Childhood Diarrhea in Sub-Saharan Africa

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Childhood Diarrhea in Sub-Saharan Africa - page 1
Childhood Diarrhea in Sub-Saharan Africa Child Health Research Project Special Report April 1998, Volume 2, Number 1
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Childhood Diarrhea in Sub-Saharan Africa - page 2
D iarrheal disease remains a leading cause of mortality and morbidity of children in Sub-Saharan Africa, a region where unique geographic, economic, political, sociocultural, and personal factors interact to create distinctive continuing challenges to its prevention and control. Whereas childhood mortality rates from diarrhea are expected to decrease by 30 to 50% in most areas of the world between 1990 and 2000, the decline in Sub-Saharan Africa is estimated to be only 3%.* Consequently, approxi- mately 40% of childhood deaths from diarrhea worldwide will occur in Sub-Saharan Africa by the year 2000, although only 19% of the world’s population under the age of five years will live in this region.* This continuing epidemic deserves sustained programmatic and research attention as international pub- lic health moves on to confront newer issues in infectious disease and the changing burdens of disease associated with the demographic transition. A number of different social, political, and economic factors are present in Sub-Saharan Africa which contribute to the constant morbidity from acute and persistent diarrhea, as well as intermittent epidemics of cholera and dysentery common to this region of the world. Morbidity and mortality from childhood diarrhea, whether due to invasive enteropathogens such as Shigella or the more commonplace rotavirus, are further compounded by inappropriate household case management and the frequent misuse of antibiotics. Limited knowledge among many health care providers of the proper treatment of diarrhea also contributes to poor outcomes. The overuse of antimicrobials exerts a selective pressure for the development of antimicrobial resistance throughout the continent. Antimicrobial resistance will increasingly limit a practitioner’s ability to successfully manage cholera and dysenteric diarrheas. This report on childhood diarrhea in Sub-Saharan Africa is intended to provide an overview of the current state of this problem and to highlight key areas for future research. Given the continued importance of diarrheal disease as a major contributor to childhood morbidity and mortality in Africa, there is a clear need for vigorous efforts to implement the new Integrated Management of Childhood Illness (IMCI) approach to improve diarrhea case management. There is also an urgent need to devel- op interventions to limit the spread of antimicrobial resistance among bacterial enteropathogens. Foreword Davidson H. Hamer, M.D. ARCH Project Scientist Jonathon Simon, M.P.H. ARCH Project Director Donald Thea, M.D., M.Sc. ARCH Project Scientist Gerald T. Keusch, M.D. ARCH Scientific Director * The Global Burden of Disease, CJC Murray & AD Lopez. 1996 Child Health Research Project Special Report, April 1998 1
Childhood Diarrhea in Sub-Saharan Africa - page 3
Table of Contents FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 BURDEN OF DISEASE FROM DIARRHEA IN SUB-SAHARAN AFRICA . . . . . . . . . . . . . . . . . . . . . . . . 3 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Morbidity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 CAUSES OF DIARRHEAL DISEASES IN SUB-SAHARAN AFRICA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 CHOLERA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 REFUGEE CAMP ASSOCIATED DIARRHEA AND DYSENTERY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 INVASIVE DIARRHEA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 MULTIDRUG RESISTANT SHIGELLOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 DRUG USE AND MISUSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 ANTIMICROBIAL RESISTANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 TREATMENT AND PREVENTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Home case management and traditional healers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Treatment in the hospital or clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Diarrheal disease control programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 CONCLUSIONS AND RESEARCH AGENDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 2 Child Health Research Project Special Report, April 1998
Childhood Diarrhea in Sub-Saharan Africa - page 4
o compile information on diarrhea in Sub-Saharan Africa, we performed a computer search of the scientific literature in the MEDLINE database from 1966 through 1997. In addition, we reviewed the bibliographies of relevant articles. A total of 298 papers were reviewed from these two sources, but many were not included in the preparation of this review because they were of insufficient scope or quality (see below). The difficulties encountered in designing and implementing prospective, community-based stud- ies of diarrhea in Africa are numerous. Recruitment obstacles may arise from caretaker fears, cultural beliefs, and a lack of family or tribal consent. Longitudinal surveillance may be hindered by ineffi- cient telecommunications, poor public transportation, wide dispersion of rural communities, low population density, inconsistent house-numbering schemes, incomplete mapping and census infor- mation, mobility of the study population, and inadequate incentives for participation. The capacity to design and carry out clinical trials is typically limited in the very regions where research is desper- ately needed. Despite the numerous obstacles to the implementation of well-designed clinical research in Sub-Saharan Africa, considerable information on many aspects of diarrheal disease has accumulated during the last two decades. Prospective community-based studies of diarrheal mortality were selected for inclusion in this review if surveillance was done at least monthly. Morbidity data were derived from prospective studies with frequent active surveillance (at least monthly) which also included a clearly stated definition of diarrhea. Though we are aware of the potential limitations of monthly recall data, there were insuffi- cient surveillance data using more frequent recall periods. Data from cross-sectional survey studies were included if relevant longitudinal data were unavailable. Outcomes evaluated included the inci- dence (number of episodes/child/time period), and prevalence (proportion of children with diarrhea at one point in time) of diarrhea, episode duration, and cumulative time spent with diarrhea. Only cross- sectional and prospective studies that provided clear definitions of diarrheal episodes and nutritional status were included in the evaluation of the relationship of nutritional status and diarrhea. Studies of specific pathogens responsible for acute or persistent diarrhea were included if they contained a clear definition of diarrhea, non-diarrheic controls, and an adequate description of microbiological methods. Because the number of prospective studies of diarrhea etiologies is limited, cross-sectional studies that met these criteria were also included. Studies of risk factors for acute or persistent diarrhea were reviewed if they contained appropriately matched controls. Studies that did not define diarrhea or did not contain an adequate control group are discussed only if they are the sole identified source of information on a specific subject. Differences in the definition of diarrhea, the type of population studied, selection of appropriate controls, presence of recall bias, and study design may be responsible for the conflicting findings seen in studies of the determinants of disease. T Methods Mortality D iarrhea is one of the top three causes of childhood mortality in Sub-Saharan Africa, estimated from community-based surveys or vital statistics registries and census data. A comprehensive review of worldwide diarrheal mortality data derived from prospective, community-based studies of sta- ble populations with low migration rates lasting at least one year showed that only three studies in Africa met these strict selection criteria, all of which were limited to children less than four years old (1) . Overall death rates ranged from 3.6 to 24 per 1,000 population in these three studies. This review was updated a decade later using studies that reported age-specific mortality data, and information from longitudinal and cross-sectional studies as well as vital registries (2) . The more recent data showed that childhood mortality rates from diarrhea in Africa remained high; the rates were similar to those found in South Asian studies and were consistently higher than in Latin America. In contrast, analysis of sur- vey data from national diarrheal disease control programs revealed a decrease in the median number of Burden of Disease from Diarrhea in Sub-Saharan Africa Child Health Research Project Special Report, April 1998 3
Childhood Diarrhea in Sub-Saharan Africa - page 5
deaths per 1000 population in children under five years old, from 11.8 in the period from 1982 to 1984 to 5.1 in 1987 - 90 ( 2 ) . Our compilation of data from prospective, community-based studies found that acute diarrhea-associated mortality rates ranged from 3.4 to 31 per 1000 children per year (Table 1). Acute diarrhea accounted for 1.9 to 37% of all deaths, with the greatest proportion of deaths from acute diarrhea usually occurring in the first year of life. Persistent diarrhea (duration more than 14 days) is also responsible for significant childhood mortality in Sub-Saharan Africa, where rates of 6.6 to 43 deaths/1000 children/year have been observed (Table 1) (3-5) . Table 1. Mortality from acute and persistent diarrhea in Sub-Saharan Africa Country Author(s) Period of study Study locale Frequency of visits Age (years) children 0-1.5 Mortality rate (deaths per 1000 per year) 19.4 (1.9% of deaths due to diarrhea) 4.8 a /6.6 b ; 9.2 a /6.7 b 31 a /43 c; 14% a /16% c of deaths due to diarrhea 3.4 The Gambia Marsden (34) 1960-62 Sukuta (semi-rural) Weekly The Gambia Greenwood et.al (173) Molbak et al. (4) 1982-83 1986-87 1987-90 Farafenni (rural) Bandim II (semi-urban) Monthly <5 Guinea- Bissau Weekly <5 Kenya Omondi- Odhiambo et al. (6) Lindskog (182) 1975-78 Machakos (rural) Biweekly <5 Malawi 1983-88 1984-85 1977-78 Chingale (rural) Malumfash I (rural) Biweekly <5 18.0 Nigeria Bradley and Gilles (16) Monthly All 37% of children <4 yrs died from diarrhea 24 Nigeria Rea (22) 1960s 2-year duration NA Lagos (urban) Juba (urban) Bagamoyo (rural) Kinshasa (urban) Every 2 to 3 weeks Monthly <5 Sudan Woodruff et al . (183) Mtango and Neuvians (172) <1 7.9% died from diarrhea 5.6; 14% of deaths due to diarrhea 12 d ; 31% of deaths due to diarrhea Tanzania 1984-85 Every 6 to 8 weeks Monthly <5 Dem. Rep. Thea (5) of the Congo 1989-90 <1 a: Acute diarrhea b: Chronic diarrhea and malnutrition c: Persistent diarrhea and malnutrition d: HIV-seronegative infants 4 Child Health Research Project Special Report, April 1998
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Mortality rates are significantly increased in the presence of HIV infection as evidenced by a well- designed and implemented study with monthly surveillance of HIV-seropositive and seronegative infants in an urban area of the Democratic Republic of the Congo (formerly Zaire) ( 5 ) . The diar- rhea-attributable mortality of 12.0 deaths per 1000 live births in the HIV-negative cohort increased to 132 deaths/1000 live births in HIV-positive infants. Much of this increase was due to a rise in deaths associated with persistent diarrhea. The case-fatality rate among children with less severe disease reported in a community-based study in Kenya involved only 0.1% of all episodes of diarrhea ( 6 ) , whereas rates among children requiring hospitalization for diarrhea ranged from 9.4 to 19% (7-10) . Persistent diarrhea, acute dehydration, mal- nutrition, sepsis, underlying HIV infection, measles, and complications of invasive diarrhea all increase the likelihood of death from diarrhea (3,5,9) . Multivariate analyses of predictors of fatal diar- rheal episodes in two case-control studies of hospitalized children less than five years old from Lesotho found that illness duration of seven or more days before hospitalization, age less than six months, and the presence of a major concurrent infection (measles, pneumonia, meningitis, or sepsis) were all independently associated with death ( 9 ) . During the postneonatal period infants are at the greatest risk of lethal diarrheal disease (1,2,6,11-14) . Thereafter, death rates from diarrhea decline with age; however, only limited data are available regarding death rates in children over five years old (14,15) . Persistent or recurrent diarrhea (two or more episodes separated by at least three days of normal stool output) are important risk factors for mortality in neonates and infants (4,5) . Higher mortality rates from diarrhea have been observed in some countries or regions during the wet season (3,16,17) or among families with lower socioeconomic status, or poor hygiene practices (18) . Morbidity The median annual incidence of diarrhea in Sub-Saharan Africa peaks among infants 6 to 12 months old and decreases progressively thereafter (13,19-24) . Most incidence studies have restricted their focus to children less than five years old, and data for older children are limited to one cross-sectional survey from Imo State, Nigeria (25) . A review of longitudinal community-based studies with frequent surveil- lance found that 6- to 11-month-old children in Africa had a median of 4.5 diarrhea episodes per year (2) . This rate was higher than that found in many Asian studies but was lower than in Latin America. However, a number of the morbidity studies from Latin America which were carried out dur- ing the 1980s used more frequent surveillance, which may yield higher incidence rates (2) . The median yearly incidence rates of diarrhea in Africa and Latin America are nearly identical if the Latin American studies with more frequent (twice weekly) surveillance are excluded. A comprehensive analysis of 73 studies from 23 countries during 1970 to 1990 found that children under five years of age in Sub-Saharan Africa experience about five episodes of diarrhea yearly (range of 1.6 to 9.9) (11) . Prospective studies of the incidence of diarrhea that covered at least a one-year interval reported a range of 1.0 to 7.3 episodes/child/year (Table 2). Pooling all studies, including those limited to the rainy season, shows a prevalence of diarrhea in children of 10.5 to 19%. Unlike the decline in mortality rates, diarrhea incidence does not appear to have changed substantially over the last decade (1,2) . Diarrhea has been estimated to be responsible for 25 to 75% of all childhood illnesses in Africa (11,25,26) . Episodes of diarrhea lead to about 14% of outpatient visits, 16% of hospital admis- sions, and account for an average of 35 days of illness per year in children less than five years old (11) . A limited number of prospective studies in Sub-Saharan Africa have found that persistent diarrhea accounts for 2.4 to 11.4% of all diarrhea episodes (27,31) but 22% of the total days of diarrhea record- ed in a rural cohort in Zimbabwe (29) . Although the definition of a new episode was similar (two to three or more diarrhea-free days between attacks), only three of these studies extended over at least a full year to eliminate the effect of seasonal variation on diarrheal incidence (29-31) . This may account, in part, for the lowest incidence, (2.4%), which was observed in the study with the shortest dura- tion (27) . Thea et al. found four episodes of persistent diarrhea per 100 child-years of observation in Child Health Research Project Special Report, April 1998 5
Childhood Diarrhea in Sub-Saharan Africa - page 7
Table 2: Morbidity from acute diarrhea in Sub-Saharan Africa Country Author(s) Study duration (months) Study locale Frequency of visits Age (years) Morbidity Ethiopia Freij and Wall (13) 12 Addis Ababa (urban) Biweekly 0-12 0-23 mo 1 : median 6.6 episodes/yr (63 days/yr) 5-12 yr: median 1.0 (4 days/yr) 7.3 episodes/child/yr The Gambia Goh 24 (31) Rowland et al. Rowland et. al. (38) Pickering et al. (184) Biritwum et al. (19) 24 Bakau (urban) Bakau (urban) Bakau (urban) Gomoa Fettah (rural) Bandim II (urban) Weekly 0-2 The Gambia Weekly 0-2 18.7% prevalence The Gambia 4 Weekly 0.5-3 12.0% prevalence (2.8 episodes/child) 1.9 episodes/child/yr Ghana 12 Weekly 0-6 Guinea- Bissau Molbak et al. (62) 12 Weekly <3 13% prevalence (2.6 episodes/100 days at risk) 2.2% average 2-weekly incidence 1.4 episodes/child/3mo (10.5% of time spent with diarrhea) 1983: 4.1-6.7 episodes/child/yr 1986: 2.5-2.9 episodes/child/yr (7) 1.9 episodes/child/3 mo (11% of time spent with diarrhea) 100 episodes/ 100 child-yrs (8) Kenya Leeuwenburg et al. (23) Tomkins (44) 36 Machakos (rural) Malumfash I (rural) Biweekly <5 Nigeria 3 Weekly <3 Nigeria Huttly et al. (175) 48 Imo State (rural) Biweekly <6 Dem. Rep. Haggerty of the Congo et al. (28) 3 Bandundu Weekly <3 D.R.O.C. Thea et al. (5) 16 Kinshasa (urban) Monthly from birth to 12 months then bimonthly Weekly <2 Zimbabwe Moy et al. (29) 22 Shamva (rural) <2 13-18 month age range (3 episodes/6 mo) 1. Morbidity measures are for gastroenteritis, which was defined as the presence of vomiting and/or diarrhea. Diarrhea was defined as at least four loose or one watery stool in a 24-hour period. 2. Maternal definition of diarrhea. 3. The mother’s opinion of whether a stool was diarrheal was verified by study investigator who agreed in the majority of cases. 4. Study done during the rainy season in which the highest incidence of diarrhea is usually found in this region. 5. Diarrhea was defined as three or more loose stools in a 23-hour period. 6. Field workers evaluated children’s stools to determine if they had diarrhea. 7. Control villages only. 1983 data are for both control and intervention villages. 8. Data are for HIV-negative children only. 6 Child Health Research Project Special Report, April 1998
Childhood Diarrhea in Sub-Saharan Africa - page 8
an HIV-seronegative birth cohort in Dem. Rep. of the Congo (5) . This incidence rate is substantially lower than that reported in other parts of the developing world (32) , however these children were all receiving frequent basic primary health care as part of an ongoing study of perinatal transmission of HIV. Differences in the frequency of surveillance and type of community studied also contribute to the wide regional variations in the incidence of persistent diarrhea. Malnutrition cute and chronic infections contribute to malnutrition by causing decreased food intake, impaired absorption, increased losses of fluid, electrolytes, protein, and iron, and by altering the normal metabolism (33) . Evidence from numerous studies of children under five years of age in developing countries suggests that both acute and persistent episodes of diarrhea predispose to or exacerbate mal- nutrition (34,35,36) , and conversely chronic malnutrition may be a risk factor for diarrhea (37) . Data from Sub-Saharan Africa illustrate the complex interaction between diarrhea and malnutrition that has been found in other developing regions of the world. Differences in measurement tools and the timing of nutritional assessments among studies may explain some of the variance in the reported results. Prospective, community-based studies in The Gambia, Uganda, and Sudan indicate that diarrheal disease leads to impaired weight gain (33,38-42) . The impact of diarrhea on weight gain was greatest in 7- to 12-month-old infants and was fourfold higher among weaned than exclusively breast-fed children (38) . A notable exception was a study in rural Zimbabwe, which failed to find a significant adverse effect of acute diarrhea on weight gain (43) . Although growth faltering was severe during and immediately after an episode of diarrhea, the return to a child’s previous growth curve was 90% complete within a month. Moreover, children with frequent diarrhea episodes had similar growth rates when compared to those with infrequent episodes. However, since both cases and controls showed mean weight and height which were only in the third percentile of the National Center for Health Statistics (NCHS) standards, inadequate dietary intake in this economically deprived popula- tion is an obvious confounding variable. Pre-existing malnutrition also increased the likelihood of diarrheal disease. Decreased weight-for- age was significantly associated with an increased incidence or prevalence of diarrhea in all studies but one (43) (Table 3). Diminished height-for-age or stunting, generally accepted as an indication of chronic undernutrition, was associated with a significantly increased risk of diarrhea in two studies (19,45) but not in another (44) . A significant association between decreased weight-for-height and diarrhea rates was observed in two of these studies (19,44) but not in the third (45) . A cross-sectional study of acute diarrhea in a rural community in the Sudan also demonstrated a significant association between low weight-for-age (<75%) and diarrhea, with an apparent dose-response relationship (46) . Furthermore, the duration of a diarrheal episode was increased in underweight, wasted, and stunted Nigerian children (44) . In two studies the effect of malnutrition on the risk of diarrhea remained after adjustment for age, water availability and quality, personal hygiene practices, and family income (45,46) . Similar findings have been reported from Bangladesh (47,48) although these failed to show an increased incidence of diarrhea in malnourished children. Severe vitamin A deficiency (manifested by xerophthalmia) was shown to be associated with an increased risk of diarrheal disease among children in Asia (49) and Ethiopia (50), while low dietary intake of vitamin A was a risk factor for diarrhea in Sudanese children (32) . Neither African study, however, controlled for the possible confounding effect of nutritional status on the incidence of diarrhea. A meta-analysis of randomized trials of vitamin A supplementation performed worldwide found a 39% reduction in mortality due to diarrheal disease in vitamin A supplemented children (52) . Similar promising findings have been obtained in studies in Sub-Saharan Africa. In two carefully designed and implemented, placebo-controlled studies in Ghana, vitamin A supplementation for non-xeroph- A Causes of Diarrheal Diseases in Sub-Saharan Africa Child Health Research Project Special Report, April 1998 7
Childhood Diarrhea in Sub-Saharan Africa - page 9
Table 3. Effects of nutritional state on the frequency of diarrhea in prospective studies of African children. Author(s) Year of study Country Study location/ Weight-for-age (cut-off level) duration Increased (<80%ile) No effect (<75%ile) Increased (<80%ile) Increased (<-2SD) Height-for-age (cutt-off) Weight-for height (<80%) Freij Wall (13) Tomkins (44) 1972-73 Ethiopia Urban/ 1 year Rural/ 3 months Rural/ 1 year Urban/ two 3 mo periods Not studied Not studied 1979 Nigeria No effect (<90%ile) Increased (<90%ile) Increased (<-3SD) Increased Biritwum (19) 1982 Ghana Increased Tomkins (45) 1981 The Gambia Increased thalmic children was associated with a 19% reduction in mortality from acute diarrhea, and evidence of reduced diarrhea morbidity as well (53,54) . The effect of supplementation was greatest on the inci- dence of severe dehydrating diarrhea, and the frequency of clinic attendance, or hospital admissions. A comparison of vitamin A and E supplementation in the Sudan demonstrated no difference in the decrease in diarrhea-associated mortality in either group (55) . Another study of a combined vitamin A and E supplement versus a vitamin E control in South Africa given at months 1, 3, 6, and 9 did not have sufficient power to evaluate the effect of the micronutrient supplement on mortality (56) . However, there was a significant reduction in diarrhea overall as well as a trend toward a reduction in hospitalization for diarrhea and the number of episodes lasting more than seven days in the vitamin A-supplemented group. Differences in study population characteristics, the dosage and the frequency of vitamin A supplementation may account for these discrepant findings. The choice of vitamin E for placebo may be inappropriate given the growing evidence that vitamin E may have beneficial effects on the immune system with a resultant reduction in the incidence of infections (57) . The role of zinc supplementation for the treatment and/or prevention of diarrheal disease has been evaluated in Sub-Saharan Africa on a very limited basis. A placebo-controlled trial in The Gambia of a high dose zinc gluconate supplement administered twice weekly was designed primarily to evaluate the effect of zinc on the growth of children in a rural community (58) . This study found that zinc supplementation failed to reduce the number of clinic visits for diarrheal disease. Nevertheless, this research provided interesting results that have served to generate new hypotheses on the role of zinc as an adjunct to the therapy or prevention of childhood infectious diseases. Pathogens Controlled prospective and cross-sectional studies of children with acute diarrhea presenting to outpatient medical facilities or admitted to the hospital in Sub-Saharan Africa typically identify (in decreasing order of frequency) rotavirus (59,60 31,61-65) ; C. jejuni (31,60-62,65,66) ; enterotoxigenic E. coli (ETEC) (31,59-62,66) ; enteropathogenic E. coli (EPEC) (60-62,65,67) ; Vibrio cholerae 0163 (61,62,66) ; Shigella (31,60-62,65,66,67) ; Aeromonas sp. (31,65-68) ; Salmonella sp. (31,60-62,65-67) ; Plesiomonas shigelloides (66,69) ; Yersinia enterocolitica (61) ; Cryptosporidium (62,70,71) ; Giardia lamblia (31,59-62,66) ; Entamoeba histolytica (59-62,66) ; Strongyloides stercoralis (31,60,62) ; and Isospora belli (62) . However, several of these organisms in some stud- ies were no more prevalent in diarrheic than non-diarrheic children, for example, C. jejuni (31,62,65,72) . Rotavirus, ETEC, EPEC, Shigella sp., and C. jejuni were responsible for the majority of cases of acute diarrhea in Sub-Saharan Africa, as in other parts of the developing world (73,74) . 8 Child Health Research Project Special Report
Childhood Diarrhea in Sub-Saharan Africa - page 10
Of all etiologies examined, rotavirus is most consistently found in cases than controls (31,59,60,62,63,66) . (Table 4) Data from both prospective and cross-sectional studies indicate that the incidence of rotavirus infection increases in the dry season (60,63,64,75) and is most frequent in children less than two years old, with the peak prevalence in children less than six months old (62) . An uncontrolled, prospective community-based study of diarrhea in Nigerian children found that rotavirus diarrhea peaked between three and five months of age and was often associated with dehydration (24) . As observed in other parts of the developing world (74,76) rotavirus was also associated with higher rates of dehydration than other enteric pathogens in a cross-sectional study in The Gambia (64) . A community-based prospective study of multiple potential pathogens found Cryptosporidium, EPEC, and rotavirus were more prevalent in cases than controls whereas ETEC, Shigella sp., V. cholerae, Salmonella sp., Campylobacter sp., and G. lamblia occurred with an equal or greater prevalence in asymptomatic controls (62) . This is one of a limited number of controlled studies in Sub-Saharan Africa with a clear definition of diarrhea that looked for Cryptosporidium, a pathogen implicated as a cause of acute and persistent childhood diarrhea in both developing and industrialized regions of the world (77) . A number of studies that failed to define diarrhea but did include asympto- matic controls have found prevalence rates of cryptosporidiosis ranging from 6 to 9% among children in Guinea Bissau, Sudan, and South Africa (78-80) . In an investigation in Democratic Republic of the Congo, Cryptosporidium accounted for 2% of episodes of acute diarrhea in non-HIV infected children (5) . In another study (70) , there was no difference in the prevalence of cryptosporidiosis in diarrheic vs. control children but about two-thirds of the asymptomatic carriers reported diarrhea in the two weeks prior to examination. Limited evidence suggests that children under two years of age are more likely to develop cryptosporidial diarrhea (62,70,79) and that the disease is seasonal (62,80) . Cryptosporidium has also been responsible for epidemics of acute diarrhea in day-care centers in South Africa (81) and community outbreaks in Guinea-Bissau (79) . Limited published data are available from Sub-Saharan Africa on etiologic agents associated with persistent diarrhea. The relative contribution of specific pathogens to this ubiquitous problem is unclear and may vary regionally. A survey of hospitalized children with diarrhea in Somalia found that rotavirus, Shigella sp., and G. lamblia were significantly more common in acute than persistent diarrhea (66) ; special stains for Cryptosporidium were not performed. A prospective, community-based one year survey in urban Guinea-Bissau found that Cryptosporidium was the only pathogen signifi- cantly more prevalent in children with persistent compared to acute diarrhea (62) and was associated with excess infant mortality which persisted into the sec- ond year of life (71) . This parasite was also found more commonly in children with persistent diarrhea in Bangladesh (76) . However, the available evidence suggests that Cryptosporidium is responsible for only a fraction of cases of persistent diarrhea (62,76) . Serial infections with different agents may underlie the development of some episodes of persistent diar- rhea (4,76,82) as well as host factors including nutritional or immunological status. The role of enteroaggrega- tive E. coli has not been adequately studied thus far. Child Health Research Project Special Report, April 1998 9
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