم ا ًّيعوبسأ اًضيرم نوشرعو نانثا ىقلتو .اًموي 28 ةدلم ا ًّيموي ينترم %0.4 زيکترب B ينسيرتوفملأا لىع يوتيح يذلا لاموسوبيل ونان مادختساب يعضوم جلاعو يعضولما )Lip-AmB 0.4 %( %0.4 زيکترب B ينسيرتوفملأا لىع يوتيح يذلا لاموسوبيل ونان ءاود )رثکلأا لىع 7( ةفآ 46 نم ًلااجمإ نوناعي لخاد تاينوميتنأ ينمولجيمب جلاعلا وهو ،يرايعلما ينطولا َجلاعلا ًةفآ 68 نم ًلااجمإ نوناعي اًضيرم نوثلاث ىقلتو .اًموي 28 ةدلم ا ًّيموي ينترم هدحو .اًّيعوبسأ ينترم ديبرتلاب جلاعلاو )ةفلآا لوح دللجا ضييبتل( ا ًّيعوبسأ ةفلآا اوعضخ اًضيرم 36 ينب نم ناضيرم غلبأ ،ةملاسلا مييقت فيو .يدللجا تاينماشيللا ءادب اًباصم اًضيرم نوتسو ةتس ةساردلا في ةکراشلما متأ :جئاتنلا ،اًح ُّرقت 84 نم نوناعي اًضيرم 14 ينب نم ،اًضيرم )%92( شرع انثا َةساردلا متأو .جلاعلا ةلصاوم لا َّضفو ،اهلمتح نكمي ةقرحب روعش نع مييقتلل .اًماتم ءافشلا مله ققتح دقو ،%0.4 زيکترب B ينسيرتوفملأا لىع يوتيح يذلا لاموسوبيل ونان لىإ ةفاضلإاب ،سيايقلا ينطولا جلاعلا لىع اولصحو نوناعي اًضيرم 22 ينب نمو .تافآ ثلاث نم يئزلجا ءافشلاو ةدحاو ةفآ نم ماتلا ءافشلا هل ققتح ،تافآ 4 نم نوناعي اوناک نيذلا ،ضىرلما دحأو مهنم 18 يفُشو ،ةساردلا اًضيرم 19 لمکأ ،ا ًّيعضوم %0.4 زيکترب B ينسيرتوفملأا لىع يوتيح يذلا لاموسوبيل ونان طقف اوقلتو ةفآ 46 نم ا ًّمات ءافش مهنم اًضيرم 15 ىدل ةفآ 33 تيفُش دقف ،30 مهددعو طقف سيايقلا ينطولا جلاعلا اوقلت نيذلا ضىرلما امأ .)%95 غلبت ةيلعافب( اًماتم .42 مويلا في ةعباتلما دنع )%48.5( سيايقلا جلاعلا عم وأ ،ةدحو )Lip-AmB 0.4 %( %0.4 زيکترب B ينسيرتوفملأا لىع يوتيح يذلا لاموسوبيل ونان مادختسا :تاجاتنتسلاا .ةثلاثلا ةلحرلما نم ةيريسر براتج في هيلع ءاصقتسلاا نم ديزم ءارجإ قحتسيو ،ةيلاع ةيلعافب زيمتيو نِمآ ينطولا Book 28-09.indb 662 09/10/2022 11:07 AM 663 Research article EMHJ – Vol. 28 No. 9 – 2022 14. Prajapati BG, Patel NK, Panchal MM, Patel RP. Topical liposomes in drug delivery: a review. IJPRT. 2012 Jan–Jun;4(1):39–44. https://doi.org/10.1016/0169-409X(90)90021-J 15. Jaafari MR, Hatamipour M, Alavizadeh SH, Abbasi A, Saberi Z, Rafati S, et al. Development of a topical liposomal formulation of Amphotericin B for the treatment of cutaneous leishmaniasis. Int J Parasitol Drugs Drug Resist. 2019 Dec;11:156–65. https://doi. org/10.1016/j.ijpddr.2019.09.004 PMID:31582344 16. Eskandari SE, Firooz A, Nassiri-Kashani M, Jaafari MR, Javadi A, Miramin-Mohammadi A, et al. Safety evaluation of nano-liposo- mal formulation of amphotericin B (sina ampholeish) in animal model as a candidate for treatment of cutaneous leishmaniasis. J Arthropod Borne Dis. 2018 Sep 30;12(3):269–75. PMID:30584550 17. Eskandari SE, Firooz A, Nassiri-Kashani M, Jaafari MR, Javadi A, Mohammadi AM, et al. Safety evaluation of topical application of nano-liposomal form of amphotericin B (SinaAmpholeish) on healthy volunteers: phase I clinical trial. Iran J Parasitol. 2019 Apr–Jun;14(2):197–203. PMID:31543907 18. Layegh P, Rajabi O, Jafari MR, Malekshah PET, Moghiman T, Ashraf H, et al. Efficacy of topical liposomal amphotericin B versus intralesional meglumine antimoniate (Glucantime) in the treatment of cutaneous leishmaniasis. J Parasitol Res. 2011;2011:656523. https://doi.org/10.1155/2011/656523 PMID:22174993 19. Oliveira LF, Schubach AO, Martins MM, Passos SL, Oliveira RV, Marzochi MC, et al. Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World. Acta Trop. 2011 May;118(2):87–96. https://doi.org/10.1016/j.actatropi- ca.2011.02.007 PMID:21420925 20. Masmoudi A, Maalej N, Mseddi M, Souissi A, Turki H, Boudaya S, et al. [Glucantime injection: benefit versus toxicity] (in French). 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El-On J, Jacobs GP, Witztum E, Greenblatt CL. Development of topical treatment for cutaneous leishmaniasis caused by Leish- mania major in experimental animals. Antimicrob Agents Chemother. 1984 Nov;26(5):745–51. https://doi.org/10.1128/AAC.26.5.745 PMID:6517557 29. Perez AP, Altube MJ, Schilrreff P, Apezteguia G, Celes FS, Zacchino S, et al. Topical amphotericin B in ultradeformable liposomes: formulation, skin penetration study, antifungal and antileishmanial activity in vitro. Colloids Surf B Biointerfaces. 2016 Mar 1;139:190–8. https://doi.org/10.1016/j.colsurfb.2015.12.003 PMID:26709977 30. Moser K, Kriwet K, Naik A, Kalia YN, Guy RH. Passive skin penetration enhancement and its quantification in vitro. Eur J Pharm Biopharm. 2001 Sep;52(2):103–12. https://doi.org/10.1016/s0939-6411(01)00166-7 PMID:11522474 31. Proksch E, Brandner JM, Jensen J. The skin: an indispensable barrier. 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Book 28-09.indb 663 09/10/2022 11:07 AM 664 Research article EMHJ – Vol. 28 No. 9 – 2022 Could self-reported symptoms be predictors of RT-PCR positivity in suspected COVID-19 cases? The Libya experience Amira El Ghiadi,1 Omnia Eddali,1 Sana Ashur2 and Laila Sabei2 1Primary Health Care Institution, Ministry of Health, Tripoli, Libya; 2Department of Family and Community Medicine, Faculty of Medicine, University of Tripoli, Tripoli, Libya (Correspondence to: Sana Ashur: drsana04@yahoo.com). Introduction COVID-19 emerged at the end of 2019 in China, and by 7 January 2020, a novel type of coronavirus was identified (1,2). The disease then spread to other countries, and was declared a Global Health Emergency of International Concern on 30 January 2020 (2), and declared a pandemic on 11 March 2020 (3). The first case in Tripoli, Libya, where this study was conducted, was confirmed on 25 March 2020 (4). The pandemic has had adverse impacts on health (5,6), education and the economy (7,8), and constituted a major challenge to health care systems (9). Early and accurate diagnosis of COVID-19 is important for disease management and control. The most accurate diagnostic test for the disease is the real-time reverse transcriptase-polymerase chain reaction (RT-PCR), which is based on the detection of the genetic material of the virus (10). However, the high global demand, and the shipment issues affected supplies to many countries. The shortage of RT-PCR resources is prominent in some developing countries, such as Libya, and has affected the early detection of COVID-19 cases. Besides RT-PCR, there are other tests with variable accuracy and complexity including antigen and antibody detection tests. Antigen rapid diagnostic tests are quick but less accurate than RT- PCR (11). They are more accurate in the first week of the development of symptoms (12), particularly in cases with high viral load (13). Antibody detection tests have limited value in the first week of the infection because of their low sensitivity (10,14). Researchers have evaluated the usefulness of symptoms in the identification of COVID-19 cases (15–21). Generally, the use of presenting symptoms in the prediction of a disease has been examined before, especially in respiratory diseases (22,23) or in diseases that have the same symptoms with respiratory diseases (24). In the context of epidemic infectious diseases, some studies have investigated the accuracy of symptoms for the diagnosis of severe acute respiratory syndrome (SARS) (25), and Ebola (26). COVID-19 has the same symptoms with several respiratory infections like the common cold and influenza, and may present with nonrespiratory symptoms. This makes differentiation a challenging task, and can lead to unnecessary use of RT-PCR resources. Symptoms could be of value in guiding the decision about who is likely to have a positive RT-PCR, especially in settings where resources are limited, as in Libya, besides reducing the demand for RT-PCR. Abstract Background: COVID-19 has symptoms similar to several other respiratory and non-respiratory diseases, which makes differentiating them a challenging task and could lead to unnecessary use of realtime reverse transcriptase polymerase chain reaction (RT-PCR) resources. Aims: The study aimed to assess self-reported symptoms as predictors for RT-PCR positivity in suspected COVID-19 cases. Methods: This was a cross-sectional study. We retrospectively reviewed the database of COVID-19 care centres in the eastern district of Tripoli, Libya, from May to December 2020. Presenting symptoms and RT-PCR test data were extracted. Results: Of the 4593 subjects, 923 (20.1%) had positive RT-PCR result. Sensitivity for COVID-19 disease diagnosis was very low (≤ 18.2%) for all symptoms, except for myalgia (82.1%). Specificity was high for all symptoms (90.7–99.8%), except for myalgia (11.0%). Loss of taste and smell had the highest positive likelihood ratio (LR) for RT-PCR positivity (LR+ = 3.59, 95% CI: 2.95–4.37). In the multiple logistic regression, three symptoms maintained significant contribution to RT-PCR positivity; these were loss of taste and smell (odds ratio (OR) = 3.90, 95% CI: 3.04–4.99), sore throat (OR = 1.50, 95% CI: 1.02–2.19), and myalgia (OR = 0.65, 95% CI: 0.49–0.85). Other significant predictors were history of contact with a COVID-19 case (OR = 0.50, 95% CI: 0.39–0.62), and being female (OR = 1.33, 95% CI: 1.15–1.55). Conclusion: The findings of this study do not support the use of self-reported symptoms for the confirmation of COVID-19 disease in suspected cases because of their poor diagnostic properties. Keywords: COVID-19, self-reported symptoms, predictors, sensitivity, specificity, respiratory disease, PCR Citation: El Ghiadi A; Eddali O; Ashur S; Sabei L. Could self-reported symptoms be predictors of RT-PCR positivity in suspected COVID-19 cases? The Libya experience. East Mediterr Health J. 2022;28(9):664–672. https://doi.org/10.26719/emhj.22.061 Received: 17/09/21; accepted: 05/06/22 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo) Book 28-09.indb 664 09/10/2022 11:07 AM 665 Research article EMHJ – Vol. 28 No. 9 – 2022 Evidence from previous research on the accuracy of symptoms in distinguishing COVID-19 cases is inconsistent (27). Several studies were undertaken in hospitals (16,17) rather than in primary care settings, or among specific groups like health care workers (15,20,21) rather than in general public cohorts. Therefore, there is a need for further evaluation of the usefulness of symptoms for the diagnosis of COVID-19 (27). In this study we examined self-reported symptoms as predictors of RT-PCR positivity in suspected COVID-19 cases. Methods Study design and settings A cross-sectional study was conducted using the database of COVID-19 rapid response team at the COVID-19 care centres in the eastern district of Tripoli, Libya. The database was retrospectively reviewed from 1 May 2020 to 31 December 2020. The total number of recorded attendees with complete data was 4708. Of this total, 115 subjects were excluded based on the eligibility criteria of this study. Study variables The outcome variable, RT-PCR test status, was defined as a binary variable (positive, negative). It was based on the examination of nasopharyngeal swab specimens using RT-PCR. In addition to the presenting symptoms, data on age, sex, nationality and contact history were extracted. Both the sociodemographic data and the symptoms were self-reported. Eligibility criteria Based on literature relevant to children’s survey methods (28–30), only the data for cases aged 8 years and older were included. Subjects with inconclusive RT-PCR results, which were coded as “repeat” in the database, were excluded. Ethical considerations Permission was obtained from the National Center of Disease Control (NCDC), Tripoli, Libya. Confidentiality was maintained as the data were anonymously coded. Statistical analysis We used SPSS, version 26, for statistical analysis. Frequency, percentage, mean and standard deviation were used to summarize the characteristics of the participants. The bivariate association between study variables and RT-PCR test status were assessed using the chi-squared test, Fisher’s exact test and the independent t-test. Sensitivity, specificity, positive and negative predictive values and likelihood ratios were estimated to evaluate the diagnostic properties of each symptom. Variables that showed significant (P < 0.05), or nearly significant (P < 0.25) crude association with the RT-PCR test status in the bivariate analysis were considered in a multiple logistic regression analysis for the predictors of positive PCR test. Results Sociodemographic characteristics and distribution of symptoms Data for 4593 subjects with suspected COVID-19 were considered in the analysis (Table 1). Mean age was 38.2 (standard deviation 16.7) years, and males represented 54.7% of the sample. Overall, 94.9% were symptomatic and most presented with more than one symptom. The most frequently reported symptom was myalgia (88.0%); this was followed by fatigue, fever, cough and loss of taste and smell, but these were reported less frequently (Figure 1). A total of 16.2% reported other symptoms less frequently: headache (4.9%), dyspnoea (4.0%), sore throat (3.4%), runny nose (3.1%) and vomiting and diarrhoea (0.8%). Unadjusted association between symptoms and RT-PCR positivity Around 20.1% of the respondents suspected of having COVID-19 were confirmed positive with the RT-PCR (Table 2). A significantly greater proportion of females than males showed positivity (P < 0.001). Positivity was greater among subjects who had no history of contact with a COVID-19 patient than among those who reported a history of contact and in those who reported having no myalgia than in those who reported having myalgia (P < 0.001 for both). The symptoms that showed statistically significant associations with RT-PCR status were loss of taste and smell, headache, sore throat, fever, fatigue, Table 1 Demographic characteristics of study subjects (n = 4593), Tripoli, Libya, 2020 Characteristic f % Age group (years) Children (8–18) 491 10.7 Young adults (8–18) 2189 47.7 Adults (41–65) 1617 35.2 Elderly (≥ 66) 296 6.4 Sex Female 2081 45.3 Male 2512 54.7 Nationality Libyan 4584 99.8 Non-Libyan 9 2.0 Contact history Yes 4159 90.6 No 434 9.4 Presentation Symptomatic 4360 94.9 Asymptomatic 233 5.1 Book 28-09.indb 665 09/10/2022 11:07 AM 666 Research article EMHJ – Vol. 28 No. 9 – 2022 myalgia and cough (P < 0.001 for all except cough P = 0.002). Validation of individual symptoms Table 3 shows the diagnostic properties of each symptom. Sensitivity was very low for all symptoms (≤ 18.2%) except for myalgia (82.1%). However, specificity was high for all symptoms (90.7%–99.8%) except for myalgia (10.5%). All symptoms had a low positive predictive value (PPV) (≤ 47.4%), and the PPV of some symptoms like abdominal pain had wide 95% confidence interval (CI) indicating uncertainty. Loss of taste and smell had the highest positive likelihood ratio for RT-PCR positivity and thus for COVID-19 diagnosis (3.59, 95%CI: 2.95–4.37). All symptoms had negative likelihood ratio of 1 or close to 1. Multivariate logistic regression analysis for RT-PCR positivity predictors In the multivariate logistic regression analysis for the predictors of positive PCR test, 3 symptoms maintained significant contribution to PCR positivity in the controlled analysis (Table 4). These were loss of taste and smell, sore throat and myalgia. Other significant factors were sex and history of contact with a COVID-19 case. Subjects who lost taste and smell were almost 4 times more likely to have a positive PCR than those who had not lost those senses [odds ratio (OR) = 3.90, 95% CI:3.04– 4.99]. Subjects who reported having sore throat had 1.5 times greater odds of having a positive PCR than those who did not (OR = 1.50, 95% CI:1.02–2.19). Females were slightly more likely to have a positive test than males (OR = 1.33, 95% CI: 1.15–1.55). Myalgia and history of contact with a COVID-19 case were negative predictors. Subjects who complained of myalgia had lower odds of having a positive test result than those who did not present with it (OR = 0.65, 95% CI: 0.49–0.85). Subjects who reported a history of contact had lower odds of RT-PCR positivity than those who had no contact history (OR = 0.50, 95% CI: 0.39–0.62). This logistic regression model had very poor properties. Based on Nagelkerke’s R2, it explains only 7.2% of the variation in having the PCR test positive. The overall accuracy is 79.9%, but it displayed a very low sensitivity (6.0%). The logistic regression model had a high specificity (98.4%), a low positive predictive value (PPV) (49.5%) and a moderate negative predictive value (NPV) (80.6%). Z = –0.700 + 1.362 × Loss of taste and smell (Yes) + 0.694 × Contact history (No) + 0.290 × gender (Female) – 0.424 × Myalgia (Yes) + 0.406 × Sore throat (Yes) Probability (positive PCR) = 1/1 + ez = 1/1+e Z –0.700 + 1.362 × Loss of taste and smell (Yes) + 0.694 × Contact history (No) + 0.290 × gender (Female) – 0.424 × Myalgia (Yes) + 0.406 × Sore throat (Yes) Discussion A substantial proportion of the suspected cases were symptomatic, but the majority had presented with myalgia more often than with any other symptoms. Fatigue, fever, cough and loss of taste and smell were much less commonly presented. This symptom pattern differs in terms of frequency of symptoms and order of commonness from that reported in some other settings (18,20,21). Initially, in the unadjusted analysis, 7 symptoms showed statistically significant association with RT- PCR status. Loss of taste and smell had the highest crude odds of RT-PCR positivity, with a 4-fold increase in the likelihood of the test being positive. As in our study, loss of taste showed the highest unadjusted odds of RT-PCR positivity among all studied symptoms in several other studies (20,21). We found that fever, cough and fatigue were associated with increased crude odds of test positivity, and this is consistent with other research (20). Sore throat was associated with an almost 2 times increase in the likelihood of having the infection. However, previous research findings on sore throat have been mixed; while some studies reported lower odds of having the disease in those who had a sore throat (20), others reported no difference unless the sore throat was combined with nasal symptoms (15), or even higher odds Figure 1 Distribution of symptoms among the study participants, Tripoli, Libya, 2020 0 20 40 60 80 100 Ot he rs No sy mp tom s Lo ss of tas te & s me ll Co ug h Fe ve r Fa tig ue M us cle pa in Book 28-09.indb 666 09/10/2022 11:07 AM 667 Research article EMHJ – Vol. 28 No. 9 – 2022 Table 2 Distribution of real-time polymerase chain reaction status and bivariate associations using data from the database of the COVID-19 pandemic rapid response team (n = 4593), Tripoli, Libya, 2020 Attribute RT-PCR status Crude OR 95% CI P +ve -ve No. % No. % All 923 20.1 3670 79.9 Sex Female 472 22.7 1609 77.3 1.34 1.16–1.54 < 0.001 Male 451 18.0 2061 82.0 ‒ Nationality Libyan 920 20.1 3664 79.9 0.50 0.12–2.01 0.397b Non-Libyan 3 33.3 6 66.7 ‒ Contact history Yes 794 19.1 3365 80.0 0.55 0.44–0.69 < 0.001 No 129 29.7 305 70.3 – Presentation Asymptomatic 60 25.8 173 74.2 1.40 1.03–1.90 0.029 Symptomatic 863 19.8 3497 80.2 ‒ Myalgia Yes 758 18.8 3282 81.2 0.54 0.44–0.66 < 0.001 No 165 29.8 388 70.2 ‒ Fatigue Yes 135 28.4 340 71.6 1.67 1.35–2.07 < 0.001 No 788 19.1 3330 80.9 ‒ Fever Yes 126 28.1 323 71.9 1.63 1.31–2.04 < 0.001 No 797 19.2 3347 80.8 ‒ Cough Yes 98 26.3 275 73.7 1.46 1.15–1.87 0.002 No 825 19.5 3395 80.5 ‒ Loss of taste & smell Yes 168 47.5 186 52.5 4.16 3.33–5.20 < 0.001 No 755 17.8 3484 82.2 ‒ Runny nose Yes 33 23.2 109 76.8 1.21 0.81–1.80 0.395 No 890 20.0 3561 80.0 ‒ Sore throat Yes 48 31.2 106 68.8 1.84 1.30–2.61 0.001 No 875 19.7 3564 80.3 ‒ Dyspnoea Yes 45 24.2 141 75.8 1.28 0.91–1.80 0.161 No 878 19.9 3529 80.1 ‒ Headache Yes 47 32.6 153 67.4 2.00 1.50–2.67 < 0.001 No 849 19.4 3517 80.6 ‒ Vomiting Yes 4 28.6 10 71.4 1.59 0.49–5.09 0.500 No 919 20.1 3660 79.9 ‒ Diarrhoea Yes 8 34.8 15 65.2 2.13 0.90–5.04 0.111b No 915 20.0 3955 80.0 ‒ Abdominal pain Yes 2 25.0 6 75.0 1.32 0.26–6.58 0.666b No 921 20.1 3664 79.9 Mean SD Mean SD Age (years) 38.6 16.9 38.2 16.7 ‒ 0.504a aIndependent t-test. bFisher’s exact test. OR = odds ratio. CI = confidence interval. Book 28-09.indb 667 09/10/2022 11:07 AM 668 Research article EMHJ – Vol. 28 No. 9 – 2022 of PCR positivity in those who did not have sore throat (21). In our study, myalgia was associated with lower crude odds of test positivity, which is not consistent with the findings in some other studies (20,21). With the exception of myalgia, all symptoms had very low sensitivity, but high specificity for detecting PCR positivity, and thus, for COVID-19 infection diagnosis. The high specificity of the symptom indicates that it correctly identifies subjects who do not have COVID-19 infection. That means those who do not have that symptom, generally do not have the infection. However, the very low sensitivity implies that sole reliance on any symptom for the diagnosis of COVID-19 would be associated with a high false- negative rate. In other words, many of the suspected subjects who actually have COVID-19 infection would not be identified. Consistent with our findings, a review of similar studies concluded that individual COVID-19 symptoms have very low sensitivity and moderate to high specificity (27). However, one study reported a relatively better sensitivity and a lower specificity for certain symptoms like loss of taste, sore throat and fever (19). Subjects who had lost taste and smell were almost 4 times more likely to test positive than those who had not lost those senses. Several studies have reported loss of taste as one of the strongest predictors of PCR positivity (15,17–21). Sore throat showed a 1.5 times increase in the odds of having a positive RT-PCR, and this was in contrast to some studies (19,21). Interestingly, myalgia maintained its contribution as a negative predictor in the controlled analysis, suspected cases who reported myalgia had lower odds of having a positive test result than those who did not report it. Myalgia is a subjective symptom, especially if measured via self-reporting, and this may partially explain this finding. The study did not control for comorbidity and a proportion of the reported myalgia may have been related to morbidities other than COVID-19. In contrast to our finding, some studies reported myalgia among the predictors of positive RT- PCR (15,19,21). As the respondents in those studies were either health care workers (15,21), or included a health care workers group (19), reporting of myalgia may have been more accurate than in our study. History of contact with a COVID-19 case contributed significantly to the PCR test result as a protective factor, those who reported contact were less likely to be positive. In contrast to our findings, and in line with the theoretical expectations, a Hong Kong study found that contact history increased the likelihood of PCR positivity 10-fold (16). The reported protective contribution in our study may have been driven by some factors that were not controlled. Considering the Health Belief Model (31,32), we suggest that being aware of a positive contact nearby may increase the self- susceptibility perception and adherence to COVID-19 preventive behaviours. This could be one reason for the reported protective contribution. Another possible Ta bl e 3 D ia gn os ti c p er fo rm an ce o f s el f- re po rt ed in di vi du al sy m pt om s o f C O V ID -1 9, T ri po li, L ib ya , 2 02 0 Sy m pt om Se ns it iv it y Sp ec ifi ci ty PP V N PV Li ke lih oo d ra ti o % 95 %C I % 95 %C I % 95 %C I % 95 %C I LR + 95 %C I LR – 95 %C I M ya lg ia a 82 .1 79 .5 –8 4. 5 10 .5 9. 6– 11 .6 18 .7 18 .2 –1 9. 2 70 .1 66 .5 –7 3. 5 0. 92 0. 89 –0 .9 5 1.6 9 1.4 3– 20 0 Fa tig ue a 14 .6 12 .4 –1 7. 0 90 .7 89 .7 –9 1.6 28 .4 24 .8 –3 2. 3 80 .8 80 .4 –8 1.3 1.5 8 1.3 1– 1.9 0 0. 94 0. 91 –0 .9 7 Fe ve ra 13 .6 11 .5 –1 6. 0 91 .2 90 .2 –9 2. 1 28 .0 24 .3 –3 2. 1 80 .7 80 .3 –8 1.1 1.5 5 1.2 8– 1.8 8 0. 95 0. 92 –0 .9 7 Co ug ha 10 .6 8. 7– 12 .7 92 .5 91 .6 –9 3. 3 26 .2 22 .2 –3 0. 7 80 .4 80 .0 –8 0. 8 1.4 2 1.1 4– 1.7 6 0. 97 0. 94 –0 .9 9 Lo ss o f t as te & sm el la 18 .2 15 .7 –2 0. 8 94 .9 94 .1– 95 .6 47 .4 42 .6 –5 2. 3 82 .1 81 .7 –8 2. 6 3. 59 2. 95 –4 .3 7 0. 86 0. 84 –0 .8 9 Ru nn y no se 3. 5 2. 4– 4. 9 97 .0 96 .4 –9 7. 5 23 .2 17 .1– 30 .7 80 .0 79 .7 –8 0. 2 1.2 0. 82 –1 .7 7 0. 99 0. 98 –1 .0 1 So re th ro at a 5. 2 3. 8– 6. 8 97 .1 96 .5 –9 7. 6 31 .1 24 .5 –3 8. 7 80 .2 80 .0 –8 0. 5 1.8 0 1.2 9– 2. 51 0. 98 0. 96 –0 .9 9 D ys pn oe a 4. 8 3. 5– 6. 4 96 .1 95 .4 –9 6. 7 24 .1 18 .7 –3 0. 7 80 .0 79 .8 –8 0. 3 1.2 7 0. 91 –1 .7 6 0. 99 0. 97 –1 .0 1 H ea da ch ea 8. 0 6. 3– 9. 9 95 .8 95 .1– 96 .4 32 .6 27 .0 –3 8. 7 80 .5 80 .2 –8 0. 8 1.9 2 1.4 7– 2. 51 0. 96 0. 94 –0 .9 8 V om iti ng 0. 4 0. 1– 1.1 99 .7 99 .5 –9 9. 8 28 .5 11 .1– 56 .0 79 .9 79 .8 –8 0. 0 1.5 9 0. 50 –5 .0 6 1.0 0 0. 99 –1 .0 0 D ia rr ho ea 0. 8 0. 3– 1.7 99 .5 99 .3 –9 9. 7 34 .7 18 .4 –5 5. 6 79 .9 79 .8 –8 0. 0 2. 12 0. 90 –4 .9 9 1.0 0 0. 99 –1 .0 0 Ab do m in al p ai n 0. 2 0. 0– 0. 7 99 .8 99 .6 –9 9. 9 25 .0 6. 3– 62 .2 79 .9 79 .8 –7 9. 9 1.3 3 0. 27 –6 .5 6 1.0 0 1.0 0– 1.0 0 a S ym pt om th at h ad d isp la ye d sig ni fic an t u na dj us te d as so cia tio n w ith P CR te st st at us . PP V = po sit iv e p re di ct iv e v al ue . N PV = n eg at iv e p re di ct iv e v al ue . CI = co nfi de nc e i nt er va l. Book 28-09.indb 668 09/10/2022 11:07 AM 669 Research article EMHJ – Vol. 28 No. 9 – 2022 explanation is that the “no contact history” group may have included a proportion of subjects with “unknown positive contacts”. A proportion of those with “contact history” may have falsely tested negative as they presented early when they realized they had contacted a positive case, and thus were counted within the negative group. This multiple regression model has a very low sensitivity, but a high specificity for diagnosis of COVID-19 infection. Although this regression model may be good at excluding those who do not have COVID-19 infection because of the high specificity, many of the subjects who have the infection will be missed if it is used. As in our study, some research has questioned the use of such models for the diagnosis of COVID-19 infection for their low sensitivity (23). Several limitations should be considered in the interpretation of our findings. Most of these limitations are related to the nature of retrospective data collection. The subjective nature of self-reporting of symptoms, especially general nonrespiratory ones like myalgia and fatigue, may have affected measurement accuracy. Another weakness of the study is that it did not control for co-morbidity due to the considerable amount of missing data on this variable in the database. Our study did not account for the time between the appearance of symptoms and performing the RT-PCR tests because this information was not available in the database. Thus, cases who had the RT-PCR test when they had just observed the symptoms may have been falsely included in the negative group due to the relatively higher false negativity of the test in the early stages of COVID-19. However, the study does have its strengths. While several previous studies were undertaken in hospitals, or among specific groups like health care workers, which limits their external validity, this study used data from a relatively large cohort of the general public presenting in COVID-19 care centres, which is deemed to enhance the generalizability of its results. Conclusions Our findings agree with previous research on the importance of loss of taste and smell as a predictor of RT-PCR positivity. However, we do not support relying on symptoms alone for COVID-19 disease diagnosis in practice because of their overall poor diagnostic properties. Further research is recommended to assess the use of symptoms as predictors of RT-PCR positivity and to address our study limitations. In particular, we recommend considering a fixed time from the appearance of symptoms to taking the RT-PCR test for all subjects, which was not feasible in our study due to the limited availability of data and its retrospective nature. The current study was conducted when the original strain of SARS-COV-2 was dominant in Libya. Thus, further research is needed because the symptom pattern and the order in which symptoms appear vary between the original SARS-CoV-2 virus strain and other variants. Table 4 Multiple logistic regression model of positive polymerase chain reaction predictors, Tripoli, Libya, 2020 Attribute B Wald P Adj OR (95% CI) Female vs male 0.290 14.548 < 0.001 1.33 (1.15–1.55) Contact vs no contact –0.694 35.607 < 0.001 0.50 (0.39–0.62) Fever vs no fever 0.230 2.979 0.084 1.25 (0.96–1.63) Cough vs no cough –0.073 0.230 0.631 0.93 (0.69–1.25) Dyspnoea vs no dyspnoea –0.043 0.044 0.833 0.95 (0.64–1.42) Sore throat vs no sore throat 0.406 4.445 0.035 1.50 (1.02–2.19) Fatigue vs no fatigue 0.009 0.004 0.950 1.00 (0.77–1.32) Loss of taste and smell vs no loss 1.362 116.699 < 0.001 3.90 (3.04–4.99) Myalgia vs no myalgia –0.424 9.327 0.002 0.65 (0.49–0.85) Headache vs no headache –0.187 0.802 0.371 0.83 (0.55–1.24) Diarrhoea vs no diarrhoea –0.038 0.006 0.937 0.96 (0.37–2.48) Constant –0.700 19.140 < 0.001 Adj OR = adjusted odds ratio. CI = confidence interval. Acknowledgement We would like to thank the rapid response team in the COVID-19care centres in the study district and the National Center of Diseases Control in Libya for supporting this study. Funding: None Competing interests: None declared. Book 28-09.indb 669 09/10/2022 11:07 AM 076 2202 – 9 .oN 82 .loV – JHME elcitra hcraeseR الأعراض التي يبلغ عنها المريض بنفسه: هل يمكن أن ُتستخدم للتنبؤ بالنتيجة الإيجابية لتحليل التنسخ العكسي لتفاعل البوليميراز المتسلسل في حالات كوفيد-91 المشتبه فيها؟ التجربة الليبية أميرة القيادي، أمنية الدالي، سناء عاشور، ليلى سبعي الخلاصة الخلفية: لمرض فيروس كورونا-9102 (كوفيد-91) أعراٌض تتشابه مع العديد من الأمراض الأخرى التنفسية وغير التنفسية، وهو ما يمثل تحدًيا في التمييز بينه وبين تلك الأمراض، وقد يؤدي ذلك إلى استنفاد الموارد المخصصة لاختبارات التنسخ العكسي لتفاعل البوليميراز المتسلسل الآني بدون ضرورة. الأهداف: هدفت هذه الدراسة الى تقييَم الأعراض التي ُيبِلغ عنها المريض بنفسه، من حيث إمكانية استخدامها للتنبؤ بالنتيجة الإيجابية لتحليل التنسخ العكسي لتفاعل البوليميراز المتسلسل في حالات كوفيد-91 المشتبه فيها. طرق البحث: كانت هذه الدراسة مقطعية ، وقد استعرضنا فيها بأثر رجعي قاعدة بيانات مراكز الرعاية المخصصة لمرضى كوفيد-91 في المنطقة الشرقية في طرابلس بليبيا، في الفترة من مايو/ أيار إلى ديسمبر/ كانون الأول 0202 . واستخلص الباحثون الأعراض وبيانات اختبارات التنسخ العكسي لتفاعل البوليميراز المتسلسل. النتائج: مِن بين مَن شملت الدراسة بياناتهم، الذين بلغ عددهم 3954 شخصًا، كانت نتيجة اختبار "تفاعل البوليميراز التنسخي العكسي المتسلسل" إيجابية لدى 329 شخًصا (1.02%). وكانت حساسية جميع الأعراض لتشخيص مرض كوفيد-91 منخفضة جدًّ ا (2.81% أو أقل)، ما عدا الألم العضلي (1.28%). وكانت الدقة النوعية عالية لجميع الأعراض (7.09 - 8.99%)، ما عدا الألم العضلي (0.11%). وكان لفقدان التذوق والشم أعلى نسبة ترجيح إيجابي لإيجابية اختبار "تفاعل البوليميراز التنسخي العكسي المتسلسل" (نسبة الترجيح الإيجابي = 95.3، عند فترة الثقة 59%: 59.2–73.4). وفي الانحدار اللوجستي المتعدد، حافظت ثلاثة أعراض على مساهمة مهمة في إيجابية اختبار "تفاعل البوليميراز التنسخي العكسي المتسلسل" . وهذه الأعراض هي فقدان التذوق والشم (نسبة الأرجحية = 09.3، عند فترة الثقة 59%: 40.3-99.4)، والتهاب الحلق (نسبة الأرجحية = 05.1، عند فترة الثقة 59%: 20.1–91.2)، والألم العضلي (نسبة الأرجحية = 56.0، عند فترة الثقة 59%: 94.0–58.0). ومن العوامل المهمة الأخرى التي يمكن استخدامها للتنبؤ بالنتيجة الإيجابية مخالطة حالة مصابة بمرض كوفيد-91 (نسبة الأرجحية = 05.0، عند فترة الثقة 59%: 93.0–26.0)، وكون المريضة أنثى (نسبة الأرجحية = 33.1، عند فترة الثقة 59%: 51.1–55.1). الاستنتاجات: نتائج هذه الدراسة لا تؤيد استخدام الأعراض التي يبلغ عنها المريض لتأكيد الإصابة بمرض كوفيد-91 بين الحالات المشتبه فيها، وذلك بسبب ضعف ارتباطها بالتشخيص. enu'd sfitcidérp sruetcaf sed reutitsnoc sli-tneiarruop séralcéd-otua semôtpmys seL ed ecneirépxe'L ? 91-DIVOC ed stcepsus sac sel zehc RCP-TR tset ua étivitisop eybiL al émuséR te seriotaripser seidalam sertua srueisulp ed xuec à serialimis semôtpmys sed etnesérp 91-DIVOC aL : etxetnoC ed secruosser xua elituni sruocer nu renîartne tiarruop te eliciffid noitaicneréffid ruel dner iuq ec ,seriotaripser non .)RCP-TR( leér spmet ne esarémylop rap enîahc ne noitacifilpma'l tset ua étivitisop al ed sfitcidérp sruetcaf euq tnat ne séralcéd-otua semôtpmys sel reulavé à tiasiv eduté'L : sfitcejbO .91-DIVOC ed stcepsus sac sel zehc RCP-TR sed seénnod ed esab al tnemevitcepsortér énimaxe snova suoN .elasrevsnart eduté enu'd tiassiga's lI : sedohtéM iuq semôtpmys seL .0202 erbmecéd à iam ed ,eybiL ne ilopirT ed latneiro tcirtsid el snad 91-DIVOC snios ed sertnec .stiartxe été tno RCP-TR tset ud seénnod sel te sétnesérp tnos es étilibisnes aL .RCP-TR al à fitisop tatlusér nu tneiatnesérp 3954 rus )% 1,02( stejus siort-tgniv tnec fueN : statluséR .)% 1,28( eiglaym al ed noitpecxe'l à ,semôtpmys sel suot ruop )% 2,81 ≤( elbiaf sèrt tiaté 91-DIVOC al ed citsongaid ud ed te tûog ud etrep aL .)% 0,11( eiglaym al ruop fuas ,)% 8,99-7,09( semôtpmys sel suot ruop eévelé tiaté éticificéps aL ,95,3 = +VR( RCP-TR al à étivitisop al ruop évelé sulp el fitisop )VR( ecnalbmesiarv ed troppar el tiatnesérp tarodo'l noitubirtnoc enu unetniam tno semôtpmys siort ,elpitlum euqitsigol noissergér al À .)73,4-59,2 : % 59 à CI : % 59 à CI ,09,3 = RO( tarodo'l ed te tûog ud etrep al ed tiassiga's li ; RCP-TR al ed étivitisop al à evitacifingis seL .)58,0-94,0 : % 59 à CI ,56,0 = RO( eiglaym al ed te ,)91,2-20,1 : % 59 à CI ,05,1 = RO( egrog ed xuam sed ,)99,4-40,3 : % 59 à CI ,05,0 = RO( 91-DIVOC ed sac nu ceva stnedécérp stcatnoc sel tneiaté sfitacifingis sfitcidérp sruetcaf sertua .)55,1-51,1 : % 59 à CI ,33,1 = RO( niniméf exes ua ecnanetrappa'l te ,)26,0-93,0 séralcéd-otua semôtpmys sed noitasilitu'l sap tnenneituos en eduté etnesérp al ed statlusér seL : noisulcnoC sétéirporp sesiavuam sruel ed nosiar ne ,stcepsus sac sel zehc 91-DIVOC ed ecnesérp al ed noitamrifnoc al ruop .seuqitsongaid MA 70:11 2202/01/90 076 bdni.90-82 kooB 671 Research article EMHJ – Vol. 28 No. 9 – 2022 References 1. 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Int Forum Allergy Rhinol. 2020;10(7):832–8. doi:10.1002/alr.22602. PMID:32363809. 20. Tostmann A, Bradley J, Bousema T, Yiek WK, Holwerda M, Bleeker-Rovers C, et al. Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands, March 2020. Euro Surveill. 2020;25(16):2000508. doi:10.2807/1560-7917.ES.2020.25.16.2000508. PMID:32347200. 21. Van Loon N, Verbrugghe M, Cartuyvels R, Ramaekers D. Diagnosis of COVID-19 based on symptomatic analysis of hospital healthcare workers in Belgium: observational study in a large Belgian tertiary care center during early COVID-19 outbreak. J Occup Environ Med. 2021;63(1):27–31. doi:10.1097/JOM.0000000000002015. PMID:32858554. 22. Monto AS, Gravenstein S, Elliott M, Colopy M, Schweinle J. Clinical signs and symptoms predicting influenza infection. Arch Intern Med. 2000;160(21):3243–7. doi:10.1001/archinte.160.21.3243. PMID:11088084. Book 28-09.indb 671 09/10/2022 11:07 AM 672 Research article EMHJ – Vol. 28 No. 9 – 2022 23. Vuichard-Gysin D, Mertz D, Pullenayegum E, Singh P, Smieja M, Loeb M. Development and validation of clinical prediction models to distinguish influenza from other viruses causing acute respiratory infections in children and adults. PLoS One. 2019;14(2):e0212050. doi:10.1371/journal.pone.0212050. PMID:30742654. 24. Hackert, VH, Dukers-Muijrers NHTM, Hoebe CJPA. Signs and symptoms do not predict, but may help rule acute Q fever in fa- vour of other respiratory tract infections, and reduce antibiotics overuse in primary care. BMC Infect Dis. 2020;20(1):690. https:// doi.org/10.1186/s12879-020-05400-0 25. Wong WN, Sek AC, Lau RF, Li KM, Leung JK, Tse ML, et al. Early clinical predictors of severe acute respiratory syndrome in the emergency department. CJEM. 2004;6(1):12–21. doi:10.1017/s148180350000885x. PMID:17433140. 26. Loubet P, Palich R, Kojan R, Peyrouset O, Danel C, Nicholas S, et al. Development of a prediction model for Ebola virus disease: a retrospective study in Nzérékoré Ebola Treatment Center, Guinea. Am J Trop Med Hyg. 2016;95(6):1362–7. doi:10.4269/ajt- mh.16-0026. Epub 2016 Oct 10. PMID:27928085. 27. Struyf T, Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Leeflang MM, et al. Signs and symptoms to determine if a patient pre- senting in primary care or hospital outpatient settings has COVID-19 disease. Cochrane Database Syst Rev. 2020;7(7):CD013665. doi:10.1002/14651858.CD013665. Update in: Cochrane Database Syst Rev. 2021 Feb 23;2:CD013665. PMID:32633856. 28. Von Baeyer CL. Children’s self-report of pain intensity: what we know, where we are headed. Pain Res Manag. 2009;14(1):39–45. doi:10.1155/2009/259759. PMID:19262915. 29. Borgers N, de Leeuw E, Hox J. Children as respondents in survey research: cognitive development and response quality 1. Bulle- tin of Sociological Methodology/Bulletin de Méthodologie Sociologique. 2000;66(1):60–75. doi:10.1177/075910630006600106 30. Borgers N, Sikkel D, Hox J. Response effects in surveys on children and adolescents; the effect of number of response options, negative wording, and neutral mid-point. Quality Quantity. 2004;38:17–33. https://doi.org/10.1023/B:QUQU.0000013236.29205.a6 31. Diefenbach MA, Leventhal, H. The common-sense model of illness representation: theoretical and practical considerations. J Soc Distress Homeless. 1996;5(1):11–38. doi:10.1007/BF02090456 32. Rosenstock IM. Historical origins of the Health Belief Model. Health Educ Monographs 1974;2(4):328–35. doi:10.1177/109019817400200403 Book 28-09.indb 672 09/10/2022 11:07 AM 673 Research article EMHJ – Vol. 28 No. 9 – 2022 Evaluation and comparison of vitamin A supplementation with standard therapies in the treatment of patients with COVID-19 Mohamad Rohani,1 Hasan Mozaffar,2 Mehdi Mesri,3 Mehdi Shokri,4 Daniel Delaney5 and Mahmood Karimy6 1Clinical Research Development Center of Amiralmomenin Hospital, Arak University of Medical Sciences, Arak, Islamic Republic of Iran. 2Department of Infectious Diseases; 6Social Determinants of Health Research Center, Saveh University of Medical Sciences, Saveh, Islamic Republic of Iran 3Department of Forensic Medicine, Clinical Toxicology Fellowship, Baqiyatallah University of Medical Sciences, Tehran, Islamic Republic of Iran. 4Student Research Committee, Arak University of Medical Sciences, Arak, Islamic Republic of Iran. 5Clinical Psychology Department, University of Rhode Island, New England, United States of America. Saveh University of Medical Sciences, Saveh, Islamic Republic of Iran (Correspondence to: Mahmood Karimy: karimymahmood@yahoo.com). Introduction In December 2019, an epidemic emerged in Wuhan, China, and drew the attention of the world (1). The virus rapidly spread to other countries and soon became a pandemic (2). On 30 January 2020, the World Health Organization declared the disease a public health emergency of international concern that threatened not only China, but also all countries (3,4). The evolutionary analyses based on genes indicated that the virus belongs to the family of beta-coronaviruses (5). Beta-coronaviruses cause a wide range of viral diseases, including more severe illnesses such as the Middle East respiratory syndrome coronavirus (MERS- CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) (6,7). In the novel coronavirus (nCoV-2019) COVID-19, the incubation period lasts about 7 days when the antibodies are not yet developed. The asymptomatic period is from the time of infection until the fifth day; and the period of onset of clinical symptoms is from the fifth to the eighth day (8,9). The most common clinical symptoms of infection are fever (87.9%), cough (67.6%), fatigue (38.1%), diarrhoea (3.7%), and vomiting (5%), and therefore COVID-19 is similar to other coronaviruses. Vitamin and mineral dietary supplements are typically safe and can be used to supply or supplement nutrients essential for bodily processes, especially immune system functioning. For instance, vitamin A reduces the risk of viral infections and has beneficial effects on the lungs and immune system function. It is an anti-inflammatory substance (10) and plays a considerable role in immunity against infectious diseases (11); its deficiency causes numerous injuries that disrupt the response to infection (12). Recent clinical trials have indicated that vitamin A reduces complications and mortality in various infectious diseases such as measles, diarrhoea, measles- related pneumonia, and human immunodeficiency virus infection (11). Its deficiency is associated with higher susceptibility, severity and duration of infection (13). Abstract Background: Incomplete data are often presented for determining the role of vitamin A supplement therapy for improv- ing treatment outcomes in patients with COVID-19. Aims: We compared treatment effects between a group that received vitamin A added to the standard COVID-19 treat- ment and another group that received the standard drug treatment alone. Methods: Participants in this triple-blind controlled trial comprised 182 COVID-19 outpatients in Saveh City, Markazi Province, Islamic Republic of Iran, in 2020. Patients were randomly divided into experimental (n = 91) and control (n = 91) groups. Patients in the control group received the national standard treatment for COVID-19 (hydroxychloroquine), and those in the intervention group received 25 000 IU/d oral vitamin A for 10 days in addition to the standard treatment rec- ommended by the national protocol. We evaluated the clinical symptoms, paraclinical criteria, and hospitalization status before and after 10 days of interventions. Results: The treatment groups did not differ significantly in clinical and paraclinical symptoms before the interven- tion. However, clinical symptoms such as fever, body ache, weakness and fatigue, paraclinical symptoms, white blood cell count, and C-reactive protein showed significantly greater decreases in the experimental group 10 days post-intervention compared with the standard treatment alone (P < 0.05). Conclusion: Vitamin A supplementation demonstrated efficacy in improving some clinical and paraclinical symptoms in patients with COVID-19. Future studies should evaluate vitamin A supplementation with a larger sample size and com- pare different dosages, especially in hospitalized patients. Keywords: COVID-19, vitamin A, treatment, hydroxychloroquine Citation: Rohani M; Mozaffar H; Mesri M; Shokri M; Delaney D; Karimy M. Evaluation and comparison of the effect of vitamin A supplementation with standard therapies in the treatment of patients with COVID-19. East Mediterr Health J. 2022;28(9):673–681. https://doi.org/10.26719/emhj.22.064 Received: 25/02/21; accepted: 29/05/22 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Book 28-09.indb 673 09/10/2022 11:07 AM 674 Research article EMHJ – Vol. 28 No. 9 – 2022 Vitamin A is necessary for consistent immunity and plays a role in the growth of T cells, T helper cells (Th cells), and B cells. In particular, vitamin A deficiency decreases the antibody-mediated responses by Th2 cells. Its deficiency disrupts innate immunity by preventing the regeneration of mucosal epithelium damaged by infection and by reducing the function of neutrophils, macrophages and natural killer cells (12,14). Given that there is no specific treatment for COVID-19 and to our knowledge no studies have evaluated the effects of vitamin A supplementation in the treatment of COVID-19, this study aimed to assess the efficacy of standard treatment plus vitamin A supplementation compared with standard treatment alone on COVID-19 symptoms, hospitalization status and paraclinical criteria. Methods Study design and participants In this triple-blind clinical trial, the sample comprised patients of Saveh Health Centre, in Islamic Republic of Iran and all of them had COVID-19. The sample size was estimated to be 64, with confidence level 0.95, power 0.80, and the probable mean difference (Cohen’s d) of the dependent variable before and after the intervention [i.e. predicted change in probability, mean score for creatinine (Cr) 0.5] using the formula proposed by Lehr (16/d2) (15). Given the possibility of sample attrition, 91 individuals were included in the study for each group (n = 182) (Figure 1). The inclusion criteria were: receiving outpatient care for COVID-19 from the health centre in Saveh, age 18–75 years, agreeing to participate in the study and completing the informed written consent forms. The exclusion criteria included: having any autoimmune diseases (lupus, multiple sclerosis, etc.), having chronic infectious disease, having concomitant or previous viral infections, being a current consumer of vitamin A supplement, pregnant and breastfeeding women, having renal failure, underlying liver disease, having heart failure and having chronic pulmonary disease. We recruited patients who visited the COVID-19 outpatient centre of Saveh, which is the only medical centre in the city, from 1 May to 1 September 2020 and had positive PCR results for COVID-19. After patients were screened for inclusion/exclusion criteria and completed informed consent, they were then randomly assigned to the 2 treatment groups using the random allocation table. Randomization and blinding The method of blinding was as follows: the main researcher packed the drugs in 2 packages A and B and placed them in the pharmacy with the pharmacist. Package A included national standard treatment for Figure 1 CONSORT flow diagram of participants (n = 182) Allocated to intervention group A (n = 91) Received allocated intervention (n = 91) Did not receive allocated intervention (give reasons) (n = 0) Excluded (n = 0) Not meeting inclusion criteria (n = 0) Refused to participate (n = 0) Other reasons (n = 0) Allocated to intervention group B (n = 91) Received allocated intervention (n = 91) Did not receive allocated intervention (give reasons) (n = 0) Lost to follow-up (give reasons) (n = 0) Discontinued intervention (give reasons) (n = 0) Analysed (n = 91) Excluded from analysis (give reasons) (n = 0) Lost to follow-up (give reasons) (n = 2) Discontinued intervention (give reasons) (n = 0) Analysed (n = 89) Excluded from analysis (give reasons) (n = 2) Assessed for eligibility (n=182) Randomized (n = 182) Allocation Follow-up Analysis Book 28-09.indb 674 09/10/2022 11:07 AM 675 Research article EMHJ – Vol. 28 No. 9 – 2022 outpatients (hydroxychloroquine) in addition to vitamin A (Zahravi Pharmaceutical Company), and package B included the national standard treatment of COVID-19 for outpatients (hydroxychloroquine) in addition to placebo. The placebo was made to look and feel like the original vitamin A, but the active ingredient was an ineffective substance (glycerin). Patients diagnosed with COVID-19 were referred to a pharmacy by the physician; and the pharmacist assigned the patients to one of the groups A or B based on the random numbers table. The pharmacist was a research assistant who did not take part in the enrolment of participants. Using permuted block randomization with a block size of 2 and an allocation ratio of 1:1, patients were allocated to the intervention and control groups. A random sequence of “intervention” and “control” was generated using a random numbers table. After installing the tables in the clinic, the intervention or control was designated as the first experimental group for the first eligible person by the sampler. It is clear that based on the random sequence method, the next word can be used. Therefore, the patients, laboratory technicians, therapists involved in prescribing, sample recipient and questionnaire responders were blind to the treatment group. The main researcher was not blind to the groups. Participants were not allowed to use any other medication during the 10 days of the study. Patients were trained to follow the prescribed treatment. They were followed up by telephone on the third and sixth days to check their health and general condition and adherence to the recommended treatment regimens, and on the eleventh day they were visited in person. Supplement administration Ninety-one patients in the control group received only the standard national treatment, and 91 patients in the intervention group received 25 000 IU/d vitamin A for 10 days in addition to the standard treatment recommended in the national protocol. Outcome measurements We examined the dependent variables before and after the treatment intervention in both groups. The clinical improvements (in combination) up to 10 days after treatment were measured using a self-report questionnaire and patient examination. Clinical improvement was defined as normal body temperature (≤ 37.2° oral), improved cough (lack of cough that was sustained for at least 24 hours and based on the patient report on a physical scale), chills, shortness of breath, headache, body ache, hyposmia, fatigue, anorexia and diarrhoea. A therapist examined the symptoms at baseline and 10 days after the treatment. The cellular count and biochemical parameters of patients were tested by trained constant operators in the reference laboratory of Saveh University of Medical Sciences (17) according to international guideline. Paraclinical improvement was defined as changes in C-reactive protein (CRP) and lymphocytes before and after the treatment, and normal ranges of: white blood cells (WBCs), erythrocyte sedimentation rate (ESR), creatine phosphokinase (CPK), Cr test, liver function tests [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)]. A turbidimetric method was used to determine CRP; CPK quantified by an ultra violet kinetic method using a special kit; WBC was measured with flow cytometry counters using a haematology analyser (ADVIA 2120) for AST and ALT via a photometric method and autoanalyser. We did not evaluate alkaline phosphatase and did not perform the liver and bile duct ultrasonography because no jaundice occurred in any of the patients. The paraclinical variables were evaluated at the beginning and on the tenth day of study. The proportion of patients who were hospitalized due to COVID-19 was examined and compared between the 2 groups. Statistical methods The data collected from the patients were given to the statistical evaluator in codes because the statistical evaluator was blinded to the treatment groups. Statistical analysis was conducted using SPSS, version 20.0. All measurement data were reported as mean and standard deviation. Treatment groups were statistically compared using independent sample t-tests. The intra- group comparisons were performed using paired t-tests. Enumeration data were reported as case numbers and percentages and these outcomes were compared using chi-squared. Alpha level was set at P < 0.05. Ethics Written informed consent was obtained from all the patients in the study. All participants were given an information sheet together with the consent form and advised that they could revoke their consent at any time without giving any reasons. The study protocol was approved by the ethics committee of Saveh University of Medical Sciences (IRSAVEHUMSREC1399.003) and registered on the Iran Clinical Trial database (IRCTID: IRCT 46974). The required permission was obtained from the hospital authorities. Results Two out of 91 patients in the experimental group did not complete the post-intervention evaluation 10 days after treatment, therefore the final analysis was performed on 91 patients in the control group and 89 in the experimental group. Mean age was 39.4 (SD 15.6) years in the experimental group and 40.8 (SD 17.3) years in the control group. Fifty-three individuals (59.5%) in the experimental group and 51 (56%) in the control group were male. Most of the patients (n = 122, 67.8%) were married, and 56 (31%) had a high school diploma. A total of 15 patients (8.3%) were drug addicts, and 81 (45%) reported moderate economic status. Forty-eight patients (26.6%) had underlying diseases, and 49 (27%) had family members with COVID-19. The chi-square test did not show any significant difference between the experimental and control groups in terms of demographic variables (P > 0.05) (Table 1). Book 28-09.indb 675 09/10/2022 11:07 AM 676 Research article EMHJ – Vol. 28 No. 9 – 2022 Evaluation of the patients’ clinical symptoms indicated that there was no significant difference between the groups in terms of fever, chills, cough, shortness of breath, headache, body ache, decreased sense of smell, weakness, and fatigue, anorexia and diarrhoea before the therapeutic intervention. However, the proportion of those reporting fever, body ache, and weakness and fatigue was significantly lower in the group that received the vitamin A supplement plus hydroxychloroquine 10 days after the intervention (P < 0.05) (Table 2). There was no statistically significant difference between the experimental and control groups in terms of paraclinical criteria - WBC, CRP, AST, ESR, CPK and Cr - before the therapeutic intervention, but there was a significantly greater reduction of CRP and WBCs in the group receiving the vitamin A supplement in comparison with the control group after the therapeutic intervention (P < 0.05) (Table 3). The results of the paired t-tests indicate that all paraclinical criteria significantly changed in the experimental group after the treatment intervention (P < 0.05) except for lymphocyte counts and Cr values: 33% of patients (31 in the experimental group and 29 in the control group) had lymphocyte counts below 1500 before the intervention, but the rate decreased to 17% (14 in the experimental group and 17 in the control group) after the intervention. There was no significant difference between the 2 groups before and after the treatment intervention for lymphocyte count. Eight patients in the experimental group (9%) and 11 in the control group (12%) were hospitalized, but there was no statistically significant difference in hospitalization rates between the 2 groups (P > 0.05). Discussion In this study, we aimed to determine whether vitamin A supplementation along with standard treatment was more efficacious in reducing COVID-19 symptoms and improving outcomes than standard treatment alone in patients presenting to an outpatient health centre. We Table 1 Comparison of quantitative variables in the intervention and control groups of patients, Saveh, Islamic Republic of Iran, 2020 Characteristic Intervention Control P-valuea No. % No. % Sex Male 53 59.5 51 56.0 0.50 Female 36 41.5 40 44.0 Employment Housewife 18 20.2 19 20.8 0.70 Government employee 20 22.5 17 18.6 Industrial worker 28 31.5 36 39.5 Retired 7 7.8 8 8.8 Other 16 18.0 11 12.0 Marital status Single 26 29.2 19 20.8 0.42 Married 59 66.3 67 73.6 Widow 4 4.5 5 5.5 Education Illiterate 12 13.5 17 18.6 0.82 Elementary 14 15.7 15 16.5 Middle school 16 18.0 19 20.8 High school diploma 31 34.8 26 28.6 Higher education 16 18.0 14 15.4 Socioeconomic status High 6 6.7 12 13.2 0.27 Moderate 45 50.5 47 51.6 Low 38 42.6 32 35.2 Smoking 14 15.7 20 22.0 0.38 Addiction 7 27.9 8 8.8 0.80 Underlying disease 23 26.9 25 27.5 0.88 COVID-19 infection among other family members 25 28.1 24 26.4 0.83 aChi-squared Book 28-09.indb 676 09/10/2022 11:07 AM 677 Research article EMHJ – Vol. 28 No. 9 – 2022 Table 2 Distribution of clinical characteristics in the clinical and control groups at baseline and 10-day follow-up, Saveh, Islamic Republic of Iran, 2020 Symptom Time Intervention group (n = 89) Control group (n = 91) P-valuea Yes No Yes No No. (%) No. (%) No. (%) No. (%) Fever Baseline 34 (38.2) 55 (61.8) 41 (45.1) 50 (54.9) 0.35 10-day follow-up 2 (2.3) 87 (97.7) 10 (11.0) 81 (89.0) 0.03 Chill Baseline 28 (31.5) 61 (68.5) 37 (40.7) 54 (59.3) 0.19 10-day follow-up 3 (3.4) 86 (96.6) 6 (6.6) 85 (93.4) 0.32 Cough Baseline 42 (47.2) 47 (52.8) 50 (54.9) 41 (45.1) 0.29 10-day follow-up 7 (8.0) 82 (92.0) 12 (13.2) 79 (86.8) 0.24 Shortness of breath Baseline 31 (35.0) 58 (65.0) 29 (32.0) 62 (68.0) 0.66 10-day follow-up 4 (4.5) 85 (95.5) 6 (6.6) 85 (93.4) 0.53 Headache Baseline 28 (31.5) 61 (68.5) 35 (39.5) 56 (61.5) 0.36 10-day follow-up 3 (3.4) 86 (96.6) 6 (6.6) 85 (93.4) 0.32 Body ache Baseline 46 (51.7) 43 (48.3) 49 (53.8) 42 (46.2) 0.77 10-day follow-up 1 (1.2) 88 (98.8) 8 (9.8) 83 (91.2) 0.01 Smell Baseline 71 (79.7) 18 (20.3) 68 (74.7) 23 (25.3) 0.41 10-day follow-up 76 (85.3) 13 (14.7) 83 (91.2) 8 (8.8) 0.22 Weakness & fatigue Baseline 49 (55.0) 40 (45.0) 60 (65.9) 31 (34.1) 0.13 10-day follow-up 4 (4.5) 85 (95.5) 11 (12.1) 80 (87.9) 0.05 Anorexia Baseline 35 (39.4) 54 (60.6) 44 (48.4) 47 (51.6) 0.22 10-day follow-up 3 (3.4) 86 (96.6) 8 (8.8) 83 (91.2) 0.12 Chest pain Baseline 32 (36.0) 57 (64.0) 32 (35.2) 59 (64.8) 0.91 10-day follow-up 7 (8.0) 82 (92.0) 9 (10.0) 82 (90.0) 0.63 Diarrhoea Baseline 15 (17.0) 74 (83.0) 18 (20.0) 73 (80.0) 0.61 10-day follow-up 2 (2.3) 87 (97.7) 5 (5.5) 86 (94.5) 0.26 aChi-square found that some clinical symptoms (fever, body ache and fatigue) were significantly more improved 10 days after treatment in the group that received the vitamin A supplement in comparison with the control group. The results for other clinical symptoms also indicated improvements over time for chills, cough, shortness of breath, hyposmia, anorexia, and diarrhoea in the vitamin A group, but these findings were not statistically significant compared with the control group. This was consistent with a study by Kahbazi et al., who found that vitamin A could reduce fever in patients with acute pyelonephritis (10). In a study on neonates, Shenai et al. found that taking vitamin A was effective in reducing the infection in breathing pathways (16). Aluisio et al. found that vitamin A supplement led to a reduction in mortality in patients with Ebola virus disease (17). In a study on very-low-birth-weight infants, vitamin A reduced the symptoms of patients with diarrhoea, fever, lethargy, acute respiratory infections, rubella and ear infections (18). In a similar study among schoolchildren, a vitamin A supplement reduced mortality rates and complications of infectious diseases of the gastrointestinal and respiratory tracts (19). Previous research has suggested that vitamin A plays an important role in maintaining the health of the mucous membranes and skin covering the nose, sinuses and mouth; immune system function; T and B lymphocytes; macrophages; and the production of antibodies (20,21). It helps in adjusting the secretion of IL-10: IL-10 is produced by T helper 2 (TH2) cells and inhibits the synthesis of the pre-inflammatory cytokines, including IFN-γ and IL- 2, in both natural killer- and T-cells. This mechanism is important in limiting inflammatory responses to certain pathogens (22). In our study, the CRP rate further decreased in the vitamin A supplement group; CRP is known as an attractive biomarker of inflammation because its concentration increases rapidly within a few hours of infection, and even before any clinical symptoms develop (23). Shaker et al. conducted a study evaluating the effectiveness of zinc and vitamin A supplement in treating and reducing upper respiratory tract infections in children (23). Consistent with our findings, they found a significant reduction in CRP in patients. This was expected because vitamin A inhibited CRP production (24). This biomarker is widely used in clinical diagnoses Book 28-09.indb 677 09/10/2022 11:07 AM 678 Research article EMHJ – Vol. 28 No. 9 – 2022 as a non-specific acute phase indicator of inflammation. It responds to infection through its rapid production by the liver and its release into the bloodstream and stimulation by several cytokines, including IL6, IL1β, and TNFα. (24,25). Our findings indicates that the WBC level in the group receiving vitamin A supplement showed a greater decrease than in the control group. Similarly, the rate for WBCs showed a significant reduction in recipients of vitamin A and zinc in a study on upper respiratory tract infections in children (23). In a similar study, the WBC level significantly decreased in tuberculosis patients who received vitamin A (26). In our study, the level of lymphocytes significantly increased in the experimental group, while there was no significant change in the control group. Previous studies have shown the beneficial effects of vitamin A supplement in children with viral diseases through the increase of lymphocyte proliferation (22,27). Vitamin A deficiency disrupts the innate immunity by preventing the natural regeneration of mucosal barriers damaged by infection and reducing the function of neutrophils, macrophages and natural killer cells. Vitamin A is necessary for consistent immunity and is involved in the growth of T helper (Th) and B cells. In particular, its deficiency decreases the antibody-mediated responses by Th2 cells (12,14). Our findings did not show any significant difference in Cr levels of patients in the experimental and control groups before and after the intervention. However, in- group comparison indicated a significant decrease in Cr in the experimental group. Creatinine level is a sign of kidney function. As none of our participants had kidney failure or dysfunction, the therapeutic intervention likely had no effect on their Cr levels. Our findings indicate that liver enzymes were less than 1.5 times the normal amount (normal: 20 in women and 30 in men) in both control and experimental groups, and they were unchanged by the pharmacological intervention. In the case of liver inflammation and hepatocellular hepatitis, the amount of transaminase increased by more than 5 times (28). Table 3 Comparison of paraclinical characteristics in the clinical and control groups at baseline and 10-day follow-up, Saveh, Islamic Republic of Iran, 2020 Test item Time Intervention group (n = 89) Control group (n = 91) P-valuea Mean (SD) Mean (SD) White blood cells (× 109 cells/l) Baseline 7437 (4807) 6378 (2374) 0.063 10-day follow-up 5941 (1922) 6283 (1799) 0.006 P-valueb 0.001 0.001 Lymphocytes (cells/µL) Baseline 2085 (1208) 2109 (1698) 0.918 10-day follow-up 2748 (1317) 2462 (1766) 0.225 P-valueb 0.001 0.507 C-reactive protein (mg/dL) Baseline 14.5 (21.8) 14.4 (17.9) 0.969 10-day follow-up 3.4 (3.9) 5.8 (9.7) 0.039 P-valueb 0.001 0.008 Erythrocyte sedimentation rate (mm/h) Baseline 24.0 (18.5) 27.0 (22.7) 0.354 10-day follow-up 15.9 (10.7) 19.8 (18.1) 0.091 P-valueb 0.001 0.001 Creatinine (mg/dL) Baseline 0.99 (0.22) 0.93 (0.22) 0.077 10-day follow-up 0.92 (0.16) 0.90 (0.16) 0.351 P-valueb 0.002 0.065 Alanine transaminase (IU/L) Baseline 28.3 (14.6) 26.5 (14.8) 0.422 10-day follow-up 22.3 (15.1) 22.1 (13.5) 0.927 P-valueb 0.001 0.007 Aspartate aminotransferase (IU/L) Baseline 33.1 (22.9) 27.7 (15.0) 0.065 10-day follow-up 23. 2 (16.2) 19.2 (16.2) 0.104 P-valueb 0.001 0.001 Creatine phosphokinase (IU/L) Baseline 112.9 (73.3) 114.7 (76.8) 0.870 10-day follow-up 70.4 (35.7) 79.2 (36.9) 0.108 P-valueb 0.001 0.001 SD = standard deviation. at-test. bPaired t-test. Book 28-09.indb 678 09/10/2022 11:07 AM 679 Research article EMHJ – Vol. 28 No. 9 – 2022 The research limitation was that, because this study used a sample from an outpatient health centre and these patients were quarantined at home, all conditions of the patients were not directly supervised. Conclusion Our results suggest that vitamin A supplement is efficacious in improving some clinical (fever, body ache, weakness and fatigue) and paraclinical symptoms (reduction of WBC and CRP) in patients with COVID-19. We suggest future studies examine outcomes with a larger sample size and compare dosage of vitamin A, especially in hospitalized patients. Funding: None Competing interests: None declared. Évaluation de la supplémentation en vitamine A et comparaison avec les thérapies standard dans le traitement des patients atteints de COVID-19 Résumé Contexte : Les données présentées pour déterminer le rôle de la supplémentation en vitamine A dans l'amélioration des résultats du traitement des patients atteints de COVID-19 sont souvent incomplètes. Objectifs : Nous avons comparé les effets thérapeutiques entre un groupe qui recevait de la vitamine A en complément du traitement standard contre la COVID-19 et un autre groupe qui recevait uniquement le traitement médicamenteux standard. Méthodes : Les participants à cet essai contrôlé en triple aveugle comprenaient 182 patients COVID-19 ambulatoires dans la ville de Saveh, province de Markazi, République islamique d'Iran, en 2020. Les patients ont été répartis aléatoirement en groupes expérimental (n = 91) et témoin (n = 91). Les patients du groupe témoin ont reçu le traitement standard national contre la COVID-19 (hydroxychloroquine) et ceux du groupe d'intervention ont reçu 25 000 UI/j de vitamine A par voie orale pendant 10 jours parallèlement au traitement standard recommandé par le protocole national. Nous avons évalué les symptômes cliniques, les critères paracliniques et le statut d'hospitalisation avant et après 10 jours d'interventions. Résultats : Il n'y avait pas de différence significative entre les groupes de traitement en ce qui concerne les symptômes cliniques et paracliniques avant l'intervention. Cependant, des symptômes cliniques tels que la fièvre, les douleurs corporelles, la faiblesse et la fatigue, les symptômes paracliniques, la numération des globules blancs et la protéine C-réactive ont montré des diminutions significativement plus importantes dans le groupe expérimental 10 jours après l'intervention par rapport au traitement standard seul (p < 0,05). Conclusion : La supplémentation en vitamine A a prouvé son efficacité dans l'amélioration de certains symptômes cliniques et paracliniques chez les patients atteints de COVID-19. Les futures études devraient évaluer la supplémentation en vitamine A avec un échantillon plus vaste et comparer différents dosages, notamment chez les patients hospitalisés. 19-ديفوك ضىرم جلاعل اهمادختسا دنع ةيرايعلما تاجلاعلاب اهتنراقمو )أ( ينماتيف تلامكم مييقت يميرك دوممحو نيلايد لايناد ،يركش يدهم ،يصرم يدهم ،رفظم نسح ،نياحور دممح ةصلالخا .19-ديفوك ضىرم ينب جلاعلا جئاتن ينسحتل )أ( ينماتيف تلامكمب جلاعلا رود ديدحتل ةلماك يرغ تانايب مدقت ام اًبلاغ :ةيفللخا تقلت ىرخأ ةعوممجو يرايعلما 19-ديفوك جلاع لىإ ةفاضلإاب )أ( ينماتيف تقلت ةعوممج ينب جلاعلا راثآ ةنراقم لىا ةساردلا هذه تفده :فادهلأا .اهدحو ةيرايعلما ةيودلأاب جلاعلا ةنيدم في ةيجرالخا تادايعلل ينعجارلما 19-ديفوك ضىرم نم اًضيرم 182 ةيثلاث ةيمعتب ةطوبضلما ةبرجتلا هذه في نوكراشلما مض :ثحبلا قرط ةعوممجو )91 = ددعلا( ةيبيرتج ةعوممج لىإ ا ًّيئاوشع ضىرلما نوثحابلا ع َّزوو .2020 ماع في ةيملاسلإا ناريإ ةيروهجم في يزاكرم ةظفاحمب هيفاس في ضىرلما ىقلتو ،)ينكورولكيسكورديلها( 19-ديفوكل ينطولا يرايعلما جلاعلا ةطباضلا ةعومجلما في ضىرلما ىقلتو .)91 = ددعلا( ةطباض لوكوتوبرلا في هب صىولما يرايعلما جلاعلا لىإ ةفاضلإاب ،مايأ 10 ةدلم مفلا قيرط نع )أ( ينماتيف نم ا ًّيموي/ةيلود ةدحو 25000 لخدتلا ةعوممج .مايأ 10 ةدمب اهدعبو تلاخدتلا لبق ىفشتسلما لاخدإ ةلاحو ةيريسرلالا يرياعلماو ةيريسرلا ضارعلأا انمَّيق دقو .ينطولا لثم ،ةيريسرلا ضارعلأا تعجارت ،كلذ عمو .لخدتلا لبق ةيريسرلالاو ةيريسرلا ضارعلأا في ًّمًّاهم اًفلاتخا جلاعلا اتعوممج فلتتخ لم :جئاتنلا ةعومجلما في اًيرثك بركأ اًعجارت ،سي لعافتلما ينتوبرلاو ءاضيبلا مدلا ايلاخ دادعتو ةيريسرلالا ضارعلأاو بعتلاو فعضلاو مسلجا ملاآو ىملحا .)0.05 نم لقأ ةيلمًّاتحلاا ةميقلا( هدحو سيايقلا جلاعلاب ًةنراقم ،لخدتلا نم مايأ 10 دعب ةيبيرجتلا Book 28-09.indb 679 09/10/2022 11:07 AM 680 Research article EMHJ – Vol. 28 No. 9 – 2022 References 1. Thompson R. Pandemic potential of 2019-nCoV. Lancet Infect Dis. 2020;20(3):280. doi:10.1016/S1473-3099(20)30068-2 2. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavi- rus–infected pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061–9. doi:10.1001/jama.2020.1585 3. Araban M, Karimy M, Koohestani HR, Montazeri A, Delaney D. Epidemiological and clinical characteristics of patients with COVID-19 in Islamic Republic of Iran. East Mediterr Health J. 2022 Apr 28;28(4):249–57. doi:10.26719/emhj.22.008 4. Kasem RA, Almansour M. COVID-19 during the crisis in the Syrian Arab Republic. East Mediterr Health J. 2021 Jan 23;27(1):5–6. doi:10.26719/2021.27.1.5 5. Wang L, Wang Y, Ye D, Liu Q. Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. Int J Antimicrob Agents. 2020 Jun;55(6):105948. doi:10.1016/j.ijantimicag.2020.105948 6. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine ceffectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269–71. doi:10.1038/s41422-020-0282-0 7. Mesri M, Saber SSE, Godazi M, Shirdel AR, Montazer R, Koohestani HR, et al. The effects of combination of Zingiber officinale and Echinacea on alleviation of clinical symptoms and hospitalization rate of suspected COVID-19 outpatients: a randomized controlled trial. J Complement Integr Med. 2021 Mar 31;18(4):775–81. doi:10.1515/jcim-2020-0283 8. Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, et al. Molecular mechanism for antibody-dependent enhancement of coronavirus entry. J Virol. 2020 Feb 14;94(5):e02015–9. doi:10.1128/JVI.02015-19 9. Kazeminia M, Jalali R, Vaisi-Raygani A, Khaledi-Paveh B, Salari N, Mohammadi M, et al. Fever and cough are two important factors in identifying patients with the Covid-19: a meta-analysis. J Military Med. 2020;22 (2):193–202. doi:10.30491/JMM.22.2.193 10. Kahbazi M, Sharafkhah M, Yousefichaijan P, Taherahmadi H, Rafiei M, Kaviani P, et al. Vitamin A supplementation is effective for improving the clinical symptoms of urinary tract infections and reducing renal scarring in girls with acute pyelonephritis: a randomized, double-blind placebo-controlled, clinical trial study. Complement Ther Med. 2019 Feb;42:429–37. doi:10.1016/j. ctim.2018.12.007 11. Semba RD. Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc. 1999 Aug;58(3):719–27. doi:10.1017/s0029665199000944 12. Shirazi KM, Nikniaz Z, Shirazi AM, Rohani M. Vitamin A supplementation decreases disease activity index in patients with ulcerative colitis: a randomized controlled clinical trial. Complementary therapies in medicine. 2018;41:215–9. Complement Ther Med. 2018 Dec;41:215–9. doi:10.1016/j.ctim.2018.09.026 13. Sijtsma S, Rombout J, West C, Van der Zijpp A. Vitamin A deficiency impairs cytotoxic T lymphocyte activity in Newcastle dis- ease virus-infected chickens. Vet Immunol Immunopathol. 1990 Oct;26(2):191–201. doi:10.1016/0165-2427(90)90067-3 14. Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr. 2001;21:167–92. doi:10.1146/annurev.nutr.21.1.167 15. Lehr R. Sixteen S‐squared over D‐squared: A relation for crude sample size estimates. Stat Med. 1992 Jun 15;11(8):1099–102. doi:10.1002/sim.4780110811 16. Shenai JP, Chytil F, Parker RA, Stahlman MT. Vitamin A status and airway infection in mechanically ventilated very‐low‐birth‐ weight neonates. Pediatr Pulmonol. 1995 May;19(5):256–61. doi:10.1002/ppul.1950190503 17. Aluisio AR, Perera SM, Yam D, Garbern S, Peters JL, Abel L, et al. Vitamin A supplementation was associated with reduced mor- tality in patients with Ebola virus disease during the West African outbreak. J Nutr. 2019 Oct 1;149(10):1757–65. doi:10.1093/jn/ nxz142 18. Kennedy KA, Stoll BJ, Ehrenkranz RA, Oh W, Wright LL, Stevenson DK, et al. Vitamin A to prevent bronchopulmonary dys- plasia in very-low-birth-weight infants: has the dose been too low? Early Hum Dev. 1997 Jul 24;49(1):19–31. doi:10.1016/s0378- 3782(97)01869-0 19. Thornton KA, Mora-Plazas M, Marín C, Villamor E. Vitamin A deficiency is associated with gastrointestinal and respiratory morbidity in school-age children. J Nutr. 2014 Apr;144(4):496–503. doi:10.3945/jn.113.185876. 20. Patrick L. Nutrients and HIV: part two--vitamins A and E, zinc, B-vitamins, and magnesium. Altern Med Rev. 2000 Feb;5(1):39–51. PMID: 10696118 21. Keflie TS, Samuel A, Woldegiorgis AZ, Mihret A, Abebe M, Biesalski HK. Vitamin A and zinc deficiencies among tuberculosis patients in Ethiopia. J Clin Tuberc Other Mycobact Dis. 2018 Jun 14;12:27–33. doi:10.1016/j.jctube.2018.05.002 22. Leal JY, Castejón HV, Romero T, Ortega P, Gómez G, Amaya D, et al. alores séricos de citocinas en niños con desórdenes por deficiencia de vitamina A [Serum values of cytokines in children with vitamin A deficiency disorders]. Invest Clin. 2004 Sep;45(3):243–56. (in Spanish) PMID: 15469069 تاساردلل يغبنيو .19-ديفوك ضىرم دنع ةيريسرلالاو ةيريسرلا ضارعلأا ضعب ينستح في ًةيلعاف )أ( ينماتيف تلامكم تتبثأ :تاجاتنتسلاا .تايفشتسلما ءلازن ضىرلما عم ةصاخو ،ةفلتخلما تاعرلجا ةنراقمو ًمًّاجح بركأ تانيعب )أ( ينماتيف تلامكم مييقت ةيلبقتسلما Book 28-09.indb 680 09/10/2022 11:07 AM 681 Research article EMHJ – Vol. 28 No. 9 – 2022 23. Shaker SM, Fathy H, Abdelall EK, Said AS. The effect of zinc and Vitamin A supplements in treating and reducing the inci- dence of upper respiratory tract infections in children. Nat J Physiol Pharmacy Pharmacol. 2018;8 (7):1010–7. doi:10.5455/njpp- pp.2018.8.0104206032018 24. Brinckerhoff CE, McMillan RM, Dayer J-M, Harris Jr ED. Inhibition by retinoic acid of collagenase production in rheumatoid synovial cells. N Engl J Med. 1980 Aug 21;303(8):432-6. doi:10.1056/NEJM198008213030805 25. Du Clos TW. Pentraxins: structure, function, and role in inflammation. ISRN Inflamm. 2013 Sep 14;2013:379040. doi:10.1155/2013/379040 26. Ahmad I, Kushwaha R, Kant S, Natu S, Singh S, Usman K, et al. Role of vitamin A and zinc supplementation on sputum smear conversion time in pulmonary tuberculosis patients. J Recent Adv Appl Sci. 2013;28:63–8. 27. Hanekom WA, Yogev R, Heald LM, Edwards KM, Hussey GD, Chadwick EG. Effect of vitamin A therapy on serologic responses and viral load changes after influenza vaccination in children infected with the human immunodeficiency virus. J Pediatr. 2000 Apr;136(4):550-2. doi:10.1016/s0022-3476(00)90024-6 28. Iluz-Freundlich D, Zhang M, Uhanova J, Minuk GY. The relative expression of hepatocellular and cholestatic liver enzymes in adult patients with liver disease. Ann Hepatol. 2020 Mar-Apr;19(2):204–8. doi:10.1016/j.aohep.2019.08.004 Book 28-09.indb 681 09/10/2022 11:07 AM 682 Research article EMHJ – Vol. 28 No. 9 – 2022 Diagnostic and treatment outcomes of patients with pulmonary tuberculosis in the first year of COVID-19 pandemic Yusuf Yakupogullari,1 Hilal Ermis,2 Zeynep Kazgan,3 Baris Otlu,1 Yasar Bayindir,4 Gazi Gulbas,2 Elif Tanriverdi1 and Emek Guldogan5 1Medical Microbiology Department; 2Chest Diseases Department; 4Infectious Diseases and Clinical Microbiology Department; 5Biostatistics and Medical Informatics Department, Medical Faculty, Inonu University, Malatya, Turkey (Correspondence to: Yusuf Yakupogullari: yusufyakoup@yahoo. com). 3Malatya Public Health Tuberculosis Department, Turkish Health Ministry, Malatya, Turkey. Introduction Mycobacterium tuberculosis, one of the oldest pulmonary pathogens in humans, infects around one-third of the global population. An estimated 9.9 million new cases and more than 1.5 million deaths from tuberculosis (TB) were reported in 2021 (1). Because no effective TB vaccine exists, it is critical to control the disease through effective diagnosis and treatment as well as the elimination of the suboptimal living conditions that contribute to the spread and reactivation of TB. The End TB Strategy, led by the World Health Organization (WHO), aims to reduce TB- related deaths by 95% and disease incidence by 90% by 2035 through early diagnosis, treatment, collaboration and resource allocation (2). Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an emerging pulmonary pathogen that has caused a pandemic affecting the entire global population since the beginning of 2020. Data from WHO have shown that SARS-CoV-2 has infected more than 400 million people worldwide, resulting in around 5.5 million COVID-19 deaths as of January 2022 (3). Studies show that the frequency of some neuropsychiatric problems has increased, and quality of life and well- being have been negatively affected while living under pandemic conditions (4,5). Survivors of severe COVID-19 often require immune-suppressive medications and have experienced decreased B- and T-cell counts (6,7). Significant reductions in hospital admissions of patients with health problems other than COVID-19 have also occurred (8). The COVID-19 pandemic has imposed a significant workload on health care facilities, particularly in the departments of chest and infectious diseases, which are critical for TB diagnosis. Therefore, the COVID-19 pandemic has the potential to exacerbate TB burden on societies by negatively impacting health care systems in addition to its effects on personal and social well-being. A WHO report indicates that substantial disruptions in TB services and case detection have occurred across the world since the beginning of the COVID-19 pandemic (9). A study conducted in the WHO European Region reported a decrease of more than one-third in TB case notifications in the second quarter of 2020 compared to the same period in 2019, and suggested that the deterioration in TB services due to the COVID-19 response may impede the region’s ability to meet the TB targets of the 2030 Sustainable Development Goals (10). Although similar declines in notifications have been reported in several Abstract Background: The COVID-19 pandemic has put a significant strain on human life and health care systems, however, little is known about its impact on tuberculosis (TB) patients. Aims: To assess the impact of COVID-19 pandemic on pulmonary tuberculosis (PTB) diagnosis, treatment and patient outcomes, using the WHO definitions. Methods: A cross-sectional study was conducted in Malatya region, Turkey (population 800 000). Data on regional PTB test numbers, case notification rates and PTB patients’ clinical characteristics and treatment outcomes were collected. Data from the first pandemic year (2020) were compared to data from the previous 3 years (2017–2019). The attitudes and experiences of patients were analysed. Results: Despite a non-significant 22% decrease in annual PTB case notifications (P = 0.317), the number of TB tests per- formed (P = 0.001) and PTB patients evaluated (P = 0.001) decreased significantly during the pandemic year compared with the previous 3 years. The proportion of patients with high (3/4+) sputum acid-fast bacilli grades (P = 0.001), TB relapse (P = 0.022) and treatment failure (P = 0.018) increased significantly. The median 64.5-day treatment delay detected in 2017–2019 increased significantly to 113.5 days in 2020 (P = 0.001), due primarily to patients’ reluctance to visit a health care facility. Conclusion: In addition to the problems with case detection, this study shows notable deterioration in several indicators related to the severity, contagiousness and poor outcomes of TB, which had already been suppressed for decades. Keywords: COVID-19, pulmonary tuberculosis, self-reported symptoms, predictors, sensitivity, specificity Citation: Yakupogullari Y; Ermis H; Kazgan Z; Otlu B; Bayindir Y; Gulbas G; et al. Diagnostic and treatment outcomes of patients with pulmonary tuberculosis in the first year of COVID-19 pandemic. East Mediterr Health J. 2022;28(9):682–689. https://doi.org/10.26719/emhj.22.060 Received: 20/10/21; accepted: 02/06/22 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo) Book 28-09.indb 682 09/10/2022 11:07 AM 683 Research article EMHJ – Vol. 28 No. 9 – 2022 countries, the details and dynamics of these reductions are not yet clear. This study aimed to determine changes in diagnostic and treatment processes and treatment outcomes (according to WHO definitions) in patients diagnosed with pulmonary tuberculosis (PTB) in the first year (2020) of the COVID-19 pandemic. Methodology Study design, patients A cross-sectional study was conducted in Malatya, a city located in mid-eastern Turkey with a population of 800 000 inhabitants. Patients in the region who were tested for and diagnosed with PTB between 1 January 2017 and 28 February 2021 were included in the study. Because the study aimed to evaluate the impact of the COVID-19 pandemic on the course of PTB annually, the first pandemic year was defined as the 1-year period from 1 March 2020 (the first COVID-19 case notification in Turkey) to 28 February 2021. Any patient who was tested for and diagnosed with PTB during the study period and was a resident of the Malatya region was included in the study. Patients with PTB and who had COVID-19 were included to determine the potential impact of this co-infection on the diagnosis and treatment processes and the outcomes of pulmonary tuberculosis. Patients who did not meet these criteria were excluded from the study. Because the COVID-19 pandemic did not impact Turkey’s health care system until March 2020, patients diagnosed in January and February 2020 were excluded. Patients who were tested for and diagnosed with PTB were identified by screening the data from the Public Health Tuberculosis Department of Malatya city and the TB diagnostic laboratory of the region located in the Turgut Ozal Medical Center, a tertiary-level health care facility at the Inonu University Medical Faculty. This study was approved by the Ministry of Health (2021-01-11T13_01_23; 12 January 2021), the Malatya Clinical Studies Ethical Board (2021/38; 3 February 2021) and the Ministry of Health Malatya Office (04.21/771- 1064; 20 April 2021). Data sources and definitions Demographic and medical data of patients tested for and diagnosed with PTB during the study period were collected from the electronic and paper records at the Public Health Tuberculosis Department, the Turgut Ozal Medical Center’s TB diagnostic laboratory and the health care facilities where patients were evaluated. The WHO criteria were used to define PTB, relapse, clinically diagnosed TB and treatment outcomes (11). A questionnaire was used to collect information from patients diagnosed during the pandemic year about their attitudes, behaviours and experiences with the TB diagnosis and treatment processes. The questionnaire had 8 questions with responses graded on a 5-point Likert scale ranging from “strongly disagree” to “strongly agree”. The survey was conducted via phone or in- person interviews. In cases of mortality, juveniles, or mental incapacity, data were obtained from the primary caregiver. Data analysis The following data for PTB patients who were diagnosed in the region during the study period were collected and analysed: demographic data (age and sex) of the patients, the acid-fast bacilli (AFB) grades in smear samples, diagnostic features (clinical diagnosis/laboratory-based diagnosis), new case or relapse, comorbidities, treatment outcomes and duration from the onset of symptoms to the initiation of anti-TB treatment. Patients’ data from the pre-pandemic (2017–2019) and pandemic (2020) periods were statistically compared. Quantitative data were presented as median (minimum–maximum) and qualitative data as numbers (percentages). The interquartile range was calculated for the patients’ ages. The conformity of quantitative data to the normal distribution was evaluated with the Shapiro– Wilk test. The one-sample chi-square, Mann–Whitney U, Kruskal–Wallis, Conover pairwise comparison and Pearson chi-square tests were used. The significance level was < 0.05. We used SPSS, version 26.0, software in the analysis. Results Pulmonary tuberculosis case notification rate and test statistics in the region A total of 2970 patients were evaluated for PTB in the region during the study period. The median age of the patients was 54 years and 60.5% of them were male. The region’s PTB case notification rate decreased to 6.51 per 100 000 population during the pandemic year, a nonsignificant 22.0% drop from the previous 3 years. This rate was 8.53 in 2017, 7.85 in 2018 and 8.94 in 2019. When compared to the average values of the previous 3 years, the annual number of PTB tests, the number of patients tested and the average number of diagnostic test sets per patient all decreased significantly during the pandemic year, by 47.4%, 39.6% and 20.0%, respectively. Table 1 presents the number of PTB laboratory tests performed and number of patients evaluated for PTB by study year in the region. Characteristics of patients During the study period, 252 patients with PTB were diagnosed, with a median age of 48 years and 156 (61.9%) of them were male. In 2020, 52 PTB patients (61.5% male, median age 51 years) were diagnosed, with 67, 62 and 71 PTB patients notified in 2017, 2018 and 2019 respectively. During the pandemic year (2020), the number of PTB patients with 3 or 4+ AFB grades in smear microscopy increased significantly to 27 (51.9%), compared to 6 (9.0%), 2 (3.2%) and 7 (9.8%) in 2017, 2018 and 2019 respectively. In Book 28-09.indb 683 09/10/2022 11:07 AM 684 Research article EMHJ – Vol. 28 No. 9 – 2022 the previous 3 years, the rate of clinical diagnosis ranged between 13.4% (in 2017) and 18.3% (in 2019), but it dropped insignificantly to 7.7% during the pandemic year (2020). In the pandemic year (2020), the number of PTB patients who relapsed and the number who delayed attending the Public Health Tuberculosis Department to start anti-TB treatment by more than 7 days increased significantly when compared to pre-pandemic years (2017–2019). When the treatment outcomes of patients who completed a 6-month standard anti-TB treatment were compared to the previous 3 years (2017–2019), a statistically significant increase in treatment failure was found during the pandemic year (2020). Between the pandemic year (2020) and the pre- pandemic years (2017–2019), there was no statistically significant difference in the patients’ co-morbidities, the rate of mortality during treatment, the number of patients with PTB-related hospitalization, or the length of hospital stay (Table 2). Duration of diagnosis and treatment processes Patients diagnosed with PTB between 2017 and 2019 received treatment within a median of 64.5 days of symptom onset, but this increased significantly to 113.5 days during the pandemic year (2020). In 2020, there were significant delays in the median time taken for a doctor’s appointment and to apply to the Public Health Tuberculosis Department to start treatment after a PTB diagnosis (Table 3). Experiences of pulmonary tuberculosis patients in the pandemic year Out of 52 PTB patients diagnosed during the pandemic year (2020), 48 were queried. A total of 31 (65.0%) PTB patients reported that they would have sought medical care earlier if there was no pandemic; 20 (41.7%) patients delayed seeking medical care due to fear of contracting COVID-19 in the health care facilities; 16 (33.3%) delayed seeking medical care due to “stay at home” advice; 20 (41.6%) had difficulty finding a doctor; 35 (72.9%) had a later appointment time than previous visits and 9 (18.8%) perceived that they received less medical attention compared with prior experiences. Pulmonary tuberculosis patients with COVID-19 In total, 9 PTB patients diagnosed during the pandemic year also had COVID-19. One patient with severe COVID-19 died. Another patient who was diagnosed with PTB following severe COVID-19 was recorded as a COVID-19-mediated PTB recurrence. Two PTB patients who also contracted COVID-19 remained positive for M. tuberculosis complex during the fifth month of the anti-TB treatment. Discussion In this study, we found significant reductions in the number of PTB patients diagnosed in Malatya during the first year of the COVID-19 pandemic. Similar reductions in TB case notification have been reported in other parts of the world; for example, the Pan American Health Organization reported that PTB case notification in continental America decreased by 15–20% during 2020 (12). Nguyen et al. reported that the diagnosis of around 20% of PTB cases required 4 or more sputum samples or deep pulmonary sampling because 2 or 3 previous samples showed negative results (13). Therefore, a strong clinical suspicion is essential in PTB diagnosis. We compared the average number of TB tests performed for each patient by year. This parameter could be regarded Table 1 Number of pulmonary tuberculosis laboratory tests performed and number of patients evaluated for PTB, Malatya, 2017–2021 Item/ characteristic Pre-pandemic year Pandemic year P-value 2017 2018 2019 2020–2021 Age (years): median (min–max), IQR 54 (0–95), 51.5 56 (0–96), 52 55 (0–95), 51 52 (0–92), 51 0.262a No. (%) No. (%) No. (%) No. (%) TB tests performed for PTB 1884 (27.2) 2136 (30.9) 1864 (27.0) 1031 (14.9) 0.001b Patients tested for PTB 875 (29.5) 840 (28.3) 757 (25.5) 498 (16.8) Sex Female 363 (41.5) 340 (40.4) 305 (40.3) 171 (34.3) 0.061c Male 512 (58.5) 500 (59.5) 452 (59.7) 327 (65.6) Patients diagnosed with PTB 67 (26.6) 62 (24.6) 71 (28.2) 52 (20.6) 0.361b Mean (SD) Mean (SD) Mean (SD) Mean (SD) TB test sets per patientd 1.97 (1.34) 2.32 (1.52) 2.2 (1.40) 1.73 (1.26) 0.001a No./100 000 No./100 000 No./100 000 No./100 000 Regional PTB case notification ratee 8.53 7.85 8.94 6.51 0.317b IQR = interquartile range. AFB = acid-fast bacilli. SD = standard deviation. aKruskal–Wallis H test. bOne-sample chi-square test. cPearson chi-square test. dTB test set included AFB microscopy+TB culture±TB-PCR. This parameter was calculated according to the TB test set performed for diagnostic purposes by excluding the TB tests performed after diagnosis (i.e. tests for follow up the treatment effectiveness). eAnnual population size in the province was obtained from the Turkish Statistics Institution. Book 28-09.indb 684 09/10/2022 11:07 AM 685 Research article EMHJ – Vol. 28 No. 9 – 2022 as a measurable indicator of the medical attention that should be provided to each patient and the degree of clinical suspicion that necessitates a thorough clinical evaluation. We found that the average number of TB tests performed per patient decreased significantly by up to a quarter in the pandemic year (2020). In spite of the significant decrease in number of TB tests, the reduction in number of PTB patient notifications in 2020 was not statistically significant. This finding could be due to an increase in the number of patients with obvious clinical symptoms, and suggests that a proportion of PTB patients, particularly those with ambiguous clinical PTB presentation, may have gone unnoticed during 2020. We found that the AFB grades of PTB patients increased substantially in the pandemic year (2020). A high sputum bacilli load was associated with the highest relative risk of transmission or active PTB among contacts (14). Given that people had been advised to stay at home since the emergence of COVID-19, the risk of indoor TB exposure may have increased during that year. About 13% of patients with TB were diagnosed clinically, and required further interventions (i.e. biopsy, histopathology) and evaluations because the TB tests were negative (13). Although not statistically significant, the number of patients diagnosed clinically decreased by more than half in 2020. This could indicate that a proportion of PTB patients who would have been diagnosed clinically may not have been detected in the first year of the COVID-19 pandemic. Recurrent PTB may yield poorer outcomes, including death and treatment failure (15). Estimates from WHO indicate that about 7% of PTB patients diagnosed annually are relapsed (9). In Turkey, TB recurrence gradually declined from 9.7% to 7.8% between 2006 and 2017 (16). We found more than 2-fold increase in the rate of relapsed PTB patients during the first pandemic year. This could be due to personal factors influenced by the pandemic such as increased psychological stress, deteriorated living standards and limited or delayed access to medical care for any chronic disease. Despite the increasing number of patients with high bacilli load, treatment failure and recurrence, we found no significant increase in the rate of hospitalized PTB patients and length of hospitalization in 2020. This Table 2 Comparison of the characteristics of 252 pulmonary tuberculosis patients who were diagnosed in Malatya, 2017–2021 Characteristic Pre-pandemic year Pandemic year P-value 2017 2018 2019 2020–2021 Age (years): median (min–max), IQR 52 (17–85), 51.5 50 (13–86), 48.5 46 (12–90), 43 51 (17–88), 43.5 0.310a No. (%) No. (%) No. (%) No. (%) Sex Female 20 (29.9) 29 (46.8) 27 (38.0) 20 (38.5) 0.271b Male 47 (70.1) 33 (53.2) 44 (62.0) 32 (61.5) AFB microscopy Negative 23 (34.3) 30 (48.4) 35 (49.3) 13 (25.0) 0.001b 1+ 33 (49.3) 27 (43.5) 20 (28.2) 7 (13.5) 2+ 5 (7.5) 3 (4.8) 9 (12.7) 5 (9.6) 3+ 2 (3.0) 1 (1.6) 4 (5.6) 11 (21.2) 4+ 4 (6.0) 1 (1.6) 3 (4.2) 16 (30.8) Basis of diagnosis Laboratory-based 58 (86.6) 51 (82.3) 58 (81.7) 48 (92.3) 0.345b Clinical 9 (13.4) 11 (17.7) 13 (18.3) 4 (7.7) Recurrence New case 61 (91.0) 58 (93.5) 66 (93.0) 42 (80.8) 0.022b Relapse 6 (9.0) 4 (6.5) 5 (7.0) 10 (19.2) Hospitalized patients 20 (29.9) 22 (35.5) 29 (41.4) 21 (40.4) 0.499b Treatment process Patients for whom treatment initiation delayed > 7 days 7 (10.4) 5 (8.1) 6 (8.5) 14 (26.9) 0.007b Treatment failurec 1 (1.9) 0 (0.0) 1 (1.9) 7 (17.0) 0.018** Outcome Mortality during treatment 5 (7.5) 8 (12.9) 5 (7.0) 7 (13.5) 0.338b Mean (SD) Mean (SD) Mean (SD) Mean (SD) Duration of hospitalization (days) 2.55 (7.26) 3.02 (6.34) 1.92 (3.74) 4.48 (8.81) 0.534b IQR = interquartile range. AFB = acid-fast bacilli. SD = standard deviation. aKruskal–Wallis H test. bPearson chi-square test. cThis analysis included the patients who were able to complete a 6-month TB treatment regime, therefore, the patients who were diagnosed clinically or died before the treatment conclusion were excluded. Book 28-09.indb 685 09/10/2022 11:07 AM 686 Research article EMHJ – Vol. 28 No. 9 – 2022 could be due to patients’ reluctance to be hospitalized, or clinicians’ attitudes about reserving beds for patients with more acute cases. In the first pandemic year, we found significant increases in the number of PTB patients who were still positive for smear AFB microscopy and/or TB culture in the fifth month of the treatment, which is defined as treatment failure according to WHO criteria (11). Research has shown that cavitary lung lesions, diabetes, high bacilli load in smear microscopy and recurrent TB are predictors of treatment failure (17,18). Given that no difference was observed in PTB patients’ characteristics in terms of diabetes and cavitary lesions in the years studied, we surmised that increasing treatment failure in the first pandemic year was most likely related to increases in high AFB load and relapses during that time. One study reported a median of 62 days for PTB patients to initiate anti-TB treatment after clinical symptoms first appeared (19). We compared 5 different periods in the diagnostic and treatment processes of PTB by study year. The “time to doctor’s visit after TB symptoms”, which could be considered one of the indicators of patients’ care-seeking behaviour, was found to have almost doubled in 2020. In another period, “doctor’s appointment time” – which could also be viewed as an indicator of the health system’s ability to cope with the increased patient load caused by the COVID-19 pandemic – was found to have increased to a median of 5 days in the 2020 pandemic year, whereas it was usually a same-day procedure between 2017 and 2019. The “time to PTB diagnosis after sample delivery” (which could also be used to assess the laboratory’s performance in PTB diagnosis) showed no delay; in contrast, an average decrease of 2 days was observed in 2020. This finding was an unexpected result and likely occurred due to the significant decrease in TB test orders in that year. There was a significant delay in the “time to access treatment after diagnosis” in 2020, which could be another indicator of patients’ care-seeking behaviour. The period “total time”, as the sum of treatment delays including patient- and health service-dependent delays, increased substantially, as much as 1.7-fold, in 2020. PTB patients diagnosed during the pandemic year (2020) were able to access anti-PTB treatment about 40 days later than patients diagnosed previously. Using a statistical method of survival analysis in future studies will help determine more accurate results for such delays. To clarify the factors contributing to these delays, we queried patients who were diagnosed with PTB in 2020. A significant proportion of PTB patients delayed seeking care due to pandemic-related factors (such as stay-at- home orders and the fear of becoming infected with SARS-CoV-2 in health care facilities), had difficulty seeing a doctor and received less medical attention in 2020. Patients’ responses indicated that during the pandemic, PTB patients experienced hesitation to seek medical help and problems in accessing effective diagnosis and treatment. We analysed 9 PTB patients diagnosed in the pandemic year (2020) who also had COVID-19 because a co-infection could influence the diagnostic and treatment process as well as treatment outcomes. Although 3 of these 9 patients had shown TB symptoms for up to 6 months, they were ultimately diagnosed with PTB during medical evaluations performed during their hospital stay for COVID-19. This finding is additional evidence that patients postponed their visits to the doctor in 2020 until it was necessary. A patient who received 1-month prednisolone due to severe COVID-19 developed treatment failure for TB. Five of these 9 patients developed COVID-19 during their anti-TB treatment but did not experience any health problems due to their co-infection. The last one of the 9 PTB patients was considered to have a COVID-19-mediated PTB relapse because that patient had no PTB symptoms before acquiring COVID-19. Due to severe COVID-19, this patient was hospitalized for about 34 days, had lymphopenia for 2 weeks and received prednisolone therapy for 2 months. This patient was diagnosed with PTB on the 22nd day following termination of corticosteroid therapy and developed treatment failure. COVID-19-mediated dysfunctions in effector lymphocytes may not improve completely even 6 months after infection (20), and many patients with severe Table 3 Comparisons of the time intervals from the onset of PTB symptoms to the start of anti-TB treatment in PTB patients diagnosed in Malatya, 2017–2021 Time interval (days) Pre-pandemic year Pandemic year P-valuea 2017 2018 2019 2020–2021 Median (min– max) Median (min– max) Median (min– max) Median (min– max) Time to doctor visit after onset of TB symptoms 45 (7–360) 60 (7–360) 50 (7–360) 89 (13–356) 0.001 Doctor’s appointment time 1 (0–4) 1 (0–4) 1 (0–5) 5 (0–40) 0.001 Time to PTB diagnosis after sample delivery 1 (0–55) 2 (0–76) 2 (1–61) 1.5 (0–58) 0.775 Time to access treatment after diagnosis 1 (0–120) 1 (1–135) 1 (0–52) 3 (0–39) 0.001 Total treatment delay 62 (10–367) 678 (9–361) 65 (10–405) 114 (13–387) 0.001 aKruskal–Wallis H test. Book 28-09.indb 686 09/10/2022 11:07 AM 687 Research article EMHJ – Vol. 28 No. 9 – 2022 COVID-19 receive corticosteroids to prevent lung damage. These immune-system problems may offer favourable conditions for TB bacilli to progress, the bacterium can survive in tissues for decades even in immunocompetent individuals. We identified PTB relapse and treatment failures in our patients, which could be attributed to severe COVID-19. When the distribution of both infections is considered, it can be predicted that such interactions between TB and COVID-19 could result in a global health problem. In this study, only PTB patients were investigated. Therefore, it is unknown how the pandemic affected the diagnosis and treatment processes and outcomes in patients with extrapulmonary TB. We conducted this study in a region where two-thirds of the health care capacity was never exceeded due to the pandemic, and the region’s TB diagnostic laboratory managed to continue to provide routine service in the meantime. As a result, PTB patients in our region did not experience extensive difficulty accessing basic diagnostic and therapeutic services during the first pandemic year. Given these limitations, we believe that the COVID-19 pandemic would result in greater regressions in TB case detection in areas where health care capacity was exceeded or TB laboratories were used for SARS-CoV-2 diagnosis. This study shows that more PTB patients may have gone undetected in the province during the pandemic year (2020) as a result of emerging problems in case detection due to changing health care-seeking behaviour among patients and the high workload at health care facilities. In addition to the increased TB burden, an increase in the number of undiagnosed patients in a population can trigger further problematic consequences, such as increased TB-related deaths, as predicted by WHO (9). Our study reveals that the COVID-19 pandemic may worsen the severity and contagiousness of PTB as well as the success of anti-TB treatment. Therefore, to prevent subsequent threats of TB resurgence, the global community must increase its efforts in raising awareness in addition to educating and encouraging people to access medical aid. As further pandemics may emerge in the years to come, appropriate strategies must be reconsidered to sustain the goals of controlling TB. Funding: None Competing interests: None declared. Résultats diagnostiques et thérapeutiques des patients atteints de tuberculose pulmonaire au cours de la première année de la pandémie de COVID-19 Résumé Contexte : La pandémie de COVID-19 a mis à rude épreuve la vie humaine et les systèmes de soins de santé, mais on sait peu de choses sur son impact sur les patients atteints de tuberculose. Objectifs : Évaluer l'impact de la pandémie de COVID-19 sur le diagnostic, le traitement et les résultats des patients atteints de tuberculose pulmonaire (TBP), en utilisant les définitions de l'OMS. Méthodes : Une étude transversale a été réalisée dans la région de Malatya, en Turquie (population de 800 000 habitants). Des données sur le nombre de tests régionaux de tuberculose pulmonaire, les taux de notification des cas, les caractéristiques cliniques des patients atteints de tuberculose pulmonaire et les résultats des traitements ont été collectées. Les données de la première année de la pandémie (2020) ont été comparées aux données des trois années précédentes (2017-2019). Les attitudes et les expériences des patients ont été analysées. Résultats : Malgré une diminution non significative de 22 % des notifications annuelles de cas de tuberculose pulmonaire (p = 0,317), le nombre de tests de dépistage de la tuberculose effectués (p = 0,001) et de patients atteints de tuberculose pulmonaire évalués (p = 0,001) a considérablement diminué pendant l'année pandémique par rapport aux trois années précédentes. La proportion de patients présentant des niveaux élevés (3/4+) de bacilles acido-alcoolo-résistants dans les expectorations (p = 0,001), de rechute tuberculeuse (p = 0,022) et d'échec thérapeutique (p = 0,018) a augmenté de manière significative. Le retard médian du traitement de 64,5 jours détecté en 2017-2019 a considérablement augmenté pour atteindre 113,5 jours en 2020 (p = 0,001), principalement en raison de la réticence des patients à se rendre dans un établissement de santé. Conclusion : Au-delà des problèmes de détection des cas, la présente étude montre une détérioration notable de plusieurs indicateurs liés à la gravité, à la contagiosité et aux mauvais résultats de la tuberculose, que les programmes de lutte avaient déjà supprimés depuis des décennies. Book 28-09.indb 687 09/10/2022 11:07 AM 688 Research article EMHJ – Vol. 28 No. 9 – 2022 References 1. Global tuberculosis report 2021. Geneva: World Health Organization; 2021 (https://www.who.int/publications/i/ item/9789240037021, accessed 18 February 2022). 2. Global strategy and targets for tuberculosis prevention, care, and control after 2015. Geneva: World Health Organization; (WHA67.1; https://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_R1-en.pdf, accessed: 10 July 2022). 3. WHO Coronavirus dashboard. Geneva: World Health Organization. 2021 (https://covid19.who.int/, accessed 18 February 2022). 4. Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8(5):416–27. doi:10.1016/S2215- 0366(21)00084-5 5. Ravens-Sieberer U, Kaman A, Erhart M, Devine J, Schlack R, Otto C. Impact of the COVID-19 pandemic on quality of life and mental health in children and adolescents in Germany. Eur Child Adolesc Psychiatry. 2021;25:1–11. doi:10.1007/s00787-021-01726- 5. PMID: 33492480 6. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, con- trolled, open-label, platform trial. Lancet. 2021;397(10285):1637–45. doi:10.1016/S0140-6736(21)00676-0 7. Lagadinou M, Zareifopoulos N, Gkentzi D, Sampsonas F, Kostopoulou E, Marangos M, et al. Alterations in lymphocyte subsets and monocytes in patients diagnosed with SARS-CoV-2 pneumonia: a mini review of the literature. Eur Rev Med Pharmacol Sci. 2021;25(15):5057–62. doi:10.26355/eurrev_202108_26463 8. Czeisler MÉ, Marynak K, Clarke KEN, Salah Z, Shakya I, Thierry JM, et al. Delay or avoidance of medical care because of COV- ID-19-related concerns – United States, June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(36):1250–7. doi:10.15585/mmwr. mm6936a4 9. Global tuberculosis report 2020. Geneva: World Health Organization; 2020 (https://www.who.int/publications/i/ item/9789240013131, accessed 18 February 2022). 10. Dara M, Kuchukhidze G, Yedilbayev A, Perehinets I, Schmidt T, Van Grinsven WL, et al. Early COVID-19 pandemic’s toll on tuberculosis services, WHO European Region, January to June 2020. Euro Surveill. 2021;26(24):2100231. doi:10.2807/1560-7917. ES.2021.26.24.2100231 11. Definitions and reporting framework for tuberculosis – 2013 revision (updated December 2014 and January 2020). Geneva: World Health Organization; 2020 (https://apps.who.int/iris/handle/10665/79199, accessed 28 August 2021). 12. Diagnosis of new TB cases in the Americas reduced by 15–20% during 2020 due to the pandemic. Washington: Pan American Health Organization; 2021 (https://www.paho.org/en/news/24-3-2021-diagnosis-new-tb-cases-americas-reduced-15-20-during- 2020-due-pandemic, accessed 10 July 2021). 19-ديفوك ةحئاج نم لىولأا ةنسلا في يوئرلا لسلا ضىرلم جلاعلاو صيخشتلا جئاتن ناجودلوج كيميإ ،يدرفبرنات فلإ ،سابلج يزاغ ،ريدنياب راسي ،ولتوأ سيراب ،ناجزاك بنيز ،سيمرإ للاه ،يرلاجوبوكاي فسوي ةصلالخا .لسلا ضىرم لىع هيرثأت نع ليلقلا لاإ فرعن لا اننأ لاإ ،ةيحصلا ةياعرلا مُظُنو شربلا ةايح لىع يربك طغض في 19-ديفوك ةحئاج تببست :ةيفللخا مادختساب ،ضىرملل ةققحتلما جئاتنلاو هجلاعو يوئرلا لسلا صيخشت لىع 19-ديفوك ةحئاج رثأ مييقت لىا ةساردلا هذه تفده :فادهلأا .ةيلماعلا ةحصلا ةمظنم تافيرعت تارابتخا ددع نع ةقطنلما تانايب نوثحابلا عجمو .)ةمسن فلأ 800 ناكسلا ددع( ايكترب ايطلام ةقطنم في ةيعطقم ةسارد تيرجُأ :ثحبلا قرط ةنسلا تانايب نوثحابلا نراق ،كلذ دعبو .جلاعلا جئاتنو ،يوئرلا لسلا ضىرلم ةيريسرلا صئاصلخاو ،تلاالحاب راطخلإا تلادعمو ،يوئرلا لسلا .مبهراتجو ضىرلما فقاوم ليلتح عم ،)2019-2017( ةقباسلا ةثلاثلا تاونسلا تانايبب )2020( ةحئالجا نم لىولأا = ةيلماتحلاا ةميقلا( يوئرلا لسلاب ةباصلإا تلااحب تاراطخلإل يونسلا ددعلا في %22 ةبسنب يربكلا يرغ ضافخنلاا نم مغرلا لىع :جئاتنلا ةيلماتحلاا ةميقلا( مييقت مله َيرجُأ نيذلا يوئرلا لسلا ضىرم ددعو )0.001 = ةيلماتحلاا ةميقلا( تَيرجُأ يتلا لسلا تارابتخا ددع نإف ،)0.317 ضىرلما ةبسن في ةيربك ةدايز كلذك تثدحو .ةقباسلا ثلاثلا تاونسلاب ًةنراقم ةحئاجلل لىولأا ةنسلا للاخ اًيربك اًضافخنا ضفخنا دق )0.001 = ةميقلا( لسلا ساكتنا ةبسنو ،)0.001 = ةيلماتحلاا ةميقلا( )3/4+( مغلبلا تانيع في ضمحلل ةدماصلا تايصعلاب ٍلاع ع ُّبشت ميهدل نيذلا نم ةترفلا في اًموي 64.5 تناك يتلا ،جلاعلا رخأت ةدلم ىطسولا ةميقلا تدازو .)0.018 = ةيلماتحلاا ةميقلا( جلاعلا لشفو )0.022 = ةيلماتحلاا ضىرلما ماجحإ لىإ لولأا ماقلما في كلذ عجريو ،)0.001 = ةيلماتحلاا ةميقلا( 2020 ماع في اًموي 113.5 لىإ لصتل ةيربك ةدايز ،2019 لىإ 2017 .ةيحصلا ةياعرلا قفارم ةرايز نع ضرم ةدشب ةقلعتلما تاشرؤلما نم ديدعلا في اًظوحلم اًروهدت ةساردلا هذه رِهظُت ،تلاالحا فاشتكاب ةقلعتلما تلاكشلما لىإ ةفاضلإاب :تاجاتنتسلاا .نمزلا نم دوقعل تاشرؤلما كلت عمق في ةحفاكلما جمارب تحجن نأ دعب كلذو ،هب ينباصلما ينب جئاتنلا فعضو هب ىودعلاو لسلا Book 28-09.indb 688 09/10/2022 11:07 AM 689 Research article EMHJ – Vol. 28 No. 9 – 2022 13. Nguyen MV, Jenny-Avital ER, Burger S, Leibert EM, Achkar JM. Clinical and radiographic manifestations of sputum culture-neg- ative pulmonary tuberculosis. PLoS One. 2015;10(10):e0140003. doi:10.1371/journal.pone.0140003 14. Lohmann EM, Koster BF, le Cessie S, Kamst-van Agterveld MP, van Soolingen D, Arend SM. Grading of a positive sputum smear and the risk of Mycobacterium tuberculosis transmission. Int J Tuberc Lung Dis. 2012;16(11):1477–84. doi:10.5588/ijtld.12.0129 15. Gadoev J, Asadov D, Harries AD, Parpieva N, Tayler-Smith K, Isaakidis P, et al. Recurrent tuberculosis and associated factors: A five - year countrywide study in Uzbekistan. PLoS One. 2017;12(5):e0176473. doi:10.1371/journal.pone.0176473 16. Türkiye’de verem savaşi 2019 raporu [Turkey’s tuberculosis report 2019]. Ankara: Health Ministry Publications, 2020 (No:1168; https://hsgm.saglik.gov.tr/depo/birimler/tuberkuloz_db/raporlar/Tu_rkiye_de_Verem_Savas_2019_Raporu_son_1.pdf, accessed 22 September 2021). 17. Koo HK, Min J, Kim HW, Lee J, Kim JS, Park JS, et al. Prediction of treatment failure and compliance in patients with tuberculo- sis. BMC Infect Dis. 2020;20(1):622. doi:10.1186/s12879-020-05350-7 18. Sauer CM, Sasson D, Paik KE, McCague N, Celi LA, Sánchez Fernández I, et al. Feature selection and prediction of treatment failure in tuberculosis. PLoS One. 2018;13(11):e0207491. doi:10.1371/journal.pone.0207491 19. Saldana L, Abid M, McCarthy N, Hunter N, Inglis R, Anders K. Factors affecting delay in initiation of treatment of tuberculosis in the Thames Valley, UK. Public Health. 2013;127(2):171–7. doi:10.1016/j.puhe.2012.11.010 20. Shuwa HA, Shaw TN, Knight SB, Wemyss K, McClure FA, Pearmain L, et al. Alterations in T and B cell function persist in conva- lescent COVID-19 patients. Med (N Y). 2021;2(6):720–35.e4. doi:10.1016/j.medj.2021.03.013 Book 28-09.indb 689 09/10/2022 11:07 AM 690 Short research communication EMHJ – Vol. 28 No. 9 – 2022 Mental health and driving behaviour of students and alumni of a university in the United Arab Emirates: a cross-sectional study Gabriel Andrade,1 Dalia Bedawi2,3 and Ibrahim Bani1 1College of Medicine, Ajman University, Ajman, United Arab Emirates (Correspondence to: Gabriel Andrade: gandrade@ajman.ac.ae). 2College of Humanities, Ajman University, Ajman, United Arab Emirates. 3College of Humanities, Tanta University, Tanta, Egypt. 3Ajman University, Ajman, United Arab Emirates. Introduction Over the last few years, the United Arab Emirates has been making significant progress in road traffic injury prevention. Following the 725 traffic-related deaths and 6681 injuries in 2016, the Government of the United Arab Emirates made a deep commitment as part of its national agenda to reduce traffic-related deaths to 3 per 100 000 people by 2021 (1). Research has provided much relevant information on this topic. Previous studies have suggested that mental health is associated with improved driving performance, and consequently, with increased traffic safety (2). However, it is not known which aspects of mental health are associated with driving performance. Since mental health is a broad category, policy-makers must focus on particular mental health markers and their relationship with particular dimensions of driving behaviour. This study addressed this question, and its correlations in the United Arab Emirates, because only few studies conducted on driving performance have paid attention to their relationship with mental health. In this study we investigated whether 5 dimensions of mental health (social dysfunction, anxiety, loss of confidence, hours of sleep, attention deficit/hyperactivity) had any correlation with dangerous driving behaviour in the United Arab Emirates. Methods This was a cross-sectional study that measured age, sex, hours of sleep, years of driving experience, mental health, driving behaviour and levels of attention deficit hyperactivity disorder (ADHD). An integrated questionnaire of 27 items was approved by the research ethics committee of Ajman University, # M-H-F-31-May. The questionnaire was sent (via email) to students and alumni of the university who live permanently in the United Arab Emirates. Participants were recruited on the basis of convenient non-probability sampling, considering availability and willingness to answer questionnaires during the COVID-19 lockdowns. Participants were informed about the nature of the study and that they could refuse to answer questions at any time. They were requested to sign consent and instructed to carefully complete all questions in the survey to avoid any potential loss of data. The survey was designed using software that would not allow the participant to go on to the next question without answering the previous one. This method ensured that the returned questionnaires would not have any missing data. Consequently, the level of missing data was 0. We sent out 350 questionnaires; 275 were returned, giving a response rate of 79%. The survey gathered demographic information (age, sex). One question asked participants how many hours Abstract Background: The United Arab Emirates has set the goal to reduce traffic-related deaths to 3 per 100 000 people by 2021. To do this, authorities must assess the factors related to risky driving behaviour. Aims: To verify if there are any correlations between driving behaviour and certain variables, including years of driving experience, daily hours of sleep, general markers of mental health, and symptoms of attention deficit hyperactivity dis- order (ADHD). Methods: Two hundred and seventy-five participants responded to a survey made up of the Manchester driver behaviour questionnaire, the general health questionnaire, the adult ADHD self-report scale, and 2 additional questions. Spearman’s coefficient was calculated for correlations between these variables, at statistical significance level P < 0.05. Results: Years of driving experience and hours of sleep had no correlations with driving performance. Markers of general mental health had a weak correlation with risky driving behaviour, and symptoms of ADHD had moderate correlation with risky driving behaviour. Conclusion: Policymakers and public health officials should screen for ADHD during driver licensing examination. Keywords: driving, mental health, United Arab Emirates, traffic safety, ADHD, students, university Citation: Andrade G; Bedawi D; Bani I. Mental health and driving behaviour of students and alumni of a university in the United Arab Emirates: a cross- sectional study. East Mediterr Health J. 2022;28(9):690–694. https://doi.org/10.26719/emhj.22.059 Received: 25/08/21, accepted: 29/05/22 Copyright © World Health Organization (WHO) 2020. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Book 28-09.indb 690 09/10/2022 11:07 AM 691 Short research communication EMHJ – Vol. 28 No. 9 – 2022 of sleep they got daily. Another question asked how many years of driving experience they had. The rest of the questions were made up of 3 questionnaires combined. The first set of questions were taken from a 12-item version of the general health questionnaire (GHQ-12), which assesses 3 non-psychotic dimensions of mental health obtained from factor loading analyses: social dysfunction, anxiety and loss of confidence (3). Social dysfunction assesses individuals’ capacity to properly function in society (e.g. Have you recently felt capable of making decisions?); anxiety assesses situations of stress and/or depression (e.g. Have you recently felt unhappy and depressed?); loss of confidence assesses situations in which the respondent does not feel they are functioning for optimal performance (e.g. Have you recently felt losing confidence?). Participants were asked to rate how frequently they experienced particular situations expressed in the items. Responses were given on a Likert scale, from 0 (not at all) to 3 (more than usually), with higher scores indicating worse mental health. The second set of questions were taken from a 9-item version of the Manchester driver behaviour questionnaire (Mini-DBQ). On the basis of previous factor loading analyses, the Mini-DBQ is structured around 3 dimensions: violations (e.g. I drive especially close or “flashing” the car in front as a signal for that driver to go faster), errors (e.g. I fail to notice, because lost in thought or distracted, someone waiting at a zebra crossing, or that a pelican crossing light has just turned red), and lapses (e.g. I forget where I left my car in a multi-level car park). Participants responded by identifying how frequently they engaged in each of the habits expressed in the items, on a Likert scale from 0 (never) to 5 (nearly all the time), with higher scores indicating poorer driving performance. The Mini-DBQ has good reliability, with a Cronbach alpha = 0.9. It has been properly validated (4). The third set of questions were taken from a 6-item version of the World Health Organization’s Adult ADHD self-report scale (ASRS), which assesses symptoms of ADHD among adults. Participants were asked about the frequency of particular situations (e.g. How often do you have trouble wrapping up the final details of a project, once the challenging parts have been done?), and they respond on the basis of a Likert scale (1 = never; 5 = very often), with higher scores indicating greater levels of ADHD. The ASRS is considered to have good reliability (5), and it has been validated across various settings (6). Given that most variables included an interval (rather than a ratio) level of measurement, Spearman’s test (instead of Pearson’s) was selected to establish correlation, in line with the recommendation of most statisticians for interval levels of measurement. Coefficients were calculated for correlations between driving behaviour (violations, lapses, errors) and general mental health (social dysfunction, anxiety, loss of confidence), years of driving experience and daily hours of sleep. Statistical significance was P < 0.05. Results We surveyed 275 participants: 64 males and 211 females. Mean age was 27.3 (standard deviation 7.24) years. Spearman’s coefficients for correlations between dimensions of driving behaviour (violations, errors and lapses) and symptoms of ADHD, years of driving experience and hours of sleep, are presented in Table 1. Results show that ASRS had a weak but statistically significant correlation with violations (r = 0.31; P < 0.01), a moderate and statistically significant correlation with errors (r = 0.49; P < 0.01) and a moderate and statistically significant correlation with lapses (r = 0.47; P < 0.01). Neither years of driving experience nor hours of sleep had any statistically significant correlation with any dimension of driving behaviour. Spearman’s coefficients for correlations between dimensions of driving behaviour (violations, errors and lapses) and dimensions of general mental health (social dysfunction, anxiety, loss of confidence) are presented in Table 2. Social dysfunction had a very weak but statistically significant correlation with violations (r = 0.15; P < 0.05) but no statistically significant correlation with errors or lapses. Anxiety had a weak but statistically significant correlation with violations (r = 0.25; P < 0.01), with errors (r = 0.27, P < 0.01) and with lapses (r = 0.29; P < 0.01). Loss of confidence had a weak but statistically significant correlation with violations (r = 0.21; P < 0.01), with errors (r = 0.27; P < 0.01) and with lapses (r = 0.25; P < 0.01). Discussion We found that years of driving experience had no correlation with any of the assessed dimensions of driver behaviour. This would imply that road safety does not improve with greater experience, and most likely, driver behaviour remains constant. Similar findings have been reported in previous research. For example, one large study found “no evidence of a group of drivers whose aberrant behaviour decreased over time” (7). More surprisingly, our study reveals that hours of sleep had no correlation with any of the dimensions of driving behaviour. This finding runs counter to previous research, in which sleep deprivation was related to poor Table 1 Correlation between the driving behaviour questionnaire and physical factors in a survey of 275 permanent residents of the United Arab Emirates Factor Spearman’s coefficient (df = 273) Violations Errors Lapses DBQ (total) ASRS 0.31** 0.49** 0.47** 0.50** Years of driving experience 0.002 –0.04 0.06 0.03 Hours of sleep 0.002 –0.08 –0.03 –0.05 ASRS = attention-deficit hyperactivity disorder self-report; DBQ= driving behaviour questionnaire **P < 0.01. Book 28-09.indb 691 09/10/2022 11:07 AM 692 Short research communication EMHJ – Vol. 28 No. 9 – 2022 driving performance (8). One possible explanation for this study’s failure to replicate such results is that, while insufficient sleep time may indeed negatively affect driving behaviour, the participants may not have had sufficient insight to self-report it in a questionnaire. Additionally, it is possible that a hidden variable may be responsible for this lack of correlation between sleep and dangerous driving behaviour. The present study assessed usual hours of sleep in participants, but specific episodes of sleep deprivation (not necessarily persistent over time) may have a correlation with dangerous driving behaviour. In fact, previous research suggests that isolated sleep deprivation episodes can detrimentally affect driving performance, regardless of general sleeping patterns (9). Our results show that general mental health scores have only a weak correlation with risky driving behaviour. These results fail to replicate previous studies in which markers of general mental health as assessed by the GHQ-12 had stronger correlations with drivers’ behaviours in countries such as the Islamic Republic of Iran. We found that social dysfunction scores had only a negative weak correlation with driving violations; loss of confidence scores had a negative (somewhat stronger but still overall weak) correlation with violations, errors and lapses in driving behaviour. Previous research in the United Arab Emirates had found that “drivers who reported feeling depressed were more than twice as likely to be at fault for their collision than drivers who did not report such feelings” (10), and more extensive research had documented that, indeed, depression may negatively impact driver safety (11). Likewise, anxiety may impair driving skills as stress may influence working memory, and it may consume mental resources needed to prevent lapses and errors in driving performance (12). Nevertheless, in our study, anxiety (and its corollary, depression) scores had only negative weak correlations with violations, error and lapses. Future research controlling for other variables may be needed to determine whether this failure to fully replicate such results was only an anomaly or whether some other variables were responsible Some caution in considering the relationship between anxiety and driving performance must be considered. In this study, the relationship between both variables was negative and monotonic (i.e. the value of one variable increased as the value of the other decreased). But research suggests that the relationship between anxiety and performance (not only in driving, but any task) may also be non-monotonic (13). Too high levels of anxiety are detrimental to optimal performance, but at the other extreme, too low levels of anxiety may also be detrimental to performance. For example, excessive relaxation may cause reduced caution in drivers (and consequently, increased errors and lapses) since drivers do not feel the stress necessary to concentrate on the task. Interestingly, symptoms of ADHD did have a much stronger correlation with dimensions of driving behaviour. The correlation with violations was only weak. This is very much expected as violations in driving behaviour relate to deliberate attempts to break traffic rules, and in this regard attention deficit and hyperactivity do not have a strong impact. However, symptoms of attention deficit and hyperactivity do have a moderate positive correlation on the propensity to commit errors and lapses while driving. Prior research has established that, indeed, symptoms of ADHD are a considerable risk in driving performance. One study concluded that “drivers (with ADHD symptoms) rate themselves as more angry, risky and unsafe drivers and reported experiencing more losses of concentration and vehicular control” (14). Our results replicate such findings to the extent that there was a moderate correlation between self-report of ADHD symptoms and self-report of risky driving habits. One plausible theoretical explanation for these results is that, inasmuch as driving in increasingly complex urban settings requires sustained attention and concentration, individuals with deficits in those particular mental skills would be more likely to engage in poorer driving performance. The impulsivity dimension of ADHD may also have a significant detrimental effect on driving performance. Previous research has established that impulsivity increases dangerous driving behaviour (15). This is expected, given that, in complex urban settings, driving decisions must be taken with confidence, yet at the same time assessing the risks involved. Overly impulsive behaviour impairs this capacity, to the extent that drivers may attempt particular manoeuvres without the necessary deliberation for their decisions. Study limitations This study had some limitations. Sampling was limited to students and alumni of Ajman University, and consequently, the results can only be taken as an initial assessment of the driving behaviour in the United Arab Emirates, but not as a robust indicator. Further studies with broader segments of the United Arab Emirates population would provide more robust conclusions. Availability for recruitment amongst participants was easier with women, and therefore sampling included significantly more women than men. This needs to Table 2 Correlations for the driving behaviour questionnaire and markers of mental health in a survey of 275 permanent residents of the United Arab Emirates Factor Spearman’s coefficient (df = 273) Violations Errors Lapses DBQ (total) Social dysfunction 0.15* –0.08 –0.09 – Anxiety 0.25** 0.27** 0.29** – Loss of confidence 0.21** 0.27** 0.25** – GHQ-12 total – – – 0.18** GHQ-12 = general health questionnaire; DBQ= driving behaviour questionnaire *P < 0.05; **P < 0.01. Book 28-09.indb 692 09/10/2022 11:07 AM 693 Short research communication EMHJ – Vol. 28 No. 9 – 2022 be considered a limitation, and further studies with a more balanced sample in the sex variable could provide stronger conclusions. Another limitation of the study was its cross-sectional nature. Data were collected at a particular moment, but in order to obtain more robust conclusions, more advanced designs (e.g. cohort and case–control studies) should be done. For practical timing purposes in the administration of the surveys, a shortened version of the general health questionnaire was used. In future studies, a comprehensive assessment of mental health should be included to thoroughly examine the dimensions of mental health and their possible relationship to driving performance. Perhaps most importantly, this study relied on self-reporting of driving behaviours. This is an important limitation, given that a more robust assessment of driving behaviour relies on independent observation. While acknowledging these limitations, some tentative conclusions and recommendations can be made. Based on the study results, policymakers and public health officials in the United Arab Emirates should support programmes aimed at improving general mental health in the population because such programmes can improve driving performance. The results show that symptoms of ADHD had a moderate correlation with risky driving behaviour, traffic safety policymakers in the United Arab Emirates should implement a twofold policy. First, greater awareness of the risks of ADHD is needed. Second, screening procedures during drivers’ licensing examination should begin to consider assessment of attention deficit and hyperactivity. Funding: None Competing interests: None declared. Santé mentale et comportement au volant des étudiants actuels et anciens d’une université aux Émirats arabes unis : étude transversale Résumé Contexte : Les Émirats arabes unis ont fixé l'objectif de réduire le nombre de décès liés à la circulation à trois pour 100 000 habitants à l’horizon 2021. Pour ce faire, les autorités doivent évaluer les facteurs liés aux comportements de conduite à risque. Objectifs : Vérifier s'il existe des corrélations entre le comportement au volant et certaines variables, dont les années d'expérience de conduite, les heures de sommeil quotidiennes, les marqueurs généraux de la santé mentale et les symptômes du trouble déficitaire de l'attention avec hyperactivité (TDAH). Méthodes : Deux cent soixante-quinze participants ont répondu à une enquête composée du Manchester Driver Behaviour Questionnaire, du General Health Questionnaire, de l'Adult ADHD Self-Report Scale et de deux questions supplémentaires. Le coefficient de Spearman a été calculé pour les corrélations entre ces variables, au niveau de signification statistique p < 0,05. Résultats : Les années d'expérience de conduite et les heures de sommeil n'avaient aucune corrélation avec les performances de conduite. Les marqueurs de la santé mentale générale et les symptômes du TDAH avaient une corrélation respectivement faible et modérée avec le comportement de conduite à risque. Conclusion : Les décideurs et les responsables de la santé publique devraient dépister le TDAH lors de l'examen du permis de conduire. ةيعطقم ةسارد :ةدحتلما ةيبرعلا تاراملإا في ةدايقلا كولسو ةيسفنلا ةحصلا نياب ميهاربإ ،يودب ايلاد ،يداردنأ لييرباج ةصلالخا كلذ قيقحتلو . ةمسن فلأ 100 لكل تلااح 3 لىإ رورلما ثداوحب ةطبترلما تايفولا نم دلحا فدهتست انهأ ةدحتلما ةيبرعلا تاراملإا تنلعأ :ةيفللخا .ةرطلخا ةدايقلا تايكولسب ةقلعتلما لماوعلا مييقت تاطلسلا لىع بيج ،فدلها تاعاسو ،ةدايقلا في ةبرلخا تاونس لمشتو ،ةنيعم تايرغتمو ةدايقلا تايكولس ينب طابترا دوجو نم ققحتلا لىا ةساردلا هذه تفده :فادهلأا .طاشنلا طرف عم هابتنلاا صقن بارطضا ضارعأو ،ةيسفنلا ةحصلل ةماعلا تماساولاو ،ا ًّيموي مونلا سايقمو ،ةماعلا ةحصلا نايبتساو ،ينقئاسلا تايكولسل ترسشنام نايبتسا نم نوكم حسم لىع اًكراشم نوعبسو ةسخمو ناتئام باجأ :ثحبلا قرط طابترلال ناميربس لماعم نوثحابلا بسحو .ينيفاضإ ينلاؤس لىإ ةفاضلإاب ،ينغلابلا ىدل طاشنلا طرف عم هابتنلاا صقن بارطضلا تياذلا غلابلإا .0.05 نع ةيلماتحلاا ةميقلا هيف لقت ةيئاصحإ ةللاد ىوتسم دنع كلذو ،تايرغتلما هذه ينب Book 28-09.indb 693 09/10/2022 11:07 AM 694 Short research communication EMHJ – Vol. 28 No. 9 – 2022 References 1. Road traffic death rate per 100 thousand population. Safe public and fair judiciary. Abu Dhabi: United Arab Emirates, Ministry of Interior; 2021 (https://www.vision2021.ae/en/national-agenda-2021/list/card/road-traffic-death-rate-per-100-thousand-popula1- tion, accessed 20 June 2022). 2. Beanland V, Sellbom M, Johnson AK. Personality domains and traits that predict self-reported aberrant driving behaviours in a southeastern US university sample. Accid Anal Prev. 2014 Nov 1;72:184–92. doi:10.1016/j.aap.2014.06.023 3. Schrnitz N, Kruse J, Tress W. Psychometric properties of the General Health Questionnaire (GHQ‐12) in a German primary care sample. Acta Psychiatr Scand. 1999 Dec;100(6):462–8. doi:10.1111/j.1600-0447.1999.tb10898.x 4. Martinussen LM, Lajunen T, Møller M, Özkan T. Short and user-friendly: the development and validation of the Mini-DBQ. Accid Anal Prev. 2013 Jan;50:1259–65. doi:10.1016/j.aap.2012.09.030. 5. Silverstein MJ, Alperin S, Faraone SV, Kessler RC, Adler LA. Test–retest reliability of the adult ADHD Self-Report Scale (ASRS) v1. 1 Screener in non-ADHD controls from a primary care physician practice. Fam Pract. 2018 May 23;35(3):336–41. doi:10.1093/ fampra/cmx11 6. Gray S, Woltering S, Mawjee K, Tannock R. The Adult ADHD Self-Report Scale (ASRS): utility in college students with atten- tion-deficit/hyperactivity disorder. PeerJ. 2014 Mar 25;2:e324. doi:10.7717/peerj.324 7. Roman GD, Poulter D, Barker E, McKenna FP, Rowe R. Novice drivers’ individual trajectories of driver behavior over the first three years of driving. Accid Anal Prev. 2015 Sep;82:61–9. doi:10.1016/j.aap.2015.05.012. 8. Papadakaki M, Kontogiannis T, Tzamalouka G, Darviri C, Chliaoutakis J. Exploring the effects of lifestyle, sleep factors and driving behaviors on sleep-related road risk: a study of Greek drivers. Accid Anal Prev. 2008 Nov;40(6):2029–36. doi:10.1016/j. aap.2008.08.01 9. Philip P, Sagaspe P, Moore N, Taillard J, Charles A, Guilleminault C, Bioulac B. Fatigue, sleep restriction and driving perfor- mance. Accid Anal Prev. 2005 May;37(3):473–8. doi:10.1016/j.aap.2004.07.007 10. AlKetbi LMB, Grivna M, Al Dhaheri S. Risky driving behaviour in Abu Dhabi, United Arab Emirates: a cross-sectional, sur- vey-based study. BMC Public Health. 2020 Aug 31;20(1):1324. doi:10.1186/s12889-020-09389-8.. 11. Shahar A. Self-reported driving behaviors as a function of trait anxiety. Accid Anal Prev. 2009 Mar;41(2):241–5. doi:10.1016/j. aap.2008.11.004 12. Pourabdian S, Azmoon H, Mirlohi AH, Hassnzadeh A. Effect of state anxiety on driver behavior with regard to self-reported in Iranian drivers. Int J Env Health Eng. 2014 Jan 1;3(1):18. doi:10.4103/2277-9183.138411 13. Abramis DJ. Relationship of job stressors to job performance: Linear or an inverted-U?. Psychol Rep. 1994 Aug;75(1 Pt 2):547–58. doi:10.2466/pr0.1994.75.1.547 14. Richards TL, Deffenbacher JL, Rosén LA, Barkley RA, Rodricks T. Driving anger and driving behavior in adults with ADHD. J Atten Disord. 2006 Aug;10(1):54–64. doi:10.1177/1087054705284244 15. Bıçaksız P, Özkan T. Impulsivity and driver behaviors, offences and accident involvement: A systematic review. Transportation Research Part F: Traffic Psychol Behav. 2016;38(1):194–223. doi:10.1016/j.trf.2015.06.001 ةحصلا تماساوو ةرطلخا ةدايقلا تايكولس ينب اًفيعض طابترلاا ناكو .ةدايقلا في ءادلأاب طبترت لا مونلا تاعاسو ةدايقلا في ةبرلخا تاونس :جئاتنلا .طاشنلا طرف عم هابتنلاا صقن بارطضا ضارعأو تايكولسلا كلت ينب اًطسوتم ناك هنكلو ،ةماعلا ةيسفنلا ءانثأ في طاشنلا طرف عم هابتنلاا صقن بارطضا نع فشكلل صحف ءارجإ ةماعلا ةحصلا ليوؤسمو تاسايسلا يعضاول يغبني :تاجاتنتسلاا .ةدايق ةصخر لىع لوصحلل يبطلا صحفلا Book 28-09.indb 694 09/10/2022 11:07 AM 695 Review EMHJ – Vol. 28 No. 9 – 2022 Risk assessment of road traffic accidents related to sleepiness during driving: a systematic review Shehzad Saleem1 1Department of Community Medicine, King Edward Medical University, Lahore, Punjab, Pakistan (Correspondence to: S. Saleem: drshehzad786@gmail. com). Introduction Sleep is a dynamic process that affects the way our bodies function (1). Sleepiness can be defined as difficulty remaining awake even while carrying out activities (2). Sleep deprivation is defined as a state caused by inadequate quantity or quality of sleep, including voluntary or involuntary sleeplessness and circadian rhythm sleep disorders (3). Sleepiness results in disrupted brain functioning, such as reduced reaction time or decreased ability for decision-making. It is a major contributor to road traffic accidents, which often occur when a driver experiences drowsiness at the wheel, or due to sleep abnormalities, lack of sleep, alcohol consumption or medication (4). About 1.3 million deaths occur each year as a result of road traffic accidents globally, causing a 3% loss of the gross domestic product of most countries (5). The US National Highway Traffic Safety Administration has estimated that worldwide every year, about 100 000 road accidents are caused by drowsiness, accounting for > 1500 deaths and > 70,000 injuries (6). In every country, road traffic accidents are a major public health problem and cause huge societal and financial burdens (7). Sleepiness causes disruption of neurological functions (8,9). Factors that contribute to the incidence of road traffic accidents range from continued driving even when feeling drowsy, having a physical condition, fewer sleeping hours, more working hours, and nutritional imbalances (10). Several studies during the last 20 years have suggested that sleepiness is among the main factors that cause road traffic accidents (11–15). Sleepiness while driving contributes to 3% to > 30% of all road traffic accidents globally (16–18), which may involve a variety of sleep conditions but also may be caused by sleep deprivation (19–20). More than 20% of the drivers feel a need to stop driving at least once due to sleepiness (21). A religious lifestyle was found to be negatively associated with the risk of road traffic accidents, as were younger drivers (22,23). This systematic review was designed for a better understanding of the relationship between sleepiness and risk of road traffic accidents. Methods Study protocol This systematic review protocol was developed keeping in view the requirements of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and guidelines 2020, without execution of a meta-analysis. The PRISMA statement is a guideline developed by an international group of 29 methodologists and experienced researchers in 2005. It comprises 27 checklists and 4-phase flow diagram to ensure transparent reporting of a systematic review [24]. Abstract Background: Injuries due to accidental crash are the 8th leading cause of death worldwide. Sleepiness results in disrupted neurological function and is a major risk factor for road traffic accidents. Aims: This systematic review assessed the relationship between sleepiness during driving and road traffic accidents. Methods: A systematic review was conducted using online databases such as Wiley Online Library, JSTOR, Medline, and PubMed. Full-text, English language articles published between May 2000 and November 2020 were retrieved. Road traffic accident was set as the outcome of interest and sleepiness during driving as the exposure. The review included studies containing adjusted risk estimates (95% confidence interval). Ten cross-sectional studies (N = 55,945), 5 case- control studies (N = 3821), and 2 cohort studies (N =16,875) were included. Results: Over 50% of the participants in the different studies experienced sleep deprivation ranging from 3.5% to 67.3%. Abe et al. reported the highest (58%) frequency of sleepiness during driving in their cross-sectional study in Japan, and Nabi et al. reported the lowest (1.1%) in their cohort study in France. Conclusion: Sleepiness and sleep deprivation were related to road traffic accidents; and sleep deprivation was the main contributor to drowsiness while driving. Keywords: road traffic accidents, sleepiness, driving, observational study, risk assessment Citation: Saleem S. Risk assessment of road traffic accidents related to sleepiness during driving: a systematic review. East Mediterr Health J. 2022;28(9):695–700. https://doi.org/10.26719/emhj.22.055 Received: 09/10/21; accepted: 11/05/22 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo) Book 28-09.indb 695 09/10/2022 11:07 AM 696 Review EMHJ – Vol. 28 No. 9 – 2022 Search strategy The reviewer searched for articles published between January 2000 and December 2020 in Wiley Online Library, JSTOR, Medline and PubMed databases. The keywords used were: road traffic accidents, sleepiness while driving, and observational study. PRISMA information flow during the phases of this systematic review is presented in Figure 1. Search eligibility criteria The reviewer included observational studies with adjusted risk estimates and outcome measure of road traffic accidents. Due to expected difficulties of quantification, excluded studies were experimental studies, case series without comparison groups and case reports. Data extraction The potentially relevant articles were screened by title and abstract and full text of the articles were retrieved from databases. Final eligibility was assessed independently keeping in view the PRISMA guideline checklist 2020, and the reviewer extracted the following details from the included studies: study design (cross-sectional, case-control and cohort), number of road accidents, frequency of sleepiness while driving, and the adjusted risk estimates of accidents resulting from sleepiness. For quality assessment purposes, the Newcastle Ottawa Scale was used with a total score for quality ranging from 0 to 9 (25). Participants’ characteristics such as age, gender, and sleep disorders and lack of sleep due to workload/ other causes were extracted. The overall frequency of sleepiness during driving was calculated using adjusted risk estimates. Study selection A total of 5651 articles were identified from Wiley Online Library, JSTOR, Medline and PubMed databases, where sleepiness while driving was among the causes of road traffic accidents. A total of 1132 duplicates (20.03%) were removed including 717 (63.33%) from JSTOR, and 415 from Medline and PubMed (36.66%). Out of the 4519 remaining articles (79.96%), 4283 were found to be unrelated (94.77%) and were excluded. The remaining 236 articles (5.22%) were fully reviewed and this led to a total of 17 observational studies (7.20%) that qualified for the systematic review. The 17 eligible studies consisted of a total of 76,641 participants worldwide (Table 1). There were 10 cross-sectional studies (55, 945 participants; 72.99%); 5 case-control studies (3821 participants; 4.98%), and 2 cohort studies (16,875 participants; 22.01%). Sixteen studies included both sexes while 2 Saudi Arabian studies were based on men due to the previous ban on female drivers. The ages of participants were < 30 years in 3 studies, 30–50 years in 8 studies, and > 50 years in 6 studies. Figure 1 PRISMA flow data Id en tifi ca tio n Duplicates records removed (n = 1132) Records identified from database searches: (n = 5851) Identification of studies via databases and registers Sc re en in g Records excluded after title and abstract screening (n = 4283) No. of records after duplicates removed (n=4519) Reports excluded: No English full-text articles (n=12) No observational studies (n = 15) No road traffic accidents (n = 34) No estimation measures (n = 62) No measure sleepiness during driving (n = 94) Duplicate studies (n = 2) Full-text articles assessed for eligibility (n = 236) In cl ud ed Studies included in systematic review (n = 17) Book 28-09.indb 696 09/10/2022 11:07 AM 697 Review EMHJ – Vol. 28 No. 9 – 2022 Results Results from all 17 studies showed that sleepiness and sleep deprivation were major contributors to road traffic accidents. The high frequency of sleepiness reported while driving, with significant odd ratios, makes this a significant risk factor for road traffic accidents. In these studies, > 50% (3.5–67.3%) of the participants agreed that they experienced sleep deprivation. Abe et al. reported the highest (58%) frequency of sleepiness during driving in their cross-sectional study (OR 12.90) in Japan, and Nabi et al. reported the lowest (1.1%) in a cohort study in France (OR 2.90) (Figure 2). Liu et al concluded that a significant decrease in injuries related to road traffic accidents can be attained if fewer people drive when they are sleepy (26). Gottlieb et al. associated sleep apnoea with a 123% greater risk of road traffic accidents than apnoea unrelated to sleep (27). This shows that sleeping for 6 hours daily is connected to a 33% greater risk of accidents than sleeping for 7 or 8 hours per night. Comparatively, Cummings et al. reported such an accident risk to be 39.5% in a case–control study in the United States of America [14]. Lloberes et al found in a cross-sectional study in Spain that 35.3% of drivers fell asleep while driving (28). Pizza et al. reported 1.9 times greater risk of accidents in individuals with poor sleep quality making them to fall asleep while driving (29). AlShareef et al. in a population-based analysis in Saudi Arabia showed the correlation between sleep and sleepiness during driving and reported that the strongest sleep predictor while driving was being a male driver (30). Most drivers in this study were men (86.5%) as women have only been allowed to drive in Saudi Arabia since June 2018. Sagaspe et al. found that 28% of drivers had at least 1 incident of uncontrollable sleepiness during driving, and about 5% of drivers had an accident or near miss due to sleepiness (31). Stutts et al. reported that almost 8% of the drivers in road traffic accidents admitted consuming alcohol before causing a crash. However, this study highlighted potential bias because the data depended on self-reports and the drivers could have blamed longer work hours and poor sleep habits for their accidents (32). Limitations of this review include the possibility of selection bias because of the methods used or participants involved. There may have been a residual confounding effect because studies were based on observational Ta bl e 1 E st im at es o f r is k as so ci at ed w it h sl op pi ne ss d ur in g dr iv in g St ud y ty pe (r ef ) Co un tr y Sa m pl e si ze (a cc id en ts ) Ag e, y r W om en Sl ee pi ne ss du ri ng d ri vi ng (a cc id en ts ) Fr eq ue nc y of sl ee pi ne ss du ri ng d ri vi ng Sl ee p di so rd er s Sl ee p de pr iv at io n O R (9 5% C I) Cr os s- se ct io na l ( 10 ) Ja pa n 24 62 (2 1) 30 –5 0 22 .0 % 14 29 (2 0) 58 .0 20 .5 42 .8 12 .9 0 (1. 72 –9 7. 69 ) Cr os s- se ct io na l ( 2) Sa ud i A ra bi a 12 19 (7 73 ) 30 –5 0 0 30 7 (2 28 ) 25 .1 1.1 67 .3 1.1 9 (0 .8 5– 1.6 7) Ca se –c on tr ol (4 ) N ew Z ea la nd 11 59 (5 71 ) <3 0 36 .6 % 71 (6 3) 6. 1 1.4 9. 0 8. 20 (3 .4 0– 19 .7 0) Ca se –c on tr ol (9 ) U SA 39 9 (11 4) 30 –5 0 31 .0 % 15 8 (N R) 39 .5 38 .8 15 .0 1.6 0 (1. 0– 2. 70 ) Cr os s- se ct io na l ( 16 ) N ew Z ea la nd 53 68 (6 44 ) 30 –5 0 48 .0 % N R N R N R — 1.5 2 (1. 15 –2 .0 2) Co ho rt (2 3) U SA 32 01 (2 22 ) 40 –8 9 45 .4 22 2 6. 9 1.3 69 .0 Cr os s- se ct io na l ( 17 ) G re ec e 13 66 (7 42 ) 30 –5 0 40 .0 N R N R N R N R 1.4 1 ( 1.1 4– 1.7 6) Cr os s- se ct io na l ( 18 ) U SA 50 6 (2 02 ) <3 0 46 .0 10 3 (5 5) 20 .3 N R 36 .7 1.7 9 (1. 07 –2 .9 9) Ca se –c on tr ol (2 1) Ch in a 84 4 (4 06 ) >5 0 3. 9 19 (8 ) 2. 25 4. 9 3. 5 0. 63 (0 .2 2– 1.8 2) Cr os s- se ct io na l ( 24 ) Sp ai n 22 9 (6 0) >5 0 5. 0 81 (N R) 35 .3 82 .5 N R 5. 05 (2 .3 0– 10 .9 0) Co ho rt (8 ) Fr an ce 13 6 74 (2 60 ) >5 0 23 .0 16 0 (N R) 1.1 N R N R 2. 90 (1 .3 0– 6. 32 ) Ca se –c on tr ol (7 ) Fr an ce 54 4 (2 72 ) 30 –5 0 49 .0 20 (1 7) 3. 6 16 .2 23 .5 9. 97 (1 .5 7– 63 .5 0) Cr os s- se ct io na l ( 15 ) Fr an ce 35 0 04 (2 52 0) >5 0 26 .0 20 2 36 (1 31 ) 57 .8 5. 2 N R 9. 48 (4 .14 –2 1.7 2) Cr os s- se ct io na l ( 25 ) It al y 33 9 (8 0) <3 0 42 .0 13 5 (4 5) 39 .8 5. 8 N R 2. 06 (1 .19 –3 .5 6) Cr os s- se ct io na l ( 26 ) Sa ud i A ra bi a 46 79 (4 74 ) <5 0 13 .6 3 11 5 10 .2 N R N R 1.9 0 (1. 38 –2 .6 0) Cr os s- se ct io na l ( 27 ) Fr an ce 47 74 (2 78 ) >5 0 54 .0 14 11 (1 38 ) 29 .5 2. 2 N R 2. 03 (1 .5 7– 2. 64 ) Ca se –c on tr ol (2 8) U SA 87 4 (4 67 ) 30 –5 0 N R 29 2 (16 9) 33 .4 47 .8 18 .3 8. 25 (4 .5 3– 15 .0 5) CI = co nfi de nc e i nt er va l; N R = no t r ec or de d; O R = od ds ra tio ; U SA = U ni te d St at es of A m er ica . Book 28-09.indb 697 09/10/2022 11:07 AM 698 Review EMHJ – Vol. 28 No. 9 – 2022 methods. Other possible risk factors for accidents, age, body mass index, medical conditions, alcohol and drug abuse, and sleep duration were not calculated in terms of ORs (adjusted) in all of the studies used for this review. Conclusion Driver fatigue or drowsiness is a road transport safety hazard. The risk of road traffic accidents increases proportionately when drivers experience sleepiness. Among the frequent explanations for sleepiness during driving were sleep disorders such as sleep apnoea and some behavioural factors, most importantly sleep deprivation. The risk factors for sleep deprivation were found to be driving at night, not getting enough sleep, and working or staying awake for long periods. Other factors were young age, male sex, office worker, smoker, shorter sleep duration, poor subjective sleep quality, moderate or severe excessive daytime sleepiness, and alcoholism. A minimum of 6 hours of sleep every day could significantly decrease the number of road traffic accidents. To reduce the incidence of accidents related to sleepiness during driving, it is important to conduct safety checks before driving, monitor sleeping patterns, record and track driving hours, and conduct psychological assessments and behavioural training. The results show that road traffic accidents are consistently associated with sleepiness during driving. Therefore, awareness campaigns and strengthening of road safety programmes should be implemented to reduce the increasing number of road traffic accidents related to sleepiness during driving. Further studies will be required for a more in- depth analysis of this subject. Funding: None Competing interests: None declared. يجهنم ضارعتسا :ةدايقلا ءانثأ ساعنلا ببسب ةيرورلما ثداولحا رطامخ مييقت ميلس دازهش ةصلالخا رطخ لماع ،ةيبصعلا فئاظولل ليطعت نم هببسي ماب ،ساعنلاو .لماعلا في ةافولل نماثلا سييئرلا ببسلا يه تامداصتلا نع ةجمانلا تاباصلإا :ةيفللخا .ةيرورلما ثداوحلل سياسأ .ةيرورلما ثداولحاو ةدايقلا ءانثأ ساعنلا ينب ةقلاعلا مييقت لىا يجهنلما ضارعتسلاا اذه في ةساردلا هذه تفده :فادهلأا كلذكو Wiley Online Library لثم تنترنلإا لىع ةحاتلما تانايبلا دعاوق مادختساب ا ًّيجهنم اًضارعتسا ثحابلا ىرجأ :ثحبلا قرط عجترسا ثيح ،PubMed ةيبطلا تانايبلا ةدعاقو )نيلادم تانايب ةدعاق( ةيجولويبلاو ةيبطلا ةيفارجويليبلا تامولعلما عاجترسا ماظنو JSTOR ةيرورلما ثداولحا ثحابلا ددحو .2020 نياثلا نيشرت / برمفونو 2000 رايآ /ويام ينب ةيزيلجنلإا ةغللاب ةروشنلما تلااقملل لماكلا صنلا ةترفب( ةلدعم رطامخ تاريدقت لىع يوتتح تاسارد ضارعتسلاا ن َّمضتو .ضرعتلا هفصوب ةدايقلا ءانثأ ساعنلاو ،مماتهلاا لمح ةجيتنلا اهفصوب Évaluation des risques d'accidents de la route liés à la somnolence au volant : une revue systématique Résumé Contexte : Les traumatismes dus à un accident représentent la huitième cause de décès dans le monde. La somnolence entraîne une perturbation des fonctions neurologiques et constitue un facteur de risque majeur d'accidents de la circulation. Objectifs : La présente revue systématique a évalué la relation entre la somnolence au volant et les accidents de la circulation. Méthodes : Une analyse systématique a été réalisée en utilisant des bases de données en ligne telles que Wiley Online Library, JSTOR, Medline et PubMed. Des articles complets, en langue anglaise, publiés entre mai 2000 et novembre 2020 ont été extraits. L'accident de la circulation a été fixé comme le résultat d'intérêt et la somnolence au volant comme l'exposition. L'analyse comprenait des études contenant des estimations de risque ajustées (intervalle de confiance à 95 %). Dix études transversales (n = 55 945), cinq études cas-témoins (n = 3821) et deux études de cohorte (n = 16 875) ont été incluses. Résultats : Plus de 50 % des participants aux différentes études ont connu une privation de sommeil allant de 3,5 à 67,3 %. Dans leur étude transversale au Japon, Abe et al. ont rapporté la fréquence de somnolence la plus élevée (58 %) et Nabi et al. la plus faible (1,1 %) dans leur étude de cohorte en France. Conclusion : La somnolence et la privation de sommeil étaient liées aux accidents de la circulation, et la privation de sommeil était le principal facteur de somnolence au volant. Book 28-09.indb 698 09/10/2022 11:07 AM 699 Review EMHJ – Vol. 28 No. 9 – 2022 References 1. Brain basics: understanding sleep [website]. National Institute of Neurological Disorders and Stroke (https://www.ninds.nih. gov/Disorders/Patient-Caregiver-Education/Understanding-Sleep, accessed 14 June 2022). 2. Sleep deprivation [website]. ResSleep; 2021 https://www.ressleep.com.au/sleep-deprivation, accessed 14 June 2022). 3. Sleep deprivation [website]. Better Health Channel; 2021 (https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/ sleep-deprivation, accessed 14 June 2022). 4. Miyama G, Fukumoto M, Kamegaya R, Hitosugi M. Risk factors for collisions and near-miss incidents caused by drowsy bus drivers. Int J Environ Res Public Health. 2020 Jun 18;17(12):4370. https://doi.org/10.3390/ijerph17124370. PMID:32570777 5. Road traffic injuries [website]. Geneva: World Health Organization (https://www.who.int/news-room/fact-sheets/detail/ road-traffic-injuries, accessed 14 June 2022). 6. Preidt, R. Sleepy drivers involved in 100,000 crashes a year [website]. WebMD; 2018 (https://www.webmd.com/sleep-disorders/ news/20181107/sleepy-drivers-involved-in-100000-crashes-a-year, accessed 14 June 2022). 7. Prevalence of motor vehicle crashes involving drowsy drivers, United States, 1999–2008. Accid Anal Prev. 2012 Mar;45:180–6. https://doi.org/10.1016/j.aap.2011.05.028 PMID:22269499 8. Medic G, Wille M, Hemels ME. Short- and long-term health consequences of sleep disruption. Nat Sci Sleep. 2017 May 19;9:151– 61. https://doi.org/10.2147/NSS.S134864 PMID:28579842 9. Connor J, Norton R, Ameratunga S, Robinson E, Civil I, Dunn R, et al. (2002). Driver sleepiness and risk of serious injury to car occupants: population based case control study. BMJ 2002 May 11;324(7346):1125. https://doi.org/10.1136/bmj.324.7346.1125 PMID:12003884 10. Philip P, Chaufton C, Orriols L, Lagarde E, Amoros E, Laumon B, et al. Complaints of poor sleep and risk of traffic accidents: a population-based case-control study. PLoS One. 2014 Dec 10;9(12):e114102. https://doi.org/ 10.1371/journal.pone.0114102. PMID:25494198 11. Nabi H, Gueguen A, Chiron M, Lafont S, Zins M, Lagarde E. Awareness of driving while sleepy and road traffic accidents: pro- spective study in GAZEL cohort. BMJ. 2006 Jul 8;333(7558):75. https://doi.org/10.1136/bmj.38863.638194.AE PMID:16798754 12. Ohayon MM. Determining the level of sleepiness in the American population and its correlates. J Psychiatr Res. 2012;46(4):422– 7. https://doi.org/10.1016/j.jpsychires.2011.06.008. PMID:22297274 13. Ellen RL, Marshall SC, Palayew M, Molnar FJ, Wilson KG, Man-Son-Hing M. Systematic review of motor vehicle crash risk in persons with sleep apnea. J Clin Sleep Med. 2006 Apr 15;2(2):193–200. PMID:17557495 14. Cummings P, Koepsell TD, Moffat JM, Rivara FP. Drowsiness, counter-measures to drowsiness, and the risk of a motor vehicle crash. Inj Prev. 2001 Sep;7(3):194–9. https://doi.org/10.1136/ip.7.3.194. PMID:11565983 15. Abe T, Komada Y, Nishida Y, Hayashida K, Inoue Y. Short sleep duration and long spells of driving are associated with the occur- rence of Japanese drivers rear-end collisions and single-car accidents. J Sleep Res. 2010 Jun;19(2):310–316. https://doi.org/10.1111/ j.1365-2869.2009.00806.x. PMID:20337905 16. Carter, N., Ulfberg, J., Nyström, B., & Edling, C. (2003). Sleep debt, sleepiness and accidents among males in the general popula- tion and male professional drivers. Accident; analysis and prevention, 35(4), 613–617. https://doi.org/10.1016/s0001-4575(02)00033- 7. PMID:12729824 17. Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep. 2004 Dec 15;27(8):1453–1462. https://doi.org/10.1093/sleep/27.8.1453. PMID:15683134 18. Philip P, Sagaspe P, Lagarde E, Leger D, Ohayon MM, Bioulac B, et al. Sleep disorders and accidental risk in a large group of regu- lar registered highway drivers. Sleep Med. 2010 Dec;11(10):973–979. https://doi.org/ 10.1016/j.sleep.2010.07.010. PMID:20961809 19. BaHammam AS, Alkhunizan MA, Lesloum RH, Alshanqiti AM, Aldakhil AM, Pandi-Perumal SR et al. Prevalence of-relat- ed accidents among drivers in Saudi Arabia. Ann Thorac Med. 2014 Oct;9(4):236–41. https://doi.org/10.4103/1817-1737.140138 PMID:25276244 PMCID: PMC4166072 20. Czeisler CA, Wickwire EM, Barger LK, Dement WC, Gamble K, Hartenbaum N, et al. Sleep-deprived motor vehicle operators are unfit to drive: a multidisciplinary expert consensus statement on drowsy driving. Sleep Health, 2016 Jun;2(2):94–9. https://doi. org/10.1016/j.sleh.2016.04.003 PMID:28923267 ،)3821 = ددعلا( دهاوشلاو تلاالحا تاسارد نم تاسارد 5و ،)55،945 = ددعلا( ةيعطقم تاسارد شرع ةساردلا تلمشو .)%95 غلبت ةقث .)16،875 = ددعلا( بارتلأا تاسارد نم ينتساردو بيآ ركذو .%67.3و %3.5 ينب ةبسنلا تحوارتو ،مونلا نم نامرح نم نوناعي ةفلتخلما تاساردلا في ينكراشلما نم %50 نم رثكأ ناك :جئاتنلا ،مهتسارد في )%1.1( لدعم ىندأ نورخآو بيان ركذ مانيب ،نابايلا في ةيعطقلما مهتسارد في ةدايقلا ءانثأ في )%58( ساعنلل رتاوت لدعم لىعأ نورخآو .اسنرف في بارتلأا تاسارد نم يهو .ةدايقلا ءانثأ في ساعنلا في سييئرلا مهاسلما مونلا نم نامرلحا ناكو ،قرطلا لىع رورلما ثداوحب مونلا نم نامرلحاو ساعنلا طبترا :تاجاتنتسلاا Book 28-09.indb 699 09/10/2022 11:07 AM 700 Review EMHJ – Vol. 28 No. 9 – 2022 21. Gander PH, Marshall NS, Harris RB, Reid P. Sleep, sleepiness and motor vehicle accidents: a national survey. Aust N Z J Public Health. 2005 Feb;29(1):16–21. https://doi.org/10.1111/j.1467-842x.2005.tb00742.x PMID:15782866. 22. Gnardellis C, Tzamalouka G, Papadakaki M, Chliaoutakis JE. An investigation of the effect of sleepiness, drowsy driving, and lifestyle on vehicle crashes. Transp Res Traff Psychol Behav. 2008 Jul;11(4):270–81. (https://www.sciencedirect.com/science/arti- cle/pii/S1369847808000107) 23. Hutchens L, Senserrick TM, Jamieson PE, Romer D, Winston FK. Teen driver crash risk and associations with smoking and drowsy driving. Accid Anal Prev. 2008 May;40(3):869–76. https://doi.org/10.1016/j.aap.2007.10.001. PMID:18460353. 24. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. BMJ. 2009;339:b2700. https://doi.org/10.1136/bmj.b2700 25. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing he quality of nonrandom studies in meta-analyses [website]. Ottawa Hospital Research Institute (http://www.ohri.ca/programs/clinical_ep- idemiology/oxford.asp, accessed 15 June 2022). 26. Liu GF, Han S, Liang DH, Wang FZ, Shi XZ, Yu J, et al. Driver sleepiness and risk of car crashes in Shenyang, a Chinese north- eastern city: population-based case-control study. Biomed Environ Sci. 2003 Sep;16(3):219–26. PMID:14631827. 27. Gottlieb DJ, Ellenbogen JM, Bianchi MT, Czeisler CA. Sleep deficiency and motor vehicle crash risk in the general population: a prospective cohort study. BMC Med. 2018 Mar 20;16(1):44. https://doi.org/10.1186/s12916-018-1025-7 PMID:29554902 28. Lloberes P, Levy G, Descals C, Sampol G, Roca A, Sagales T, et al. Self-reported sleepiness while driving as a risk factor for traffic accidents in patients with obstructive sleep apnoea syndrome and in non-apnoeic snorers. Respir Med. 2000 Oct;94(10):971–6. https://doi.org/10.1053/rmed.2000.0869 PMID:11059950 29. Pizza F, Contardi S, Antognini AB, Zagoraiou M, Borrotti M, Mostacci B, et al. Sleep quality and motor vehicle crashes in adoles- cents. J Clin Sleep Med. 2010 Feb 15;6(1):41–5. PMID:20191936 30. AlShareef SM. Excessive daytime sleepiness and associations with sleep-related motor vehicle accidents: results from a nation- wide survey. Sleep Breath. 2021 Sep;25(3):1671–6. https://doi.org/10.1007/s11325-020-02260-5. PMID:33242183. 31. Sagaspe P, Taillard J, Bayon V, Lagarde E, Moore N, Boussuge J, et al. Sleepiness, near-misses and driving accidents among a representative population of French drivers. J Sleep Res. 2010 Dec;19(4):578–84. https://doi.org/10.1111/j.1365-2869.2009.00818.x PMID:20408921 32. Stutts JC, Wilkins JW, Scott Osberg J, Vaughn BV. Driver risk factors for sleep-related crashes. Accid Anal Prev. 2003 May;35(3):321-31. https://doi.org/10.1016/s0001-4575(02)00007-6 PMID:12643949. Book 28-09.indb 700 09/10/2022 11:07 AM WHO events addressing public health priorities 701 EMHJ – Vol. 28 No. 9 – 2022 Workshop for sharing best practices in sexual and reproductive health in the Eastern Mediterranean Region1 Citation: World Health Organization. Workshop for sharing best practices in sexual and reproductive health in the Eastern Mediterranean Region. East Mediterr Health J. 2022;28(9):701. https://doi.org/10.26719/2022.28.9.701 Copyright © World Health Organization (WHO) 2022. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo). 1 This is a summary of the report of a workshop for sharing best practices in sexual and reproductive health in the Eastern Mediterranean Region, available at: https://applications.emro.who.int/docs/WHOEMWRH111E-eng.pdf. Introduction There has been an increase in access to sexual and reproductive health (SRH) services, including contraceptives and voluntary counselling and testing for sexually transmitted infections, in the Eastern Mediterranean Region (EMR) (1). Improvements have been reported in several countries such as Afghanistan, Lebanon, Islamic Republic of Iran, Jordan, Libya, Morocco, Somalia, and Sudan (1). However, countries need to document and share lessons and experiences from these improvements to help shape the SRH research agenda in the region, and increase adoption, sustainability and impact of SRH initiatives by increasing the health and well-being of populations. In March 2021, the WHO Regional Office for the Eastern Mediterranean convened a virtual workshop on sharing best practices in SRH in the EMR. The workshop aimed to facilitate sharing of innovative methodologies, tools and approaches used to improve SRH services by countries in the region and discuss how to scale-up and sustain the outstanding initiatives. The workshop included 72 participants from 8 countries and territories in EMR and WHO. Summary of discussions Effective knowledge-sharing is a good strategy for providing essential evidence for policies and interventions and encouraging adoption of best practices. Based on mathematical modelling conducted in Afghanistan, Iraq, Morocco, Pakistan, Somalia, and Sudan, the benefits of continuing to provide SRH services at health facilities and in the community far outweigh the risks of infections during a pandemic such as the COVID-19. However, the magnitude of the benefits and the number of lives saved will depend on the effectiveness of interventions included in the model, baseline coverage of services, level of coverage disruption, number and impact of the mitigation measures, household size, and age structure of the population. During the ongoing pandemic, Morocco and Pakistan have been using the digital platforms for training, data collection, counselling, information sharing, and other SRH services. Lebanon, with guidance from the Ministry of Public Health, continues to involve professional, non- governmental and community-based organizations in the provision of SRH services. Participants agreed on the need to continue and advance the use of information technology and digital platforms for training, counselling, provision of SRH information, and to secure additional resources for services. They noted the importance of actively involving non-governmental organizations in service provision during emergencies and their catalytic role in maintaining essential SRH services. To make such support effective, coordination and clear guidance are essential, as they would help prevent duplication and overlapping of services and ensure the convergence and standardization of services based on the relevant national, regional, and global guidelines (2). Recommendations • WHO Member States are to identify SRH-related best practices for documentation and publication, organ- ize dissemination forums for SRH-related best prac- tices, and scale-up and sustain innovative initiatives by institutionalizing them. • WHO will provide technical and financial support for advocacy with the relevant authorities for identifica- tion, documentation, dissemination, adoption, and scale-up of innovative initiatives. References 1. Logie CH, Abela H, Turk T, Parker S, Gholbzouri K. Sexual and reproductive health self-care interventions in the Eastern Medie- terranean Region: findings from a cross-sectional values and preferences survey to inform WHO normative guidance on self- care interventions. Health Res Policy Sys 2021:19(57). https://doi.org/10.1186/s12961-020-00659-w. 2. World Health Organization. WHO consolidated guideline on self-care interventions for health: sexual and reproductive health and rights. Geneva: World Health Organization, 2019. https://apps.who.int/iris/bitstream/handle/10665/325480/9789241550550- eng.pdf. Book 28-09.indb 701 09/10/2022 11:07 AM Eastern Mediterranean Health Journal IS the official health journal published by the Eastern Mediterranean Regional Office of the World Health Organization. It is a forum for the presentation and promotion of new policies and initiatives in public health and health services; and for the exchange of ideas, concepts, epidemiological data, research findings and other information, with special reference to the Eastern Mediterranean Region. It addresses all members of the health profession, medical and other health educational institutes, interested NGOs, WHO Collaborating Centres and individuals within and outside the Region. طسوتلما قشرل ةيحصلا ةلجلما ةماعلا ةحصلا في ةديدلجا تاردابلماو تاسايسلا ميدقتل برنم ىهو .ةيلماعلا ةحصلا ةمظنمب طسوتلما قشرل ىميلقلإا بتكلما نع ردصت ىتلا ةيمسرلا ةلجلما ىه قشر ميلقإب اهنم قلعتي ام ةصاخو ،تامولعلما نم كلذ يرغو ثاحبلأا جئاتنو ةيئابولا تايطعلماو ميهافلماو ءارلآا لدابتلو ،اله جيوترلاو ةيحصلا تامدلخاو ةمظنم عم ةنواعتلما زكارلماو ،ةينعلما ةيموكلحا يرغ تماظنلما اذكو ،ةيميلعتلا دهاعلما رئاسو ةيبطلا تايلكلاو ،ةيحصلا نهلما ءاضعأ لك لىإ ةهجوم ىهو .طسوتلما .هجراخو ميلقلإا فى ةحصلاب ينمتهلما دارفلأاو ةيلماعلا ةحصلا La Revue de Santé de la Méditerranée Orientale EST une revue de santé officielle publiée par le Bureau régional de l’Organisation mondiale de la Santé pour la Méditerranée orientale. Elle offre une tribune pour la présentation et la promotion de nouvelles politiques et initiatives dans le domaine de la santé publique et des services de santé ainsi qu’à l’échange d’idées, de concepts, de données épidémiologiques, de résultats de recherches et d’autres informa- tions, se rapportant plus particulièrement à la Région de la Méditerranée orientale. Elle s’adresse à tous les professionnels de la santé, aux membres des instituts médicaux et autres instituts de formation médico-sanitaire, aux ONG, Centres collaborateurs de l’OMS et personnes concernés au sein et hors de la Région. Correspondence Editor-in-chief Eastern Mediterranean Health Journal WHO Regional Office for the Eastern Mediterranean P.O. Box 7608 Nasr City, Cairo 11371 Egypt Tel: (+202) 2276 5000 Fax: (+202) 2670 2492/(+202) 2670 2494 Email: emrgoemhj@who.int Members of the WHO Regional Committee for the Eastern Mediterranean Afghanistan . Bahrain . Djibouti . Egypt . Islamic Republic of Iran . Iraq . Jordan . Kuwait . Lebanon Libya . Morocco . Oman . Pakistan . Palestine . Qatar . Saudi Arabia . Somalia . Sudan . Syrian Arab Republic Tunisia . United Arab Emirates . Yemen طسوتلما قشرل ةيلماعلا ةحصلا ةمظنلم ةيميلقلإا ةنجللا ءاضعأ نادلبلا ةيملاسلإا ناريإ ةيروهجم . ايبيل . سنوت . نيرحبلا . ناتسكاب . ةدحتلما ةيبرعلا تاراملإا . ناتسناغفأ . ندرلأا برغلما . صرم . نانبل . تيوكلا . رطق . ينطسلف . نماُع . قارعلا . لاموصلا . نادوسلا . تيوبيج . ةيروسلا ةيبرعلا ةيروهملجا نميلا . ةيدوعسلا ةيبرعلا ةكلملما Membres du Comité régional de l’OMS pour la Méditerranée orientale Afghanistan . Arabie saoudite . Bahreïn . Djibouti . Égypte . Émirats arabes unis . République islamique d’Iran Iraq . Libye . Jordanie . Koweït . Liban . Maroc . Oman . Pakistan . Palestine . Qatar . République arabe syrienne Somalie . Soudan . Tunisie . 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EMHJ is a trilingual, peer reviewed, open access journal and the full contents are freely available at its website: http://www/emro.who.int/emhj.htm EMHJ information for authors is available at its website: http://www.emro.who.int/emh-journal/authors/ EMHJ is abstracted/indexed in the Index Medicus and MEDLINE (Medical Literature Analysis and Retrieval Systems on Line), ISI Web of knowledge, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Lexis Nexis, Scopus and the Index Medicus for the WHO Eastern Mediterranean Region (IMEMR). © World Health Organization (WHO) 2022. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO licence (https://creativecommons.org/licenses/by-nc-sa/3.0/igo). 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ISSN 1020-3397 Cover image © WHO Cover 28-08.indd 4,6 14/09/2022 12:25 PM La Revue de Santé de la Méditerranée orientale Eastern Mediterranean Health Journal EMHJ – Vol. 28 No. 09 – 2022 Volume 28 No. 09 September/Septembre 9 ددع / نوشرعلاو نماثلا دلجلما لوليأ/ربمتبس 2022 Eastern M editerranean H ealth Journal Vol. 28 N o. 09 – 2022 Women always function as the gatekeepers to the formal/informal health sector. Despite global and regional progress in advancing women’s health, the COVID-19 pandemic forced governments and development partners in the EMR and beyond to re-set their priorities. A renewed commitment to women’s health is inescapable to expedite progress towards the SDGs in an integrated manner. Editorial Women’s health in the Eastern Mediterranean Region: time for a paradigm shift Mohamed Afifi, Maha El-Adawy and Rana Hajjeh .........................................................................................................................................................................................635 Research articles Engagement of private healthcare sector in reproductive, maternal, newborn, child and adolescent health in selected Eastern Mediterranean countries Meesha Iqbal, Anam Shahil Feroz, Khalid Siddeeg, Karima Gholbzouri, Jamela Al-Raiby, Nilmini Hemachandra, Sarah Saleem and Sameen Siddiqi ....................................................................................................................................................................................................................... 638 Translation and cultural adaptation of the WHO generic tuberculosis patient cost survey to an Egyptian context Ramy Ghazy, Rasha Ashmawy,Omar Reyad, Samar Abd ElHafeez, Mai El-Shishtawy, Heba Khedr, Ehab El-Rewiny, Haider El-Saeh, Mohamed Yacoub, Nancy Ali and Rasha Mosallam ...................................................................................................................... 649 Pilot study of safety and efficacy of topical liposomal amphotericin B for cutaneous leishmaniasis caused by Leishmania major in Islamic Republic of Iran Ali Khamesipour, Akram Mohammadi, Mahmoud Jaafari, Seyed Eskandari, Minoo Tasbihi, Amir Javadi, Farzaneh Afshari, Hossein Mortazavi and Alireza Firooz ........................................................................................................................................................................... 658 Could self-reported symptoms be predictors of RT-PCR positivity in suspected COVID-19 cases? The Libya experience Amira El Ghiadi, Omnia Eddali, Sana Ashur and Laila Sabei ...................................................................................................................................................................... 664 Evaluation and comparison of vitamin A supplementation with standard therapies in the treatment of patients with COVID-19 Mohamad Rohani, Hasan Mozaffar, Mehdi Mesri, Mehdi Shokri, Daniel Delaney and Mahmood Karimy ............................................................................673 Diagnostıc and treatment outcomes of patients with pulmonary tuberculosis in the first year of COVID-19 pandemic Yusuf Yakupogullari, Hilal Ermis, Zeynep Kazgan, Baris Otlu, Yasar Bayindir, Gazi Gulbas, Elif Tanriverdi and Emek Guldogan ................................................................................................................................................................................................................................................. 682 Short research communication Mental health and driving behaviour of students and alumni of a university in the United Arab Emirates: a cross-sectional study Gabriel Andrade, Dalia Bedawi and Ibrahim Bani..........................................................................................................................................................................................690 Review Risk assessment of road traffic accidents related to sleepiness during driving: a systematic review Shehzad Saleem ......................................................................................................................................................................................................................................................... 695 WHO event addressing public health priorities Workshop for sharing best practices in sexual and reproductive health in the Eastern Mediterranean Region ..........701 Cover 28-09.indd 1,3 09/10/2022 11:07 AM