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Role of Food Antigen Elimination in Treating Children With Persistent Diarrhea and Malnutrition in Zambia

2002; Lippincott Williams & Wilkins; Volume: 34; Linguagem: Inglês

10.1097/00005176-200205001-00013

1536-4801

Beatrice Amadi,

Food Security and Health in Diverse Populations

Diarrhea continues to be a leading cause of morbidity and mortality in developing countries (1). Oral rehydration therapy has successfully decreased deaths related to acute diarrhea. Despite improved survival, the overall incidence of diarrheal disease has not decreased. In developing countries, up to 30% of admissions are because of diarrhea (2). In Zambia, diarrhea and malnutrition are significant contributors to childhood morbidity and mortality. According to the Zambia Demographic and Health Survey (ZDHS) of 1996, children younger than 5 years of age comprise 20% of the population (population of Zambia, 8.5 million). The mortality rate for children younger than 5 years is 191 deaths for each 1,000 live births, and infant mortality is 109 deaths per 1,000 live births. Of children younger than 5 years, 42% are stunted compared with an international reference population (National Center for Health Statistics), indicating chronic malnutrition (3). Diarrhea and malnutrition are among the top five reasons for admission to the pediatric unit at the University Teaching Hospital (UTH) in Lusaka, and together diarrhea and malnutrition are responsible for 40% of the deaths in children younger than 5 years. The human immunodeficiency virus (HIV) epidemic has reached a critical phase in Zambia and is having a major impact on child health services. The number of children infected with HIV is increasing dramatically. Approximately 30% of pediatric admissions to the UTH are HIV related. Diarrheal disease and malnutrition are common in children with AIDS, and this contributes to the high mortality figures recorded by the ZDHS. Acute diarrhea is associated with significant structural and functional damage to the small intestinal mucosa, as shown in postmortem (4) and biopsy studies (5). Recovery of the mucosa after diarrhea is usually complete (5). However, in some children, recovery may be delayed, and prolonged abnormality of the small intestinal mucosa results in persistent diarrhea (defined as diarrhea lasting 14 days or more and of presumed infectious origin) (6) and is usually associated with malnutrition. This prolonged abnormality of the small intestinal mucosa is referred to as postenteritis enteropathy (7) and may result from either 1) persistent infection or reinfection (infective enteropathy) or 2) sensitization to food antigens, of which cow milk–sensitive enteropathy is the clearest example. Other foods that may be implicated include wheat and soy (7,8). Many factors are involved in causing persistent diarrhea and malnutrition, which may be defined as a syndrome associated with systemic and intestinal infections on a background of protein and calorie depletion. A strong association can be found with micronutrient deficiencies, immune dysfunction, and complex metabolic disturbances. The current management of persistent diarrhea and malnutrition at UTH follows World Health Organization (WHO) guidelines (9) (Table 1). The children are fed a skimmed milk–based liquid diet, a 100 kcal/100 mL feed made by adding sugar and oil to skimmed milk. This is then followed by a soy-based porridge, high energy and protein supplement (HEPS) (400 kcal/100 mL). The children are usually fed by cup and spoon, or if unable to take oral feeds, by nasogastric tube in the form of a milk drip. Fermented milk is used for children with suspected lactose intolerance, that is, children who passed increased watery stool while on the skimmed milk diet. When available, vitamins and mineral supplements are given. Antibiotic therapy is often necessary because these children have severe infections (e.g., septicemia, pneumonia, etc). Because malaria is endemic in Zambia, antimalarials are given. Finally, there is emphasis on oral rehydration, whether by cup and spoon or by nasogastric tube in the form of a drip. If intravenous fluids are necessary (in the case of severe dehydration and shock), they are given for shorter periods of 4 to 6 hours, with close monitoring and a change to the oral route as soon as improvement is noted.TABLE 1: Current management of PDM in ZambiaMETHODS Rationale We set out to test the hypothesis that the postenteritis enteropathy associated with cow milk–protein allergy may play a role in prolonging and exacerbating persistent diarrhea and malnutrition in some of these children. A cow milk–based diet may fail to correct the abnormality because it provides continued antigenic stimulation and will perpetuate the small intestinal mucosal damage. Up to 30% of children who are sensitized to cow milk develop sensitization to soy; therefore, a soy-based diet may be as harmful as a cow milk diet. Because of this, we decided to carry out an open, randomized study to compare outcome with either the standard diet for persistent diarrhea and malnutrition or an amino acid–based elemental feed (Neocate, SHS International Ltd., UK) that excluded cow milk, soy, and cereal antigens. Study Setting The study was performed in the malnutrition ward in the pediatric department at UTH, Lusaka. The ward has 61 beds/cots. All severely malnourished children, aged 6 months to 5 years, are admitted to this ward. During the peak season, as many as 150 children are admitted, and bed sharing is unavoidable. During off-peak periods, there are usually between 30 and 55 patients. Mothers or caregivers are usually present and sit by the bedside throughout the day and night. Study Design This was a controlled trial in which children were randomized to receive 4 weeks of nutritional therapy with either standard skimmed milk / soy diet (control group) or Neocate (Neocate group). The randomization occurred after a child had been recruited to the study by opening the next in a series of sealed envelopes. The 4-week treatment period was selected because children normally stay on the ward for 2 to 4 weeks. After obtaining signed parental or caretaker consent, an initial assessment was performed that included a full history of the illness and a physical examination with anthropometric measurement of nutritional status (weight, height, mid–upper arm circumference). Malnutrition was defined using the Wellcome classification as underweight, kwashiorkor, marasmus, or marasmic-kwashiorkor. Children with measles, chicken pox, neurologic disorders (e.g., cerebral palsy), and those exclusively breast-fed were excluded. Each child was assessed for the presence or absence of systemic infection (pneumonia, septicemia, meningitis, malaria, and tuberculosis), and dehydration. Tuberculosis was diagnosed using gastric lavage for acid-fast bacilli and chest radiography. Some children were given antituberculous chemotherapy on clinical grounds, usually after failure to respond to antibiotic therapy for pneumonia. Blood culture, full blood count, and blood biochemistry tests were performed. Intestinal infection was diagnosed by examination of three stool samples, submitted for parasitologic and bacteriologic analysis. Anonymous, retrospective HIV testing with counseling for separate tests if clinically required was performed. The patients were monitored closely during the study. Daily stool and feed charts were maintained and fluid balance determined. Children were weighed three times each week throughout the study, and all initial investigations (except chest radiography and HIV testing) were repeated at the end of 4 weeks. Endpoints of the study included weight gain, diarrhea, activity, developmental milestones, and mortality. The Research Ethics Committee of the University of Zambia gave approval for the study. RESULTS During a period of 2 years (April 1998 to May 2000), 200 children aged 6 to 24 months were recruited into the study. The treatment groups were well matched in terms of sex, age, and diagnosis with regard to nutritional status, HIV, tuberculosis, and initial pathogens isolated, with no statistically significant differences between them (Table 2). Children were also well matched in terms of weight-for-age z scores.TABLE 2: Baseline patient characteristicsA total of 155 patients completed the 4 weeks of treatment; 39 died, 3 withdrew because the mothers were needed at home, and 3 were discharged prematurely during an outbreak of cholera that temporarily disrupted the study. The children fed Neocate experienced significantly greater improvement in weight gain (Table 3). This was true in both the Neocate group as a whole (P = 0.002) and in both HIV-positive (P = 0.007) and HIV-negative (P = 0.01) children. Hemoglobin concentration also increased to a significantly greater extent in the Neocate group (Table 3). For all other endpoints assessed (serum albumin concentration, diarrhea, activity, and developmental milestones), both groups experienced equal improvements.TABLE 3: Median (interquartile range [IQR]) gain in weight-for-age z scores and haemoglobinMortality at 4 weeks was similar in the Neocate and control groups (22% versus 17% respectively, P = 0.48). However, there was a significant correlation between mortality and severity of initial diagnosis in terms of nutritional status and being HIV positive (Table 4).TABLE 4: Nutritional and HIV status and mortalityAmong the various pathogens isolated, Cryptosporidium parvum was significantly associated with mortality. Although both types of feed were generally well tolerated, some of the children receiving skimmed milk and some receiving Neocate had osmotic diarrhea. In the Neocate group, glucose polymers in the feed probably caused this diarrhea. CONCLUSIONS Neocate given exclusively for 4 weeks in children with persistent diarrhea and malnutrition was associated with a 41% better gain in weight and a significantly greater increase in hemoglobin concentration. The benefit in weight gain was seen in children who were HIV seropositive and in those who were seronegative. These positive results were seen despite a high prevalence of intestinal and systemic infection. Further research is required to determine whether better treatment of intestinal infections (e.g., cryptosporidiosis) would result in a better outcome and whether improved management of the osmotic impact of glucose polymers would lead to earlier resolution of the diarrhea.