Epidemiology of diarrhoeal disease: implications for control by vaccines

Epidemiology of diarrhoeal disease: implications for control by vaccines Robert E. Black Vaccines present perhaps the most attractive solution to ihe worldwide problem of diarrhoeal disease. Epidemioloqical evidence has important implications for the development and use o[ such vaccines, and results of studies on diarrhoeal diseases in developing and developed countries, in particular among children, and travellers' diarrhoea are reviewed. The virulence and pathoqenicity of various enteropathoqens are discussed, and the extent to which immunity may be acquired. It is concluded that the development of appropriate vaccines may be a complex task. Keywords: Diarrhoea: enteropathogens; epidemiology; infantile virulence: pathogenicity; immunity

INTRODUCTION

DIARRHOEA IN DEVELOPING

Diarrhoeal diseases are a global problem 1. Children in developing countries have frequent diarrhoeal episodes, resulting in growth faltering and high rates of mortality. Even adults in these settings may develop serious illness and die as a consequence of infection with organisms such as Vibrio cholerae and Shiqella dysenteriae type 1. Children in more developed countries also suffer from infectious diarrhoea leading to costly hospitalizations, and sometimes death 2. Furthermore, travellers from these settings to developing countries have a high incidence of infectious diarrhoea, resulting in discomfort and inconvenience 3. While diarrhoeal diseases can be effectively managed by oral replacement of fluid and electrolytes, and occasionally antibiotics, prevention would be preferable. Prevention can be achieved through a reduction in transmission of the infectious agents causing diarrhoea, as has happened in regard to most enteric pathogens in developed countries. However, even in these relatively sanitary settings, infection with some pathogens continues to be common, suggesting a limit to what can be expected by public health interventions. Furthermore, universal access in developing countries to clean water, food and a hygienic home environment will not be attained for many years, necessitating the search for other means of prevention. Perhaps the most promising possibility for specific prevention is the use of vaccines directed at important pathogens causing diarrhoea. Implications for the development and deployment of enteric vaccines will be sought by reviewing epidemiological studies of diarrhoeal diseases in developing countries, in developed countries and in travellers.

Diarrhoeal diseases are estimated to account for up to a quarter of infant and childhood deaths in developing countries; figures of 3.7 4.6 million unnecessary deaths each year have been widely quoted 1'4. Diarrhoea also results in a heavy burden of illness for children in developing countries, often being present for 10 15% of the child's first 5 years of life 5'°. These illnesses contribute to the malnutrition that is prevalent among developing country children 7. A number of community-based studies with household surveillance of diarrhoea have been done in developing countries. These studies are ideal to determine the overall incidence of diarrhoea, and indicate rates of two to ten episodes per child each year in these settings (Table 1 ). The incidence of diarrhoea is generally highest in the first or second year of life and declines thereafter in older children ( Table 2 ). Such information on rates of diarrhoea was used by the United States Institute of Medicine ( I O M ) to estimate the annual incidence of diarrhoeal disease among children in developing countries 4. The highest estimate of five episodes per child each year was for children in Africa, followed by progressively lower rates for Latin America, Asia, and Oceania (Table 3). A large number of viral, bacterial and parasitic enteropathogens can result in diarrhoea in susceptible children 1~. Among these, rotavirus and Shiqella species were considered to be of high priority for development of vaccines for use in developing countries 4. Enterotoxigenic Escherichia eoli and Campylobacter jejuni will also be reviewed, given the high frequency with which these pathogens are found during diarrhoea in developing country children. A more recently described group of enteropathogens, the enteroadherent E. coli, will be considered because of their possible relationship with persistent diarrhoea, a condition with a high rate of

Department of International Health, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland 21205, USA 0264~410X/93/020100-07 :i ~ 1993 B u t t e r w o r t h - H e i n e m a n n

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COUNTRIES

E p i d e m i o l o g y of d i a r r h o e a l diseases." R.E. Black Table 1 Incidence of diarrhoeal episodes in children from communitybased studies in developing countries

Study

Age group (years)

Total episodes

Child-years

Diarrhoeal incidence (per 100 child-years)

Indonesia 8 Guatemala 9 Bangladesh s''° Peru T M Peru '= Bangladesh '3 Bangladesh TM Egypt TM Nigeria 16

0 1 0 1 0 4 < 1 0 2 0 4 0 5 0-4 0 1

618 262 941 1299 5302 2609 1074 3048 386

199 78 169 132 657 573 550 980 148

311 334 557 984 807 455 195 311 261

Table 2

Incidence of diarrhoeal episodes by child age group from community-based studies in developing countries A g e group (years) Study

< 1

1

2

3

4

Peru'2 Bangladesh '3 Bang lagesh14 Bangladesh" BraziP" Nigeria TM

823" 579 244 351 1222 306

854 537 295 498 1511 167

602 432 239 429 1220

361 147

235 109

Bangladesh, Zaire, Brazil and Thailand (Table 5). In these studies, as in the community-based studies, enterotoxigenic E. coil and C. jejuni were frequently found. Shigella spp. were also identified in a modest proportion of the cases. However, in the clinic- or hospital-based studies of diarrhoea, rotavirus was identified in a much higher proportion ( 8 - 4 6 % ) of all cases. It should be noted that the studies in clinical settings often concentrated on children in the first or second year of life, reflecting the fact that this is the predominant age group with more severe illnesses requiring medical attention or hospitalization. Recent attention has been paid to particular strains of E. coli that demonstrate adherence properties in tissue culture assays. Three forms of enteroadherent E. coil have been designated autoagglutinating (AA), diffuse-adhering (DA) and localized-adhering (LA). These organisms are frequently found during diarrhoea in developing country children but are also commonly found in healthy children. It has also been reported that the AA form of these organisms may be particularly associated with persistent diarrhoeal episodes lasting more than 14 days (Table 6). This was reported from studies in India, Bangladesh and Mexico, while other studies in

305 870

720

"Incidence of diarrhoea per 100 child-years

Table 4 Percentage of stool specimens positive for selected enteropathogens during diarrhoea and from healthy controls in community-based studies of children under 5 years of age in developing countries

C. jejuni

ETEC a Table 3

Estimated annual incidence of diarrhoeal disease in children under 5 years of age by region" Age group ( y e a r s )

Region

<2

2-4

<5

Africa Latin A m e r i c a Asia Oceania

710~ 6.0 5.25 3.5

3.0 2.0 1.5 1.0

5 4 3 2

"Adapted from Institute of Medicine" ~Episodes per child-year

mortality in developing country children 2°. Finally, V. cholerae infections will be mentioned because of the continuing problems with endemic and epidemic cholera. Few community-based studies of enteropathogens associated with diarrhoea in developing countries have been done due to the difficulty of maintaining household surveillance of diarrhoea and collecting appropriate specimens. Studies in Bangladesh, The Gambia, Egypt and Peru, generally found that enterotoxigenic E. coli were the most frequently identified enteropathogens, but that these organisms were also frequently found in healthy children living in the same communities (Table 4). Likewise, C. jejuni were also found during diarrhoea and often in similar frequency in healthy controls. Shigella species were found in a small proportion of diarrhoeas, typically dysenteric illnesses. Rotavirus was identified in 3 6% of the diarrhoeas detected by household surveillance and in a smaller percentage of healthy controls of similar age. Studies of aetiological agents in clinical settings have been more numerous, as illustrated by studies from

Shigella

Rotavirus

Study

D~

C~

D

C

D

C

D

C

Bangladesh 5 The Gambia 2' Egypt 22 Peru 23

27 10 27 7

4 6 18 7

4 2 10

7 < 1 10

13 2 2 2

1 <1 < 1 <1

4 6 3 3

< 1 1 < 1 1

"Enterotoxigenic Escherichia coil OD = diarrhoea, C = control

5 Percentage of stool specimens positive for selected enteropathogens during diarrhoea in clinic- or hospital-based studies of children under 5 years of age in developing countries Table

Study

Age group (years)

ETEC a

C. jejuni

Shigella

Rotavirus

Bangladesh Rural 24 Urban 25 Zaire 26 Brazil 27 Thailan& 8

< 2 < 1 <2 < 1 <5

28 20 15 7 9

25 19 3 12

5 6 1 5 13

46 35 8 14 20

aEnterotoxigenic Escherichia coil

Table 6

Percentage of stool specimens from acute and persistent ( ~>14 days) diarrhoea and from healt.hy controls associated with aggregative Escherichia coil in five studies in developing country children

Study India 29 Bangladesh

TM

M e x i c o 3° Bangladesh 31 Peru 23

Acute diarrhoea

Persistent diarrhoea

12.3

34.9

17.9 8.5 22.3 11.0

27.4 50.9 18.6 12.0

Healthy controls -

19.6 5.0 21.4 -

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Bangladesh and Peru found a similar rate of isolation of this type of E. eoli in acute and persistent diarrhoea. Although Vibrio cholerae 0 group 1 causes a very small proportion of all diarrhoeal episodes among developing country children, it deserves consideration for other reasons. In cholera-endemic areas, it has been estimated that there may be more than 2 million cases, resulting in 37 000 deaths each year, in children under 5 years of age 4. The number of cases in older children and adults is likely to total several-fold higher figures. Furthermore, cholera has the potential to result in large-scale, disruptive epidemics when introduced into new areas of the world. The recent introduction into Latin America resulted in hundreds of thousands of cases and more than 2000 deaths during the first epidemic in Peru in the last century. DIARRHOEA

IN DEVELOPED

COUNTRIES

The magnitude of the problem of diarrhoeal disease in developed countries has declined in this century with economic and public health improvements. Nevertheless, the problems have not disappeared. In the United States, it has been estimated that there are up to 38 million cases of diarrhoea among children less than 5 years old, resulting in a large number of physician visits and hospitalizations, and even up to 425 deaths each year (Table 7) 2. It should be noted that most of the hospitalizations occur in the first 2 years of life and the rate of mortality from diarrhoea is markedly higher in the first 6 months of life. Community-based studies of diarrhoeal diseases in the United States and Canada indicate that children under 5 years of age have between one and two episodes of diarrhoea per year in each of their first 5 years of life (Table 8). In studies where age-specific rates could be determined, children 1-3 years of age had the highest rates; infants and older children had lower incidences. Although a long list of enteropathogens can be found associated with diarrhoeal diseases in community-based studies or in clinical settings, the proportion of all episodes with an enteropathogen identified is lower than

Table 7 Estimates of annual diarrhoea episodes, physician visits, hospitalizations and deaths among children < 5 years old in the United States Event

Per year

Diarrhoea cases Physician visits Hospitalizations Deaths

21.5 38 million 2.1 3.7 million 220 000 325 425

Adapted from Glass, R.I. et al?

Table 8 Incidence of diarrhoeal episodes by child age group from community-based studies in Canada and the United States

Study

Age group (years)

Diarrhoeal incidence (per child-year)

Cleveland 32 Charlottesville TM Winnipeg 33 Washington, DC 34 Tecumseh 3~

0 4 0 3 0 4 0--4 0-4

1.9 2.5 1.4 1.2 1.0

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Table 9 Percentage of stool specimens positive for selected enteropathogens during diarrhoea and in healthy controls in an outpatient clinic-based study of children under 2 years of age in Baltimore, Maryland

Enteropathogen

Diarrhoea (n = 246)

Control (n 155)

Rotavirus Aeromonas spp. Salmonella spp. Enteric adenovirus Shigella spp. Enterotoxigenic Escherichia coli

22 6 5 4 0 0

10 7 0 0 0 0

Adapted from Kotloff, K.L. et al? 6

in developing countries. In a recent study in Baltimore, Maryland, rotavirus was found in 22% of the diarrhoeal episodes among children under 2 years of age in a paediatric outpatient clinic 36. Aeromonas spp., Salmonella spp. and enteric adenoviruses were found in a small fraction of the diarrhoea cases. Shigella spp. and enterotoxigenic E. coli were not found in this study. Overall, 43% of the episodes had a potential enteropathogen identified ( Table 9). DIARRHOEA DEVELOPED

IN TRAVELLERS TO DEVELOPING

FROM COUNTRIES

Travel from a developed to developing country setting exposes the travellers to a far more contaminated environment than they are accustomed to at home. Thus, it is not surprising that travellers have a high incidence of diarrhoea during or shortly following their trip. Among 27 studies of travellers to Latin America, Asia and Africa, approximately one-half of the individuals developed diarrhoea during or shortly after their trip (Table 10)3. In studies in which appropriate microbiological methods were used, an enteropathogen was found in most of the episodes of travellers' diarrhoea. The predominant agent in nearly all studies was enterotoxigenic E. coli ( Table I I ). Generally, between one-third and one-half of the travellers' diarrhoeal episodes were associated with this enteropathogen. The proportion of strains producing the heat-stable toxin, the heat-labile toxin or both, varied from study to study. Of course, Shigella spp., Salmonella spp., rotavirus, and other agents are also associated with some of the episodes of travellers' diarrhoea. VIRULENCE It is of interest in regard to establishing the importance of various enteropathogens to consider the apparent virulence of the illnesses resulting from infection. Virulence is the severity of disease that occurs, calculated as ~severe' cases divided by total cases. It has been observed that some enteropathogens are more likely than others to cause diarrhoea resulting in hospital visits and dehydration. In community-based studies in rural Bangladesh, rotavirus was found to result in dehydration in 36% of episodes, a much higher proportion than that for enterotoxigenic E. coli or for other enteropathogens (Table 12) 5'37. This finding is consistent with the observation in both developing and developed countries that rotavirus infection is found in a higher proportion of hospitalized diarrhoeal cases than in milder cases found in the community ~s.

Epidemiology Table :10

Diarrhoeal attack rates for travellers from industrialized countries to Latin America, Asia and Africa Attack rate ( % ) Region

Number of studies

Median

Range

Latin America Asia Africa

18 6 3

53 54 54

21-100 21-57 36-62

From Black, RE?

Table 11

Association of enterotoxigenic Escherichia coli with travellers' diarrhoea by region of the world Percentage with enterotoxigenic E. coli Region

Number of studies

Median

Range

Latin America Asia Africa

19 8 3

46 14 36

26-72 0 37 31-71

From Black, R.E?

12 Percentage of children developing dehydration during diarrhoeal episodes in two community-based studies in rural Bangladesh

Table

Enteropathogen

No. of episodes

No. with mild moderate dehydration

Percentage with dehydration

Rotavirus Enterotoxigenic E. coli Other

78 322 846

28 17 18

36 5 2

o f d i a r r h o e a l diseases." R.E. B l a c k

children. In Mexico, C. jejuni was found to have the highest pathogenicity in the first 6 months of life and then a lower pathogenicity in two successive age groups, perhaps suggesting the development of immunity to the organism 4°. In Peru, the pathogenicity of Shioella species was higher in younger than older infants. Conversely, the pathogenicity of rotavirus was higher in older infants than in younger infants. This latter finding may suggest that transplacental or breast milk antibodies protected against rotavirus in the first 6 months of life. Mixed infections with two or more enteropathogens were common in the studies in Peru, and the possible interaction of these agents was examined by comparing the pathogenicity of mixed infections with that of single infections (Table 14) 11. Mixed infections with rotavirus had a pathogenicity of 0.86 compared with single rotavirus infections with 0.67, a non-significant difference. There are a number of possible reasons for the low to intermediate levels of pathogenicity found with enteropathogens. These include the possibility that only a subset of the organisms is actually pathogenic, e.g. possesses certain virulence factors that result in diarrhoea, and that this subset is not differentiated by current laboratory screening techniques. Environmental and epidemiological aspects may also play a role. For example, the ingestion of a large dose of the pathogen or consuming it with food that buffers the gastric acid defensive barrier could lead to a higher likelihood of disease occurring from the exposure. Furthermore, passive and active immune factors clearly play a role by providing partial or full protection against illness, but may not always prevent transient infection.

Adapted from Black, R.E. et al. 5"37

ACQUIRED

PATHOGENICITY An important aspect of the epidemiology of diarrhoeal diseases is the ability of an infectious agent to induce disease and the influence on this by host defences and other factors. The ability of an enteropathogen to induce disease is referred to as pathogenicity, which is calculated as the number of persons infected who have the disease divided by the total persons infected. It has long been recognized that many, if not most, exposures to enteropathogens result in asymptomatic infection, rather than illness. For example, with cholera, the most severe diarrhoeal disease known, it has been demonstrated that about 75% of infections with the current strain of V. cholerae E1 Tor are asymptomatic 39. Only 2% of all infections result in severe illness with typical features recognized as cholera. Thus, it should not be surprising to find that a high proportion of faecal specimens taken when diarrhoea is not present contain known enteropathogens. For example, in the communitybased studies described earlier, high rates of asymptomatic infection with all of the common viral, bacterial and parasitic enteropathogens have been found. The pathogenicity of single enteropathogens has been evaluated in several community-based studies ( Table 13 ). In Peru, the pathogenicity of C. jejuni enterotoxigenic E. coli ranged from 0.35 0.4111. This indicates that only about one out of three infections was associated with disease. Interestingly, the pathogenicity of infections with these two organisms did not differ by age among young

IMMUNITY

After infection with enteropathogens and the diarrhoeal illnesses that occur in early childhood, partial or complete Table 13

Pathogenicity of selected enteric pathogens by age Age group (months)

Pathogen

Country

0 5

6-11

12 23

Campylobacter jejuni

Peru Mexico Peru

0.41 0.50 0.35

0.35 0.20 0.39

0.15

Peru Peru

0.82 0.55

0.47 0.82

Enterotoxigenic Escherichia coli Shigella spp. Rotavirus

Adapted from Black, R.E. et al. 1' and Calva, J.J. et al. 4°

Table 14

Pathogenicity of single versus mixed infections with selected pathogens in infants 0-11 months old, periurban Lima, Peru, 1982-1984

Pathogen Campylobacter jejuni Enterotoxigenic E. coli Enteropathogenic E. coli Rotavirus Mixed rotavirus with other

No. infections with diarrhoea

Total infections

Pathogenicity

138 82

365 222

0.38 0.37

87

172

0.51

41 18

61 21

0.67 0.86 a

ap < 0.002 versus C. jejuni, ETEC or EPEC, not significant versus rotavirus Adapted from Black, R.E. et al. 11

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o f d i a r r h o e a l d i s e a s e s : R.E. B l a c k

immunity may be acquired against illness or even infection. The high incidence of diarrhoea in young children and the lower incidence in older children and adults, as well as the reduction in apparent pathogenicity with age already mentioned, suggest that this process occurs. However, a complete understanding of the development of natural immuity is not possible since few

Table 15 Toxin type of enterotoxigenic Escherichia coli (ETEC) in pairs of first and second episodes of ETEC-associated diarrhoea, Matlab, Bangladesh, 1978-1979

Toxin type in second episode Toxin type in first episode

ST

LT

ST,"LT

ST LT ST/'LT

60 39 41

27 24 17

45 16 17

Table 16 Pathogenicity on first infections with enterotoxigenic Escherichia coil and on second infections with ETEC of the same toxin type, Lugar Sobre la Tierra Blanca, Mexico, 1985 1987

Enterotoxin type

First infection

Second infection with same toxin type

LT LT/ST ST

0.19 0.57 0.41

0.23 0.20 0.25

Adapted from Cravioto, A. et al. 4~

Table 17 Risk of diarrhoea in infants reinfected with enterotoxigenic Escherichia coli producing the same or different colonization factor antigens, Lugar Sobre la Tierra Blanca, Mexico, 1985 1987

Diarrhoea Yes

No

Colonization factor antigen

n

%

n

%

Same Different

4 20

15 53

22 18

85 47

p < 0.01 Adapted from Cravioto, A. et al."'

studies of sufficient detail, size and duration have been performed. Selected epidemiological evidence will be reviewed to determine the implications of these studies of natural protection for vaccine development and application. Enterotoxigenic E. coli have numerous serotypes, colonization factors and enterotoxins. Thus, in spite of the high frequency of this enteropathogen in developing countries, the evaluation of acquired immunity has been problematic. Using unpublished data from a study in Bangladesh 5, the relative proportions of the different toxin types of enterotoxigenic E. coli were compared for organisms associated with the first versus the second episodes of diarrhoea ( Table 15 ). In 286 pairs of episodes, the toxin type in the second episode occurred in the expected proportion based on the toxin types for all first episodes. Thus, there was no evidence of protection due to immunity to that toxin type from the first episode of diarrhoea. In Mexico, it was found that enterotoxigenic E. coli producing only the heat-stable toxin, or both heat-stable and heat-labile toxins, were more likely to cause diarrhoea on the first infection than on the second, but that organisms producing only heat-labile toxin were equally likely to cause illness on first and second infections (Table l6) 41. This result seems counterintuitive since the heat-labile toxin is immunogenic and the heat-stable toxin is not. However, acquired protection with the heat-stable toxin-producing E. coli may be due to immunological response to other associated factors, such as colonization factors, rather than to the toxin. This is further suggested by the finding in the same study that there was a reduced risk of diarrhoea in infants reinfected with enterotoxigenic E. coli producing the same, compared with different, colonization factor antigens ( Table 17 ). Acquired protection from shigellosis has been difficult to demonstrate in community-based studies. In a cohort study in Bangladesh 5, the incidence of a repeat episode, i.e. a second or third episode of shigellosis, was similar to the incidence of first episodes (Table 18). It is possible that for S.Jtexneri there was some protection, as indicated by the rate of one episode per year for first infections versus 0.6 episodes for second episodes. However, the

Table 18 Incidence rate (per child-year) for first, second and subsequent episodes of shigellosis as a measure of natural protection in a cohort of 197 children less than 5 years old in rural Bangladesh, 1978 1979

First episode

Second episode

Third episode

Pathogen

Child-years

Inc.

Child-years

Inc.

Child-years

Inc.

All Shigella spp. Shigella flexneri Shigella sonnei

122.0 136.1 163.4

0.73 1.05 0.09

55.1 38.1 8.9

0.67 0.60 0.11

22.7 14.1 0.2

0.97 0.64 0

Inc., incidence rate per child-year

Table 19

Incidence rates for first and second episodes of rotavirus-associated diarrhoea by age, Bilbeis, Egypt, 1981 1983 First episode

Second episode

Age ( months )

Person-years

Episodes

Incidence rate

Person-years

Episodes

Incidence rate

0 11 12 24

266.1 135.8

64 22

0.24 0.16

18.1 37.7

6 6

0.33 0.16

From Reves, R.R. et al. 42

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Epidemiology

rate of S. sonnei-associated episodes did not drop after the first episode. The sharp reduction in the incidence of rotavirus diarrhoea after the first 2 years of life would seem to indicate that protection is acquired rapidly. This is also suggested by data from Mexico that showed a lower pathogenicity of a second, as opposed to a first, rotavirus infection with a drop from 0.41 to 0.1441. However, a cohort study from Egypt found the same incidence of second rotavirus infections as for first infections (Table 19). Unfortunately, the studies to date have not adequately examined the various serotypes of rotavirus to determine if there is serotype-specific protection.

5

6

7

8

9

CONCLUSION Diarrhoeal diseases continue to be a major problem for children of developing countries, and still represent a significant burden for developed country children as well. A large number of enteropathogens have been associated with diarrhoea, but some deserve special attention because of their frequency as agents of diarrhoea or the particularly severe illnesses that result. Enterotoxigenic E. coli and Shigella spp. are clearly of importance for diarrhoea in developing country children and for travellers to developing countries. Vibrio cholerae is an important organism because of its continued presence in endemic areas and its potential for epidemic spread. Rotavirus is of utmost importance as a cause of dehydrating watery diarrhoea and mortality in developing country children, and serious illnesses requiring costly hospitalizations in developed country children. However, the findings from epidemiological studies in developing countries should make us cautious about the possibility of developing effective vaccines that can be employed to prevent a substantial amount of the morbidity and mortality from diarrhoeal diseases. Such vaccines need to be delivered to very young infants who suffer the most serious consequences of diarrhoeal diseases. For some enteropathogens, it may be difficult to immunize very young infants who may have partial passive immunity, including that derived from breast milk immune factors. To deliver an enteric vaccine easily, it would be best if immunization could be achieved in one or a small number of doses. The observation that acquired immunity after illness is incomplete may suggest that protective immunity is highly specific and may also suggest that several exposures to even this specific set of antigens are needed for the development of high-level protection. This would seem to make the development of vaccines against heterogeneous groups of enteric pathogens a difficult task.

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3

4

Claeson, M. and Merson, M.H. Global progress in the control of diarrheal diseases. Pediatr. Infect. Dis. J. 1990, 9, 345 355 Glass, R.I., Lew, J.F., Gangarosa, R.E., LeBaron, C.W. and Mei-Shang, H. Estimates of morbidity and mortality rates for diarrheal diseases in American children. J. Pediatr. 1991, 118, $27 $33 Black, R.E. Epidemiology of travelers' diarrhoea and relative importance of various pathogens. Rev. Infect. Dis. 1990, 12(1), $73 $79 Institute of Medicine. The prospects of immunizing against Salmonella typhi. In: New Vaccine Development: Establishing Priorities. Volume II. Diseases of Importance in Developing Countries. National Academy Press, Washington, DC, 1986

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