Surveillance and control of acute diarrhoeal diseases: report on a WHO meeting, Rome, 8–11 April 1980

EURO Reports and Studies 44 C.. INDEX[,' Surveillance and Control of Acute Diarrhoeal Diseases Report on a WHO Meeting REGIONAL OFFICE FOR EUROPE World Health Organization COPENHAGEN

EURO Reports and Studies 44 I p I V f1 0 ~ 7 / 1 - Surveillance and Control of Acute Diarrhoeal Diseases Report on a WHO Meeting Rome 8-11 April 1980 lllllll lllll lllll lllllllllllllll lllll lllllllllllll .. 000 2 80'-iS " REGIONAL OFFICE FOR EUROPE World Health Organization COPENHAGEN 1981 ICP/BVM 007 ISBN 92 890 1210 2 © World Health Organization 1981 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. For rights of reproduction or translation, in part or in toto, of publications issued by the WHO Regional Office for Europe application should be made to the Regional Office for Europe, Scherfigsvej 8, DK- 21 00 Copen- hagen </), Denmark. The Regional Office welcomes such applications. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or con- cerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not men- tioned. Errors and omissions excepted , the names of proprietary products are distinguished by initial capital letters. The views expressed in this publication are those of the participants in the Meeting and do not necessarily represent the decisions or the stated policy of the World Health Organization. PRINTED IN DENMA RK ISSN 0250-8710 CONTENTS 1. Introduction . . .. .............. ... . .. . 2. Review of the problem in the Mediterranean countries. 3. Ways and means of control 3.1 Strategy for control. . 3.2 Epidemiological information 3.3 Laboratory services . ... . . 3.4 Treatment .... .. .. . . . 3.5 Medicines that should not be used in the treatment of diarrhoea . 3.6 Environmental sanitation and hygiene . 3.7 Health education .... .. ... . 3.8 Immunization ........ . . . . 3.9 Alternative approaches in control. 4. National control programmes . 5. International collaboration 6. Conclusions .... 7. Recommendations Annex I Information on diarrhoeal diseases in Europe, and typhoid in the Medi- Page 2 8 8 9 10 10 11 12 12 12 13 13 16 19 19 terranean countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Annex II Selected illustrative material on diarrhoeal diseases and their control 25 Annex III Laboratory activities for diarrhoeal diseases . Annex IV List of WHO collaborating centres . ... . . Annex V List of national reference centres for enterobacteriaceae. Annex VI List of participants ..................... . 31 40 42 50 WHO MEDITERRANEAN MEETING ON THE SURVEILLANCE AND CONTROL OF ACUTE DIARRHOEAL DISEASES Rome, 8-11 April 1980 1. INTRODUCTION The Meeting, convened by the WHO Regional Office for Europe in collabo- ration with the Italian Government, was held at the Istituto Superiore di Sanita, Rome, from 8 to 11 April 1980. It was opened by Dr M. Postiglione, Director, Disease Prevention and Control, on behalf of Dr Leo A. Kaprio, Director, WHO Regional Office for Europe. Professor L. Giannico, Director-General, Ministry of Public Health, and Professor F. Pocchiari, Director, Istituto Superiore di Sanita, welcomed the participants on behalf of the host country. Representatives of nine Mediterranean countries (Algeria, Greece, Italy, Malta, Morocco, Spain, Tunisia , Turkey and Yugoslavia) took part in the Meeting (see Annex VI - list of participants). Representatives of other Mediterranean countries, including some in the WHO Eastern Mediterranean Region, were also invited, but were unable to attend. Professor A. Zampieri was elected Chairman and Professor J. Papavassiliou Vice-Chairman. Professor B. Cvjetanovic acted as Rapporteur and Dr B. Veli- mirovic as Secretary. The Meeting had been organized at the request of several governments of the European Region in response to resolution WHA3 l .44, adopted by the Thirty-first World Health Assembly in 1978, urging Member States to identify diarrhoeal diseases as a major priority area for action. Its purpose was to review the problem of acute diarrhoeal diseases, including cholera and enteric fevers, in the Mediterranean area; to discuss recent scientific advances in various aspects of these diseases and their control; and to make appropriate recommendations on the development of national programmes for the control of diarrhoeal diseases in the context of primary health care. In particular, the Meeting was asked to make specific recommendations relating to: (a) epidemiological surveillance and exchange of information between national health authorities and WHO; (b) diagnosis of diarrhoeal diseases caused by old and newly recognized pathogens and their laboratory identification; ( c) treatment based on oral rehydration therapy, including operative aspects of the production, distribution and use of oral salt packages; (d) support for water and sanitation programmes and related he:i!th education programmes ; (e) WHO/UNICEF activities within the framework of the global Diar- rhoeal Disease Control Programme. The participants reviewed the present situation with regard to diarrhoeal diseases and their control, and considered alternative treatment, prevention and control measures in their respective countries as well as ways and means of setting up effective national control programmes and of developing co- operation among Mediterranean countries in this field. They also examined the information provided in relevant WHO documents on diarrhoeal diseases, and on the development of the global WHO/UNICEF Programme for Control of Diarrhoeal Diseases.a, b Conclusions and recommendations on the develop- ment of appropriate national and international activities were formulated and adopted. 2. REVIEW OF THE PROBLEM IN THE MEDITERRANEAN COUNTRIES The participants reviewed the present epidemiological situation with regard to diarrhoeal diseases and discussed current control activities in their respective countries. It was agreed that diarrhoeal diseases are a major cause of morbidity and mortality in infants and young children in all the Mediter- ranean countries. In these countries the problem of diarrhoeal diseases has many specific aspects. The mild climate which attracts tourists from the north also allows rapid multiplication of germs in food and beverages and favours food poisoning; increasing urbanization and the growing volume of traffic facilitate the spread of enteric infections nationally and internationally; the existence of less developed areas with inadequate levels of environmental sanitation and the lack of personal hygiene facilities are the main factors responsible for diarrhoeas in children, the existence of endemic typhoid, and occasional outbreaks of cholera. The extensive population movements from countries of northern Europe to the Mediterranean area in connexion with tourism, and the migration of manpower in the opposite direction, are overtaxing sanitary facilities a Programme for control of dia"hoeal diseases. Scientific working group reports 1978-1980. Geneva, World Health Organization (document CDD/80.1). b Programme for control of dia"hoeal diseases. Guidelines for the trainers of community health workers on the treatment and prevention of acute diarrhoea. Geneva, World Health Organization (document WHO/CDD/SER/80.1). 2 at certain places and periods and are facilitating the spread of infectious diseases which are a cause of international concern. The system of notification of enteric infections ( enteric fevers, salmonel- loses, shigelloses, cholera, gastroenteritis and other diarrhoeal disease due to enterotoxigenic E. coli, rotavirus and other newly recognized pathogens) is inadequate for making a full assessment of the magnitude of the problem, its health and economic implications, and epidemiological factors, including the mode of spread. Information on the incidence of these diseases based on statistical returns is only indicative (see Annex I). However, it shows that the problem exists and that there is a need to know more about it in order to obtain a sound basis for control activities. In spite of their many inadequacies, data derived from surveillance and survey procedures provide additional indications that these diseases constitute a considerable health problem and also an important economic problem, particularly in view of their potential adverse effects on tourism and trade. Diarrhoeal diseases occur relatively more often in adults , namely tourists, than is the case elsewhere, where diarrhoea is predominant in children. It is therefore necessary to keep the problem under constant review through surveillance . One country, which has made an effort to improve the notification of diarrhoeal diseases, has observed a tenfold or greater apparent increase of incidence in the last two decades or so, bringing the rate of severe entero- colitis reported per l O 000 population to 40 or higher, though this is still far below the actual incidence. While outbreaks of cholera receive great publicity and often lead to overdramatization, endemic typhoid causes far more harm to health, and other diarrhoeal diseases, besides being a major killer of young children, account for the overwhelming majority of hospitalized cases and deaths. The countries of the Mediterranean basin, though bordering on the same sea and having a similar climate and other common characteristics, differ greatly in their background as far as socioeconomic development, cultural and educational traditions and lifestyles, food habits, levels of personal hygiene and environmental sanitation, and systems of health services are concerned . Differences exist not only among countries but also among various areas of the same country which are at different levels of development. It is obvious, therefore, that the problems of diarrhoeal diseases and possible solutions to them need to be considered in the light of these differences. Diarrhoeal diseases are present everywhere in the Mediterranean area, but the size of the problem varies from place to place , as do the incidence of these diseases and their health and economic consequences. In some developing countries as many as 25% of all paediatric beds are occupied by patients with diarrhoeal diseases. Even among the most developed of the Mediterranean countries about I 0% of all admissions to 3 children's wards are due to diarrhoeal diseases; 90% of the diarrhoeal cases occur in children under 2 years of age . In the Mediterranean countries, as in the rest of the world, the high mortality rates in children under 5 years of age are directly related to mor- tality resulting from diarrhoeal diseases. Treatment facilities and standards differ from country to country. Some countries have a great shortage of health personnel and health services are inadequate; self-care and the participation of mothers in child care are there- fore crucial factors. In other countries diarrhoeal diseases are relatively rare and are dealt with by professional staff, thus enabling quite different ap- proaches to be used. While domiciliary oral rehydration by mothers is of paramount importance in the first group of countries, in the second group it is a question of ensuring proper education for health workers and making better use of resources. While some countries with more developed health services consider their available treatment facilities and methods of managing diarrhoeal diseases to be adequate, others regard their facilities as quite inadequate and have explored the possibility of extending them by making oral rehydration avail- able outside hospitals and outpatient clinics. The results are encouraging. Several countries have reported that mothers have accepted the oral rehydra- tion technique after it has been explained to them and shown to be effective. In addition to oral rehydration, one country has introduced the administra- tion of a high-protein diet supplement in conjunction with oral rehydration in an area where malnutrition has been frequent in the past. This has facili- tated the resorption of food and electrolytes and the elimination of adverse effects of diarrhoea on the nutritional status of children. Oral rehydration administered by auxiliary health workers and/or mothers proved effective in about 83% of cases of diarrhoea, thus decreasing substantially the need for institutional treatment. Facilities for the treatment of cholera and typhoid are available in all countries. The main problem in the developing countries is to make oral rehydration rapidly available with extensive coverage in rural and suburban populations. The relative importance of diarrhoeal diseases differs from country to country. Cholera, although relatively rare in comparison with other diarrhoeal diseases, constitutes the greatest problem as far as consequences for inter- national travel, tourism and trade are concerned. In 1979 six countries in the Mediterranean area were affected by cholera. Limited outbreaks occurred among some population groups due to a lack of environmental sanitation and personal hygiene or following the consumption of raw or partly cooked seafoods harvested from the water of coastal areas contaminated by untreated sewage. However, the disease has not spread internationally in the Medi- terranean area in recent years. Imported cases were also reported in northern Europe, involving tourists and migrant workers from Mediterranean countries. 4 11tis indicates that, in spite of its potentiality to spread, cholera does not represent a great danger for travellers and tourists . Because of traditional prejudices concerning cholera that exist among members of the public, and even in some administrations as well, many still believe that the disease is extremely dangerous. While the presence of cholera in the Mediterranean cannot be denied, the problem is often exaggerated, while relatively much more serious problems such as typhoid and other diarrhoeal diseases are underestimated. Cholera is nevertheless a major eause of disruption in trade and tourism, due to the imposition of restrictive measures by some countries. The Inter- national Health Regulations (IHR) do not call for , indeed do not allow, such measures, because it is evident that the provision of safe water, efficient sewage disposal and improved personal hygiene are more effective against this disease. Experience has shown that cholera immunization requirements cannot prevent the spread of the disease internationally. In fact, there has never been any scientific basis that they could. National health administra- tions have to accept the fact that a cholera vibrio can enter any country over a period of time, but that high levels of environmental sanitation and personal hygiene make that country nonreceptive to cholera. In the absence of an adequate sanitary environment, the only measure which will prevent the spread of the disease is the early detection of cases, their prompt treatment and the implementation of relevant control measures. The elements necessary for early detection include access to some form of primary health care and the possibility for a diagnosis to be made. The absence of official reporting leads to unofficial speculation by some health administrations about the situation in countries other than their own. Countries which take excessive measures in terms of vaccination certificate requirements , obligatory medication and trade restrictions unfortunately do so both on the grounds of official reports and on the basis of rumours. However, the proper basis for any communicable disease control system within or between countries is the collaborative, prompt and continuous interchange of epidemiological information ; this is also an indispensable condition in the control of cholera. The use of restrictive measures by some countries within or even beyond the limits of the IHR is a cause of great concern and leads some to propose that cholera should be removed from the IHR, at least on a regional scale. The participants considered that one of the most effective steps would be to endeavour, with the assistance of the information media and by health education, to dispel unjustified fears about cholera and demystify this dis- ease , which is no more than one among a number of diarrhoeal diseases found, in particular, in the Mediterranean area, where facilities for treatment and rapid control measures do exist. It is gratifying to note that in the control of cholera emphasis has now moved from vaccination to environmental sani- tation, food control , personal hygiene and health education . 5 Typhoid is endemic in the Mediterranean area. The incidence in some countries is very high, but the actual magnitude of the problem in these coun- tries is still not well assessed. As surveillance improves, the incidence shows a sharp rise , indicating that the health returns of the past have been based on gross under-·reporting. However, because of their efforts to improve environ- mental sanitation, some countries have observed a gradual decrease in the incidence, which nevertheless does not mean that the problem has been solved. In some countries it has been noted that the incidence of paratyphoid B is increasing. Salmonelloses have been shown to be very frequent in all countries where surveillance was undertaken. They are associated with food contamina- tion, but the inadequate information available at present does not provide a sufficient lead in most instances regarding the mode of spread and the role of different types of food, their preparation, storage practices, etc. An increase in multiple drug resistance associated with certain serotypes has been observed. This proves the importance of surveillance of Salmonella and its drug resistance patterns. An increase in the disease in man due to the for- merly zoophilic strain Salmonella agona has also been noted in the Medi- terranean countries. Shigelloses are relatively less common than Salmonelloses in most coun- tries . While in some countries Sh. sonnei is most prevalent, in others it is Sh. jlexneri. One country reported that about one third of all Shigel/a isolates were Sh. dysenteriae, type I. In the light of the recent large outbreaks of drug-resistant Sh. dysenteriae in central America and south-east Asia, the surveillance of Shigel/a and its resistance patterns assumes greater practical public health importance. The need for cooperation among workers in the fields of health, agriculture (veterinarians) and pharmaceutical services in surveillance of the uses of antibiotics and in the establishment of policies for the rational use of antibiotics in order to decrease antibiotic pressure and thus prevent the emergence of resistant strains has been emphasized . Most governments have formally advised the medical profession against the use of antibiotics in salmonelloses and shigelloses except in severe cases of shigellosis and typhoid fever {and cholera). This measure seems justified , as the countries which were able to study the prevalence of diarrhoeal diseases due to viral agents have confirmed that viruses are the cause of about one half of all diarrhoeal cases in children aged up to two years, in which antibiotics prove to be useless . In fact , the indiscriminate use of antibiotics is harmful and the establishment of firm policies and regulations on their use would be an advantage. Gastroenteritis is most frequently reported as a cause of diarrhoea without indication of the causative organism, partly because of lack of laboratory services, and partly because it is impossible and economically unjustifiable to confirm each case of diarrhoea by laboratory examination. 6 The evidence provided by studies carried out in several countries with laboratory facilities indicates that enteropathogenic and enterotoxigenic E. coli is perhaps the most frequent cause of diarrhoea. However, in some areas surveys have shown that rotavirus may be responsible for up to 50% of cases of diarrhoea in children, while in others it was estimated to be the cause of only some I 0%. Since in some localities during a high incidence of diar- rhoea the usual bacteriological examinations yield no bacterial pathogens, it is assumed that rotavirus and other viruses must be prevalent. Other pathogens relatively newly recognized (such as Vibrio parahaemo- lyticus, Yersinia enterocolitica and Campylobacter jejuni) have been found present in most places when looked for. However, their epidemiology and relative importance in the Mediterranean area have not yet been sufficiently studied to permit an assessment of their pubic health importance in the countries concerned. Laboratory facilities for diagnostic purposes and epidemiological surveil- lance are being extended in most countries but there is still a need to support further the development of these facilities. Their more extensive and judi- cious use by epidemiological services will provide most valuable information on the causes of diarrhoeal diseases. There is much to be done to establish closer collaboration among clinicians, epidemiologists and laboratory workers in order that more effective use can be made of these facilities . Several countries are using their laboratories extensively for monitoring en- vironmental contamination with pathogenic enterobacteriaceae and V. cholerae in particular , in order to monitor the safety of drinking-water sources as well as coastal areas of the sea. The collaboration and efforts of Mediterranean countries, together with UNEP, aimed at controlling seawater contamination on beaches are contributing to the prevention of enteric and diarrhoeal diseases in tourists and the general population. The control of diarrhoeal diseases in most countries is based on im- proving environmental sanitation and food hygiene. Efforts are being made to step up the programme for increasing the population covered by safe water supplies and basic sanitation , particularly in areas with extensive tourist activities . The present International Drinking-Water Supply and Sanitation Decade represents an important stimulus to improve existing conditions. All countries with a relatively high incidence of diarrhoeal diseases in children have made plans for and/or are to a greater or lesser degree carry- ing out some activities for the prevention of dehydration in young children and, to some extent also, for the control of these diseases through proper sanitation. Concepts relating to ways and means of combating diarrhoeal diseases obviously differ among countries at various levels of socioeconomic develop- ment and with various systems of health care and social organization. While all countries are committed to public health and preventive medicine, some have not yet been able to develop these services fully and have to rely on 7 self-care by the population in preventing dehydration and the spread of disease. Community development programmes for those in rural areas and some other underprivileged population groups will , by improving sanitary, educational and economic standards, create all the necessary prerequisites for eliminating the underlying causes of the high incidence of diarrhoeal diseases. International problems related to diarrhoeal diseases and their con- trol have considerable health and economic implications. A major part of the typhoid cases and all cholera cases in northern European countries are imported by tourists or migrant workers from the Mediterranean area. While there is a great deal of goodwill and mutual understanding among all the countries concerned, conflicts of interest do , nevertheless, arise in relation to travel and trade, and considerable economic losses are sometimes suffered. 3. WAYS AND MEANS OF CONTROL 3.1 Strategy for control The ways and means of controlling and preventing diarrhoeal diseases differ according to the etiology and epidemiology of the disease concerned. The value of control measures depends, on the one hand, on their effective- ness and the degree of coverage of the population and, on the other, on local conditions and circumstances. An appropriate strategy for the control of diarrhoeal diseases implies not only proper selection of control measures but also the effective implementa- tion of a well-devised and well-planned programme of action. National con- trol programmes should be based on a well-selected and well-defined control methodology and strategy, time-related targets, and other relevant opera- tional aspects. Logistic support has to be provided if tangible results are to be obtained . In the development of national control programmes it is necessary to consider the available control measures and resources and the best ways and means of integrating the programme in the existing health system and, in particular, in the system of primary health care. The immediate objective is to reduce mortality and diarrhoea-related malnutrition through the implementation of oral rehydration therapy, coupled with education on dietetic management and improved child care and hygienic practices. The long-term objective is to reduce morbidity and mor- tality from acute diarrhoeal diseases through improved water supply and sanitation and better child care practices. 8 3.2 Epidemiological information To ensure sound decision-making on the control measures and control strategies to be applied, it is important to collect essential epidemiological information on the causative organism and the mode of spread in order to propose effective control action. Etiological studies have shown that, besides the relatively well-known bacterial causes of enteric infections and diarrhoeal diseases, there are other bacterial and viral pathogens. The major part of diarrhoeal diseases are caused by these less-known pathogens. Besides V. cholerae 01, Salmonella and Shigella, enteropathogenic E. coli are the most frequent cause of diar- rhoea. They produce a potent enterotoxin similar to that produced by V. cholerae. The pathogenic strains of enterotoxic E. coli, through the action of their pili, adhere readily to the mucous membrane, colonize the gut, and then produce the enterotoxin which through a complex enzymatic mecha- nism prevents the absorption of the fluid secretion in the gut. Thus, de- hydration is rapidly produced, especially in small children. (Selected illustra- tive material on diarrhoeal diseases and their control is given in Annex II, sections A-F.) Yersinia enterocolitica and Campylobacter jejuni are found in diarrhoeal cases as well as in the environment, as is Vibrio parahaemolyticus. The epidemiology of these infections in the Mediterranean countries is still only partially known, thus making application of specific control measures in- effective. There are a great many viral diarrhoeal diseases, caused by rotaviruses, Norwalk-like viruses, astroviruses, calicviruses, adenovirus-like particles, Otafuke agents, coronaviruses and enteroviruses, to list only a few. Their prevention requires very stringent sanitary measures and their treatment excludes the use of antibiotics. Epidemiological surveillance and investigations provide information on the mode of spread of enteric pathogens of different etiology. Such informa- tion, which is essential for effective control, should provide data on increased incidence and possible epidemic outbreaks, and also on high-risk groups and the most frequent modes of spread. In foodbome infections, data on specific types of food or food-handling are useful in deciding upon the control action to be undertaken. On the basis of well scrutinized and properly analysed epidemiological information an effective control strategy can be developed. An international surveillance programme for the control of foodborne infections and intoxications in Europe started in 1980. This establishes an early alert system to provide rapid information. The "early alert" report should be made, for instance, when: (1) internationally distributed foods or feeds have resulted in outbreaks or contaminated lots have been identified; 9 (2) outbreaks occur associated with international caterers and carriers (air, t rain , ship); (3) illness occurs among or is introduced by members of migrant or tourist groups; (4) outbreaks of unusual food borne diseases are recorded in a country; (5) outbreaks concern a disease of a severe nature ; (6) other matters considered to be an emergency by the country making the report are observed. The F AO/WHO Collaborating Centre for Research and Training in Food Hygiene , Berlin (West), will function as the international collaborating centre in the surveillance programme and will collect , evaluate and disseminate data and related information to all concerned. 3.3 Laboratory services These are useful for diagnosis, application of appropriate treatment , ascertaining the mode of spread and establishing appropriate control measures. Environmental factors , such as those relating to water and food contami- nation, housing, and sewage disposal, are strongly linked to the occurrence of diarrhoeal diseases. It is essential to coordinate the work of various types of laboratory service directly or indirectly concerned with human health, such as food safety, wastewater and drinking-water laboratories. 3.4 Treatment A treatment which has proved effective and feasible on a large scale, even in areas with very limited resources, is oral rehydration with a fluid composed of electrolytes and glucose ; the latter facilitates the absorption of electrolytes from the fluid. Thus an osmotic balance is rapidly achieved and the ill effects of dehydration are avoided at little cost. The use of oral rehydration fluid has also been shown to be effective in the prevention of ensuing malnutrition. ln view of the fact that dehydration is the primary cause of high mortality rates from acute diarrhoeal diseases, oral rehydration therapy should be con- sidered the most appropriate technology for reducing mortality. Oral rehydra- tion therapy based on the administration of correct oral fluid , while allowing food intake , provides a balanced water and electrolyte replacement at low cost and saves lives. It can be administered not only in hospitals , health centres , health stations or clinics, but also by community-based health workers, and by mothers and relatives with some guidance. Rehydration with this fluid improves appetites, allowing better feeding and continued weight gain. The ingredients of the oral solution may be provided in an aluminium oral rehydration solution (ORS) packet. 1n hospitals and large health centres, IO the solution may also be prepared in bulk for daily needs, thus saving the packets for peripheral levels. It has been shown that the composition of both the oral and the intra- venous fluid is critical. The WHO/UNICEF-recommended formula of the oral rehydration powder: sodium chloride sodium bicarbonate potassium chloride glucose water 3.5 g 2.5 g 1.5 g 20.0 g 1 litre should therefore be maintained, as preparations consisting of various other mixtures of salts and sugars often lead to failure and are strongly discouraged, particularly where inexpensive treatment based on the above formula is feasible from the economic and other points of view. It should be noted that ORS has reduced the cost of treatment by 70%. Guidance on dietetic management must always accompany oral rehydra- tion. This should include the promotion of uninterrupted breast-feeding and the offering of usual foods during diarrhoeal episodes, beginning as soon as the child wishes to eat, additional foods being offered during convalescence. Cases of severe diarrhoea will, in addition, require intravenous fluid. Health workers must be trained to recognize such cases, which should be referred to physicians or to facilities where intravenous fluid is available. Training curricula should also emphasize the fact that almost all the time- honoured antidiarrhoeal drugs are ineffective, unnecessary, costly, and possibly harmful. The mode of action of oral rehydration is shown in a schematic presenta- tion in Annex 3, Fig. 2. Laboratory diagnosis is useful in connexion with the application of appropriate antibiotics if and when such treatment is required. The use of antibiotics in treatment ( except in typhoid and severe cases of shigelloses) is not indicated. If used extensively, they lead to increased drug resistance in enterobacteriaceae. Drug prophylaxis (with antibiotics and other antimicrobials) should be attempted only in very exceptional situations in well defined closed populations and under medical supervision. The medicines that should not be used in the treatment of diarrhoea are listed below. 3.5 Medicines that should not be used in the treatment of diarrhoea A number of medicines that are of no value or are even dangerous are often used to treat diarrhoea. Money and time are wasted in their use. These medicines are: neomycin (damages the intestinal mucosa and can cause malab- sorption); 11 purgatives {worsen diarrhoea and dehydration); tincture of opium, paregoric or atropine ( dangerous for children and dysentery patients because of decreased intestinal transit time); cardiotonics such as epinephrine or Coramine (nikethamide); shock that is due to hypovolaemia must be corrected by intravenous fluids and not by these drugs ; steroids (expensive, useless , and may cause adverse side effects); oxygen (expensive, unnecessary); charcoal and kaolin (no value); pectin and bismuth (no value); Mexaform (no value and can be dangerous); Lomotil (no value and can be dangerous in infants). Strict supervision by health and veterinary authorities to prevent the in- discriminate use of antibiotics is important, so as to guard against the de- velopment of drug resistance, which then makes treatment with antibiotics {when this is indicated because of the severity of the disease) ineffective. 3.6 Environmental sanitation and hygiene Environmental sanitation and personal hgyiene are very effective in preventing all bacterial infections. However, they are more effective against cholera and typhoid than in combating enterotoxigenic E. coli and viral diarrhoeas because of the differences in the critical challenge dose and the ability of the microorganism to survive and possibly multiply in the environ- ment and spread by various vehicles. The role of carriers, which varies ac- cording to the disease, is of paramount importance. 3.7 Health education Health education is an effective back-up to the appropriate use of sani- tary facilities in the prevention of diarrhoeal diseases and in efforts to im- prove personal and food hygiene. Health education is the concern of every health worker, who should consider it one of his basic duties to motivate the population to make their proper contribution through self-care and partici- pation in the diarrhoeal diseases programme (in the delivery of oral rehydra- tion and the promotion of sanitary measures). 3.8 Immunization This is only effective against specific diseases, namely typhoid and, to a much lesser degree, cholera. At present there are no other effective vaccines 12 which can be used on a large scale in public health practice . Their effective- ness is limited as far as the duration and degree of protection is concerned . Repeated immunization gives diminishing returns and thus represents an expenditure on consumer goods rather than an investment of permanent value ( e.g. sanitation). 3.9 Alternative approaches in control It is the task of public health workers to seek ways and means of control in the light of the local situation and of the advantages, disadvantages and cost-effectiveness of various control measures , in order to decide on the most effective and least expensive control programme to be applied . The problem is illustrated schematically in Table I, which is self-explanatory. 4. NATIONAL CONTROL PROGRAMMES Control measures available for achieving the required objectives are: oral rehydration , epidemic control , maternal and child care , environmental sanitation, personal hygiene and health education. Oral rehydration , a simple, inexpensive yet effective means of combating diarrhoeas and malnutrition, is the tool to be used in the first instance in reducing high infant mortality due to diarrhoeal diseases . Feasibility and acceptability studies conducted in Member States show that this therapy can be introduced relatively easily in the periphery , provided that ORS is readily available . Epidemic control is vitally important. The epidemiological service should collect data on the incidence of diarrhoeal diseases according to age , in order to identify high-risk groups ; it is also possible to build up a case-recording and reporting system around the delivery of oral rehydration therapy. Such reporting will facilitate the evaluation of the programme and will also enable disease patterns to be recognized in particular localities. Changes in the seasonal pattern, levels of severity or age distribution may herald an epidemic, necessitating prompt notification, epidemiological and laboratory investiga- tion , and the application of containment measures . Laboratory services are expensive from both the technical and manpower aspects. They have to be continuously assessed if they are to be maintained at a reasonable cost and the quality of their work is to be improved. Several primary or front-line laboratories attached to a secondary or regional labora- tory will assist the horizontal coordination of all national laboratory activities and their effective use for epidemiological and treatment purposes. An assess- ment of the appropriate balance of the real needs versus the available means , 13 ...... -I>- Criteria for comparison Effectiveness Cost Advantages Disadvantages Table 1. Alternative approaches in the use of various control measures to prevent enteric infections and diarrhoeal diseases Sanitation Health education Vaccination Combined measures• - about 50% protection - protection varies according - 50-80% protection against - high if well time~caled, against all enteric infections to epidemiological condi- typhoid, paratyphoid B and e.g. begin with health edu- - long-lasting effect tions and people's motiva- cholera cation and vaccination while - cumulative effect in time tion and cooperation - short duration of protection beginning preparations for - declining in time long-term sanitation - low if improperly combined - relatively high initially - relatively low - relatively low initially - high - low cost of maintenance - high cost-effectiveness - very costly in long run - cost -effectiveness usually - high cost-effectiveness because of need for re- lower than when only one pealed vaccination method is used - cost-effectiveness doubtful - effect gradually forth - - effect rapidly forthcoming - immediate effectb - rapid and complete effect comiref - lasting effect - low initial cost - immediate and lasting effect - long-lasting effect - if provided as support to - cumulative effect - cumulative effect vaccination and/or sanita- - supports economic develop- - supports economic develop- tion render, these more ment ment effective - high initial investment - low effectiveness if not - short-lasting effect - very high cost - risks becoming ineffective if properly carried out and - gives false sense of security - very high initial investment not supported by health without people's participa• - high cost of maintaining - likely to fail if not SUS· education and people's CO· tion level of immunity tained by continuous efforts operation - low effectiveness if specific - only a few specific infec- message is not included lions are prevented • Combined measuru should be well planned according to the local epidemlologicel situation and avellebte resources . b The only sanitary measure which is Immediately effective Is drinking-water chlorination in waterborne epidemics and food control measures in specific food borne In fections . together with an understanding of the values, benefits and limitations of various laboratory techniques, is essential for the provision of an effective support service to national diarrhoeal diseases surveillance and control pro- grammes. On the basis of experience obtained in many countries, WHO has de- veloped approaches and guidelines on laboratory activities, which include selected procedures of importance in the surveillance of diarrhoeal diseases (see Annex III - Laboratory activities for diarrhoeal diseases). At the national level there is a need for central reference laboratories to ensure the quality of work. At the periphery (level of primary health care), where front-line laboratories are functioning, the most important activities are rapid and adequate sampling and transport , rapid screening tests (e.g. ELIZA), and the identification of pathogens. The supply of simple but reliable equipment and of good-quality reagents is essential for all laboratories, and the supply of simple kits for work in the periphery extends population coverage and facilitates surveillance. Maternal and child care practices, in particular breast-feeding, are most important in the prevention of diarrhoeas. Education on hygienic weaning practices and on the preparation and use of locally available weaning foods which are acceptable and nutritionally adequate is essential. The improvement of water supply and sanitation is important in order to reduce morbidity from diarrhoeal diseases. Diarrhoeal diseases control should therefore be integrated, within the framework of primary health care, with the programmes and activities of other relevant sectors, including that dealing with the provision of safe water and better sanitation facilities and their proper acceptance, utilization and maintenance. Personal hygiene should be linked with environmental sanitation. When elementary sanitary systems are made available there can only be an improve- ment in the control of diarrhoeal diseases, provided that the wastewater disposal facilities are properly used by the population. Health education, provided with the delivery of oral rehydration therapy during diarrhoeal episodes, is accepted by mothers and other members of the community much better than at other times. Educational messages should emphasize the importance of clean food in the care of the child, dietary needs during diarrhoeal incidents , and the beneficial effects of breast-feeding and proper weaning practices. Health education should comprise information on the role of food and water in the transmission of diarrhoeal diseases and the effectiveness of hand-washing and proper hygienic practices when pre- paring and storing food. Every health worker should be trained to contribute to health education by implementing the strategies concerned and should be encouraged to spend time in educating mothers, as they are most receptive during the delivery of services. The national programme usually consists of two major components, implementation and research, both of which include a training element. It 15 is essential that national control programmes be integrated in general health services in the context of primary health care, with the focus on rural and periurban areas. Close collaboration with related health sectors such as maternal and child health services, nutrition, health education , environ- mental sanitation and water supply and communicable diseases control, and integration with these at the peripheral level, are essential. Programme formulation should include analysis of the epidemiological situation , current activities and available resources, the establishment of objectives and time-related targets, the identification of training and logistic needs after considering the reallocation of available human and material resources , and the establishment of a sound logistic basis before programme implementation is attempted . National and particularly local conditions and experience must be prin- cipal determinants in the formulation of a control strategy. The steps to be followed in the development of national control programmes are shown in Table 2. The identification of a national coordinator with the necessary compe- tence, motivation and influence to ensure implementation of the programme, including training and evaluation , may contribute to the programme's success ; in addition, the establishment, where possible , of interministerial health committees to coordinate activities in this field might be helpful. The contri- bution of other sectors, e.g. agriculture , education and commerce, could also be exploited. Unless active national commitment and participation are se- cured , no long-term impact can be expected. In formulation of the national programme, besides all aspects of implementation of the envisaged strategy, there should also be provision for an in-built mechanism for evaluating progress and effectiveness, as well as shortcomings requiring prompt rectifi- cation. Research activites should also be planned, as they are still needed despite the considerable technological advances that have been made . There is an urgent need to develop operational research on simple and improved tools fo r achieving greater coverage and better control of diarrhoeal diseases, using the resources available. The use of multidisciplinary research teams may be the most appropriate means of promoting research in this field. The strengthening of institutions and the development of collaborative research may also yield valuable results. 5. INTERNATIONAL COLLABORATION Technical cooperation between WHO and Member States in diarrhoeal diseases control has a high degree of social relevance as it can contribute 16 Table 2. Major steps in the development of a national programme for the control of diarrhoeal diseases 1. Initiation of programme 2. Programme planning 3. Obtaining resources 4 . Implementation 5. Evaluation 1. Initiation (a) Assessment of magnitude of problem (b) Need for programme (c) Feasibility, acceptability (d) Assessment of potentialities for execution of programme (e) Agreement of authorities (fl Interest and cooperation of public 2. Planning (a) Establish objectives and operational targets (b) Specific strategy for achieving objectives and targets (c) Determine administrative channels for implementing programme (d) Plan activities of programme to implement selected strategy (e) Estimate resources, manpower and material, after reallocation of existing resources 3. Resource provision (a) Identification and training of managerial personnel (b) Production of promotional and educational material (c) Development of capability for production of oral rehydration powder packages (d) Acquisition of other required resources (e) Integration of diarrhoeal diseases programme with others (f) Coordination with international agencies 4. Implementation (a) Promotion and publicizing of programme at all levels (b) Training of field personnel in oral rehydration (c) Distribution of oral rehydration powder through health care system and others (d) Collection of evaluation data and modification of programme as required 5. Evaluation (a) Operational evaluation - No. of ORS packages : distribution and need - No. of personnel trained and used in field - No. of sanitary facilities provided and maintained (b) Impact of the programme - No. of deaths due to diarrhoeal diseases - No. of cases of diarrhoea treated in hospitals - Awareness and acceptance of ORS by mothers - Sales of supplies for bottle-feeding of babies 17 significantly to an improvement in the health status of the population by applying a programme which the population can afford and which will promote the development of national self-reliance in matters of health, based on the concepts of primary health care. The WHO programme for control of diarrhoeal diseases is closely re- lated to the programme for control of zoonoses, which includes salrnonel- loses. The WHO zoonoses programme, in which UNDP and some Eastern Mediterranean countries are participating, has a WHO centre in Athens as its focal point. Another related programme started in 1980 is the WHO surveillance programme for control of foodborne infections and intoxi- cations in Europe in which several Mediterranean countries are taking part. This is based on the FAO/WHO Collaborating Centre in Berlin (West). Furthermore, the WHO Regional Office for Europe is cooperating with some governments in the programme for the study of economic aspects of enteric diseases and hepatitis and the control of these diseases. ln view of their specific epidemiological situation, Mediterranean countries may find it useful to combine one or more of the above activities with those relating to diarrhoeal diseases. WHO, in collaboration with UNICEF, is a promoter of and partner in technical cooperation with countries and provides critical inputs to national control programme development if requested. This cooperation may be connected with programme formulation, the training of national instructors, the education of the community (including the development of teaching and learning aids), the procurement and production of essential supplies for oral rehydration, and evaluation. UNICEF is assisting in establishing local facilities for the production of ORS. WHO is preparing guidelines on national programme development and manuals in clinical management, epidemic control and laboratory techniques ; it is also developing a mechanism for the rapid dissemination of technical information. Cooperation between WHO collaborating centres and national reference centres is essential if technical competence is to be raised and meaningful information obtained on the prevalence of diarrhoeal diseases. Lists of WHO collaborating centres and national reference centres are given in Annexes IV and V respectively. Cooperation at international level among officers responsible for the national surveillance of communicable diseases, including enteric infections and diarrhoeal diseases, would greatly assist the control of these diseases in the Mediterranean area. WHO/UNICEF technical collaboration with Member States in the diar- rhoeal diseases control programme has recently been further strengthened, and a joint WHO/UNICEF programme to support the national production, packaging and distribution of ORS has been established. In the field of sanitation, the United Nations, UNEP, the World Bank and other organizations are collaborating with governments . It is envisaged that 18 this collaboration will be stepped up during the present International Drinking- Water Supply and Sanitation Decade, which is aimed at assisting, in particular, rural and suburban populations in greatest need of water supplies; these same populations have the highest incidence of diarrhoeal disease. The opportunities for collaborative efforts between governments and intergovernmental organizations to promote national diarrhoeal diseases control programmes and related activities are perhaps greater now than ever before. 6. CONCLUSIONS Diarrhoeal diseases constitute a priority problem in Mediterranean countries because of the high incidence of these diseases and their adverse effects on health and economies. Cholera, when present, accounts for only a small proportion of all diarrhoeal cases. The emphasis placed by WHO and its Member States on the development of primary health care services aimed at the periphery, the family, and children (who suffer most from diarrhoeal diseases), affords an opportunity to implement the life-saving techniques of rehydration as part of those services. The priority given to the promotion of environmental health by the United Nations in its International Drinking-Water Supply and Sanitation Decade provides a further stimulus for action in this field. At the present time there is an outstanding opportunity to combat diar- rhoeal diseases, and national authorities should spare no effort to develop national programmes for this purpose in collaboration with WHO and other international agencies. While the problem of diarrhoeal diseases is common in varying degrees to all Mediterranean countries , the needs and resources of those countries differ greatly. Hence, national diarrhoeal diseases control programmes, which should be an integral part of general health services, need to be adapted to the specific conditions of the countries concerned. 7. RECOMMENDATIONS To governments 1. The magnitude of the health and economic problems created by acute diarrhoeal diseases, including cholera and typhoid, should be assessed by 19 setting up surveillance systems for the early detection and epidemiological inves- tigation of outbreaks and the provision of information required for the long-term planning of effective and economically viable national control programmes. 2. The various national services and professional disciplines involved should be coordinated with a view to developing a coherent and harmonious national programme of action for the control of diarrhoeal diseases in the context of primary health care. 3. National plans of action for the control of diarrhoeal diseases should be set up in accordance with each country's needs, on the basis of the resources available and the support that can be offered by international agencies , as well as through technical cooperation among developing countries. 4. National programmes with clear objectives, time-related targets and specific strategies should be established to implement activities for the control of diarrhoeal diseases and to secure international and bilateral collaboration. 5. These national programmes should comprise the following essential activities: (a) the production of packages of oral rehydration salts of good quality at reasonable cost; (b) the training of professional, administrative and other workers to apply control strategies; (c) the promotion of health education by all health workers and the development of health education material relating to appropriate child care, personal and food hygiene and the proper use and maintenance of water supplies and sanitary facilities ; (d) the use of oral rehydration therapy in teaching hospitals and the inclusion of this subject in curricula. 6. The indiscriminate use of antibiotics and other drugs in the management of diarrhoeal diseases should be discouraged. 7. The dissemination of epidemiological data and the results of operational studies on diarrhoeal diseases control should be promoted . Countries should be invited to submit such information in April and October each year to WHO for publication in the Weekly epidemiological record. The relevant information from national and WHO collaborating centres should also be pub- lished in the Weekly epidemiological record. The mass media should be kept properly informed so that they can cooperate in control activities and help to dispel the public's fear of cholera. 8. It is the duty of every health worker to provide health education con- cerning the prevention of diarrhoeal diseases. Breast-feeding practices, sound nutritional practices and correct methods of child care should be widely promoted and encouraged. 20 9. Environmental sanitation and food control should be strengthened every- where, and especially in rural areas, tourist establishments and camping loca- tions. 10. Operational research and studies on simple and inexpensive technology for the diagnosis, treatment , control and prevention of diarrhoeal diseases at the national level should be supported by national authorities. ToWHO 11 . WHO and other relevant international agencies should promote collabora- tion with the Mediterranean countries and technical cooperation among de- veloping countries in all ac tivities, including epidemiological investigations and research work likely to facilitate the control of diarrhoeal diseases . 12. WHO should provide Member States with technical cooperation in all stages of the development of the diarrhoeal diseases control programme. 13 . Member States should be provided with extensive information on the development of diarrhoeal diseases control in the various countries and on WHO's diarrhoeal diseases control programme, so that the new knowledge and experience gained in this field can be immediately applied by countries as appropriate in the promotion of their national programmes. 14. Advanced training in the control of diarrhoeal diseases should be made available for epidemiologists, bacteriologists and other specialists. Courses, seminars and workshops sponsored by WHO would be useful in this con- nexion. Periodic international meetings of managers of national control programmes and meetings of research workers should be encouraged and sponsored by WHO and/or UNICEF. 2 1 Annex I INFORMATION ON DIARRHOEAL DISEASES IN EUROPE, AND TYPHOID IN THE MEDITERRANEAN COUNTRIES This information is based on the health statistics provided by national health authorities to WHO. The differences in the systems of notification and the incompleteness of reporting make international comparison dif- ficult. Table 1. Cases (C) and deaths (0) due to enteric infections and diarrhoeal diseases 1973 1974 1975 1976 Salmonella C 20406 16 053 60115 81 586 D 214 128 + + Other C 143 422 123 791 162 384 605 556 gastrointestinal diseases a D 196 211 + + 1977 47 282 + 583 056 + a Gastritis , duodenitis, enteritis and colitis , except diarrhoea of the newborn . 22 Table 2. Typhoid fever in Mediterranean countries 1960 1965 1970 1975 1976 1977 --- Rate per Number Rate per Number Rate per Number Rate per Number Rate per Number Rate per Number 100 000 of 100 000 of 100 000 of 100 000 of 100 000 of 100 000 of pop. cases pop . cases pop. cases pop. cases pop. cases pop. cases Algeria 29.8 3 2148 9.7 1 1498 5.8 835'3 18.4 3 081 27.4 4 746 France 5.0 2261 8 3.3 160~ 2.4 1 211 8 2.0 1 061 8 1.9 1 oos8 Greece 19.2 1 597 9.9 843 7.8 684 7.0 633 7.3 665 59:t' Italy 30.5 15 068 22.7 11 957 21 .7 11 624 12.9 7 217 12.5 7 001 Morocco 20.6 2 39cf 44.6 5 945'3 63.0 9 418'3 27 .0 4 681 8 20.3 3 628'3 Spain 33 .2 10 001 8 12.3 3 91~ 9.9 3 32if 6 .2 2 185'3 5.8 2 092 Tunisia 6 .8 28~ 13.3 591 8 23.6 1 21cf 12.4 70~ 7.9 4548 Turkey 24.2 6.884 12.4 4 019 9.7 3 402 2.1 810 1.7 695 Yugoslavia 17.0 3 123 10.7 2 020 5.8 1 172 2.8 608 2.3 493 2.4 530 - a Including paratyphoid fevers . b No population figures . Sources: World health statistics report , 26(9) (1973) and 30(1) (1977). N World health statistics quarterly, 31 (1) ( 1978). w World health statistics annual , 1979, Vol. 2 ; and previous years. N Table 3. Bacillary dysentery in Mediterranean countries .j::. 1960 1965 1970 1975 1976 1977 - Rate per Number Rate per Number Rate per Number Rate per Number Rate per Number Rate per Number 100 000 of 100 000 of 100 000 of 100 000 of 100 000 of 100 000 of pop. cases pop. cases pop. cases pop . cases pop. cases pop. cases Algeria 0.7 ad' 6 .6 1af/1 3.2 452'9 15.2 2 544b 15.5 2 689 France 0.08 3-f 0.1 50 0.2 106 1.3 663 Greece 11.0 917 7.2 613 6.6 582 2 .3 210 3.6 327d 961 8 Italy 0.2 95 0 .2 88 0.06 33 0.4 232 0.3 196 Morocco 596.8 69 388, 659.4 87 848, Spain 5.1 1 535 6 .3 2 026 6.9 2 312 3 .2 1 123 5 .4 1 938 Tunisia 11 .6 11' 0.4 20 0.05 3 Turkey 0.2 69 0.6 175 2 .7 950 1.7 649 3 .1 1 247 Yugoslavia 45.2 8.3238 243 .3 47 45J8,g 182.9 37 25a8,g 198.0 42 283g 115.6 37 860 210.7 45 759 - a Not bacillary. 8 No population figures. b Including amoebiasis. f All forms. C 1966. g Including enterocolitis. d Cases reported to the state health authority . Annex II SELECTED ILLUSTRATIVE MATERIAL ON DIARRHOEAL DISEASES AND THEIR CONTROL A. Mode of action of enterotoxin in causation of diarrhoea and the mode of action of oral rehydration Cholera is a prototype of a number of diarrhoeal diseases that are me- diated by enterotoxins, some of which are immunologically related to the cholera enterotoxin. The most important of these is the Escherichia coli heat-labile toxin {LT). Collectively, the other enterotoxic enteropathies by far exceed cholera as causes of morbidity and mortality in the world. The cholera enterotoxin's mode of action has been defined at the mol- ecular level. It is a protein of 84 000 MW consisting of 2 immunologically distinct regions designated A (active) and B {binding). The B region (pre- viously called choleragenoid) is of approximately 56 000 MW. This region of the toxin is responsible for binding the holotoxin to host-cell membrane receptors that contain a particular glycolipid, the GMt ganglioside. This binding enables the 28 000-MW A region to penetrate the host cell where it acts, enzymatically, to cleave NAD and to transfer ADP-ribose to the GTP- binding protein associated with the host-cell enzyme, adenylate cyclase. This ADP-ribosylation of GIP-binding protein prevents the breakdown of GTP to GDP, and effectively locks adenylate cyclase in its active state. The net result is the continuous formation of excessive amounts of cyclic-AMP {cAMP). This leads to a cascade of events, as yet uncertain, that cause intestine epi- thelial cells to oversecrete electrolytes followed by water - the cholera stool. These events are illustrated in the following figure. Enterotoxin entering the gut 1. Binding with host -cell membrane 2. Excessive formation of cyclic-AMP 3 . Oversecretion of electrolytes and water Diarrhoeal stool 25 B. Mode of action of oral rehydration therapy Oral rehydration has as function to replace electrolytes and water in the blood stream that have been depleted by diarrhoea. The electrolytes are carried through the intestinal mucous membranes by dextrose, which is easily absorbed. The process is shown below in a sin1plified scheme. Action of enterotoxin: oversecretion and loss of electrolytes and water : dehydration 26 Oral rehydration fluid Diarrhoeal stool 2 Replacement of lost electro- I ytes and water carried through the mucous membrane by dextrose Blood vessels C. Assessment of dehydration and of fluid deficit in infants Signs and symptoms Appearance Skin elasticity Eyes Tears Anterior fontanelle (when open) Mucous membranes Radial pulse Fever (rectal temperature) Urine flow Respiration Heart (auscultation l Estimated fluid deficit Degree of dehydration (% loss of body weight) Milif (4-5%) thirsty, alert, restless normal normal present normal moist(±) normal (good volume) nil(±) normal normal normal 40-50 ml/kg (e.g. 240-300 ml in a 6-kg child) Moderate (6-9%) thirsty; restless, or lethargic but irritable when touched, or drowsy decreased - mild to moderate (+to++) sunken (detectable) absent depressed dry rapid/weak present no urine for several hours, or small quantity of dark urine passed (mother can tell) deep(±), rapid tachycardia 60-90 ml/kg (e .g. 360-540 ml in a 6 -kg child) Severe, with or without shock (;;,, 10%) drowsy; limp, cold, sweaty and often cyanotic extremities; may be comatose marked decrease(+++) grossly sunken absent depressed very dry rap id, feeble, on rare occasions impalpable present no urine for several hours (;;,, 8 hours usually) deep/rapid tachycardia, feeble 100- 120 ml/kg (e.g. 600- 720 ml in a 6 -kg child) a A baby with mild dehydration may not have any obvious physical signs and may present only with a history of watery diarrhoea and intense thirst. 27 D. Assessment of the degree of dehydration and amount of fluid deficit in older children and adults Degree of dehydration (% loss of body weight) Signs and symptoms Mild Moderate8 Severe8 (4-5%) (6-9%) (> 10%) Appearance alert, restless alert, postural usually conscious, thirsty hypotension, apprehensive, with cold, thirsty sweaty, often cyanosed extremities, wrinkled skin of fingers and toes, muscle cramps Skin normal decreased marked loss (+++) elasticity (+to++) Eyes normal sunken gross I y sun ken (detectable) Mucous moist± dry very dry membranes Radial pulse normal rapid/weak feeble or even (good volume) impalpable Systolic normal normal+ low < 90 mm systolic, blood pressure often unrecordable Urine f low normal may or may not no urine passed for be diminished several hours, and bladder empty Respiration normal deep, ± rapid deep/rapid Estimated 40-50 ml 60-90 ml 100-110ml fluid deficit per kg per kg per kg a Cholera and cholera-like diarrhoea may lead to moderate or severe dehydration within several hours of onset of watery diarrhoea. Signs of shock, e.g., cold sweaty extremities, weak and rapid or impalpable radial pulse, very low or unrecordable blood pressure, are common in severe cases. 28 E. Guide for rehydration therapy in infants Admission Degree of dehydration and type and amount of flui~ weight Moderatec Severe with shoc k (approximate Mil'.1, I.V . Ringer's lactated age) ORS ORSb plus ORSb 3 kg 150 ml in 4 hrs 300 ml in 6 hrs Give I.V . Ringer's lac- (1-2 months) tate at a rate of 30 ml per kg in one hour, 5 kg 250 ml in 4 hrs 500 ml in 6 hrs then 20 ml per kg per (3-4 months) hour for 2 more hours, to make a total of 7 kg 350 ml in 4 hrs 700 ml in 6 hrs 70 ml of Ringer's lac- (6-9 months) tate per kg in 3 hours. Stop I.V. and start 10 kg 500 ml in 4 hrs 1000 ml in 6 hrs ORS to make up the (1-2 years) remaining deficit : 50 ml per kg over the next 12 kg 600 ml in 4 hrs 1200 ml in 6 hrs 3 hours.8 (2-3 years) a The amounts are calculated on the basis of the maximum fluid deficits given in section C. b ORS = oral rehydration solution containing, in mmol per litre: sodium 90, po- tassium 20, chloride 80, bicarbonate 30, and glucose 111 . c Although the estimated deficit in moderate dehydration is up to 90 ml per kg (section C), the fluid amounts have been calculated on the basis of 100 ml per kg to allow a small extra amount for anticipated purging during rehydration. d If Ringer's lactate is not available, use an alternative. e Example : a baby weighing 5 kg will receive 150 ml I.V. Ringer's lactate during the first hour, then 100 ml per hour for 2 hours; this is followed by 250 ml of ORS in the next 3 hours. 29 w 0 F. Guide for rehydration and maintenance therapy in adults and older children Therapy Rehydration Maintenance Dehydration status Severe Moderate or mild Type of fluid I .V . Ringer's lactate (or alternatives- see section 10) ORS ORS Estimated fluid deficit 100 ml/kg body weight Moderate: 80 ml/kg body weight Mild : 50 ml/kg body weight Rate of administration (a) Give half the estimate (e.g., 2.5 litres in a 50-kg adult) as fast as possible (simultaneous I.V. drips at 2 different sites may be needed in a "pulseless" patient) until a good volume radial pulse is obtained. Give the total initial deficit in 2 to 3 hours. (b) Check signs as in Table 6; if signs of dehydration are absent then go on to maintenance; if not, continue I.V. administration until the signs disappear. Adults: 750 ml per hour. Children : 200-300 ml per hour. Replace fluid as fast as the patient can take it (average time of rehydration: 3 - 5 hours). Higher rates may be re- quired for continued purging. If signs worsen or intractable vomiting prevents oral intake, then give I.V . as under severe dehydration. Replace stool losses volume for volume. If they cannot be measured, estimate the losses using the clinical status of the patient as a guide. Adults: up to 750 ml per hour. Children: up to 200-300 ml per hour. If stool output is higher, vomiting is intractable or signs of dehydration appear, then I .V. Ringer's lactate (20-40 ml/kg depending on severity) until signs disappear; then give ORS. Annex III LABORATORY ACTIVITIES FOR DIARRHOEAL DISEASES 1 . Basic programme Salmonella Shigella Vibrio cholerae 2. Enlarged programmes Enterotoxic £. coli Campylobacter Yersinia Rotavirus Yeasts and fungi 3. Combinations according to : national priorities available facilities These programmes envisage coverage of the people with diarrhoeal diseases and when necessary also isolation of pathogens from effluents or from water, preferably by using Moor's swab method and/or Millipore filter technique . 4. More elaborate tests for identification, still feasible at peripheral level 4.1 Enrichment media 4.1.1 Liquid - Selenite F : Not for Shigella - Alkaline peptone: For V. cholerae 4.1.2 Solid - Media of low selectivity McConkey Eosin methylene blue - Media of high selectivity Desoxycholate-citrate : Not E. coli Salmonella-Shigella : Not Shigella 31 Bismuth sulfate Brillant green Alkaline nutrient agar Thiosulfate-citrate-bile salt - Recommended minimal set McConkey plus desoxycholate-citrate plus alkaline N.A. 4.2 Industrially-produced media for identification - API - Enterotube - Pathotec - a/b Enteric differential system - Quick test tablets The details of the methods mentioned above can be found in the fol- lowing WHO documents: (I) Simplified procedures for the isolation and identification of enteric pathogenic bacteria. Geneva, World Health Organization {WHO/BAC/78.2). {2) Guidelines for the laboratory diagnosis of cholera. Geneva, World Health Organization, 1974 (WHO/LAB/78.2). 32 w w Fig. 1. Example of the simple graphic presentation of the therapeutic scheme + Mild dehydration (3 -5" loss) + 1. ORS 50 ml/kg in 4 hours 2 . Unrestricted breast-feeding 3 . Half-strength feed and Guidel ines for flu id therapy o f infants at treatment centre Triage by history and physical examination Moderate dehydration 16 -9% loss) • 1. ORS 100 m l/kg in 6 hours 2. Unrestricted breast-feeding during this period and after ~~~"t,,,':"~~'.1'..':i infants J / 4 . Semi-sol id food in in fants > 4 months I hy • f fully Assess hydrat ion at 6 hours -. If improved but still has signs of dehydration • If no Assess hydration at 4 hours / l .- . / If no If dehydration dehydration signs develop l improvement or deterioration • Give 1.V . Ringer's lactate 20 ml/kg/h until signs are absent 1 . Continue ORS at the same hourly rate until dehydration djsappean 2 . Con tinue breast -feedi ng and o ffer plain water • Maintenance therapy - OAS and feeding Severe dehydration with o r without shock (>1~1oss) I.V . Ringer's lactate 70 ml/kg in 3 hours Assess hydration at 3 hours • • If improved If not improved + • Give ORS 50 ml/kg in 3 hours Give more I.V. 20 ml/kg/h until signs are absent Assess hydration at 6 houn + • + If fully If improved If rehydrated but still hes de te riorat ion signs of + dehydration l Cont inue I .V . at 20ml/kg/ h until signs are absen t 1. Give ORS a t the same hourly rate until dehydra tion disappear, 2. Continue breast-feeding and offer p lain water Fig. 2. Example of the simple graphic promotional presentation of dehydration and its therapy (a) Signs of dehydration this child's skin fold (b) What makes an ORS packet? .... ~i'": ..... -. .-,.. ~ 1". POTASSIUM SODIUM CHLORIDE ICARBOIATE "\.. \ 1.5 g 2.5 g Sealed packet 34 ..~ SODIUM CHLORIDE I 3.5 g ~-v ~ GLUCOSE ~ 20 g 1 li tre drinking water Table 1. Daily fluid losses in healthy children and adults Insensible Renal Faecal Total 7-kgmale 45 ml/kg 40 ml/kg 10-15 ml/kg 95-100 ml/kg 70-kgmale 22.5 ml/kg 20.0 ml/kg 2.5 ml/kg 45.0 ml/kg Table 2. Daily maintenance fluid requirements by age Oral rehydration fluid 331 mmol/litre Age ml/kg 1-3 days 60-100 4-10 days 125-150 3 months 140-165 6 months 130-155 9 months 125-145 1-3 years 115- 135 4-6 years 90-110 7- 9 years 70-90 Adult 40-50 Fig. 3. Free water in oral rehydration fluid Glucose 240 ml [ ------ - - - - - - Plasma 290 mmol/litre 760 ml HCO3 35 Appendix 1 ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) FOR DETERMINING ROTA VIRUS Binding antibody Anti-rotavirus rabbit serum ( 1 % lgG) l Control rabbit serum (1 % lgG) Washing Washing solution Stool specimens 36 Dilute in 1.59 g Na2 CO3 (15 mmol) 2.93 g NaHCO3 (35 mmol) 0.20 g NaN3 (3 mmol) H2 O ad 1000 ml pH 9.6 Maintain at +4°C for maximum 14 days Dilute l :2000 Add 10 microlitres to 10 ml of buffer. Mix (Erlenmeyer) and add 5 ml of mixture to 5 ml of fresh buffer (Tank). Add l 00 microlitres of the final mix- ture per well. Incubate for 1 hour at ambient temperature. Throw away the contents of the wells and wash by immersion in the washing solution and repeat the process twice. Leave the plate with wells filled for l O min. Repeat twice. 29 .20 g NaCl 0.20 g KCl 0.20 g KH2 PO4 1.15 g Na2 HPO4 • 2H2 O 0.5 ml Tween 20(R) H2 O ad 1000 ml + 5 g bovine albumin serum (0.5 mo!) (2.7 mmol) (1.5 mmol) (6.5 mmol) pH 7.2 Add 5 volumes of physiological saline serum to l volume of the specimen to be tested; shake vigorously with the help of glass beads. Centrifuge l 000 x G for l 0 mins. Add l 00 microlitres of Washing Rabbit serum conjugated with peroxydase Washing Staining To stop staining surface liquid to 0.9 ml (small test tubes) of buffer : 1 litre of washing solution 5 g bovine albumin Add 100 microlitres per well ( covered with anti-rotavirus rabbit serum and control serum respectively). Incubate for 30 mins at 37°C. As above Dilute l: 1000 in the same solution as that used for the final dilution of stools, adding 10 microlitres of con- jugate to IO ml of buffer in the tank. Mix. Add 100 microlitres of diluted conjugate per well. Incubate for 30 mins at 37°C. As above, plus: Add I 00 microlitres per well of staining buffer: C6 Hs 01·H2 0 (citric acid) 5.1 g (24.3mmol) Na2 HPO4 · H2 O 9.15g(51.4mmol) H2 O ad 1000ml pH 5.0 Throw away Add 100 microlitres per well of staining solution : 40 mg OPD (2.2 mmol) prepared 20 microlitres 30% H2 0 2 (2 mmol) extemporaneously 100 ml staining buffer pH 5 Add 150 microlitres per well of 2 N H2 SO4 Read results with naked eye or by photometer. 37 Appendix 2 AN EXAMPLE OF INFORMATION ON BASIC RULES OF TREATMENT OF DIARRHOEAL DISEASES An effective treatment consists of rehydration ( oral if possible; if not, intravenous replacement of lost fluids and electrolytes). Rehydration is the only essential component of the treatment. Diet Once the patient is fully hydrated and has recovered his appetite, and even before diarrhoea has stopped, well-cooked, easily digested food (rice, bananas, yoghourt, cereals, lentils, etc.) that is part of the normal diet should be given. Thus resorption of electrolytes and water is enhanced and mal- nutrition prevented. Antibiotic therapy Antibiotics are not needed for the treatment of acute diarrhoea, except in: severe bacillary dysentery persisting for 3 or more days, particularly that due to Shige/la dysenteriae, and severe cholera. For severe bacillary dysentery, the drugs of choice are ampicillin or trimethoprim/sulfamethoxazole (TMP/SMX): Ampicillin - 100 mg/kg/day (oral or parenteral) in 4 divided doses for 5 days (note: ampicillin resistance may be common in some areas). TMP/SMX - Children: TMP 10 mg/kg/24 hrs and SMX 50 mg/kg/24 hrs in 2 divided doses for 5 days. Adults: TMP 160 mg and SMX 800 mg twice daily. Second-choice drugs are: Nalidixic acid - 55 mg/kg/day in 4 divided oral doses for 5 days. Tetracycline - 50 mg/kg/day in 4 divided doses for 5 days (Note: tetracycline resistance may be common in some areas). Ch/oramphenicol - may also be used but because of adverse reactions should be avoided if possible (dosage: 50 mg/kg/day for 5 days). 38 For severe cholera, the drug of choice is : Tetracycline - Children: 50 mg/kg/day in 4 divided doses for 3 days. Adults: 500 mg every 6 hours for 48 hours . 39 Annex IV UST OF WHO COLLABORATING CENTRES Year of Last designation redesignation WHO Collaborating Centre for Reference and Research on Salmonellae Pasteur Institute 25 rue du Docteur Roux 75724 Paris France 1965 1977 WHO Collaborating Centre for Shigella Bacteriology Division Center for Disease Control Atlanta, Georgia 30333 USA 1964 1977 WHO Collaborating Centre for Phage-typing and Resistance of Enterobacteria Central Public Health Laboratory Colindale Avenue London NW9 SHT United Kingdom 1961 1978 WHO Collaborating Centre for Reference and Research on Vibrios National Institute of Cholera and Enteric Dis- eases (Indian Council of Medical Research) 3 Dr M. Ishaque Road (Kyd Street) Calcutta 700 016 India 1963 1977 WHO Collaborating Centre for Reference and Research on Escherichia and Klebsiella National Serum Institute Amager Boulevard 80 2300 Copenhagen S Denmark 1949 1977 40 WHO Collaborating Centre for Reference and Research on Bacterial Vaccines "Human" Institute for Serobacteriological Production and Research X Szalias u tea 5 Budapest Hungary Institute of Veterinary Medicine Thielaliee 88/92 1000 Berlin (West) 33 WHO Collaborating Centre for Campylo- bacter jejuni Department of Microbiology and Infectious Diseases St Pierre University Hospital Rue Haute 322 I 000 Brussels Belgium 1973 1977 41 Annex V LIST OF NATIONAL REFERENCE CENTRES FOR ENTEROBACTERIACEAE Algeria National Salmonella and Phage-typing Centre Enterobacteriaceae Department Pasteur Institute Algiers Albania National Reference Centre for Salmonella, Shigella and Escherichia Enteric Infections Department Central Laboratory for Microbiological Production and Research 481 rue B. Curri Tirana Austria National Salmonella and Phage-typing Centre Federal Research Institute for Bacteriology and Serology Universitatsstrasse 6/2 Graz Belgium 42 National Salmonella and Shigella Centre Institute of Hygiene and Epidemiology 14 rue Juliette Wytsman Brussels National Enteric Phage-typing Centre Pasteur Institute of Brabant 28 rue des Remorqueurs Brussels Bulgaria National Salmonella Centre Research Institute of Epidemiology and Microbiology Boulevard VL. Zaimov 26 Sofia National Shigella Centre Research Institute of Epidemiology and Microbiology Boulevard VL. Zaimov 26 Sofia National Escherichia Coli Centre Research Institute of Epidemiology and Microbiology Boulevard VL. Zaimov 26 Sofia Czechoslovakia National Salmonella Reference Laboratory Institute of Epidemiology and Microbiology Srobarova 48 Prague 10 National Reference Laboratory for Phage-typing of Enterobacteria Research Institute of Epidemiology and Microbiology Sasinkova 9 Bratislava National Reference Laboratory for Enterobacteria with Facultative Pathogenic Action Faculty of Medical Hygiene Srobarova 48 Prague 10 Denmark National Salmonella Reference Centre State Serum Institute Amager Boulevard 80 2300 Copenhagen S 43 National Escherichia Centre State Serum Institute Amager Boulevard 80 2300 Copenhagen S National Reference Centre for Enteric Bacteriology Enteric Bacteriology Department State Serum Institute Amager Boulevard 80 2300 Copenhagen S Finland National Reference Laboratory for Bacteria State Serum Institute Mannerheimintie 166 Helsinki 28 France National Salmonella Centre Pasteur Institute 25 rue du Docteur Roux 75724 Paris National Shigella Centre Pasteur Institute 25 rue du Docteur Roux 75724 Paris National Centre for Phage-typing of Enteric Bacteria Pasteur Institute 25 rue du Docteur Roux 75724 Paris Germany, Federal Republic of National Salmonella Centre Robert Koch Institute Federal Health Office Postfach 1 Berlin (West) 33 44 National Reference Centre for Phage-typing of Salmonellae and Staphylococci Institute for Medical Microbiology and Immunology University of Bonn Venusberg 5300 Bonn Greece National Salmonella Surveillance Centre Microbiology Laboratory School of Hygiene 196 Leoforos Alexandras Athens Centre for Phage-typing of Salmonella and Other Enterobacteria Alexandra Hospital Laboratory Athens National Reference Laboratory for Phage-typing of Salmonella Laboratory of the Faculty of Medicine University of Athens Athens Hungary National Salmonella Centre National Public Health Institute Budapest National Salmonella Centre Institute of Microbiology University Medical School Rakoczi u t. 2 P~cs Iceland National Reference Laboratory for Bacteria Department of Pathology and Bacteriology University of Iceland v. Barousstig Reykjavik 45 Italy Reference Centre for Pathogenic Enterobacteriaceae in Northern Italy University Institute of Hygiene Via Francesco Sforza 35 Milan Reference Centre for Pathogenic Enterobacteriaceae in Central Italy University Institute of Hygiene Via S. Zeno 35 Pisa Reference Centre for Pathogenic Enterobacteriaceae in Southern and Insular Italy University Institute of Hygiene Via Divisi 83 Palermo Morocco National Reference Laboratory for Bacteria Bacteriological Laboratory National Institute of Hygiene Rabat Netherlands National Reference Laboratory for Salmonella and Enterobacteriaceae National Institute of Public Health Sterrenbos 1 Utrecht Norway 46 National Reference Laboratory for Enteric Bacteria Department of Bacteriology State Institute for Public Health Geitmyrsvn 75 Oslo 4 Poland National Centre for Phage-typing of Salmonella Institute of Marine Medicine UL Hibnera I 0 Gdansk National Shigella Centre Department of Bacteriology National Institute of Hygiene UL Chocimska 24 Warsaw Portugal National Salmonella and Shigella Centre Camara Pestana Institute of Bacteriology Lisbon National Centre for Phage-typing of Enterobacteria Dr Ricardo Jorge Institute of Hygiene Campo dos Martires da Patria 91 Lisbon Romania National Reference Centres for Salmonella, Escherichia and Enteric Phage-typing Dr I. Cantacuzino Institute of Microbiology, Parasitology and Epidemiology Splaiul Independentei No . I 03 Bucharest Spain National Centre for Salmonella and Phage-typing of S. typhi National School of Health Ciudad Universitaria Madrid 47 Sweden National Reference Centre for Bacteria State Bacteriological Laboratory Fack 764 Stockholm 1 Switzerland National Salmonella Centre Bacteriological Veterinary Institute of the University of Berne Veterinary Hospital .Llinggasstrasse 122 3012 Berne National Shigella Centre Institute of Hygiene, Bacteriology and Virology University of Lausanne 19 rue du Dr Cesar-Roux 1000 Lausanne Turkey National Salmonella Centre Central Institute of Hygiene Ankara USSR 48 National Salmonella Reference Laboratory Central Institute of Epidemiology of the Ministry of Health of the USSR 3a Novogireevskaja ulica Moscow National Shigella Reference Laboratory Leningrad Pasteur Institute 9 ulica Akademika Pavlova Leningrad National Escherichia Reference Laboratory Mecnikov Institute for Research on Vaccines and Sera Sa pereulok Mecnikova Moscow United Kingdom National Salmonella Reference Laboratory (including Escherichia) Central Public Health Laboratory Colindale Avenue London N.W.9 National Shigella Reference Laboratory Dysentery Reference Laboratory Central Public Health Laboratory Colindale Avenue London N.W.9 National Enteric Reference Laboratory Central Public Health Laboratory Colindale A venue London N.W.9 Yugoslavia National Salmonella Centre Department of Bacteriology Institute of Public Health Rockefellerova 7 Zagreb 1 49 Annex VI LIST OF PARTICIPANTS Algeria Dr Boulefred, Director of Health, Quargla Greece Professor J .A. Papadakis, Athens School of Hygiene Professor G. Papaevangelou, Athens School of Hygiene Professor J. Papavassiliou, Department of Microbiology, Faculty of Medicine, National University of Athens (Vice-Chainnan) Italy Dr V. Piccardo, Director-General of Public Health, Rome Professor A. Zampieri, Director, Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanita, Rome (Chainnan) Malta Dr P. Cuschieri, Bacteriologist, Department of Bacteriology, St Luke's Hospital, Guardamangia Dr A. Mifsud, Professional Officer (Paediatrics), Special Care Baby Unit , Karin Orech Hospital, Guardamangia Morocco Mr A. Azizi, c/o Ministry of Health, Rabat Professor N. Benmansour, Director, National Institute of Hygiene , Rabat Spain 50 Dr L. Valenciana, Director-General of Public Health, Ministry of Public Health and Social Security, Madrid Dr L. Canada Royo , Assistant Director-General of Preventive Medicine, Ministry of Public Health and Social Security, Madrid Tunisia Dr R. Benammar, Deputy Director of Preventive and Social Medicine, Ministry of Health, Tunis Turkey Dr N. Alkis, Director, Refik Saydam Central Institute of Hygiene, Ankara Dr M. Onver, Chief, Communicable Diseases, Ministry of Health and Social Assistance, Ankara Yugoslavia Professor A. Radsel-Medvescek, Clinic for Infectious Diseases, Clinical Centre, Ljubljana Dr S. Sotirovski, Head, Epidemiological Department, Republican Insti- tute for Health Protection, Skopje Observers Dr M. Castellani-Pastoris, Department of Bacterial and Viral Diseases, Istituto Superiore di Sanita, Rome, Italy Professor L. Dardanoni, Director, Institute of Hygiene, University of Palermo, Italy Dr G. Donelli, Director, Electromicroscopy Division, Department of Cell Biology and Immunology, Istituto Superiore di Sanita, Rome, Italy Dr P. Gianfrilli, Department of Bacterial and Viral Diseases, Istituto Superiore di Sanita, Rome, Italy Dr D. Greco, Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanita, Rome, Italy Dr M. Mazzotti , Department of Bacterial and Viral Diseases, Istituto Superiore di Sanita, Rome, Italy Temporary advisers Dr W.B. Baine, Laboratory of Epidemiology and Biostatistics, lstituto Superiore di Sanita, Rome, Italy Professor B. Cvjetanovic, Institute of Immunology, Zagreb, Yugoslavia (Rapporteur) 51 Professor G. de Felip, Director of Research, lstituto Superiore di Sanita, Rome , Italy World Health Organization Regional Office for Europe 52 Dr F. Gatti , Rabat-Agdal , Morocco Dr M. Postiglione, Director, Disease Prevention and Control Dr B. Velimirovic , Regional Officer for Communicable Diseases (Sec- retary) Dr A.W. Wahba, Regional Officer for Appropriate Technology for Health Headquarters Dr I.D. Carter, Chief, Epidemiological Surveillance of Communicable Diseases Dr D. Barua, Programme Manager, Diarrhoeal Diseases Control Programme WHO publications may be obtained, direct or through booksellers, from : ALGERIA ARGE'ITINA AUSTRALIA AUSTRIA BANGLADESH BELGIUM BRAZIL BURMA CANADA CHINA COLOMBIA CYPRUS CZECHO- SLOVAKIA DENMARK ECUADOR EGYPT EL SALVADOR FIJI FINLAND FRANCE GERMAN DEMOCRATIC REPUBLIC GERMANY. FEDERAL REPUBLIC OF GHANA GREECE HAITI HONG KONG HUNGARY ICELAND INDIA INDONESIA IRAN IRAQ IRELAND ISRAEL ITALY JAPAN KOREA REPUBLIC OF KUWAIT LAO PEOPLE'S DEMOCRATIC REPUBLIC LEBANON Sc>c1ete Nauonale d"Ed1t1on et de D,Uusion. 3 bd Zirout Youcer. ALGIEllS Carlos H11'1Ch SRL Flonda 165. Galenas Guemes, Escrnono 453/46S. BUENOS AlllES Ma,/ Ordtr Sal,s · AuSlralian Government P\Jblish1ng Scmce. P.O. Bo• 84. CANIERllA A.CT. 2600 . or 01,r rh, rn11111,r from AUSlrahan Government P\Jblish,ng Scma, Bookshops at: 70 Alinga Slrec1. CANIElllA CITY A.CT 2600 : 294 Adelaode Slrec1, Bll1SIANE. Queensland 4000 : 347 Swanston Slr<e1. MEL- IOUlNE. VIC 3000: 309 P111 Slrec1. SYDNEY. N.S.W 2000 ; Mt Newman House. 200 SI. Georse·s Terrace. PE1TI1. WA 6000; Industry House. 12 Pme Slr<e1. AOELAIOE, SA SOOO ; I 56-162 Macquane Slr<e1, HOIAlT, TAS 7000 - Hunter P\Jblicat,oru. S8A G1pps Slr<e1. CowNCwooo, VIC 3066 - R. Hill & Son Ltd., 608 SI. Kilda Road. MELIOUlNE. VIC 3004 ; Lawson House. 10-12 Clark Slrec1. Caow·s NEST, NSW 206S Gerold & Co .. Graben JI . 1011 V1ENNA I The WHO Programme Coordinator. G.P 0 . Box 2SO. DACCA S - The Associa110n of Voluntary A~ncies. P 0 . Box S04S. DACCA S Orrice 1n1crna11onal de L1bra1ne. 30 avenue Marnix. I0SO llllusnu - Subscnplloru to World H,alrh 01111 Jean de Lannoy, 202 avenue du R01. 1060 Baussas 81blioteca Reg,onal de Med1Ctna OMS/OPS. Unidade de Venda de P\JblfCalX}es. Caixa l'mlal 20.381 , Vila Clemen11no. <M023 s;.o PAULO, S.P. ,,, India. WHO Reg10nal Office S1111</• and bulk copi,s of 1ndmdual publicat10,u /not subscnplloru): Canadian P\Jblic Health Association. 133S Carling Avenue. Suite 210. OTTAWA. Ont. K IZ 8N8. Subscnp11oru • Subscnp11on ord,rs. accompani,d h, rh,qu, mo,k out to the Royal Bank of Canada. Ottawa, Acx:ount World Health Orpn,zat,on, sllould IN s,n, 10 th, World Health Orpn1za11on. P 0 . Box 1800. Postal Sla110n B, OTTAWA. Ont. KIP SIU. Co,,.. spond,nc, ron<rm1ns subscnp11oru should IN odd1T,s,d 10 th, World Health Organiza110n, Dutnbu110n and Sales. 1211 GENEVA 27. Switzerland China Nat10nal P\Jblica110ns lmpon Corporation. P.O. Box 88. lkUINC (l'EKJNG) Dlstnlibros Ltd .. Pio Alfonso Garcia. Carrera 4a. Nos 36-119. CutTACENA P\Jblishers' Distnbutors Cyprus. 30 Democratias Ave Ay1os Dhomeuous. P.O. Box 4l6S. NICOSIA An,a. Ve Smeckach 30. 111 27 l'aAGUE I Munksgaard Expon and Subscnpt,on Scmoc. Nerre Segade JS. 1370 COPENHAGEN K L1brena Cienurica S.A .. P.O. Box 362, Luque 223. GUAYAQUIL Osms Ofrioc for Books and Reviews. SO K.asr El N,I Slrec1. CAJlO L,brena Estudianul. Edific,o Comercial 8 No 3. Avenida Llbertad. SAN SAl.vAOOII The WHO f'rosramme Coordinator. P.O. Box 113. SIJVA Akateem,nen Kirjakauppa. Keskuskatu 2. 00101 HELSINKI 10 Llbra1rie Ame11e. 2 rue Cas1mir-Delav1811", 7S006 PAlllS Buchhaus Le1pz1g. Postfach 140. 701 l.al'ZIC Govi-Vcrlag GmbH. G1nnhe1merstrasse 20. Postfach S360. 6236 EscHIOlN - W. E. Saarboch. Postfach IOI 610. Follerstrasse 2. S000 COLOCNE I - Alex. Hom, Sp .... 1- 9, Postfach 3340. 6200 W1ESaAOEN Fides Enterprues. P.O. Box 1628, ACCllA G.C Eleftheroudakis S.A .. L1braine internationale. rue Nikis 4, ATI<ENS (T. 126) Max Bouchereau. Libraine "A la Caravelle", Boite postale 111-8, POIIT·AU· PalNCE Hons Kon1 Government lnformatlOn Services. Beac:onsrield Howe, 6th Floor. Queen's Road, Central. VK'TOltJA KultUnL P.O.8. 149. 8uOAPOT 62 - Akademiai Konyvesbolt. Vi,c, utca 22. 8uDAPEST V SnaebJ'lm Jons.t0n & Co .. P.O. Box 1131. Hafnarstraet1 9. REYKJAVIK WHO Rcg,onal Office roe South-East Asia. World Heakh House. lndraprastha Estate. Ring Road. NEW DELHI 110002 - Oxford Book .l Stat,onery Co .. Sandia House, NEW DELHr 110001 ; 17 Park Slr<e1. CALCUTTA 700016 (SulMig,nt) M/s Kalman Book Serv100 Ltd .. Kw1tang Raya No. 11, P.O. Box 31~/Jkt. JAKAllTA Iranian Amalprnated Distribution Aacn<Y, ISi Khiaban Soraya. TEHOAN Ministry or Information. National Howe for P\Jblish1ng. Dlstribuung and Advenisins, BAGHDAD The Slauonery Off 100. DulUN 4 He,liFr & Co .. J Nathan Slrauss Slrec1. JERUSAUM Ed,z,on, Minerva Medico. Corso Bramante 83-8S. 10126 Tua1N; Via Lamarmora 3. 20100 MILAN Maruzen Co. Ltd .. P.O. Box SOSO, Too:vo lnternat,onal. 100-31 The WHO f'rosramme Coordinator. Central P.O Box S40, Seoul The Kuwait Boobhopl Co. Ltd., Thunayan AJ.Ghanem Bldg. P 0 . Box 2942. KuwArr The WHO Programme Coordinator. P 0 . Box 343. VIENTIANE The Levant Distnbutor, Co. SA.R.L . Box I 181 . Makdass1 SI.-. Hanna Bldg. lkraUT A/1/81 WHO publications may be obtained, direct or through booksellers, from: LUXEMBOURG MALAWI MALAYSIA MEXICO MONGOLIA MOROCCO MOZAMBIQUE NEPAL NETHERLANDS NEW ZEALAND NIGERIA NORWAY PAKISTAN PAPUA NEW GUINEA PHILIPPINES POLAND PORTUGAL SIERRA LEONE SINGAPORE SOllTH AFRICA SPAIN SRI LANKA SWEDEN SWITZERLAND SYRIAN ARAB REPUBLIC THAILAND TUNISIA TURKEY UNITED KINGDOM UNITED STATES OF AMERICA USSR VENEZUELA YUGOSLAVIA ZAIRE L1bra1ne du Centr,,, 49 bd Royal. LuxEMIOORG Malawi Book Scrv1oe, P 0. Box 30044, Ch1ch11i, lllANTYllE 3 The WHO Programme Coordinator, Room 1004, Fitzpatrick Buildin1, Jalan Raja Chulan. KUALA LUMl'\JR 0~2 - Jubilee (Book) Stor,, Lid. 97 Jalan Tuanku Abdul Rahman, P 0 . Box 629, KUALA luMl'\JR 01~ - Parry's Book Center, K. L Hilton Hotel, Jin. Tr,,acher. P.O. Box 960, KUALA LUMl'\JR La P,.,nsa Medica Mexicana. Edicioncs Cientiricas, P...., de las Facultadcs 26, Apt. Postal 20-413. MEXICO CITY 20. 0 .F. sn India. WHO Regional Offioe Editions La Pone. 281 avenue Mohammed V, iluAT I NLD, Caixa Postal 4030, MAIVTO Rt India, WHO Regional Office Medical Books Europe av. Noordcrwal 38, 7241 BL l..ocHDI Government Pnn1in1 Office, Publications Section, Mulll'8ve Street, Pnvate Bag. WEUJNGTON I: Walter Street, WEUJNGTON; World Trade Buildin1, Cubocade, Cuba Street, WEUJNOTON. Govtmmtnt Bookshops at: Hannaford Bunon Buildin1, Rutland Street, Pnvate Bag. AUC"1AND; 159 Her,,ford Street. Pnvate Bag. CHlllSTCHURCH; Alexandra Street, P.O. Box 857, HAMILTON; T & G Bu11din1, Princes Street, P.O .. Box 1104, DIJNEDIN - R. Hill & Son Lid, Ideal House, Cnr Gillies Avenue & Eden Street, Newmarket, AUC"1AND I Unovenity Bookshop Nip,na Lid, Univenity of Ibadan, IIIADAN J. G . Tanum A/S. P.O. Box 1177 Scntrum. OsLO I Mirza Book Ap,ncy, 6S Shahrah-E-Quaid-E-Azam, P.O. Box 729, l.AHOU 3 The WHO Programme Coordinator, P.O. Box 5896, lloRoko World Health Otpnization, Reaional Orfioe for the Western Pacilic, P.O. Box 2932, MANILA - The Modem Book Company Inc., P.O. Box 632, 922 Rizal Avenue, MANILA 2800 Skladnica K.s~nka, ul Mazowiccka 9, 00052 WAIISAW {txctpl JHnodica/s) - BKWZ Ruch, ul Wronia 23, 00840 W"""-w (JHnodica/s only) Livraria Rodn,ucs. 186 Rua do Ouro. LlsaoN 2 Njala Univcnity Collcp, Bookshop (Univen11y of Sierra Leone), Private Mail Bag. FIIEm)WN The WHO Programme Coordinator, 144 Moulmein Road, G .P.O. Box 3457, SINGAPOR£ I -Select Books (Pie) Lid, 215 ta"8lin Shoppin1 Centre, 2/F. 19 Tan1hn Road, SINGAPORE 10 Van Schaik's Bookstore (Ply) Lid, P.O. Box 724, 268 Church Street, l'REroluA 0001 Comcmal Athcncum S.A.. Conscjo de Ciento 1~136, 8ARCUONA IS; General Mosaardi> 29. MADRID 20 - Libreria Diaz de Santos. Laaasca 95 y Maldonado 6, MADRto 6 ; Balmes 417 y 419, BARCTWNA 22 Stt India, WHO Regional Offioe Akticbolagct C.E. Fntzes Kun1I. Hovbokhandcl. R~ringsgatan 12. 10327 STOCIOtOOI Medizinischcr Verlaa Hans Huber, Ungass Strasx 76, 3012 8£RN£ 9 M. Farras Kekh,a, P.O. Box No. 5221 , Al.Effl) sn India, WHO Regional Offioe Soc1ete Tunisienne de Diffus10n, S avenue de Canhage, TUNIS Hasct Ki1apcv1, 469 lsuklal Caddcsi, llcyoglu, ISTANllJL H.M. Stationery Office : 49 Hiat, Holbom. l.oNDON WCIV 6HB; Ila Castle Street, EDINIURGH EH2 JAR ; 41 The Haya, CARDIFF CFI IJW: 80 Chichester Street, Ila.FAST BTI 4JY ; Brazcnnosc Street. MANCHESTER M60 SAS: 258 Broad Slreet, BIRMINGHAM Bl 2HE: Southey House, Wine Street, BRISTOi. BSI 2BQ. All mail ordtrs should~ Rnl 10 P.O. Box 569. l.oNOON SEI 9NH Singlt and bulk cop1ts of 1ndividwl publica11ons (nor subscnp11ons): WHO Publicallons Centr,, USA. 49 Sheridan Avenue, At.aANY, N.Y. 12210. Subscnp11ons.· Subscnp11on ordtrs. accompamtd b,· chtck mad, our 10 tht Chemical Bank, New York, Aa:ount World Health Orpnization. should~ stnt 10 rht World Health Orpnizat,on, P.O. Box 5284. Church Street Siatoon, NEW YORK, N.Y. 10249: Co,..spondtnc, con- cmt1ng subscnpllons should~ add~=d 10 rh, World Health Orpmzation, Distribution and Sales. 1211 G£N£VA 27, Switzerland. Publlca11ons a~ also ava,lablt from rht Umted Nations Bookshop, NEW YORK. N.Y. 10017 /~101/ only) For rrothrs in rht USSR ,,q,ming Rws,an tdirions. Kol1\50molskij prospckt 18, Medianska,a Kn,p. Moscow - For rradtrs ouwd, rht USSR ~'fllinng Russian tdi11ons: Kuzncckij most I 8. Mcidunarod• naia Knip. Moscow G-200 Edi1onal lnteramcricana de Venezuela C.A., Apanado S0.785. CARACAS I0S - Libr,,ria dcl Este. Apar• l8do 60.337, CARACAS 106 - Libr,,ria Medica Paris, Apanado 60.681 , CARACAS 106 Juaoslovenska Knjip, Teraz,jc 27/11. 11000 Ba.GRAD£ Libra1ric univeni1a1rc, avenue de la Paix N° 167, B.P. 1682. KINSHASA I Special terms for developing cow,tries are obtainable on application to the WHO Programme Coordinators or WHO Regional Offices listed above or to the Wortd Health Organization, Distribution and Sales Service, 1211 Geneva 27, Switzerland. Orders from ccuntries where sales agents have not yet been appointed may also be sent to the Geneva address, but must be paid for in pounds starting, US dollars, or Swiss francs. Price: Sw. fr. 4.- Prices are subject to change without notice.