- 74 - CONTROL OF DIARRHOEAL DISEASES C. Ann Martinez, a Dhiman Barua b & Michael H. Merson c During its early years, the primary concerns of the World Health Organization (WHO) in the field of diarrhoeal dis- eases were epidemic control, standardization and qual- ity control of vaccines, and administration of the Inter- national Sanitary Regulations,d adopted in 1951. While acute enteric infections were generally recognized to be an enormous endemic problem in the developing coun- tries, it was cholera-one of the six original quarantina- ble diseases because of its propensity for rapid epidemic spread-that received the greatest attention. Indeed, one of the first tasks of the Interim Commission of WHO was helping to combat the 194 7 outbreak in Egypt, which was the first occasion in some 30 years that the disease had spread west of the Indian subcontinent. During the rest of the 1940s and 1950s, however, the disease remained a problem only in its endemic foci in • Technical Officer. Diarrhoeal Diseases Control Programme, World Health Organization, Geneva. b Consultant, Diarrhoeal Diseases Control Programme. World Health Organization. Geneva. c Director, Diarrhoeal Diseases Control Programme. World Health Organization, Geneva. d The title was changed in 1969 to International Health Regulations. India and Pakistan and the immediate vicinity. During this period a WHO Expert Committee was convened to review practical methods of cholera control and three study groups were organized to suggest lines of future research. Many articles were published in the Bulletin of the World Health Organization, including a series of 11 written by Pollitzer which later were compiled into a classic monograph on the subject of cholera (1). At the same time, recognizing also the importance of typhoid fever, the first steps were taken to evaluate available typhoid vaccines in a properly controlled field trial and in laboratory studies. These years also saw the designation of international reference centres for sal- monella (1948) and shigella (1954). The sixties The seventh cholera pandemic In 1961 came a major turning-point when cholera caused by the eltor vibrio began to spread beyond its endemic focus in Sulawesi, Indonesia. This was the beginning of the seventh pandemic of cholera (Fig. 1). By 1963 it had FIG. 1 INCIDENCE OF CHOLERA AND NUMBER OF COUNTRIES NOTIFYING CASES, 1951-1986 INCIDENCE DU CHOLERA ET NOMBRE DE PAYS AVANT NOTIFIE DES CAS, 1951-1986 50 400 380 45 360 340 40 320 ~ ~ COUNTRIES - PAYS 300 e -5 35 .!! " 0,, ,: .. .., .. Cl.., i~ 30 0:-s c,: _;g 25 E~ :,m o> .... o~ 20 .8 ~ E~ :la, z.i; 15 E .. 280 ~ 260 E c .!!. 240 .. .. u 220 I 200 .. ,, c .. 180 .. :, 0 160 -s c .:a 140 .. " .. .. 120 u 0 z 100 10 80 .. 60 i 5 40 0 I 20 0 0 1951 55 60 65 70 75 80 86 Years - Ann6es Rapp. trimest. statist. sanit. mond., 41 ( 19881 - 75 - extended to a large number of countries in Asia and in 1965-1966 progressed as far westward as Uzbekistan (USSR), the Islamic Republic of Iran and Iraq. These events, unfortunately, were accompanied by severe hin- drances to international travel and trade as countries imposed restrictions in excess of the International Health Regulations (IHR) in a vain effort to prevent the introduc- tion of cholera from other countries. WHO responded to these developments with a greatly expanded programme of activities which included the organization of training courses and provision of training materials; the creation of two interregional teams to help countries in controlling cholera ; assistance in organizing laboratory diagnosis, treatment and the improvement of sanitation, and the provision of supplies for these activ- ities; procurement of vaccines (though their use was discouraged); promotion of research; and publication of a large number of scientific papers and reviews. A news- letter, Cholera information, disseminated up-to-date epi- demiological and technical news to public health work- ers and was much appreciated. Between 1962 and 1968 an expert committee, two scientific groups on cholera research and a scientific group on cholera immunology were convened to discuss the problems caused by the changing pattern of the disease and determine priorities for research, and in 1967 a top-level international con- ference attempted to promote a more rational approach to cholera control. An international reference centre for vibrios was established in 1963. A joint research programme carried out with the Indian Council of Medical Research and the Governments of Japan and the Philippines, and collaboration with scien- tists of the Cholera Research Laboratory (Bangladesh) contributed fundamental knowledge of many aspects of cholera. Important findings on the pathophysiological changes in cholera enabled clinicians to improve and later simplify intravenous rehydration and diminish case- fatality rates from up to 60% to 1-2%. Oral rehydration fluid was developed and used for the maintenance of hydration, and clinical and laboratory studies demonstrated the benefits of antibiotics in treat- ment. A series of controlled field trials and laboratory studies of commonly used vaccines showed that even the most potent ones conferred only about 50% protec- tion for less than six months and some were of hardly any value. Educational activities were undertaken to inform public health workers about the limited role of current vaccines in cholera control. The WHO Require- ments for Cholera Vaccine, originally adopted in 1958, were duly revised in 1968, with a further addendum in 1973. Diarrhoeal diseases and enteric fevers Despite the preoccupation with cholera, increasing at- tention was also paid to typhoid and paratyphoid fevers and diarrhoeal diseases in general. Control and research activities were guided by the recommendations of a study group on diarrhoeal diseases (1958) and an expert committee on enteric infections (1963). Between 1960 and 1965 a diarrhoeal diseases advisory team carried out cross-sectional surveys in seven countries in Asia, Africa and South America which contributed to know- ledge of the epidemiology and etiology of diarrhoeal dis- eases and confirmed their relationship with social and environmental factors. Numerous interregional training courses were organized on the diagnosis, treatment and control of enteric infections, and an international refer- ence centre for the phage typing of enterobacteria was designated in 1961. Wld hlth statist. quan .. 41 ( 1988) A major research undertaking in the 1960s was a series of controlled field trials of typhoid and paratyphoid vac- cines, covering nearly 2 million people; at the same time 18 laboratories in various countries cooperated in the evaluation of potency tests for these vaccines. These studies indicated a lack of protective efficacy of the Vi antigen, found the acetone-dried and inactivated typhoid vaccine to be somewhat better than the phenol-killed and phenol-preserved one and demonstrated the effec- tiveness of a paratyphoid B vaccine when given in two doses. Based on these findings, WHO Requirements for Typhoid Vaccine were formally adopted in 1966. The seventies Cholera reaches Africa 1970 was another milestone in the history of cholera and international public health when the disease leaped across a vast expanse of unaffected territory to reach Western Africa. Here it invaded one country after an- other in quick succession, and in the same and following years also reached Eastern and Northern Africa and some countries of Europe. In all, 25 new countries in 1970 and 14 in 1971 were affected by cholera, whereas previously the spread had been limited to not more than six in any one year (Fig. 1). In almost all countries, except those of Western Europe, the disease has become endemic and is continuing to manifest itself in seasonal outbreaks or as sporadic cases. The emergency assistance programme had to be reactivated and the cholera team was reinforced with consultants to help it respond to the many requests for its services. WHO assisted in the establishment of rehy- dration centres at strategic sites in three of its Regions: Africa, South-East Asia and the Eastern Mediterranean. In Africa three WHO depots were established to expe- dite the supply of rehydration fluid and antibiotics. WHO persuaded commercial firms to produce packets of oral rehydration salts (ORS) and distributed them with guide- lines for oral rehydration; this helped health workers to gain experience and confidence in the use of oral rehy- dration. In the first year or two there was a large demand for the supply of vaccines, despite their limited efficacy, and WHO provided 36.5 million doses in 1970 and 31 million in 1971. In 1973 an international reference centre for bacterial vaccines was established which pro- vided facilities for the potency testing of vaccines to ensure that those used were of adequate quality. By 1972, however, countries had gained more experience and confidence in confronting cholera and requests for vaccine declined to only 4 million doses a year. In 1973, the World Health Assembly abolished the requirement of cholera vaccination for international travel in the IHR. Emphasis continued to be placed on health education, sanitary measures including food safety, early detection of epidemics and cases and proper treatment; there was a decline in case fatality and panic gradually subsided. During this period WHO continued to be very active in organizing consultations, seminars and training activ- ities. It issued guidelines for laboratory diagnosis and treatment, and in 1970 the first edition of a compilation of the most recent information on all aspects of cholera, with emphasis on practical measures for its control (2). Although the fear of cholera appeared to decline with time, there was little improvement in notifications to WHO and restrictive measures on travel and trade in excess of the IHR continued to be imposed against cholera-affected countries, although on a reduced scale. 76 - Bacterial drug resistance Another problem that aroused considerable public health concern during the 1970s was the increase in antibiotic resistance in enteric bacteria. In 1968, a large outbreak of bacillary dysentery due to multiresistant Shigella dysenteriae occurred in Central America and Mexico, and in the 1970s similar outbreaks became fre- quent in Asia. Multiresistant Salmonella typhi also caused large epidemics, notably in Mexico in 1972 and later in Asia. In 1974, therefore, the activities of the existing international reference centre for the phage typ- ing of enterobacteria were expanded to include work on the resistance of these organisms. In 1977, a meeting was convened to review the problem and recommend simple measures of surveillance that would generate internationally comparable data, the aim being to facili- tate the appropriate use of antibiotics and promote the early recognition of epidemics. Breakthroughs in research Research on diarrhoeal diseases and particularly on cho- lera accelerated considerably in the 1970s. WHO contin- ued to collaborate closely in the multiple projects carried out by the Indian Council on Medical Research and the Governments of Japan and the Philippines, and provided support to many basic and operational studies. Several new viral and bacterial agents were identified as causes of dia, rhoea, notably rotavirus, enterotoxigenic Escheri- chia coli, Campylobacter jejuni, Vibrio parahaemolyticus, V. cholerae non-01 and Yersinia enterocolitica, offering new possibilities for a better understanding of the patho- genesis of the acute diarrhoeas and for the development of improved methods of diagnosis, treatment and pre- vention, including vaccines. A scientific group on oral enteric vaccines in 1971 and a consultation in 1972 sti- mulated laboratory and field research for the develop- ment of such vaccines. While a number of promising oral vaccines were developed for typhoid and shigella dysen- tery. none proved in controlled trials to be adequate for public health use. However, much new information was learned about the importance of intestinal immunity in protecting against enteric infection, raising the hope that protection could be achieved through the development of more effective oral vaccines. But it was in the area of therapy that the most significant advances were made. Most importantly, WHO field studies demonstrated the effectiveness of a single oral rehydration salts (ORS) for- mulation, which had been agreed upon during a WHO seminar in 1972, in the treatment of all diarrhoeas in addition to cholera, in all age groups; it was shown that it could be effectively delivered by health centres and aux- iliaries and that when children received it in conjunction with dietary education they fared better in terms of body weight. In addition, doxycycline in a single dose of 300 mg was found to be nearly as effective as tetracycline for shortening the period of vibrio excretion in cholera patients, thus reducing the risk of transmission among close contacts. Changing attitudes In the mid-1970s a new outlook on cholera and diarrhoeal diseases began to prevail. Acute diarrhoeas had always been known to be a much greater problem in the devel- oping world than cholera. However, in the absence of a simple strategy to reduce the ill effects of acute diar- rhoeas, there was no political will on the part of national health authorities to undertake activities for their control. The demonstration of the simplicity and effectiveness of oral rehydration in reducing diarrhoea-related mortality and malnutrition, in addition to its benefit in cholera ther- apy. succeeded in convincing public health administra- tars around the world that diarrhoeal diseases control should become an essential component of national pri- mary health care programmes. This conviction and drive resulted in the adoption of an important resolution by the Thirty-first World Health Assembly in 1978 and the crea- tion of a global diarrhoeal diseases control programme (COD). The eighties Objectives of the COD Programme From the outset the COD Programme has had as its objectives the reduction of mortality and morbidity due to diarrhoeal diseases and their associated ill effects, especially malnutrition, in children under 5. To attain these objectives, it has been built up on two main com- ponents: a health services (or control) component and a research component. One of the first tasks of the Programme was to obtain more reliable data on the size of the problem. This was done by undertaking a thorough survey of the literature, which indicated that, in 1980, the acute diarrhoeal dis- eases caused an estimated 1 OOO million episodes of illness and some 4.5 million deaths in children under 5 in the developing countries (excluding China) (3). Given the immensity of the task, the support and active collaboration of other international, bilateral and non- governmental organizations has been of crucial impor- tance. In the early 1980s the United Nations Children's Fund (UNICEF) became a major partner in country pro- gramme activities and the Programme has to date re- ceived financial support from 29 agencies, governments and other contributors. The intensified efforts of national health personnel, with support from WHO and other agencies, have led to real progress in recent years bo~h in national COD programmes, as can be seen from Fig. 2 illustrating the Programme's targets and progress to date, and in research. Country control activities In planning national diarrhoeal diseases control activ- ities, priority has been given to the strategy of case management, particularly oral rehydration therapy (ORT) and feeding during and after diarrhoea, in order to reduce diarrhoea-associated mortality, case-fatality, malnutri- tion and treatment costs. Increasing emphasis is also being given to three other major strategies that have been shown to be cost-effective in reducing diarrhoea mortality and morbidity, namely: • Improved nutrition uninterrupted breast-feeding for the first 2 years of life - proper weaning practices • Use of safe water collecting an ample quantity of water from the safest source protecting water from contamination • Good personal and domestic hygiene hygienic excreta disposal, including the use of latrines and care in disposing of babies' stools. - washing hands. At the end of 1987, 112 countries had plans for national COD programmes (Fig. 2). Programmes were opera- tional in 96 of those countries (86%), which comprise an estimated 98% of the total population in the developing countries. Rapp. trimest. statist. sanit. mond., 41 ( 1988) - 77 FIG. 2 CURRENT PROGRAMME TARGETS AND STATUS CATEGORY OF TARGET No. of operational programmes Percentage of children with diarrhoea having access to oral rehydration salts Percentage of children with diarrhoea receiving oral rehydration therapy Percentage of staff trained in supervisory skills Percentage of staff trained in case management No. of programme reviews carried out No. of countries producing oral rehydration salts WHO 8 71 480 0 §§§§ Up to the end of 1985 50 Percentage of target 100 f 1 ] During 1986 ~ Up to the end of 1986 FIG. 2 BUTS ACTUELS ET ETAT D'AVANCEMENT DU PROGRAMME CATEGORIE DE BUT Nombre de programmes operationnels Pourcentage d'enfants atteints de diarrhee ayant acces aux SRO a Pourcentage d'enfants atteints de diarrhee a qui est administree la TRO b Pourcentage du personnel forme aux techniques de supervision Pourcentage du personnel forme a la prise en charge des cas Nombre d'evaluations du programme Nombre de pays produisant des SRO a WHO 1171481 a SRO : sels de r{!hydratation orale. b TRO therapie par rehydratation orale. 11 PROGRES 0 50 100 Pourcentage de reali sation 1989 CURRENT TARGET SITUATION 115 96 80% 59% 50% 23% 20% 7% 20% 6% 80 59 60 55 ~During 1987 BUT POUR SITUATION 1989 EN 1987 115 96 80% 59% 50% 23% 20% 7% 20% 6% BO 59 60 55 §§§§ Progres jusqu'a fin 1985 (11 ] Progres en 1986 ~ Progres jusqu'a fin 1986 c:J Progres en 1987 Training is a major programme activity, with emphasis on courses in supervisory skills for mid-level staff and training in programme management for senior-level health workers . The supervisory skills course, initiated in 1983 and frequently combined with the EPI course, has Wld hlth statis t. quart., 41 (1988) to date been attended by over 10 OOO part1c1pants . Training in technical aspects, especially clinical manage- ment, has received priority. Much of it has been carried out at diarrhoea training units which have been estab- lished in existing facilities specially strengthened for the - 78 - purpose. A special training package has been developed to assist the directors of such units . It is estimated that to date at most 6% of target health staff have received appropriate training . The Programme is also developing training materials to help strengthen the teaching of diar- rhoeal diseases control (especially ORT) to medical stu- dents, nurses and other paramedical staff and has pro- duced numerous manuals and guidelines for general dis- tribution . In an effort to make ORT more widely available, the Pro- gramme is seeking both to promote the use of appro- priate fluids in the home and to ensure widespread avail- ability of ORS. Many countries have now formulated a locally appropriate strategy for the preparation and use of household solutions in the home early in diarrhoea to prevent dehydration . Successful implementation of this strategy may not only have a major impact on diarrhoea mortality, but also reduce the diarrhoea case load at health facilities and the need for ORS packets . WHO and UNICEF have been assisting countries to produce their own ORS in a country-specific dose and presentation. Pilot plants for automatic and semi-automatic produc- tion have been set up in Thailand and Sri Lanka, respec- tively, and have been used for training production staff from other countries . Detailed technical guidelines for production have also been issued. Fifty-five countries are now producing ORS packets locally. Information, education and motivation of the public form a major element of national COD programmes, many of which have produced appropriate materials with support from WHO and other agencies. A manual containing specific guidelines on communication for national pro- gramme managers has been issued and will be followed up by collaborative activities in this area in an increasing number of countries. Since its inception, the Programme has realized the importance of developing evaluation mechanisms for its many different activities, to enable it to measure the progress made towards achieving objectives at the na- tional, regional and global levels. Data collected system- atically from countries and obtained from other sources on the extent of the diarrhoea problem, access to ORS, use of ORS and household solutions and training of health workers are reviewed annually as a means of monitoring the progress of the global programme. Data on morbidity, mortality and treatment are collected using the WHO/COD household cluster sample survey method, originally designed in 1981 and progressively refined. By the end of 1987, results were available from 276 surveys conducted in 60 countries; they showed interesting regional differences in diarrhoea-associated mortality and incidence, with the highest rates in the African Region. Formal reviews or evaluations of national programmes have been carried out in 47 countries . The constraints identified in national programmes have tended to be similar and include: inadequacies in the training of health staff in case management, a need for improved supervi- sion, lack of a coordinated approach to health education and communication, insufficient attention to the identif- ication of operational problems and means for their solu- tion, inadequate information and surveillance systems and an excessive use of antidiarrhoeal drugs and antibio- tics. Rates of access to ORS and use of ORT (4) in developing countries, presented in Fig. 3 and Table 1, demonstrate a significant upward trend. In 1986, 59% of the population of the developing countries (excluding China) are esti- mated to have had access to a source of ORS, and an estimated 23% of diarrhoea cases in children under 5 were treated with ORT. This rate of use of ORT may have prevented some 700 OOO deaths from diarrhoea in 1986. In 29 countries, the ORS access rate was in excess of 50% and the ORT use rate greater than 20%; these countries represent 62% of the total population of the developing countries . Efforts are now being directed towards determining the proportion of cases that are treated correctly. FIG. 3 DIARRHOEAL DISEASES CONTROL: ACCESS TO ORS BY WHO REGION AND GLOBALLY, 1982-1986 LUTTE CONTRE LES MALADIES DIARRHEIQUES: ACCES AUX SRO PAR REGION OMS ET DANS LE MON DE ENTIER, 1982-1986 '/ ·~ 0 n'-----JL-..IC""1:....J.--""""'-.....L'-'-1'C,C.l,-""""",--.L..:...4.--L- ~..J.:..:"1.....l--""'""-,.,.L/,~· ...._.,__ ...... .__L..:L.__L-..J Eastern South-East Asia Western Global Africa Afrique !lDll] 1982 Americas Am0riques LJ1983 • Excluding China - Chine exceptee. Mediterranean Asie du Sud-Est Pacific a Monde entier Mediterranee Pacifique orientale occidental a ~1984 LJ1985 LJ1986 Rapp. trimest. statist. sanit. mond , 41 ( 1988) - 79 - TABLE 1. DIARRHOEAL DISEASES CONTROL: ESTIMATED MINIMUM USE RATES FOR ORS AND ORT IN CHILDREN AGED 0-4 YEARS, 1983-1986, BY WHO REGION AND GLOBALLY TABLEAU 1. LUTTE CONTRE LES MALADIES DIARRHEIQUES: TAUX ESTIMATIFS MINIMAUX DES SRO ET DE LA TRO CHEZ LES ENFANTS DE 0-4 ANS, 1983-1986, PAR REGION OMS ET DANS LE MONDE ENTIER Region - Region 1983 Africa - Afrique . . . . .... . ..... 1 Americas - Ameriques .... . .... 2 Eastern Mediterranean - Mediterranee orientale 6 South-East Asia - Asie du Sud-Est 9 Western Pacific• - Pacifique occidental• 9 Global" - Monde entier• ...... 5 • Excluding China - Chine exceptee. Epidemic control As in the past, WHO has continued to collaborate closely with countries in the control of epidemics, particularly of cholera. By 1987 the seventh pandemic had spread to 94 countries in all regions of the world except Latin Amer- ica; it continues to be reported by over 30 countries each year (Fig. 1). While the number of notified cases has been declining, large outbreaks with high case-fatality rates (particularly at the beginning) occurred in a number of Western African countries in 1984 and 1985, and in both refugee and indigenous populations in several Eastern African countries in 1985. The Programme advocates control of the disease through properly managed na- tional COD programmes which permit better surveillance for early detection, appropriate treatment and the diffu- sion to the public of realistic and practical messages on prevention. e Guidelines are available also for the control of epidemics due to Shigella dysenteriae type 1t which has become an increasing problem in the past decade. Research Since 1984 a considerably expanded programme of biomedical and epidemiological research has been in operation, managed by three scientific working groups on : immunology, microbiology and vaccine develop- ment ; case management ; and epidemiology and disease prevention. The first is concerned with the development of new and improved vaccines and diagnostic tests; the second supports research to find more efficient ORT solutions, optimal diets for feeding during and after diar- rhoea, effective antisecretory drugs and antibiotics for the treatment of dysentery; and the third funds research to determine the risk factors for development of severe and persistent diarrhoea, and the most cost-effective means of implementing specific interventions that can reduce diarrhoeal disease morbidity and mortality. The total number of projects supported by the Pro- gramme between 1980 and 1987 was 452. In addition, institution-strengthening support was given to seven institutes to allow them to improve their facilities and capacity for conducting clinical trials or epidemiological research, and to Mah idol University, Bangkok (Thailand). to establish a Centre for the Trial of Vaccines against Infectious Diseases. The 1980s also saw the designation of six new international collaborating centres, two for research and training in diarrhoeal diseases and one each for ORT, environmental and epidemiological aspects of • World Health Organization. Guidelines for cholera control. (Docu- ment WHO/CDD/SER/80.4 Rev.1, 1986). f World Health Organization. Guidelines for the control of epidemics due to Shigella dysenteriae 1. (Document WHO/CDD/SER/88.12, 1988) Wld hlth statist. quart., 41 ( 1988) ORS use rate ORT use rate Taux d'utilisation des SRO Taux d'utilisation de la TRO 1984 1985 1986 1984 1985 1986 3 5 7 4 8 12 12 10 20 12 10 36 12 17 23 21 22 29 9 12 13 14 25 26 13 20 17 27 32 29 8 11 14 12 18 23 diarrhoeal diseases, Campylobacter jejuni and human rotaviruses. In the area of ORT, clinical trials have shown that a more stable formulation of ORS containing trisodium citrate, dihydrate, is as effective as ORS containing sodium bicarbonate and may result in less stool output in high- purging patients. Twenty-five projects are under way or have been completed to develop ORS formulations that have the additional benefit of reducing the volume and duration of diarrhoea. Two of these have confirmed that ORS containing cooked rice powder in place of glucose results in a 13-42% reduction in daily diarrhoea output, a 17-30% reduction in the duration of diarrhoea and a 15- 49% reduction in total stool volume. Other studies are evaluating ORS solutions that contain other cereals or maltodextrin in place of glucose and/or have amino acids (e.g. L-alanine) or dipeptides added to the other ingre- dients. Studies on feeding during diarrhoea have also been given high priority as a way to reduce the nutritional consequences of diarrhoea. Worldwide studies on the etiology of acute diarrhoea have demonstrated that the pathogens implicated most frequently as causes of diarrhoea in children in develop- ing countries are rotavirus, enterotoxigenic Escherichia coli (ETEC), enteropathogenic E. coli (EPEC), Shige//a and C. jejuni; there are no consistent regional differences in the frequency of identification of specific organisms; and the etiology in some 35-40% of cases remains un- explained, suggesting that other pathogenic agents, as yet unrecognized, may be responsible. Simple assays for recognition of the heat-labile toxin (LT) produced by ETEC have been developed which can be used in developing country laboratories. A serotyping scheme for C. jejuni has been found suitable for serotyp- ing most strains isolated in developing countries. Pro- gress has also been made in the development of a more discriminative phage-typing scheme for Vibrio cholerae 01. An ELISA procedure to detect human rotavirus has been developed and evaluated, and other simple proce- dures are under investigation. In the area of vaccine development, efforts have contin- ued to be focused primarily on the creation of oral vac- cines, using living or non-living antigens, with the aim of stimulating lasting intestinal immunity. Field trials are under way to evaluate the efficacy of a liquid formulation of live oral attenuated Ty21a typhoid vaccine, which has been shown to evoke 68% protection over four years when given in an enteric-coated capsule. Field trials of a live oral bovine rotavirus vaccine carried out in devel- oped countries showed it to be both safe and moderately effective against severe rotavirus diarrhoea; however, further trials in developing countries were disappointing - 80 - and the vaccine has been withdrawn by the manu- facturer. Subsequent trials of an attenuated oral rhesus rotavirus vaccine showed that a single dose gives 90% protection, especially against severe disease, but that protection is serotype specific. Field trials are now under way using genetic reassortant strains for the four main human serotypes. As regards cholera vaccine, recent field test results have shown that an oral vaccine con- taining either whole vibrios or whole vibrios plus the purified B subunit of cholera toxin provides 60% protec- tion for at least two years, the protection being greater in subjects over 6 years of age. Efforts are continuing also to develop hybrid Shigella vaccines that use a non- pathogenic E. coli strain as a carrier for protective anti- gens of Shigella, and also vaccines made from avirulent Shigella mutants. In summary, it can be said that there are good prospects of developing practical and effective vaccines within the next few years against rotavirus diarrhoea and typhoid fever, while substantial progress can be expected to- wards vaccines against cholera, shigellosis and ETEC diarrhoea. It is hoped that some of these vaccines, when developed, will be incorporated into existing national immunization programmes. Future prospects The activities of the COD Programme were reviewed in detail by the World Health Assembly in 1982 and 1987 and received its whole-hearted approval. Member States were urged to intensify their diarrhoeal disease control activities as part of primary health care, and WHO was requested to increase its collaboration with countries in strengthening national programmes in order to reach the objectives of 80% access to ORS and 50% use of ORT by 1989; if these can be attained, it can be expected that by then at least 1.5 million childhood deaths due to diarhoea will be prevented annually. Na- tional COD programmes also offer the best prospects for controlling epidemics due to enteric pathogens. SUMMARY During its early years, WHO was primarily concerned with epidemic control, standardization and quality con- trol of vaccines, and administration of the International Sanitary Regulations. d Among the acute enteric infec- tions, cholera received the greatest attention because of its propensity for rapid epidemic spread. When the sev- enth pandemic of cholera began in 1961, WHO re- sponded with a greatly expanded programme of activ- ities which included cooperation with countries in train- ing and control efforts, and research on treatment and prevention, especially vaccine development. At the same time, numerous training courses were held on ent- eric infections and a series of controlled field trials estab- lished the degree of protection conferred by existing typhoid and paratyphoid vaccines. In 1970, when the cholera pandemic spread to Africa, the emergency assistance programme was reactivated, with increasing attention to the provision of appropriate treatment, especially oral rehydration therapy. rather than the supply of ineffective vaccines. The requirement of cholera vaccination for international travel in the Inter- national Health Regulations was abolished in 1973 by the World Health Assembly. Another public health problem of importance during the 1970s was the increase in antibiotic resistance of enteric bacteria, especially Shigella dysenteriae 1 and Salmon- ella typhi, first in Central America and Mexico and later in Asia. There was a notable acceleration in research on diar- rhoeal diseases and especially on cholera during this period, with the discovery of several new viral and bac- terial agents of diarrhoea, advances in knowledge of intestinal immunity indicating that better protection might be achieved with oral vaccines, and the demon- stration of the effectiveness of a single formulation of oral rehydration salts (ORS) in the treatment of all diar- rhoeas including cholera. The latter development was instrumental in convincing public health administrators that diarrhoeal diseases control should become an es- sential component of primary health care and led to the creation of a global Diarrhoeal Diseases Control (COD) Programme. The COD Programme, which has the objective of reduc- ing childhood mortality and morbidity due to diarrhoeal diseases and their associated ill effects, especially mal- nutrition, consists of two main components: a health services/control component and a research component. The priority strategy for control is case management, particularly oral rehydration therapy. followed by im- proved nutrition, use of safe water, and good personal and domestic hygiene. Activities of the health services component include collaboration with countries in the planning and implementation of national COD pro- grammes, management and technical training, increas- ing the availability of oral rehydration therapy through the use of household solutions and ORS produced locally, health education and communication, and evaluation. As regards research, a considerably expanded programme of biomedical and epidemiological research has been in operation since 1984 in the areas of immunology, micro- biology and vaccine development, case management, and epidemiology and disease prevention. To date, sup- port has been awarded to 452 projects in 86 countries and important advances have been made in developing improved ORS formulations, determining the epidemi- ology and etiology of diarrhoeal diseases in developing countries, and developing simple diagnostic tests and improved vaccines. If the targets set by the WHO/COD Programme for 1989 can be attained, it is expected that by then at least 1.5 million childhood deaths due to diarrhoea will be pre- vented annually. Rapp. trimest. statist. sanit. mond., 41 (1988) - 81 - RESUME Lutte contre les maladies diarrheiques A ses debuts, l'OMS s'interessait avant tout a la lutte contre les epidemies, a la standardisation des vaccins et au controle de leur qualite, ainsi qu'a !'administration du Reglement sanitaire international. Parmi les infections intestinales aigues, c'est le cholera qui retenait le plus I' attention en raison de sa propension a prendre rapide- ment des proportions epidemiques. Au moment de la septieme pandemie de cholera en 1961, l'OMS a reagi en etendant largement son programme d'activites qui a englobe une cooperation aux efforts de formation et de lutte des pays et des recherches sur le traitement et la prevention, notamment le developpement de vaccins. Parallelement, on a mis sur pied de nombreux cours de formation sur les infections intestinales et une serie d' es- sais controles sur le terrain ant permis de determiner le degre de protection confere par les vaccins antitypho- paratyphordiques existants. En 1970, date OU la pandemie du cholera s'est etendue a l'Afrique, le programme d'aide d'urgence a ete reactive et l'on s'est preoccupe de plus en plus d'assurer un trai- tement approprie, notamment par la therapie de rehydra- tation orale, plutot que de fournir des vaccins peu effi- caces. La clause exigeant le vaccin anticholerique pour les voyages internationaux qui figurait dans le Reglement sanitaire international a ete supprimee en 1973 par I' As- semblee mondiale de la Sante. Un autre probleme important de sante publique pendant les annees 70 a ete I' accroissement de la resistance aux antibiotiques des enterobacteries, notamment Shigella dysenteriae 1 et Salmonella typhi, d'abord en Amerique centrale et au Mexique, puis en Asie. Au cours de cette periode, on a assiste a une accelera- tion sensible de la recherche sur les maladies diarrhei- ques, surtout sur le cholera. C'est ainsi que l'on a decou- vert plusieurs nouveaux agents diarrheiques viraux et bacteriens, fait progresser nos connaissances sur l'im- munite intestinale, ce qui a permis de determiner qu'une meilleure protection pourrait ~tre assuree par des vac- cins buccaux, et demontre l'efficacite d'une formulation unique de sels de rehydratation orale (SRO) pour le trai- tement de !'ensemble des diarrhees, y compris le chole- ra. Grace a cette derniere realisation, on a pu convaincre les administrateurs de la sante publique de la necessite de faire de la lutte contre les maladies diarrheiques un element essential des soins de sante primaires et l'on a mis sur pied un programme mondial de lutte contre les maladies diarrheiques (LMD). Le Programme LMD, qui vise a reduire chez les enfants la mortalite et la morbidite par maladie diarrheique et les autres effets nocifs de ces maladies, notamment la mal- nutrition, a deux composantes principales: une compo- sante services de sante et lutte et une composante recherche. La strategie de lutte prioritaire consiste en une prise en charge des cas, surtout par la therapie de rehydratation orale, suivie d'une amelioration de la nutri- tion, de !'utilisation d'une eau saine et d'une bonne hygiene personnelle et domestique. Parmi les activites de la composante services de sante figurent la collabo- ration avec les pays, la planification et !'execution des programmes LMD nationaux, la formation gestionnaire et technique, les mesures visant a rendre la therapie de rehydratation orale accessible a tous par le recours aux solutions domestiques et aux SRO produits localement, !'education et la communication pour la sante, et enfin !'evaluation. Ence qui concerne la recherche on execute, depuis 1984, un programme considerablement elargi de recherches biomedicales et epidemiologiques dans les domaines suivants: immunologie, microbiologie et de- veloppement des vaccins, prise en charge des cas, epi- demiologie de la prevention des maladies. Jusqu'ici, 452 projets ant ete soutenus dans 86 pays et d'importants progres ant ete faits dans la mise au point de formula- tions de SRO ameliorees, la determination de I' epidemio- logie et de l'etiologie des maladies diarrheiques dans les pays en developpement, la conception d'epreuves dia- gnostiques simples et le developpement de vaccins ameliores. Si les objectifs fixes par le Programme LMD de l'OMS pour 1989 sont atteints, on devrait alors eviter chaque an nee un minimum de 1,5 million de deces d' enfants dus a la diarrhee. REFERENCES - REFERENCES 1. POLLITZER R. Cholera. Geneva, World Health Organ- ization, 1959. (Monograph Series No. 43). POLLITZER. R. Le cholera. Geneve, Organisation mon- diale de la Sante, 1959. (Serie de monographies N°43). 2. DE ARAOZ. J. ET AL. Principles and practices of cholera control. Geneva, World Health Organization, 1970. (Public Health Papers No. 40). DE ARAOZ. J. ET AL Principes et methodes de la lutte contre le cholera. Geneve, Organisation mondiale de la Sante, 1970. (Cahiers de sante publique N° 40). 3. SNYDER. J. D. & MERSON, M. H. The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data. Bulletin of the World Health Organization, 60 (4): 605-613 (1982). Wld hlth statist. quan .• 41 ( 1988) SNYDER. J. D. & MERSON. M. H. Ampleur du probleme des diarrhees aigues: analyse des donnees de sur- veillance active (resume]. Bulletin de /'Organisation mondiale de la Sante, 60 (4): 612 (1982). 4. TULLOCH. J. & BURTON. P. Global access to oral rehy- dration salts and use of oral rehydration therapy. World health statistics quarterly, 40 (2): 110-115 (1987). TULLOCH. J. & BURTON. P. Acces aux sels de rehydra- tation orale et utilisation de la therapie de rehydrata- tion orale: situation mondiale. Rapport trimestriel de statistiques sanitaires mondiales, 40 (2): 110-115 (1987).
- 74 - CONTROL OF DIARRHOEAL DISEASES C. Ann Martinez, a Dhiman Barua b & Michael H. Merson c During its early years, the primary concerns of the World Health Organization (WHO) in the field of diarrhoeal dis- eases were epidemic control, standardization and qual- ity control of vaccines, and administration of the Inter- national Sanitary Regulations,d adopted in 1951. While acute enteric infections were generally recognized to be an enormous endemic problem in the developing coun- tries, it was cholera-one of the six original quarantina- ble diseases because of its propensity for rapid epidemic spread-that received the greatest attention. Indeed, one of the first tasks of the Interim Commission of WHO was helping to combat the 194 7 outbreak in Egypt, which was the first occasion in some 30 years that the disease had spread west of the Indian subcontinent. During the rest of the 1940s and 1950s, however, the disease remained a problem only in its endemic foci in • Technical Officer. Diarrhoeal Diseases Control Programme, World Health Organization, Geneva. b Consultant, Diarrhoeal Diseases Control Programme. World Health Organization. Geneva. c Director, Diarrhoeal Diseases Control Programme. World Health Organization, Geneva. d The title was changed in 1969 to International Health Regulations. India and Pakistan and the immediate vicinity. During this period a WHO Expert Committee was convened to review practical methods of cholera control and three study groups were organized to suggest lines of future research. Many articles were published in the Bulletin of the World Health Organization, including a series of 11 written by Pollitzer which later were compiled into a classic monograph on the subject of cholera (1). At the same time, recognizing also the importance of typhoid fever, the first steps were taken to evaluate available typhoid vaccines in a properly controlled field trial and in laboratory studies. These years also saw the designation of international reference centres for sal- monella (1948) and shigella (1954). The sixties The seventh cholera pandemic In 1961 came a major turning-point when cholera caused by the eltor vibrio began to spread beyond its endemic focus in Sulawesi, Indonesia. This was the beginning of the seventh pandemic of cholera (Fig. 1). By 1963 it had FIG. 1 INCIDENCE OF CHOLERA AND NUMBER OF COUNTRIES NOTIFYING CASES, 1951-1986 INCIDENCE DU CHOLERA ET NOMBRE DE PAYS AVANT NOTIFIE DES CAS, 1951-1986 50 400 380 45 360 340 40 320 ~ ~ COUNTRIES - PAYS 300 e -5 35 .!! " 0,, ,: .. .., .. Cl.., i~ 30 0:-s c,: _;g 25 E~ :,m o> .... o~ 20 .8 ~ E~ :la, z.i; 15 E .. 280 ~ 260 E c .!!. 240 .. .. u 220 I 200 .. ,, c .. 180 .. :, 0 160 -s c .:a 140 .. " .. .. 120 u 0 z 100 10 80 .. 60 i 5 40 0 I 20 0 0 1951 55 60 65 70 75 80 86 Years - Ann6es Rapp. trimest. statist. sanit. mond., 41 ( 19881 - 75 - extended to a large number of countries in Asia and in 1965-1966 progressed as far westward as Uzbekistan (USSR), the Islamic Republic of Iran and Iraq. These events, unfortunately, were accompanied by severe hin- drances to international travel and trade as countries imposed restrictions in excess of the International Health Regulations (IHR) in a vain effort to prevent the introduc- tion of cholera from other countries. WHO responded to these developments with a greatly expanded programme of activities which included the organization of training courses and provision of training materials; the creation of two interregional teams to help countries in controlling cholera ; assistance in organizing laboratory diagnosis, treatment and the improvement of sanitation, and the provision of supplies for these activ- ities; procurement of vaccines (though their use was discouraged); promotion of research; and publication of a large number of scientific papers and reviews. A news- letter, Cholera information, disseminated up-to-date epi- demiological and technical news to public health work- ers and was much appreciated. Between 1962 and 1968 an expert committee, two scientific groups on cholera research and a scientific group on cholera immunology were convened to discuss the problems caused by the changing pattern of the disease and determine priorities for research, and in 1967 a top-level international con- ference attempted to promote a more rational approach to cholera control. An international reference centre for vibrios was established in 1963. A joint research programme carried out with the Indian Council of Medical Research and the Governments of Japan and the Philippines, and collaboration with scien- tists of the Cholera Research Laboratory (Bangladesh) contributed fundamental knowledge of many aspects of cholera. Important findings on the pathophysiological changes in cholera enabled clinicians to improve and later simplify intravenous rehydration and diminish case- fatality rates from up to 60% to 1-2%. Oral rehydration fluid was developed and used for the maintenance of hydration, and clinical and laboratory studies demonstrated the benefits of antibiotics in treat- ment. A series of controlled field trials and laboratory studies of commonly used vaccines showed that even the most potent ones conferred only about 50% protec- tion for less than six months and some were of hardly any value. Educational activities were undertaken to inform public health workers about the limited role of current vaccines in cholera control. The WHO Require- ments for Cholera Vaccine, originally adopted in 1958, were duly revised in 1968, with a further addendum in 1973. Diarrhoeal diseases and enteric fevers Despite the preoccupation with cholera, increasing at- tention was also paid to typhoid and paratyphoid fevers and diarrhoeal diseases in general. Control and research activities were guided by the recommendations of a study group on diarrhoeal diseases (1958) and an expert committee on enteric infections (1963). Between 1960 and 1965 a diarrhoeal diseases advisory team carried out cross-sectional surveys in seven countries in Asia, Africa and South America which contributed to know- ledge of the epidemiology and etiology of diarrhoeal dis- eases and confirmed their relationship with social and environmental factors. Numerous interregional training courses were organized on the diagnosis, treatment and control of enteric infections, and an international refer- ence centre for the phage typing of enterobacteria was designated in 1961. Wld hlth statist. quan .. 41 ( 1988) A major research undertaking in the 1960s was a series of controlled field trials of typhoid and paratyphoid vac- cines, covering nearly 2 million people; at the same time 18 laboratories in various countries cooperated in the evaluation of potency tests for these vaccines. These studies indicated a lack of protective efficacy of the Vi antigen, found the acetone-dried and inactivated typhoid vaccine to be somewhat better than the phenol-killed and phenol-preserved one and demonstrated the effec- tiveness of a paratyphoid B vaccine when given in two doses. Based on these findings, WHO Requirements for Typhoid Vaccine were formally adopted in 1966. The seventies Cholera reaches Africa 1970 was another milestone in the history of cholera and international public health when the disease leaped across a vast expanse of unaffected territory to reach Western Africa. Here it invaded one country after an- other in quick succession, and in the same and following years also reached Eastern and Northern Africa and some countries of Europe. In all, 25 new countries in 1970 and 14 in 1971 were affected by cholera, whereas previously the spread had been limited to not more than six in any one year (Fig. 1). In almost all countries, except those of Western Europe, the disease has become endemic and is continuing to manifest itself in seasonal outbreaks or as sporadic cases. The emergency assistance programme had to be reactivated and the cholera team was reinforced with consultants to help it respond to the many requests for its services. WHO assisted in the establishment of rehy- dration centres at strategic sites in three of its Regions: Africa, South-East Asia and the Eastern Mediterranean. In Africa three WHO depots were established to expe- dite the supply of rehydration fluid and antibiotics. WHO persuaded commercial firms to produce packets of oral rehydration salts (ORS) and distributed them with guide- lines for oral rehydration; this helped health workers to gain experience and confidence in the use of oral rehy- dration. In the first year or two there was a large demand for the supply of vaccines, despite their limited efficacy, and WHO provided 36.5 million doses in 1970 and 31 million in 1971. In 1973 an international reference centre for bacterial vaccines was established which pro- vided facilities for the potency testing of vaccines to ensure that those used were of adequate quality. By 1972, however, countries had gained more experience and confidence in confronting cholera and requests for vaccine declined to only 4 million doses a year. In 1973, the World Health Assembly abolished the requirement of cholera vaccination for international travel in the IHR. Emphasis continued to be placed on health education, sanitary measures including food safety, early detection of epidemics and cases and proper treatment; there was a decline in case fatality and panic gradually subsided. During this period WHO continued to be very active in organizing consultations, seminars and training activ- ities. It issued guidelines for laboratory diagnosis and treatment, and in 1970 the first edition of a compilation of the most recent information on all aspects of cholera, with emphasis on practical measures for its control (2). Although the fear of cholera appeared to decline with time, there was little improvement in notifications to WHO and restrictive measures on travel and trade in excess of the IHR continued to be imposed against cholera-affected countries, although on a reduced scale. 76 - Bacterial drug resistance Another problem that aroused considerable public health concern during the 1970s was the increase in antibiotic resistance in enteric bacteria. In 1968, a large outbreak of bacillary dysentery due to multiresistant Shigella dysenteriae occurred in Central America and Mexico, and in the 1970s similar outbreaks became fre- quent in Asia. Multiresistant Salmonella typhi also caused large epidemics, notably in Mexico in 1972 and later in Asia. In 1974, therefore, the activities of the existing international reference centre for the phage typ- ing of enterobacteria were expanded to include work on the resistance of these organisms. In 1977, a meeting was convened to review the problem and recommend simple measures of surveillance that would generate internationally comparable data, the aim being to facili- tate the appropriate use of antibiotics and promote the early recognition of epidemics. Breakthroughs in research Research on diarrhoeal diseases and particularly on cho- lera accelerated considerably in the 1970s. WHO contin- ued to collaborate closely in the multiple projects carried out by the Indian Council on Medical Research and the Governments of Japan and the Philippines, and provided support to many basic and operational studies. Several new viral and bacterial agents were identified as causes of dia, rhoea, notably rotavirus, enterotoxigenic Escheri- chia coli, Campylobacter jejuni, Vibrio parahaemolyticus, V. cholerae non-01 and Yersinia enterocolitica, offering new possibilities for a better understanding of the patho- genesis of the acute diarrhoeas and for the development of improved methods of diagnosis, treatment and pre- vention, including vaccines. A scientific group on oral enteric vaccines in 1971 and a consultation in 1972 sti- mulated laboratory and field research for the develop- ment of such vaccines. While a number of promising oral vaccines were developed for typhoid and shigella dysen- tery. none proved in controlled trials to be adequate for public health use. However, much new information was learned about the importance of intestinal immunity in protecting against enteric infection, raising the hope that protection could be achieved through the development of more effective oral vaccines. But it was in the area of therapy that the most significant advances were made. Most importantly, WHO field studies demonstrated the effectiveness of a single oral rehydration salts (ORS) for- mulation, which had been agreed upon during a WHO seminar in 1972, in the treatment of all diarrhoeas in addition to cholera, in all age groups; it was shown that it could be effectively delivered by health centres and aux- iliaries and that when children received it in conjunction with dietary education they fared better in terms of body weight. In addition, doxycycline in a single dose of 300 mg was found to be nearly as effective as tetracycline for shortening the period of vibrio excretion in cholera patients, thus reducing the risk of transmission among close contacts. Changing attitudes In the mid-1970s a new outlook on cholera and diarrhoeal diseases began to prevail. Acute diarrhoeas had always been known to be a much greater problem in the devel- oping world than cholera. However, in the absence of a simple strategy to reduce the ill effects of acute diar- rhoeas, there was no political will on the part of national health authorities to undertake activities for their control. The demonstration of the simplicity and effectiveness of oral rehydration in reducing diarrhoea-related mortality and malnutrition, in addition to its benefit in cholera ther- apy. succeeded in convincing public health administra- tars around the world that diarrhoeal diseases control should become an essential component of national pri- mary health care programmes. This conviction and drive resulted in the adoption of an important resolution by the Thirty-first World Health Assembly in 1978 and the crea- tion of a global diarrhoeal diseases control programme (COD). The eighties Objectives of the COD Programme From the outset the COD Programme has had as its objectives the reduction of mortality and morbidity due to diarrhoeal diseases and their associated ill effects, especially malnutrition, in children under 5. To attain these objectives, it has been built up on two main com- ponents: a health services (or control) component and a research component. One of the first tasks of the Programme was to obtain more reliable data on the size of the problem. This was done by undertaking a thorough survey of the literature, which indicated that, in 1980, the acute diarrhoeal dis- eases caused an estimated 1 OOO million episodes of illness and some 4.5 million deaths in children under 5 in the developing countries (excluding China) (3). Given the immensity of the task, the support and active collaboration of other international, bilateral and non- governmental organizations has been of crucial impor- tance. In the early 1980s the United Nations Children's Fund (UNICEF) became a major partner in country pro- gramme activities and the Programme has to date re- ceived financial support from 29 agencies, governments and other contributors. The intensified efforts of national health personnel, with support from WHO and other agencies, have led to real progress in recent years bo~h in national COD programmes, as can be seen from Fig. 2 illustrating the Programme's targets and progress to date, and in research. Country control activities In planning national diarrhoeal diseases control activ- ities, priority has been given to the strategy of case management, particularly oral rehydration therapy (ORT) and feeding during and after diarrhoea, in order to reduce diarrhoea-associated mortality, case-fatality, malnutri- tion and treatment costs. Increasing emphasis is also being given to three other major strategies that have been shown to be cost-effective in reducing diarrhoea mortality and morbidity, namely: • Improved nutrition uninterrupted breast-feeding for the first 2 years of life - proper weaning practices • Use of safe water collecting an ample quantity of water from the safest source protecting water from contamination • Good personal and domestic hygiene hygienic excreta disposal, including the use of latrines and care in disposing of babies' stools. - washing hands. At the end of 1987, 112 countries had plans for national COD programmes (Fig. 2). Programmes were opera- tional in 96 of those countries (86%), which comprise an estimated 98% of the total population in the developing countries. Rapp. trimest. statist. sanit. mond., 41 ( 1988) - 77 FIG. 2 CURRENT PROGRAMME TARGETS AND STATUS CATEGORY OF TARGET No. of operational programmes Percentage of children with diarrhoea having access to oral rehydration salts Percentage of children with diarrhoea receiving oral rehydration therapy Percentage of staff trained in supervisory skills Percentage of staff trained in case management No. of programme reviews carried out No. of countries producing oral rehydration salts WHO 8 71 480 0 §§§§ Up to the end of 1985 50 Percentage of target 100 f 1 ] During 1986 ~ Up to the end of 1986 FIG. 2 BUTS ACTUELS ET ETAT D'AVANCEMENT DU PROGRAMME CATEGORIE DE BUT Nombre de programmes operationnels Pourcentage d'enfants atteints de diarrhee ayant acces aux SRO a Pourcentage d'enfants atteints de diarrhee a qui est administree la TRO b Pourcentage du personnel forme aux techniques de supervision Pourcentage du personnel forme a la prise en charge des cas Nombre d'evaluations du programme Nombre de pays produisant des SRO a WHO 1171481 a SRO : sels de r{!hydratation orale. b TRO therapie par rehydratation orale. 11 PROGRES 0 50 100 Pourcentage de reali sation 1989 CURRENT TARGET SITUATION 115 96 80% 59% 50% 23% 20% 7% 20% 6% 80 59 60 55 ~During 1987 BUT POUR SITUATION 1989 EN 1987 115 96 80% 59% 50% 23% 20% 7% 20% 6% BO 59 60 55 §§§§ Progres jusqu'a fin 1985 (11 ] Progres en 1986 ~ Progres jusqu'a fin 1986 c:J Progres en 1987 Training is a major programme activity, with emphasis on courses in supervisory skills for mid-level staff and training in programme management for senior-level health workers . The supervisory skills course, initiated in 1983 and frequently combined with the EPI course, has Wld hlth statis t. quart., 41 (1988) to date been attended by over 10 OOO part1c1pants . Training in technical aspects, especially clinical manage- ment, has received priority. Much of it has been carried out at diarrhoea training units which have been estab- lished in existing facilities specially strengthened for the - 78 - purpose. A special training package has been developed to assist the directors of such units . It is estimated that to date at most 6% of target health staff have received appropriate training . The Programme is also developing training materials to help strengthen the teaching of diar- rhoeal diseases control (especially ORT) to medical stu- dents, nurses and other paramedical staff and has pro- duced numerous manuals and guidelines for general dis- tribution . In an effort to make ORT more widely available, the Pro- gramme is seeking both to promote the use of appro- priate fluids in the home and to ensure widespread avail- ability of ORS. Many countries have now formulated a locally appropriate strategy for the preparation and use of household solutions in the home early in diarrhoea to prevent dehydration . Successful implementation of this strategy may not only have a major impact on diarrhoea mortality, but also reduce the diarrhoea case load at health facilities and the need for ORS packets . WHO and UNICEF have been assisting countries to produce their own ORS in a country-specific dose and presentation. Pilot plants for automatic and semi-automatic produc- tion have been set up in Thailand and Sri Lanka, respec- tively, and have been used for training production staff from other countries . Detailed technical guidelines for production have also been issued. Fifty-five countries are now producing ORS packets locally. Information, education and motivation of the public form a major element of national COD programmes, many of which have produced appropriate materials with support from WHO and other agencies. A manual containing specific guidelines on communication for national pro- gramme managers has been issued and will be followed up by collaborative activities in this area in an increasing number of countries. Since its inception, the Programme has realized the importance of developing evaluation mechanisms for its many different activities, to enable it to measure the progress made towards achieving objectives at the na- tional, regional and global levels. Data collected system- atically from countries and obtained from other sources on the extent of the diarrhoea problem, access to ORS, use of ORS and household solutions and training of health workers are reviewed annually as a means of monitoring the progress of the global programme. Data on morbidity, mortality and treatment are collected using the WHO/COD household cluster sample survey method, originally designed in 1981 and progressively refined. By the end of 1987, results were available from 276 surveys conducted in 60 countries; they showed interesting regional differences in diarrhoea-associated mortality and incidence, with the highest rates in the African Region. Formal reviews or evaluations of national programmes have been carried out in 47 countries . The constraints identified in national programmes have tended to be similar and include: inadequacies in the training of health staff in case management, a need for improved supervi- sion, lack of a coordinated approach to health education and communication, insufficient attention to the identif- ication of operational problems and means for their solu- tion, inadequate information and surveillance systems and an excessive use of antidiarrhoeal drugs and antibio- tics. Rates of access to ORS and use of ORT (4) in developing countries, presented in Fig. 3 and Table 1, demonstrate a significant upward trend. In 1986, 59% of the population of the developing countries (excluding China) are esti- mated to have had access to a source of ORS, and an estimated 23% of diarrhoea cases in children under 5 were treated with ORT. This rate of use of ORT may have prevented some 700 OOO deaths from diarrhoea in 1986. In 29 countries, the ORS access rate was in excess of 50% and the ORT use rate greater than 20%; these countries represent 62% of the total population of the developing countries . Efforts are now being directed towards determining the proportion of cases that are treated correctly. FIG. 3 DIARRHOEAL DISEASES CONTROL: ACCESS TO ORS BY WHO REGION AND GLOBALLY, 1982-1986 LUTTE CONTRE LES MALADIES DIARRHEIQUES: ACCES AUX SRO PAR REGION OMS ET DANS LE MON DE ENTIER, 1982-1986 '/ ·~ 0 n'-----JL-..IC""1:....J.--""""'-.....L'-'-1'C,C.l,-""""",--.L..:...4.--L- ~..J.:..:"1.....l--""'""-,.,.L/,~· ...._.,__ ...... .__L..:L.__L-..J Eastern South-East Asia Western Global Africa Afrique !lDll] 1982 Americas Am0riques LJ1983 • Excluding China - Chine exceptee. Mediterranean Asie du Sud-Est Pacific a Monde entier Mediterranee Pacifique orientale occidental a ~1984 LJ1985 LJ1986 Rapp. trimest. statist. sanit. mond , 41 ( 1988) - 79 - TABLE 1. DIARRHOEAL DISEASES CONTROL: ESTIMATED MINIMUM USE RATES FOR ORS AND ORT IN CHILDREN AGED 0-4 YEARS, 1983-1986, BY WHO REGION AND GLOBALLY TABLEAU 1. LUTTE CONTRE LES MALADIES DIARRHEIQUES: TAUX ESTIMATIFS MINIMAUX DES SRO ET DE LA TRO CHEZ LES ENFANTS DE 0-4 ANS, 1983-1986, PAR REGION OMS ET DANS LE MONDE ENTIER Region - Region 1983 Africa - Afrique . . . . .... . ..... 1 Americas - Ameriques .... . .... 2 Eastern Mediterranean - Mediterranee orientale 6 South-East Asia - Asie du Sud-Est 9 Western Pacific• - Pacifique occidental• 9 Global" - Monde entier• ...... 5 • Excluding China - Chine exceptee. Epidemic control As in the past, WHO has continued to collaborate closely with countries in the control of epidemics, particularly of cholera. By 1987 the seventh pandemic had spread to 94 countries in all regions of the world except Latin Amer- ica; it continues to be reported by over 30 countries each year (Fig. 1). While the number of notified cases has been declining, large outbreaks with high case-fatality rates (particularly at the beginning) occurred in a number of Western African countries in 1984 and 1985, and in both refugee and indigenous populations in several Eastern African countries in 1985. The Programme advocates control of the disease through properly managed na- tional COD programmes which permit better surveillance for early detection, appropriate treatment and the diffu- sion to the public of realistic and practical messages on prevention. e Guidelines are available also for the control of epidemics due to Shigella dysenteriae type 1t which has become an increasing problem in the past decade. Research Since 1984 a considerably expanded programme of biomedical and epidemiological research has been in operation, managed by three scientific working groups on : immunology, microbiology and vaccine develop- ment ; case management ; and epidemiology and disease prevention. The first is concerned with the development of new and improved vaccines and diagnostic tests; the second supports research to find more efficient ORT solutions, optimal diets for feeding during and after diar- rhoea, effective antisecretory drugs and antibiotics for the treatment of dysentery; and the third funds research to determine the risk factors for development of severe and persistent diarrhoea, and the most cost-effective means of implementing specific interventions that can reduce diarrhoeal disease morbidity and mortality. The total number of projects supported by the Pro- gramme between 1980 and 1987 was 452. In addition, institution-strengthening support was given to seven institutes to allow them to improve their facilities and capacity for conducting clinical trials or epidemiological research, and to Mah idol University, Bangkok (Thailand). to establish a Centre for the Trial of Vaccines against Infectious Diseases. The 1980s also saw the designation of six new international collaborating centres, two for research and training in diarrhoeal diseases and one each for ORT, environmental and epidemiological aspects of • World Health Organization. Guidelines for cholera control. (Docu- ment WHO/CDD/SER/80.4 Rev.1, 1986). f World Health Organization. Guidelines for the control of epidemics due to Shigella dysenteriae 1. (Document WHO/CDD/SER/88.12, 1988) Wld hlth statist. quart., 41 ( 1988) ORS use rate ORT use rate Taux d'utilisation des SRO Taux d'utilisation de la TRO 1984 1985 1986 1984 1985 1986 3 5 7 4 8 12 12 10 20 12 10 36 12 17 23 21 22 29 9 12 13 14 25 26 13 20 17 27 32 29 8 11 14 12 18 23 diarrhoeal diseases, Campylobacter jejuni and human rotaviruses. In the area of ORT, clinical trials have shown that a more stable formulation of ORS containing trisodium citrate, dihydrate, is as effective as ORS containing sodium bicarbonate and may result in less stool output in high- purging patients. Twenty-five projects are under way or have been completed to develop ORS formulations that have the additional benefit of reducing the volume and duration of diarrhoea. Two of these have confirmed that ORS containing cooked rice powder in place of glucose results in a 13-42% reduction in daily diarrhoea output, a 17-30% reduction in the duration of diarrhoea and a 15- 49% reduction in total stool volume. Other studies are evaluating ORS solutions that contain other cereals or maltodextrin in place of glucose and/or have amino acids (e.g. L-alanine) or dipeptides added to the other ingre- dients. Studies on feeding during diarrhoea have also been given high priority as a way to reduce the nutritional consequences of diarrhoea. Worldwide studies on the etiology of acute diarrhoea have demonstrated that the pathogens implicated most frequently as causes of diarrhoea in children in develop- ing countries are rotavirus, enterotoxigenic Escherichia coli (ETEC), enteropathogenic E. coli (EPEC), Shige//a and C. jejuni; there are no consistent regional differences in the frequency of identification of specific organisms; and the etiology in some 35-40% of cases remains un- explained, suggesting that other pathogenic agents, as yet unrecognized, may be responsible. Simple assays for recognition of the heat-labile toxin (LT) produced by ETEC have been developed which can be used in developing country laboratories. A serotyping scheme for C. jejuni has been found suitable for serotyp- ing most strains isolated in developing countries. Pro- gress has also been made in the development of a more discriminative phage-typing scheme for Vibrio cholerae 01. An ELISA procedure to detect human rotavirus has been developed and evaluated, and other simple proce- dures are under investigation. In the area of vaccine development, efforts have contin- ued to be focused primarily on the creation of oral vac- cines, using living or non-living antigens, with the aim of stimulating lasting intestinal immunity. Field trials are under way to evaluate the efficacy of a liquid formulation of live oral attenuated Ty21a typhoid vaccine, which has been shown to evoke 68% protection over four years when given in an enteric-coated capsule. Field trials of a live oral bovine rotavirus vaccine carried out in devel- oped countries showed it to be both safe and moderately effective against severe rotavirus diarrhoea; however, further trials in developing countries were disappointing - 80 - and the vaccine has been withdrawn by the manu- facturer. Subsequent trials of an attenuated oral rhesus rotavirus vaccine showed that a single dose gives 90% protection, especially against severe disease, but that protection is serotype specific. Field trials are now under way using genetic reassortant strains for the four main human serotypes. As regards cholera vaccine, recent field test results have shown that an oral vaccine con- taining either whole vibrios or whole vibrios plus the purified B subunit of cholera toxin provides 60% protec- tion for at least two years, the protection being greater in subjects over 6 years of age. Efforts are continuing also to develop hybrid Shigella vaccines that use a non- pathogenic E. coli strain as a carrier for protective anti- gens of Shigella, and also vaccines made from avirulent Shigella mutants. In summary, it can be said that there are good prospects of developing practical and effective vaccines within the next few years against rotavirus diarrhoea and typhoid fever, while substantial progress can be expected to- wards vaccines against cholera, shigellosis and ETEC diarrhoea. It is hoped that some of these vaccines, when developed, will be incorporated into existing national immunization programmes. Future prospects The activities of the COD Programme were reviewed in detail by the World Health Assembly in 1982 and 1987 and received its whole-hearted approval. Member States were urged to intensify their diarrhoeal disease control activities as part of primary health care, and WHO was requested to increase its collaboration with countries in strengthening national programmes in order to reach the objectives of 80% access to ORS and 50% use of ORT by 1989; if these can be attained, it can be expected that by then at least 1.5 million childhood deaths due to diarhoea will be prevented annually. Na- tional COD programmes also offer the best prospects for controlling epidemics due to enteric pathogens. SUMMARY During its early years, WHO was primarily concerned with epidemic control, standardization and quality con- trol of vaccines, and administration of the International Sanitary Regulations. d Among the acute enteric infec- tions, cholera received the greatest attention because of its propensity for rapid epidemic spread. When the sev- enth pandemic of cholera began in 1961, WHO re- sponded with a greatly expanded programme of activ- ities which included cooperation with countries in train- ing and control efforts, and research on treatment and prevention, especially vaccine development. At the same time, numerous training courses were held on ent- eric infections and a series of controlled field trials estab- lished the degree of protection conferred by existing typhoid and paratyphoid vaccines. In 1970, when the cholera pandemic spread to Africa, the emergency assistance programme was reactivated, with increasing attention to the provision of appropriate treatment, especially oral rehydration therapy. rather than the supply of ineffective vaccines. The requirement of cholera vaccination for international travel in the Inter- national Health Regulations was abolished in 1973 by the World Health Assembly. Another public health problem of importance during the 1970s was the increase in antibiotic resistance of enteric bacteria, especially Shigella dysenteriae 1 and Salmon- ella typhi, first in Central America and Mexico and later in Asia. There was a notable acceleration in research on diar- rhoeal diseases and especially on cholera during this period, with the discovery of several new viral and bac- terial agents of diarrhoea, advances in knowledge of intestinal immunity indicating that better protection might be achieved with oral vaccines, and the demon- stration of the effectiveness of a single formulation of oral rehydration salts (ORS) in the treatment of all diar- rhoeas including cholera. The latter development was instrumental in convincing public health administrators that diarrhoeal diseases control should become an es- sential component of primary health care and led to the creation of a global Diarrhoeal Diseases Control (COD) Programme. The COD Programme, which has the objective of reduc- ing childhood mortality and morbidity due to diarrhoeal diseases and their associated ill effects, especially mal- nutrition, consists of two main components: a health services/control component and a research component. The priority strategy for control is case management, particularly oral rehydration therapy. followed by im- proved nutrition, use of safe water, and good personal and domestic hygiene. Activities of the health services component include collaboration with countries in the planning and implementation of national COD pro- grammes, management and technical training, increas- ing the availability of oral rehydration therapy through the use of household solutions and ORS produced locally, health education and communication, and evaluation. As regards research, a considerably expanded programme of biomedical and epidemiological research has been in operation since 1984 in the areas of immunology, micro- biology and vaccine development, case management, and epidemiology and disease prevention. To date, sup- port has been awarded to 452 projects in 86 countries and important advances have been made in developing improved ORS formulations, determining the epidemi- ology and etiology of diarrhoeal diseases in developing countries, and developing simple diagnostic tests and improved vaccines. If the targets set by the WHO/COD Programme for 1989 can be attained, it is expected that by then at least 1.5 million childhood deaths due to diarrhoea will be pre- vented annually. Rapp. trimest. statist. sanit. mond., 41 (1988) - 81 - RESUME Lutte contre les maladies diarrheiques A ses debuts, l'OMS s'interessait avant tout a la lutte contre les epidemies, a la standardisation des vaccins et au controle de leur qualite, ainsi qu'a !'administration du Reglement sanitaire international. Parmi les infections intestinales aigues, c'est le cholera qui retenait le plus I' attention en raison de sa propension a prendre rapide- ment des proportions epidemiques. Au moment de la septieme pandemie de cholera en 1961, l'OMS a reagi en etendant largement son programme d'activites qui a englobe une cooperation aux efforts de formation et de lutte des pays et des recherches sur le traitement et la prevention, notamment le developpement de vaccins. Parallelement, on a mis sur pied de nombreux cours de formation sur les infections intestinales et une serie d' es- sais controles sur le terrain ant permis de determiner le degre de protection confere par les vaccins antitypho- paratyphordiques existants. En 1970, date OU la pandemie du cholera s'est etendue a l'Afrique, le programme d'aide d'urgence a ete reactive et l'on s'est preoccupe de plus en plus d'assurer un trai- tement approprie, notamment par la therapie de rehydra- tation orale, plutot que de fournir des vaccins peu effi- caces. La clause exigeant le vaccin anticholerique pour les voyages internationaux qui figurait dans le Reglement sanitaire international a ete supprimee en 1973 par I' As- semblee mondiale de la Sante. Un autre probleme important de sante publique pendant les annees 70 a ete I' accroissement de la resistance aux antibiotiques des enterobacteries, notamment Shigella dysenteriae 1 et Salmonella typhi, d'abord en Amerique centrale et au Mexique, puis en Asie. Au cours de cette periode, on a assiste a une accelera- tion sensible de la recherche sur les maladies diarrhei- ques, surtout sur le cholera. C'est ainsi que l'on a decou- vert plusieurs nouveaux agents diarrheiques viraux et bacteriens, fait progresser nos connaissances sur l'im- munite intestinale, ce qui a permis de determiner qu'une meilleure protection pourrait ~tre assuree par des vac- cins buccaux, et demontre l'efficacite d'une formulation unique de sels de rehydratation orale (SRO) pour le trai- tement de !'ensemble des diarrhees, y compris le chole- ra. Grace a cette derniere realisation, on a pu convaincre les administrateurs de la sante publique de la necessite de faire de la lutte contre les maladies diarrheiques un element essential des soins de sante primaires et l'on a mis sur pied un programme mondial de lutte contre les maladies diarrheiques (LMD). Le Programme LMD, qui vise a reduire chez les enfants la mortalite et la morbidite par maladie diarrheique et les autres effets nocifs de ces maladies, notamment la mal- nutrition, a deux composantes principales: une compo- sante services de sante et lutte et une composante recherche. La strategie de lutte prioritaire consiste en une prise en charge des cas, surtout par la therapie de rehydratation orale, suivie d'une amelioration de la nutri- tion, de !'utilisation d'une eau saine et d'une bonne hygiene personnelle et domestique. Parmi les activites de la composante services de sante figurent la collabo- ration avec les pays, la planification et !'execution des programmes LMD nationaux, la formation gestionnaire et technique, les mesures visant a rendre la therapie de rehydratation orale accessible a tous par le recours aux solutions domestiques et aux SRO produits localement, !'education et la communication pour la sante, et enfin !'evaluation. Ence qui concerne la recherche on execute, depuis 1984, un programme considerablement elargi de recherches biomedicales et epidemiologiques dans les domaines suivants: immunologie, microbiologie et de- veloppement des vaccins, prise en charge des cas, epi- demiologie de la prevention des maladies. Jusqu'ici, 452 projets ant ete soutenus dans 86 pays et d'importants progres ant ete faits dans la mise au point de formula- tions de SRO ameliorees, la determination de I' epidemio- logie et de l'etiologie des maladies diarrheiques dans les pays en developpement, la conception d'epreuves dia- gnostiques simples et le developpement de vaccins ameliores. Si les objectifs fixes par le Programme LMD de l'OMS pour 1989 sont atteints, on devrait alors eviter chaque an nee un minimum de 1,5 million de deces d' enfants dus a la diarrhee. REFERENCES - REFERENCES 1. POLLITZER R. Cholera. Geneva, World Health Organ- ization, 1959. (Monograph Series No. 43). POLLITZER. R. Le cholera. Geneve, Organisation mon- diale de la Sante, 1959. (Serie de monographies N°43). 2. DE ARAOZ. J. ET AL. Principles and practices of cholera control. Geneva, World Health Organization, 1970. (Public Health Papers No. 40). DE ARAOZ. J. ET AL Principes et methodes de la lutte contre le cholera. Geneve, Organisation mondiale de la Sante, 1970. (Cahiers de sante publique N° 40). 3. SNYDER. J. D. & MERSON, M. H. The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data. Bulletin of the World Health Organization, 60 (4): 605-613 (1982). Wld hlth statist. quan .• 41 ( 1988) SNYDER. J. D. & MERSON. M. H. Ampleur du probleme des diarrhees aigues: analyse des donnees de sur- veillance active (resume]. Bulletin de /'Organisation mondiale de la Sante, 60 (4): 612 (1982). 4. TULLOCH. J. & BURTON. P. Global access to oral rehy- dration salts and use of oral rehydration therapy. World health statistics quarterly, 40 (2): 110-115 (1987). TULLOCH. J. & BURTON. P. Acces aux sels de rehydra- tation orale et utilisation de la therapie de rehydrata- tion orale: situation mondiale. Rapport trimestriel de statistiques sanitaires mondiales, 40 (2): 110-115 (1987).