Effect of rotavirus infection and malnutrition on uptake of a dietary antigen in the intestine

Intestinal absorption of ovalbumin (OVA), a dietary macromolecule, was studied in malnourished and normally nourished suckling mice after experimentally induced infection with rotavirus. All mice developed diarrhea within 24 to 48 h postinoculation. The malnourished animals exhibited more severe symptoms and an increased number of rotavirus-containing enterocytes in intestinal sections as compared to well-nourished mice when examined 3 d postinoculation, at the peak of diarrhea. Histopathologic examination revealed villus atrophy and pronounced vacuolization of villus enterocytes in association with malnutrition and rotavirus infection. The combination of malnutrition and viral infection resulted in more severe mucosal damage, including disruption of microvillus borders. After a single oral dose of 100 micrograms OVA at 3 d postinoculation, the concentration of OVA in serum, gastric content, intestinal lavage fluid, and intestinal tissue homogenates was measured at different time intervals. The concentrations of OVA in intestinal tissue were significantly higher in malnourished animals, whereas lower values were found in rotavirus-infected animals. In all mice, OVA was rapidly absorbed and could be consistently detected in the serum within 5 min. OVA levels peaked at 45 to 60 min and then gradually declined. In malnourished infected animals, the uptake of OVA was rapid and resulted in significantly higher serum levels when compared to well nourished or uninfected controls, respectively. The peak uptake of OVA per g body wt was about 4.5 times more in malnourished infected compared to well-nourished infected mice and 2.5 times higher in normally nourished infected animals when compared to uninfected controls. These results indicate that rotavirus infection in association with malnutrition may cause a significant rise in gut permeability to environmental macromolecules.     

An electron microscopic investigation of time-related changes in the intestine of neonatal mice infected with murine rotavirus

Seven-day-old mice were infected orally with murine rotavirus (EDIM) and regions of the gut examined at 24 h intervals up to 7 days by electron microscopy. Structural changes were correlated with data on viral antigen production, thymidine kinase activity, and clinical signs of diarrhea. No pathological changes were detected in the colon. Infection and structural damage were confined to the small intestine, with middle regions showing the most pronounced changes. Constriction of villus bases, edema of the lamina propria, and vacuolation of enterocytes occurred at 24 h postinfection (PI), i.e., before evidence of major virus replication. Transient villus atrophy occurred at 48 h PI. Recovery of villus length was evident by 72 h PI accompanied by evidence of marked enterocyte replication at villus bases. Many enterocytes were damaged with little evidence for the presence of virus particles. By 96 h PI, villi had almost recovered from infection although some enterocytes were still damaged; no virus particles were detected in these cells. A second phase of villus damage and edema of the lamina propria occurred at 120 h PI; the pathology resembled that at 24-48 h PI. By 144 to 168 h PI, recovery of the mucosa from infection was virtually complete. We suggest that many of the pathological features following rotavirus infection result from rotavirus-induced ischemia of villi and that diarrhea results from malabsorption of fluid by damaged villi and hypersecretion of ions released from increased numbers of dividing cells at villus-crypt borders.     

Diminished polymorphonuclear leukocyte adherence and chemotaxis following protein-calorie malnutrition in newborn rats

Recent advances in neonatal care have permitted the survival of very low birth weight infants who are difficult to nourish, and ultimately develop clinical and biochemical signs of malnutrition. These infants may be at greater risk for nosocomial infection than normally nourished hosts. We have compared neutrophil adherence and chemotactic responses in a newborn rat model of protein-calorie malnutrition. Wistar rats at 14 days gestation received either a normal (24% protein) or isocaloric (2.5% protein) diet. On day 5, rat pups were divided into three groups: pups allowed to nurse on their own dam (normal); normally nourished pups foster nursed onto a malnourished mother (depleted); or malnourished pups foster nursed to a normal dam (repleted). Granulocytes from depleted pups demonstrated significantly diminished adherence and chemotaxis when compared to normal or repleted pups. Thus, abnormalities of neutrophil function in malnourished newborn rats may contribute to increased susceptibility to bacterial infection.     

Acute gastroenteritis: clinical features according to etiologic agents

The clinical manifestations in 595 children hospitalized with gastroenteritis during a 15-month time frame were studied. They were divided into eight groups according to etiologic agent: rotavirus (203 patients); Salmonellae (98); Escherichia coli (55); Campylobacter (36); Shigella (22); combined rotavirus and salmonellae (44); combined rotavirus and other bacteria (26); and no pathogen (111). The mean duration of diarrhea was shortest in the rotavirus and "no pathogen" groups (4.8 and 5.6 days, respectively) and longest with pure and mixed salmonella infections (12.3 and 12.9 days, respectively). Associated manifestations were most frequent with salmonellae and least frequent with rotavirus and E. coli infections. Malnutrition also was most common with salmonellae and lowest with rotavirus and E. coli. There were no differences in the frequency of hypernatremia. Hyponatremia was most frequently encountered with salmonella (25% compared to 9% in the rest of the patients). Evidence of septicemia was found in 22 patients, 21 of whom were in the salmonella groups. The four deaths in this series (0.7%) also were in the salmonellae groups. The clinical severity of salmonella infection in developing countries, particularly in young and malnourished children, warrants attention to more intensive management. The selective use of antibiotics may help reduce the mortality and morbidity of gastroenteritis.     

Disaccharidase activities in small intestine of rotavirus-infected suckling mice: a histochemical study

A histochemical study of the time course of the appearance and location of lactase and alpha-glucosidase (used to detect sucrase and maltase) activities was carried out on control and rotavirus-infected mice from 7 to 14 days old. The overall pattern of enzyme activity was in agreement with previous quantitative studies on the activities of these enzymes. No evidence was obtained to support the idea that lactase deficiency was the result of repopulation of villi (denuded of lactase-producing villus cells) with immature lactase-negative cells. Low lactase activity was more likely to reflect profound changes in metabolically crippled cells, and recovery of lactase activity with recovery of normal metabolic functions. The location of enzyme activity to brush border regions rather than the cytoplasm of villus enterocytes enhances the significance of previous quantitative studies on these enzymes. The timing and duration of diminished lactase activities were such that they were unlikely to cause the induction or perpetuation of diarrhea in murine rotavirus diarrhea. The appearance in infected animals of alpha-glucosidase 3 days earlier than normal indicates that, in addition to reversible changes seen with lactase, developmental changes were accelerated that affected both crypt and villus cells.     

The effect of intrauterine malnutrition on the term infant. A 14-year progressive study

The developmental outcome of 33 newborn infants with clinical intrauterine malnutrition at birth and 13 clinically well nourished infants from a middle to high socio-economic population have been followed from birth to 12-14 years of age. Psychometric studies revealed a lowering of the IQ score in malnourished infants compared to well nourished infants (104 +/- 15 compared to 121 +/- 13, p less than 0.05) and a need for special education (p less than 0.03). Forty-five percent of the malnourished infants' birth weights were above the 10th percentile on the Colorado Intrauterine Growth Grid. The Full Scale IQ of malnourished infants with BW greater and less than 10th percentile on the Colorado Intrauterine Growth Grid were comparable. Malnourished infants with birth weights greater than 10th percentile had lower IQ scores than well nourished infants (101 +/- 13 compared to 121 +/- 13, p less than 0.006). Thirty-nine percent of the infants with handicaps would have been missed if only infants with birth weights less than 10th percentile were considered high risk.     

THE COLOSTRUM-DEPRIVED, ARTIFICIALLY REARED NEONATAL PIG AS A MODEL ANIMAL FOR STUDYING ROTAVIRUS GASTROENTERITIS

Rotavirus gastroenteritis is one of the main causes of acute diarrhea in young humans and animals worldwide. The colostrum-deprived, artificially reared neonatal pig has been extensively used in our laboratory as a model animal for studying an experimentally induced rotaviral gastroenteritis. Details on procurement of newborn pigs, immunologic characteristics, and artificial rearing conditions of colostrum deprived neonatal pigs as well as on rotavirus inoculation, clinical manifestations, and evaluation of intestinal damage caused by rotavirus infection are described. Our experimentally induced rotavirus gastroenteritis model has been characterized clinically by anorexia, diarrhea, occasional vomiting, and high titers of rotavirus shedding in feces. Data reported here provide additional information, particularly on feeding regimens of pigs before rotavirus inoculation, extent of anorexia, severity of diarrhea, and extent of fecal virus shedding, as well as on the effect of rotavirus infection and size of rotavirus inocula on intestinal damage, growth, and mortality during the postinfection period. On the basis of these results and others previously reported by us and by other researchers, and because of the intestinal anatomy and physiology similarities to that of human infants, the colostrum-deprived, artificially reared neonatal pig is the most suitable and useful model animal for studies designed to evaluate prevention and treatment of rotaviral gastroenteritis.     

Extraintestinal rotavirus infections in children with immunodeficiency.

Some rotavirus strains, including vaccine candidates, have been demonstrated to cause hepatitis in immunodeficient and malnourished mice and to grow in human liver cells. To determine whether rotavirus spreads outside the intestine in naturally infected children, we examined tissues from four immunodeficient children affected with severe combined immunodeficiency disease, acquired immunodeficiency disease syndrome, or DiGeorge syndrome. Chronic rotavirus-related diarrhea, which persisted until death, had also developed in each child. Using indirect immunoperoxidase techniques, we identified rotavirus antigen in the liver and kidney with a hyperimmune guinea pig antiserum prepared to double-shelled rotavirus particles. Similar immunostaining with an antiserum to a rotavirus nonstructural protein (NS26) provided evidence of active virus replication. The observed reactivity was eliminated specifically when serial sections were immunostained with the same antiserum that had been absorbed with either double-shelled rotavirus particles or NS26. Immunostaining was not observed in the liver of children with other diseases (alpha 1-antitrypsin deficiency, inspissated bile syndrome, and acute rejection of a transplanted liver). These findings demonstrate that rotavirus infections in children can extend beyond the intestinal tract. Further studies are warranted to determine whether extraintestinal rotavirus replication occurs in children without severe immunodeficiency, such as malnourished children.     

The Effect of Intrauterine Malnutrition on the Term Infant

The developmental outcome of 33 newborn infants with clinical intrauterine malnutrition at birth and 13 clinically well nourished infants from a middle to high socio-economic population have been followed from birth to 12–14 years of age. Psychometric studies revealed a lowering of the IQ score in malnourished infants compared to well nourished infants (104 ± 15 compared to 121 ± 13, p < 0.05) and a need for special education ( p < 0.03). Forty-five percent of the malnourished infants'birth weights were above the 10th percentile on the Colorado Intrauterine Growth Grid. The Full Scale IQ of malnourished infants with BW greater and less than 10th percentile on the Colorado Intrauterine Growth Grid were comparable. Malnourished infants with birth weights > 10th percentile had lower IQ scores than well nourished infants (101 ± 13 compared to 121 ± 13, p < 0.006). Thirty-nine percent of the infants with handicaps would have been missed if only infants with birth weights < 10th percentile were considered high risk.     

Rotavirus diarrhea in Jewish and Bedouin children in the Negev region of Israel: epidemiology, clinical aspects and possible role of malnutrition in severity of illness

We conducted a 1-year prospective study in the Negev region of southern Israel to determine the epidemiologic and clinical patterns of rotavirus diarrhea. A total of 605 patients were studied, 392 Bedouins and 213 Jews, 441 of whom had diarrhea (449 episodes) and 164 did not. Rotavirus was the most common organism detected in children with diarrhea (63 of 444; 14%) but was rarely found in controls (3 of 163; 2%) (P less than 0.001). In 22% (12 of 54) of the rotavirus-positive patients, at least one other organism was also detected. The rate of rotavirus detection decreased as age increased, from 18% in the first year to 8% in the third year of life. Hospitalization with rotavirus diarrhea occurred more frequently in the summer. However, during winter, when diarrhea was less prevalent in the community, the proportion of cases associated with rotavirus was higher. Compared with controls, malnourished children were more likely to be hospitalized. However, rotavirus was detected in similar proportions among well-nourished and malnourished cases with diarrhea. The most prevalent rotavirus serotype was type 1 (in 69%), followed by types 4 and 2 (18 and 13%, respectively). We estimated that during the study period, approximately 2% of all Bedouin infants vs. only 0.2% of Jewish infants were hospitalized with rotavirus disease in their first year of life. Clinical signs and symptoms and stool appearance were not useful in predicting rotavirus detection. Malnutrition seems to be an important indicator of disease severity, which may explain why the toll of rotavirus-associated morbidity and mortality is particularly high among children in developing countries.     

Intestinal permeability assessed with polyethylene glycols in children with diarrhea due to rotavirus and common bacterial pathogens in a developing community

Intestinal permeability was assessed with different-sized polyethylene glycols (PEG 400 and PEG 1,000) in small children with acute diarrhea. All children with acute diarrhea absorbed and excreted less PEG of all molecular sizes into the urine when compared with healthy control children (p less than 0.001). Children with acute rotavirus infection excreted significantly less PEG of all sizes than children with Shigella, Salmonella, and enteropathogenic Escherichia coli (EPEC) infection (p less than 0.001-0.01), suggesting a more severe mucosal lesion caused by rotavirus. In patients with severe malnutrition there was also a significant decrease in absorption of PEGs observed. In addition, malnourished patients with rotavirus diarrhea showed a pronounced decrease of PEGs in comparison with well-nourished patients. The ratio between the recovery of a large PEG molecule, 1,074 Da, and a small molecule, 370 Da, was utilized to assess the absorption of large molecules in relation to that of smaller ones. On applying this ratio, it was noted that the intestine in children with Shigella and EPEC infection was relatively more permeable to larger molecules than in healthy controls, while in rotavirus and Salmonella infection it was less permeable to larger molecules. In this study significant differences in the permeability characteristics were observed, suggesting etiology-specific effects on the mucosal barrier.     

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目的通过分子流行病学调查研究兰州地区婴幼儿病毒性腹泻的病原学特点。方法采用酶联免疫吸附试验(ELISA)及逆转录聚合酶链反应(RTPCR),对2003年7月至2004年6月兰州地区收集的624例婴幼儿腹泻粪便标本随机抽取271例进行轮状病毒(RV)、杯状病毒(HuCV)及星状病毒(AstV)检测。结果在271例标本中共检出RV感染153例(56.46%),其中G394例(61.44%),G24例(2.61%),G93例(1.96%),未发现G1、G4型和混合感染;在随机抽取的69例G分型阳性标本中,检出P[8]型28例(40.58%);RV的感染对象主要为6～23月龄的婴幼儿,发病高峰在10、11月份(86.27%、73.81%)。在118例RVELISA阴性标本中检出HuCV感染13例(11.02%),其中诺如病毒(NLV)GⅡ型11例,札如病毒(SLV)2例,未检出NLVGⅡ型,发病年龄1～18个月(11.31±4.53个月);同时检出AstV感染7例(5.93%),发病年龄4～12个月(8.27±2.69)个月,其中有1例合并有SLV感染,另有1例为迁延性腹泻。HuCV和AstV感染均未表现出明显的季节性。结论RV是兰州婴幼儿病毒性腹泻的主要病原,其流行的主要血清型为G3型,HuCV和AstV亦是重要病原之一。     

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目的了解天津地区腹泻患儿星状病毒感染的临床与流行病学特点。方法以酶联免疫吸附法检测腹泻患儿粪便中星状病毒抗原以及轮状病毒抗原。结果2003年天津市儿童医院344例住院腹泻患儿中,星状病毒抗原检出率16.6%(57/344),同时合并轮状病毒感染者9.9%(34/344),发病年龄集中于1个月至2岁,感染多发生于冬季,临床症状与轮状病毒感染相似,预后良好。结论星状病毒感染可能是天津等中国北方地区儿童腹泻的重要病因之一,开展病原学检测有助于避免滥用抗生素及预防暴发流行。     

Rotavirus in Ireland: national estimates of disease burden, 1997 to 1998

BACKGROUND: We estimated the disease burden caused by rotavirus hospitalizations in the Republic of Ireland by using national data on the number of hospitalizations for diarrhea in children and laboratory surveillance of confirmed rotavirus detections. METHODS: We examined trends in diarrheal hospitalizations among children <5 years old as coded by ICD-9-CM for the period January, 1997, to December, 1998. We collated data on laboratory-confirmed rotavirus detections nationally for the same period among children <2 years old. We calculated the overall contribution of rotavirus to laboratory-confirmed intestinal disease in children <5 years old from INFOSCAN, a disease bulletin for one-third of the population. We compared data from all sources and estimated the proportion of diarrheal hospitalizations that are likely the result of rotavirus in children <5 years old. RESULTS: In children <5 years old, 9% of all hospitalizations are for diarrheal illness. In this age group 1 in 8 are hospitalized for a diarrheal illness, and 1 in 17 are hospitalized for rotavirus by 5 years of age. In hospitalized children <2 years old, 1 in 38 have a laboratory confirmed rotavirus infection. CONCLUSIONS: The disease burden of rotavirus hospitalizations is higher than in other industrialized countries. Access to comprehensive national databases may have contributed to the high hospitalization rates, as well as a greater tendency to hospitalize children with diarrhea in Ireland.     

轮状病毒感染对新生大鼠肠上皮屏障的影响

目的探讨轮状病毒感染对大鼠肠上皮屏障的影响。方法 7日龄清洁级SD大鼠30只,随机分为对照组和轮状病毒感染组,每组15只,予以人工喂养。轮状病毒感染组在喂养的第4天(即10日龄)给予轮状病毒1×106PFU灌胃,观察其腹泻病程,并分别于感染后第1、4、7天处死,采集血液及小肠组织,观测肠黏膜形态,检测血浆D-乳酸、肠道黏蛋白mucin2、细胞间连接蛋白claudin-1表达量及肠上皮细胞凋亡。结果轮状病毒感染组较对照组大鼠的D-乳酸水平升高,以感染后第4天最显著,在第1、4、7天的差异均有统计学意义(P均<0.01);轮状病毒感染组较对照组mucin2表达量在感染后第1天增多(P<0.05),感染后第4天减少(P<0.05),第7天两组无差异(P>0.05);轮状病毒感染组较对照组claudin-1表达量在感染后第1天无差异(P>0.05),感染后第4天及第7天增加(P<0.05),以第4天最显著;轮状病毒感染组较对照组感染后第4天肠上皮细胞凋亡明显增加。结论轮状病毒感染性腹泻可能与肠上皮屏障受损有关。     

Randomized, placebo-controlled, clinical trial of hyperimmunized chicken egg yolk immunoglobulin in children with rotavirus diarrhea

BACKGROUND: Hyperimmunized bovine colostrum containing antibodies has been shown to be effective in the treatment of rotavirus diarrhea. Antibodies derived from eggs of immunized hens may be a less expensive and more practical alternative. In this study, children with proven rotavirus diarrhea were treated with immunoglobulin extracted from eggs of chicken immunized with human rotavirus strains. METHODS: In a randomized, double-blind study, 79 children with known rotavirus diarrhea were assigned to receive either 10 g hyperimmune egg yolk (HEY) daily in four equally divided doses for 4 days (HEY group) or a similar preparation obtained from nonimmunized chicken (placebo group). The daily stool frequency and amount, oral rehydration solution iORS) intake, and presence of rotavirus in the stool were monitored for 4 days. RESULTS: In the HEY-treated group, there was significant reduction in stool output (in grams per kilogram per day; HEY vs. placebo; 87+/-59 vs. 120+/-75, P = 0.03), and significant reduction of ORS intake (in milliliters per kilogram per day) (HEY vs. placebo; 84+/-46 vs. 122+/-72, P = 0.008) on day 1 and clearance of virus on day 4 (HEY vs. placebo; 73% vs. 46%, P = 0.02). There was, however, no difference in diarrheal duration between the groups. CONCLUSIONS: Treatment with HEY against four human rotavirus strains resulted in modest improvement of diarrhea associated with earlier clearance of rotavirus from stools. These results indicate an encouraging role of HEY in the treatment of rotavirus-induced diarrhea in children. Further studies are needed to optimize the dose and neutralization titer and thus improve the efficacy of egg yolk immunoglobulin IgY derived from immunized hens.     

Severity of rotavirus infection in relation to serotype, monotype and electropherotype

The aim of this study was to determine whether the severity of symptoms associated with rotavirus infection was related to the serotype of the infecting virus. Severity of clinical symptoms in 108 children admitted to hospital for treatment of rotavirus diarrhoea was retrospectively assessed using a scoring system for frequency and duration of vomiting and diarrhoea, degree of fever, acidosis and dehydration, and presence of electrolyte imbalance. Children were 6-30 months old and were fully weaned at onset of symptoms prior to admission to hospital. No other enteric pathogens were detected during the course of the illness. Serotypes and monotypes were identified using a panel of monoclonal antibodies. Gel electrophoresis of rotavirus RNA was performed to determine electropherotypes. Children surveyed were infected with serotype 1 (47), serotype 2 (15) or serotype 4 (46) rotaviruses. Comparisons of severity of clinical symptoms according to infecting serotype revealed no statistically significant differences between serotype 1, 2 or 4 infections. In addition, no differences were detected between different rotavirus strains within each serotype (as judged by electropherotype) including monotypes 1a or 1c. This study failed to reveal differences in virulence between rotavirus strains of different VP7 serotypes infecting young children.     

Effects of early malnutrition and nutritional rehabilitation in rats

OBJECTIVE: To verify the effects of malnutrition and nutritional rehabilitation regarding seizure threshold, body weight and brain weight in rats. METHODS: Pregnant Wistar rats and their pups were used. Part of the rat pups were submitted to a malnutrition protocol and the rest served as nourished controls. At P15, malnourished and control rats were submitted to status epilepticus induced by flurothyl; and the rehabilitation period started after recovery from seizures. At P30, all rats were submitted to single flurothyl-induced seizures and the threshold was determined. After the seizures, the rats were sacrificed, the brain removed and weighed. Rat pups were weighed daily from age P2 to P30. RESULTS: Significant differences as to body weight between malnourished and nourished rats were observed from P5 onwards. At P30, even after nutritional rehabilitation, there were still differences in terms of body weight. Nourished (mean 1.47 g -/+ 0.17) and male (mean 1.47 g -/+ 0.16) rats had brain weight slightly higher than that presented by malnourished (mean 1.42 g -/+ 0.17) and female (mean 1.38 g -/+ 0.12) rats; however, the difference was not significant. Differences observed in the threshold for the first clonic and tonic seizure at ages P15 and P30 between the groups were not statistically significant. CONCLUSIONS: Our results suggest that malnutrition does not influence seizure threshold in rat pups submitted to flurothyl-induced seizures. Early nutritional rehabilitation seems to have a protective effect on seizure threshold in previously malnourished animals.     

Chronic rotavirus infection in immunodeficiency

The characteristics of rotavirus infection in 23 children with a variety of primary immunodeficiency diseases were studied. Stools and sera were tested for rotavirus by means of the enzyme-linked immunosorbent assay and the enzyme-linked fluorescent assay, respectively. Four immunodeficient patients had diarrhea during the study period and all had rotavirus infection; rotavirus was not detected in the stools of the 19 asymptomatic immunodeficient patients. Forty-six control children with diarrhea were tested and 22 had rotavirus infection; rotavirus was not detected in 39 asymptomatic control children. One immunodeficient patient with X-linked agammaglobulinemia and one with severe combined immunodeficiency had chronic, symptomatic rotavirus infection with rotavirus excretion lasting more than six weeks. The other two immunodeficient patients and eight control children eliminated the rotavirus from their stools in periods ranging from two to 12 days. Rotavirus antigen was detected in the sera of three of the four immunodeficient patients; none of the 14 control infants tested had rotavirus antigen detected in their sera. This study indicates that rotavirus may produce a chronic infection in immunodeficient children.     

Vitamin A supplements and diarrheal and respiratory tract infections among children in Dar es Salaam, Tanzania

OBJECTIVE: To determine the effect of vitamin A supplementation on the risk of diarrhea and of acute respiratory infection. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Dar-es-Salaam, Tanzania. SUBJECTS: Six hundred eighty-seven children, 6 to 60 months old, hospitalized with pneumonia, who received vitamin A or placebo at baseline and at 4 and 8 months after discharge from hospital.Main outcome variables: Incidence and duration of episodes of diarrhea and respiratory tract infections during the year after discharge from the hospital. RESULTS: Relative to those receiving placebo, children receiving vitamin A had a significantly smaller risk of severe watery diarrhea (multivariate odds ratio = 0.56, 95% CI = 0.32-0.99, P =.04) but a higher risk of cough and rapid respiratory rate (multivariate odds ratio = 1.67, 95% CI = 1.17-2.36, P =.004). Vitamin A supplementation was also associated with increased risk of acute diarrhea among normally nourished children or children with stunted growth but was relatively protective among children with wasting disease (P value for interaction =.01). The apparently increased risk of respiratory tract infection was limited to children who were seronegative for human immunodeficiency virus (HIV) (P value for interaction =.07). CONCLUSIONS: Vitamin A supplements provide a low-cost intervention against morbidity in HIV-infected and undernourished children. Supplements may also have serious non-lethal adverse outcomes in well-nourished individuals. Whether these apparent detrimental effects of vitamin A are transient or long-term needs to be examined.