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Journal of Pediatric Gastroenterology & Nutrition:

Diarrhea and Malnutrition: A Challenge for Pediatricians

Gracey, Michael

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Aboriginal Health Policy and Programs Branch, Health Department of Western Australia, and School of Public Health, Curtin University, Perth, Australia

Address correspondence and reprint requests to Dr. M. Gracey at Health Department of Western Australia, 2nd Floor, “C” Block, 189 Royal Street, Perth, 6004, Australia.

Infectious diarrhea remains one of the most prevalent serious health problems facing infants and young children around the world. We are given a timely reminder about this subject elsewhere in this issue of the Journal by Bhutta and Hendricks, who provide a developing world perspective on the nutritional treatment of persistent diarrhea in childhood. With improved case management of immense numbers of infants and young children with acute infectious diarrhea in developing countries over recent years, survival rates have improved, and increasing numbers of survivors are experiencing persistent diarrhea and its long-term consequences, which can be debilitating and life-threatening. This is a particularly difficult challenge for pediatricians in so-called developing countries because of the immensity of the problem, its clinical complexities, the potential costs involved in “high tech” approaches to solutions, and the political and socioeconomic dimensions inherent in providing better living standards and health care for children in less developed parts of the world.

The first estimate of global morbidity and mortality from diarrheal disease based on active surveillance data, collected from 24 selected longitudinal studies of children conducted over three decades, was published in 1982 (1). That investigation showed that using 1980 population estimates, there were annually 744 million to one billion episodes of diarrhea and 4.6 million deaths from diarrheal disease in children <5 years of age in Africa, Asia (excluding China), and Latin America. A 10-year update of that situation showed that the incidence of diarrhea (2.6 episodes per child per year) was virtually unchanged, but the estimated global mortality (3.3 million deaths per year; range of 1.5-5.1 million) was lower (2). The lower estimated mortality is encouraging, but diarrhea is still a massive pediatric problem globally.

Yet diarrheal disease, as a pediatric challenge, is not confined to so-called developing countries, although its impact is greatest there. In the United States, for example, there were, on average, 500 reported diarrheal disease deaths annually over a recent 10-year period in infants and children between 1 month and 4 years of age; 80% of those deaths were in infants <12 months of age (3).

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The potential impact of diarrheal episodes on nutritional status (through the negative impacts of stool losses, vomiting, anorexia, withholding of food, and the catabolic effect of infection) seems obvious, and the synergistic interactions of diarrhea and malnutrition are well recognized (4-10). However, the role of diarrhea as a major cause of malnutrition and widespread growth retardation has been challenged (11) despite the fact that diarrheal episodes undoubtedly are able to provoke transient growth faltering (5,6). A study from Colombia estimates that the average two to eight diarrheal episodes per year experienced by children in developing countries during the first 3 years of life causes a cumulative negative effect on body height of between 2.5 and 10 cm at 36 months (12). This study also suggests that nutritional supplementation can completely offset the negative effect of diarrheal disease on growth.

The influence of malnutrition on diarrheal episodes seems to be variable; malnutrition generally causes more prolonged diarrhea, and some studies have shown a higher incidence of diarrhea (7). A community-based, prospective study of >700 children in a rural, lowland area of Bangladesh showed a diarrheal incidence of 4.6 episodes per year (9). About three-quarters of the children were <2 standard deviations (Z scores) under weight and height for age, and about one-third were below -2 Z scores for weight for height. About 20% of the children were anergic, and these children had a 50% higher incidence of diarrhea. The association between undernutrition and diarrhea incidence was only modest, but a history of diarrhea in the previous 3 months was a strong predictor for diarrhea in the following 3 months. The same study found that malnutrition and impaired cell-mediated immunity were independent risk factors for diarrheal episodes. Whatever the complexities of the interactions between diarrhea and malnutrition, these are undoubtedly problems that have their greatest impact in the first 3 years of life and, particularly, during the second half of infancy (6-12 months) and in the second year of life (1,2,13-16).

A problem with interpreting published information about diarrhea and malnutrition is lack of uniformity in definitions of terms and severity of illness. To define a normal stool in a healthy infant can be difficult; it often depends on perceptions by mothers or others about what is normal. The median number of daily stools in >600 healthy Italian children ranged from 2.7 in the first year of life to one daily in children >6 years (17). There can be wide variability in the frequency and consistency of stools in healthy babies, with some normal neonates passing up to six stools and some infants passing up to four stools daily. Breast-fed infants pass more stools than do other infants. After 12 months of age, the passage of three or more loose stools daily is generally considered abnormal. Acute diarrhea usually means that the onset was within the past 24 h. It is also important to record whether the stools are watery or dysenteric (abnormally loose or fluid stools mixed with blood or mucus). Chronic diarrhea means that the diarrhea has lasted ≥ 14 days whether the stools are watery, loose, bulky, or dysenteric (18). Persistent diarrhea refers to an illness that lasts ≥ 14 days and does not respond readily or promptly to appropriate treatment because of the underlying pathology, such as AIDS-related infections (19).

Independent international comparisons of children's growth and nutritional status can be facilitated by use of the simple Z-score method, which allocates a standard deviation (Z) score to measurements from each child against such reference values as those produced by the United States' National Center for Health Statistics (20-22). This method can be applied across age groups and for sexes combined to estimate nutritional status of children in communities or regions. In order to distinguish acute malnutrition (wasting or emaciation) from chronic malnutrition (stunting) in groups of children, the following three indicators should be used: weight for age (W/A), height for age (H/A), and weight for height (W/H) (23). Well-kept records of growth, including growth charts, are very helpful in the assessment of the nutritional status of groups of children as well as individuals (23-26) and in order to assess the effectiveness of such interventions as nutritional therapy. It is suggested that weight for age is a better predictor of subsequent mortality in children 6-36 months old in a diarrhea epidemic developing country setting (Bangladesh) for the subsequent 12 months than is weight velocity (monthly weight loss or gain in grams) (27).

A recent report from Uganda about >4,000 village children ≤5 years of age showed that mortality rates were higher in those with lower anthropometric indexes and that mid-upper-arm circumference (MUAC) was the most sensitive predictor of mortality, followed by W/A, H/A, and W/H (28). However, their lowest MUAC cutoff measurement of 10.5 cm predicted only a little more than one-third (36.5%) of deaths, while their cutoffs of 11.5 cm and 12.5 cm predicted 18.7% and 10.9% of mortality, respectively. Those investigators found that MUAC increased the predictive power of the other measurements (W/A, H/A, W/H), but the inclusion of these anthropometric ratios did not enhance the predictive usefulness of MUAC measurements. Additional information (about the presence of edema, bloody diarrhea, acute respiratory infections, and absence of breast-feeding) is associated with a higher risk of mortality than a low MUAC alone (29). The use of MUAC to screen children most at risk could be very useful in circumstances where large numbers of vulnerable young children are at risk (e.g., in refugee camps, during famines, and in areas endemic for malnutrition) and where resources and skilled personnel are limited, particularly because the method is sensitive, age independent, easy to use, and does not require complicated or expensive equipment (28).

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The patterns of infectious diarrhea that occur in infants and young children differ greatly throughout the world. In cooler and temperate regions, for example, childhood gastroenteritis tends to be a winter illness. In Scandinavia, most diarrheal infections occur in winter and spring and ≤80% are attributed to rotavirus; during several epidemics from the late 1970s to the late 1980s in Tampere, Finland, 575 patients <3 years of age were hospitalized with acute gastroenteritis (30). Over that period, the average age of patients rose, and the proportion <12 months of age fell from 50 to 26%. The “average” patient was 18 months old, had had diarrhea for 3 days when admitted, was only mildly to moderately dehydrated, and responded well to treatment. Rotavirus gastroenteritis is now known to be seasonal, with winter peaks followed by summer troughs, as shown, for example, by the regular public health surveillance system in England and Wales (31). In the tropics, diarrheal episodes tend to be distributed throughout the year, although seasonal increases can occur in the dry season, the wet season, the hot season, the cool season, or various combinations, depending on the prevailing local climate and associated risk factors, such as environmental contamination, crowding, community hygiene, and the occurrence of vectors that can spread diarrhea-causing microorganisms (14).

In tropical northwest Australia, where I have worked in Aboriginal communities for many years, diarrhea is much more common during the early, wet, summer season, which is the hottest and most humid part of the year, and when heavy monsoonal rains arrive from Southeast Asia; this time is recognized locally as the “diarrhea season” (32,33). The association of childhood diarrhea with the 5-month annual wet season in the Gambia, on the west coast of Africa, is one of the most conspicuous features of diarrheal disease there (34), although a regular, smaller epidemic in the cool, dry season has also been documented (35). Seasonal patterns to childhood diarrhea have been noted in many other tropical locations, e.g., Pakistan (36) and Thailand, where there are two definite seasonal peaks: the summer one, associated with bacterial infections, and the winter one, related to viruses (37).

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There is a long and seemingly always enlarging list of etiologic agents that can cause infectious diarrhea; they fall into three main categories: viruses, bacteria, and parasites. A review of data from 34 studies on the etiology of childhood gastroenteritis was undertaken in order to investigate seasonal patterns of rotavirus gastroenteritis and their implications for transmission of the virus (38). Rotavirus was detected in 11-71% of children (median 33%); rates of detection were independent of the geographical region or the level of economic development as well as of the method of detection used. As already mentioned, although rotavirus infections are widely considered a winter disease in temperate zones, Cook et al. (38) found that their incidence peaked in winter primarily in the Americas and that peaks in autumn or spring are common in other parts of the world.

In tropical localities within 10° of the equator, eight of the 10 published reports showed no seasonal trend, and in most of the world rotavirus is present year round, suggesting that low-level transmission could maintain the infection. That comprehensive review of published reports on rotavirus infections shows an epidemiological pattern—seasonal in cooler months, universal spread in temperate and tropical regions in developed and less developed settings—that is similar to childhood viruses (such as measles) that are spread by the respiratory route rather than the more usual fecal-oral route of transmission of enteric pathogens. Others have also suggested that respiratory droplet spread may be significant in the transmission of rotavirus infections (39). Other viruses may be important causes of diarrheal disease in humans; they include Norwalk virus, Norwalk-like viruses (small, round, structured viruses), enteric adenoviruses, caliciviruses, and astroviruses (40). It is generally thought that rotavirus is the most important cause of childhood viral gastroenteritis worldwide. In the United States alone it is considered responsible for 3.5 million episodes of gastroenteritis in infants and young children annually (41).

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Diarrhea caused by enteric bacterial infections is very important worldwide, especially in tropical developing countries, and is a serious problem among older children and adults as well as in infants and young children (42). The range of causative microorganisms is very large; they include Escherichia coli, the invasive bacteria (Salmonella, Shigella, Campylobacter, Yersinia, enteroinvasive E. coli), vibrios, and such anaerobes as Clostridium spp. (43). The mechanisms by which bacteria and rotavirus cause diarrhea have been reviewed recently (44); E. coli can provoke diarrhea through several mechanisms, including toxin production, enteroinvasion, enteroadherence, enteroaggregation, and cytotoxicity, which manifests through its ability to induce enterohemorrhagicity (45). Improved laboratory methods to detect enteric pathogens and to investigate underlying pathogenic mechanisms (44,46-48) combined with more detailed and controlled epidemiological investigations has helped to discover roles for “newer” bacterial causes of diarrhea, for example, Aeromonas spp. (49), Campylobacter (50) and cyanobacteria, or blue-green algae (51-53). There have been important advances made in understanding diarrhea caused by E. coli and about the mechanisms involved; Echeverria et al. (45) and Booth and McNeish (44) have written useful reviews. Escherichia coli O157:H7 has become recognized as an important human diarrhea pathogen over the past decade, and excellent reviews are available (54-57).

The hamburger-borne outbreaks that occurred in California, Idaho, Nevada, and Washington in January 1993 drew public and professional attention to the seriousness of disease caused by enterohemorrhagic strains of E. coli, such as O157:H7, and their public health importance: there were >500 micro-biologically confirmed episodes in that 1993 out-break; 41 affected persons developed the hemolytic-uremic syndrome, and four children died (58). Food-borne diarrheal disease, caused by various agents, is of huge public health importance and may represent tens of millions of episodes annually in North America alone; the direct and indirect costs may run to billions of dollars (59). Foods prepared in homes under unhygienic living conditions, as occurs in poorer parts of developing countries, are often contaminated with pathogens and are, therefore, a major risk factor for diarrheal disease.

Up to 70% of the 1,400 million episodes of diarrheal diseases that occur in children <5 years of age are due to pathogens that can be transmitted through food; pathogenic strains of E. coli are a major proportion of the organisms involved (60). Bacterial food-borne diarrhea can be caused by other agents, such as Salmonella or Campylobacter, or can be due to the action of preformed toxins, as for example, with staphylococcal intoxication (food poisoning) and clostridial toxins. In the United Kingdom, campylobacteriosis, listeriosis, and infection with Salmonella enteritidis phage-type 4, which is associated with poultry and eggs, are an increasingly serious public health concern (61). Common-source outbreaks of S. enteritidis disease have also been reported from the United States (62,63).

International travel can cause episodes of diarrhea commonly known as “traveler's diarrhea” or by some local nickname, such as “Delhi belly” or “Montezuma's revenge.” This diarrhea can affect infants and young children as well as older travelers (64). Up to 50% of episodes are due to enterotoxigenic E. coli, but other varieties of E. coli can be involved, as can other enteric pathogens, including Salmonella, Shigella, Aeromonas, viruses, and parasites (64-68). This variety of causative agents emphasizes the importance of personal hygiene, such as that associated with feeding practices, for youngsters from industrialized countries (e.g., Australia, North America, Western Europe) when they are traveling in high-risk areas endemic for diarrhea.

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Intestinal parasitic infestations are prevalent in many tropical, developing parts of the world and are serious hazards to health. Some parasites, such as hookworms, can have profound nutritional consequences related to repeated gastrointestinal blood loss; others, such as Enterobius and Trichuris trichiura, usually do not have serious clinical consequences. Still others appear much more likely to cause diarrhea and other gastrointestinal symptoms.

Infection with the flagellated protozoan Giardia intestinalis (G. lamblia) is prevalent in infants and children in many parts of the world, especially where standards of personal and community hygiene are poor. Apart from fecal-oral transmission from infected humans, infected domestic animals (e.g., dogs) may in turn infect humans (69,70). One of many reports of food-borne outbreaks implicated a restaurant in Washington State where ice contaminated by a food handler may have been the vehicle for transmission of the infection (71). Cryptosporidium has become recognized lately as an important human intestinal parasite. This widely distributed parasite can cause severe, life-threatening diarrhea in immunocompromised hosts and is well recognized as a cause of diarrheal outbreaks in children (e.g., in day-care centers) and of chronic diarrhea in children without evidence of immune deficiency. Cryptosporidium is distributed worldwide, and pediatricians should be alert for it in children with diarrhea. Pediatric gastroenterologists should be particularly aware of cryptosporidiosis in children referred to them for investigation of puzzling episodes of diarrhea (72-74). Detection of fecal cysts in patients with diarrhea who have traveled in North Africa or the Indian subcontinent should raise the suspicion of infection with cyanobacteria or cyanobacterium-like body, mentioned earlier; it appears to be a new water-borne enteric pathogen in humans, for which the name Cyclospora cayetanensis has been proposed (52,53).

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There have been major advances in treatment of childhood diarrheal dehydration over recent years; foremost among them is the widespread use of oral rehydration therapy (ORT). These advances are important contributions to the lowered mortality from acute childhood diarrhea that has already been noted (2). The World Health Organization (WHO) through its Diarrhoeal Diseases Control Programme, with the participation of national programs in many developing countries, has helped to bring affordable ORT to infants, children, and families in hospitals and clinics as well as to villages and marketplaces in the countryside. This therapy has been shown to be feasible, efficacious, and safe in hospital treatment and at the primary care level in developing countries for prevention of metabolic complications of diarrhea and dehydration and in shortening hospitalization (75-78). ORT is gradually becoming accepted in the Western world (79), although it has been referred to as the “underused simple solution” because of the resistance of pediatricians and other medical practitioners (physicians) in such countries as the United States (80,81). This therapy can be unpalatable to some patients and can lead to vomiting, particularly if it is given too rapidly and in volumes that infants and young children find difficult to tolerate. There are also widely held perceptions that intravenous fluids are usually needed in children with acute diarrheal episodes even if fluid losses are mild or modest. There is a need to teach pediatricians, other doctors, and the public that oral therapy is not inferior because it may not appear to be “high tech” and that most children with acute diarrhea can be successfully treated with ORT.

Patients who are already dehydrated need to be treated in two phases: (a) rehydration, to replace fluids lost in stools and vomitus, and (b) maintenance, to replace continuing abnormal maintenance needs. Most patients with mild to moderate dehydration can be treated orally this way. Not all patients can be treated successfully with ORT alone, and those who are more than moderately dehydrated will need initial intravenous rehydration and correction of metabolic complications. For ORT to be successful and well accepted, patients who are old enough to understand, their parents, nurses, and health workers should be informed about the rationale for ORT, why and how it is being given and that it is a treatment for or against dehydration but not against an intestinal infection that might be the underlying cause for the diarrheal episode (82). The WHO has developed an excellent wall chart (also available in a small pocket-size folder) that explains assessment and treatment of diarrheal dehydration (83). These guidelines are based on sound physiological, clinical, and treatment principles that are applicable in the Western world as well as in developing countries; they are also very useful teaching aids for medical, nursing, and allied health professionals and trainees. This chart categorizes children with diarrhea as having “no dehydration,” “some dehydration,” or “severe dehydration” and, on this basis, allocates them to one of three treatment plans, ranging from treatment at home to the administration of intravenous fluids. Advice is also provided about breast-feeding and the treatment of bloody diarrhea, persistent diarrhea, and malnutrition.

Dietary treatment is a very important, but often poorly managed aspect of treatment of childhood diarrhea. Earlier approaches that permitted the bowel to rest for some days are outmoded and tended to worsen the potentially negative nutritional impacts of stool losses, vomiting, infection, and widespread inappropriate feeding practices in nutritionally vulnerable infants and young children (12,78,84). There are several important basic principles. (a) Breast-feeding should be continued during diarrhea, and additional fluids should be given to replace fluids and electrolytes that are lost with abnormal fecal losses. (b) Most young children with acute diarrhea can be successfully treated with continued feeding of undiluted nonhuman milks. Routine dilution of milk and routine use of lactose-free formula, without a clinical indication, are therefore not needed, especially when ORT and early feeding, in addition to milk, make up the basic approach to treatment (85,86). (c) In children who are being fed milks other than breast milk, these can be reintroduced after rehydration has been achieved. Lactose-free formulas may be needed for patients with severe mucosal damage and secondary lactose intolerance (87), while a small proportion of children, particularly those who are young and malnourished, may be intolerant of all dietary carbohydrates, including monosaccharides (87,88). (d) Food-based ORT (e.g., based on rice powder or other cereals or local staples) can be used to help reduce fecal losses (89-92), although there is no difference between standard WHO ORS solution and rice ORS solution in terms of stool volume or duration of diarrhea (93); these issues are discussed in much more detail elsewhere in this issue in the context of dietary treatment of children with persistent diarrhea in developing countries (94). (e) In children aged 4-6 months who have already been weaned, soft or semisolid foods should be offered as soon as the child is rehydrated, there is no need to withhold or restrict feeding until the diarrhea has stopped. These foods should be mashed or pureed and offered in small amounts at least six times daily. Soft or solid foods should not be introduced to exclusively breast-fed infants who are recovering from diarrhea. (f) Extra food should be given for at least 2 weeks after the diarrhea has stopped, and sufficient dietary energy (calories) should be provided in order for any W/H deficit to be corrected. (g) Attention may be required to correct specific micronutrient deficiencies, e.g., of vitamin A (95-97) or zinc (98).

Drugs have very little role in good treatment of infants and children with acute diarrhea (84), yet they are often used indiscriminately, particularly antimicrobials and so-called antidiarrheal remedies, which may come from pharmaceutical sources but often from unprofessional and unregulated suppliers. In Pakistan, 75% of children with diarrhea were given antibiotics, particularly patients from upper socioeconomic classes (36). There are several reasons why antibiotics should not generally be used in childhood gastroenteritis, including the fact that some episodes (e.g., those caused by viruses) would not respond. Many enteric bacteria are already antibiotic resistant, indiscriminate usage of antibiotics encourages the development of plasmid-transmitted drug resistance, and antibiotic treatment can prolong carriage of some microorganisms, such as Salmonella. Furthermore, antibiotics are expensive and have significant side effects. WHO approves the use of antibiotics only for dysentery and for suspected cholera with severe dehydration (99). For shigellosis, oral therapy for 5 days with the antibiotic recommended in your area is suggested; it might be trimethoprim-sulfamethoxazole, ampicillin, nalidixic acid, norfloxacin, or ciprofloxacin (100). Enteroinvasive E. coli can be treated the same way as shigellosis. Antibiotics are appropriate for the treatment of bacterial infections that can produce bacteremia, such as typhoid fever, for which chloramphenicol or ampicillin can be used (43). Antibiotics are often indicated for other reasons, such as treatment of a coexistent respiratory infection or other serious infection, particularly in young, small, and compromised infants and young children.

Antiparasitic drugs should be used for amebiasis only after antibiotic treatment of bloody diarrhea for shigellosis has failed or if there is microscopic evidence of trophozoites of Entamoeba histolytica with erythrocytes in the feces. It may be reasonable to treat patients with cysts or trophozoites of Giardia intestinalis (G. lamblia), identified by microscopy in stool specimens or upper-intestinal aspirates, because in areas where giardiasis is common, asymptomatic carriage is not unusual. WHO recommends treatment in such patients when diarrhea has lasted ≥ 14 days (83). Children with strongyloidiasis should be treated with thiabendazole in an attempt to eradicate the infection to prevent autoinfection, but this treatment is not always effective, and recurrent courses may be required (101).

Antidiarrheal drugs (such as opiates) and antiemetics should not be used in infants or children; they are not efficacious and can be dangerous. The WHO has produced an excellent booklet on the rational use of drugs in the treatment of acute diarrhea in children (99).

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As many as 3-20% of episodes of acute diarrhea in children in developing countries become persistent, i.e., they last ≥ 14 days (102-105). This category encompasses episodes of presumed infectious diarrhea that have an acute onset and persist for this period of time or longer; it specifically excludes known causes of chronic or recurrent diarrhea, such as tropical sprue, gluten-sensitive enteropathy (celiac disease), other hereditary diarrheal disorders, or blind-loop syndrome (103). With the increasingly successful treatment of patients with acute diarrhea, those episodes that become persistent are assuming greater importance, particularly because they have adverse nutritional consequences and cause about one-third to one-half of all childhood diarrheal deaths, Persistent diarrhea (PD) is reviewed in detail by Bhutta and Hendricks in this issue; they consider the epidemiology and pathogenesis of this condition and give particular attention to nutritional treatment from a developing country perspective.

A cluster of risk factors that predispose infants and children to PD has been identified by WHO (103). Some of them include (a) host factors, such as young age (particularly <12 months), malnutrition, and impaired immune function; (b) environmental factors, among them overcrowding, inadequate hygiene, living in close contact with animals, and fecal-oral transmission of enteric pathogens; (c) previous infections, such as recent acute diarrhea, previous PD, or respiratory tract infection; (d) pre-illness feeding practices, for example, recent introduction of milk; (e) microbial isolates during the acute phase, such as enteroadherent E. coli, Shigella, and multiple pathogens; and (f) drugs usage during acute diarrhea, for example, antimicrobial therapy or antiparasitic drugs.

The etiology and pathogenesis of PD are complex and as Bhutta and Hendricks comment in this issue, multiple interrelated factors, including nutritional status, immune function, and underlying gastrointestinal infections and their consequences all play important roles. Many episodes are likely to be due to undetected or unrecognized enteric pathogens, particularly in poorer parts of the world, where the problem is prevalent and the resources are often not available for sophisticated laboratory investigations. The evidence compellingly gives a key role to enteric infection in the pathogenic mechanisms involved in PD (18,94). Prolonged mucosal damage with incomplete tissue repair associated with impaired intestinal digestion and absorption appear to be common, so much so that I would question the wisdom and usefulness of intestinal biopsy in the treatment of patients with PD (as defined herein) unless there is a clinical suspicion or some other indication to investigate for another underlying condition, such as celiac disease.

Bacterial contamination of the small intestinal contents in infants with enteropathogenic E. coli (EPEC) and other fecal-type microorganisms has been suggested as a causative factor in the pathogenesis of persistent diarrhea (106-109). Bhan et al. (110) found that >50% of Indian infants and children aged ≤2 years with persistent diarrhea had high aerobic bacterial populations (>105 organisms/ml) in their jejunal secretions, with recognized enteric pathogens (including enteroadherent E. coli, enterotoxigenic E. coli, enteropathogenic E. coli, Salmonella, and Giardia) in upper-intestinal aspirates in >20% of patients. In the study by Penny et al. (108), 16 of 40 infants in the acute phase of their diarrheal illnesses had pathologically high numbers (>104 colony-forming bacteria/ml) in their upper-intestinal secretions, and in more than half of the infants infected with EPEC, a fecal-type of flora was found in the duodenum, which, in three-quarters of the affected patients, was the same EPEC serotype isolated from the stools. Infants with persisting diarrhea had significantly more fecal-type organisms in the upper intestine than either those with acute diarrhea or convalescent patients. There was also a significant further increase in Enterobacteriaceae in infants whose persistent diarrhea occurred after infection with EPEC.

Given the complexities of the intestinal microflora and the technical difficulties involved in its investigation and in the documentation of detailed populations of aerobic and strict or facultative anaerobic bacteria, it is not surprising that there have been some inconsistencies between studies cited by Bhutta and Hendricks (94). They also cite the interesting experience of the South African workers who, for years, have used and reported beneficial results from the administration orally of a mixture of gentamicin, metronidazole, and the bilesalt binding resin cholestyramine in infants with severe, persistent diarrhea (111), although the results of this study are difficult to interpret because of its complex design. Their experience suggests that continuing microbial contamination, corrected by antibiotic administration coupled with cholestyramine, is important in PD, but short-term intermittent antibiotic treatment failed to show any consistent, meaningful benefit in terms of growth in Burmese village children (112). Other studies on gentamicin and cholestyramine in the treatment of persistent diarrhea have not confirmed the South African results (113,114).

PD might also be caused by secondary sugar intolerance (87) or intolerance to foreign proteins, such as cow's milk (115), perhaps because of facilitation of sensitization to these substances through altered intestinal permeability associated with mucosal injury (116). These causes need to be recognized promptly so that appropriate dietary therapy can be given to allow nutritional rehabilitation and recovery of intestinal damage. As Bhutta and Hendricks observe (94), PD is a major challenge to pediatricians and their colleagues in terms of nutritional treatment; indeed, chronic or persistent diarrhea in infants and children can be considered “nutritional disease/s” (117). Available options are considered in some detail in the review by Bhutta and Hendricks; of particular interest to pediatricians in developing countries and in primary care contexts are the prospects of affordable, locally produced, and familiar staple diets and multi-mixes in the dietary and nutritional treatment of children during and after PD.

It should also be recognized that infestations with intestinal parasites have become important causes of chronic diarrhea in children who are infected with the human immunodeficiency virus (HIV) or have the acquired immunodeficiency syndrome or are otherwise immunologically compromised. Now that HIV infection is such a massive problem in some developing countries, it presents particularly challenging problems for pediatricians and other health professionals (118).

Diarrheal disease and malnutrition constitute a continuing dual dilemma and challenge for pediatricians and other health workers involved in the care of infants and children, particularly in developing countries and in disadvantaged populations. Factors that contribute to these continuing problems include poverty, overcrowding, environmental contamination, disease vectors, pathogenic microorganisms, inadequate community knowledge about nutrition and hygiene, early cessation of breast-feeding, inappropriate feeding practices, food short-ages, inadequate nutritional treatment of diarrheal episodes, undernutrition, inappropriate usage of drugs or other “remedies,” civil disruption (e.g., through natural disasters or military conflicts).

Clearly, pediatricians are unable to address all these problems, but they should always be prepared to be children's advocates as well as their clinical attendants. Some of the main strategies that need to be addressed in reducing the burden of diarrheal diseases are discussed by Bhutta and Hendricks (94). These strategies include promotion of breast-feeding, hand-washing, control of flies, improved excreta disposal, and community-based hygiene education (16,119). The self-perpetuating cycle of poverty, poor sanitation, inadequate housing, undereducation, and repeated infections and malnutrition is pivotal in the Diarrhea-Malnutrition Syndrome in many parts of the world. Pediatric gastroenterologists, pediatricians, nutritionists, community health workers, and other professionals (e.g., schoolteachers and local government officials) should be at the forefront of efforts to overcome these problems facing infants and children who live in developing populations.

Extensive work has been done over many years to produce vaccines against childhood diarrheal diseases; these vaccines have had mixed success, but there has been important progress made over the past decade in developing vaccines against enteric infections of the greatest public health importance (120). Large-scale trials of rotavirus vaccine have been conducted, and they should soon lead to the availability of vaccines suitable for national programs of child immunization (R.I. Glass, personal communication). The benefits that this and other advances bring to children growing up in developing countries will be awaited eagerly over the years to come.

Pediatricians from the Western world often wonder what they can do to help with the massive problems that we have attempted to address. Becoming more aware of the problems is, in itself, helpful because that can assist in developing dialogue between pediatricians in developed and developing countries. This communication is now being actively facilitated by the establishment of closer links between groups or societies of pediatricians or pediatric gastroenterologists in different regions—Europe, North America, and Asia and the Pacific, to mention just a few areas of increasing professional liaison. Trainee positions, fellowships, and other ways of encouraging pediatricians from developing countries to gain experience in centers of excellence abroad are other useful strategies. Such arrangements can be enhanced if the trainers spend time in the trainees' environments to learn at first hand about the pediatric problems in the region as well as the availability of pediatric resources, while at the same time learning something of the cultural and other characteristics of the area. It is to be hoped that there will be much more collaboration of this type in the future.

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