Sean R. Moore

Malnutrition as an enteric infectious disease with long-term effects on child development

Malnutrition is a major contributor to mortality and is increasingly recognized as a cause of potentially lifelong functional disability. Yet, a rate-limiting step in achieving normal nutrition may be impaired absorptive function due to multiple repeated enteric infections. This is especially problematic in children whose diets are marginal. In malnourished individuals, the infections are even more devastating. This review documents the evidence that intestinal infections lead to malnutrition and that malnutrition worsens intestinal infections. The clinical data presented here derive largely from long-term cohort studies that are supported by controlled animal studies. Also reviewed are the mechanisms by which enteric infections lead to undernutrition and by which malnutrition worsens enteric infections, with implications for potential novel interventions. Further intervention studies are needed to document the relevance of these mechanisms and, most importantly, to interrupt the vicious diarrhea-malnutrition cycle so children may develop their full potential.

Persistent Diarrhea Signals a Critical Period of Increased Diarrhea Burdens and Nutritional Shortfalls: A Prospective Cohort Study among Children in Northeastern Brazil

Persistent diarrhea (PD; duration >/=14 days) is a growing part of the global burden of diarrheal diseases. A 45-month prospective cohort study (with illness, nutritional, and microbiologic surveillance) was conducted in a shantytown in northeastern Brazil, to elucidate the epidemiology, nutritional impact, and causes of PD in early childhood (0-3 years of age). A nested case-control design was used to examine childrens diarrhea burden and nutritional status before and after a first PD illness. PD illnesses accounted for 8% of episodes and 34% of days of diarrhea. First PD illnesses were preceded by a doubling of acute diarrhea burdens, were followed by further 2.6-3.5-fold increased diarrhea burdens for 18 months, and were associated with acute weight shortfalls. Exclusively breast-fed children had 8-fold lower diarrhea rates than did weaned children. PD-associated etiologic agents included Cryptosporidium, Giardia, enteric adenoviruses, and enterotoxigenic Escherichia coli. PD signals growth shortfalls and increased diarrhea burdens; children with PD merit extended support, and the illness warrants further study to elucidate its prevention, treatment, and impact.

Longitudinal Study of Cryptosporidium Infection in Children in Northeastern Brazil

A prospective, 4-year cohort study of children born in an urban slum in northeastern Brazil was undertaken to elucidate the epidemiology of Cryptosporidium infection in an endemic setting, describe factors associated with Cryptosporidium-associated persistent diarrhea, and clarify the importance of copathogens in symptomatic cryptosporidiosis. A total of 1476 episodes of diarrhea, accounting for 7581 days of illness (5.25 episodes/child-year), were recorded: of these, 102 episodes (6.9%) were persistent. Cryptosporidium oocysts were identified in 7.4% of all stools, and they were found more frequently in children with persistent diarrhea (16.5%) than in those with acute (8.4%) or no (4.0%) diarrhea (P<.001). Low-birth-weight children and those living in densely crowded subdivisions were at greater risk for symptomatic infection. Disease course was highly variable and was not associated with the presence of copathogens. Recurrent Cryptosporidium infection and relapsing diarrhea associated with it were moderately common. In light of these data, the applicability of the current World Health Organization diarrheal definitions to Cryptosporidium-associated diarrheal episodes may need to be reconsidered.

Magnitude and Impact of Diarrheal Diseases

Among the increasingly unacceptable costs of the diseases of poverty are the largely unmeasured but potentially huge human and economic long-term costs of common tropical infectious diseases, especially those such as repeated dehydrating and malnourishing diarrheal diseases (and enteric infections, even without overt liquid stools) that are so prevalent in the developmentally critical first year or two of early childhood. We review here the high costs of diseases of poverty, increasing diarrhea morbidity (despite decreasing mortality), and new emerging evidence for long-term consequences of early childhood diarrhea on growth and on physical and cognitive development, effects that may translate into costly impairment of human potential and productivity.

Early childhood diarrhea predicts impaired school performance.

Objective: Diarrhea is a leading cause of mortality worldwide; however, its long-term morbidity is poorly understood. Recently, early childhood diarrhea (ECD) has been associated with impaired physical fitness, growth and cognitive function 6 to 9 years later. We studied the effects of ECD on school functioning in a shantytown in northeastern Brazil. Design: We administered 77 educational surveys. Complete diarrhea surveillance (ie, >90%) in the first 2 years of life and demographic and anthropometric information were available for 73 children. Age at starting school was calculated for 62 children, whereas age appropriateness for the current grade (AFG) was calculated for all 73 children who were >6 years old. Stepwise regression was used to examine the independent effect of ECD on school functioning after controlling for socioeconomic factors, maternal education, breast feeding, growth and cognitive functioning. Results: ECD correlated with age at starting school (r = 0.55, P = 0.0005) and remained a significant predictor even after controlling for family demographics, days of breast feeding, early growth and TONI-3 test of nonverbal intelligence. This was true despite significant correlations of ECD with growth shortfalls and impaired cognitive functioning. ECD also correlated with AFG (r = 0.38, P = 0.001). Only TONI-3 test scores explained this association, suggesting that ECD may hinder school performance, but only in part school readiness, by impairing cognitive function as measured by performance on the TONI-3 nonverbal intelligence test. Conclusions: These findings document effects of early childhood diarrhea on later school readiness and performance and hence potential long-term human and economic costs of ECD, which warrant further attention and far greater investment for the control of ECD and its consequences.

Prolonged Episodes of Acute Diarrhea Reduce Growth and Increase Risk of Persistent Diarrhea in Children

BACKGROUND & AIMS Prolonged episodes of acute diarrhea (ProD; duration 7-13 days) or persistent diarrhea (PD; duration ≥14 days) are important causes of undernutrition, yet the epidemiology and nutritional impact of ProD are poorly understood. METHODS We conducted a 10-year cohort study of 414 children from a Brazilian shantytown who were followed from birth; data were collected on diarrhea, enteric pathogens, and anthropometry. RESULTS During 1276 child-years of observation, we recorded 3257 diarrheal episodes. ProD was twice as common as PD (12% and 5% of episodes, respectively); ProD and PD together accounted for 50% of all days with diarrhea. ProD was more common in infants whose mothers had not completed primary school (relative risk [RR], 2.1; 95% confidence interval: 1.02-2.78). Early weaning was associated with earlier onset of ProD (Spearman ρ = 0.309; P = .005). Infants with ProD were twice as likely to develop PD in later childhood (log rank, P = .002) compared with infants with only acute diarrhea (AD; duration <7 days), even after controlling for confounders. Childrens growth was more severely stunted before their first episode of ProD, compared with AD (mean height-for-age Z score (HAZ) -0.81 vs -0.51, respectively, P < .05, unpaired t test). Following ProD, HAZ (ΔHAZ = -0.232) and weight-for-age (ΔWAZ = -0.26) significantly decreased (P < .005 in paired t tests). ProD was associated with Cryptosporidium and Shigella infections. CONCLUSIONS ProD accounts for significant morbidity and identifies children at risk of a vicious cycle of diarrhea and malnutrition. Further studies are needed to address the recognition and control of ProD and its consequences in resource-limited settings and assess its role in PD pathogenesis.

A longitudinal study of Giardia lamblia infection in north‐east Brazilian children

OBJECTIVE To evaluate the epidemiology of Giardia lamblia infection, investigate factors which might be associated with clinical manifestations and recurrence, and examine the role of copathogens in disease course.

Interactions of diarrhea, pneumonia, and malnutrition in childhood: recent evidence from developing countries

Purpose of review This review highlights recent progress toward understanding complex interactions between diarrhea, pneumonia, and undernutrition among children in low-income and middle-income countries. Recent findings New studies parallel earlier reports that diarrhea and pneumonia impair childrens growth and that underlying malnutrition is a major risk factor for these conditions. Episodes of diarrhea may predispose to pneumonia in undernourished children. Additional studies support breastfeeding and micronutrient supplementation for the prevention and control of diarrhea and pneumonia. Malnutrition may partially account for the reduced efficacy of oral rotavirus vaccines in low-income countries. Immunization of pregnant women against influenza also appears to reduce intrauterine growth retardation. Immunization of infants against Streptococcus pneumoniae may improve their growth. New genetic studies indicate that polymorphisms in apolipoprotein E or the leptin receptor modulate childrens risk for diarrhea and Entamoeba histolytica infection, respectively, thereby linking two genes important for lipid metabolism to enteric infections. Summary Significant advances have been made in understanding the vicious cycle of malnutrition, diarrhea, and pneumonia in developing countries. Future challenges will be to translate this progress into effective and widely accessible public health measures.

Retinol and Retinol-Binding Protein: Gut Integrity and Circulating Immunoglobulins

Vitamin A (retinol) is required to maintain immunity and epithelial turnover and is a key micronutrient needed for combating infection. Vitamin A actions on the immune system are diverse and cannot be accounted for by a single effect or mechanism. The actions of retinol in maintaining gut integrity in humans and immunoglobulin levels in mice was investigated. For 30 children, performance on the lactulose/mannitol test, a test commonly used to assess intestinal barrier function, was inversely correlated (P=.012) with serum retinol concentrations. Thus, children with lower serum retinol, and presumably poorer vitamin A nutritional status, are more likely to have impaired intestinal integrity. Knockout mice that have impairments in plasma retinol transport have circulating immunoglobulin levels that are half those observed in matched wild type mice. No differences were observed in B and T cell populations present in spleen, thymus, and bone marrow.

Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in Northeast Brazil

Critical to the design and assessment of interventions for enteropathy and its developmental consequences in children living in impoverished conditions are non-invasive biomarkers that can detect intestinal damage and predict its effects on growth and development. We therefore assessed fecal, urinary and systemic biomarkers of enteropathy and growth predictors in 375 6–26 month-old children with varying degrees of malnutrition (stunting or wasting) in Northeast Brazil. 301 of these children returned for followup anthropometry after 2-6m. Biomarkers that correlated with stunting included plasma IgA anti-LPS and anti-FliC, zonulin (if >12m old), and intestinal FABP (I-FABP, suggesting prior barrier disruption); and with citrulline, tryptophan and with lower serum amyloid A (SAA) (suggesting impaired defenses). In contrast, subsequent growth was predicted in those with higher fecal MPO or A1AT and also by higher L/M, plasma LPS, I-FABP and SAA (showing intestinal barrier disruption and inflammation). Better growth was predicted in girls with higher plasma citrulline and in boys with higher plasma tryptophan. Interactions were also seen with fecal MPO and neopterin in predicting subsequent growth impairment. Biomarkers clustered into markers of 1) functional intestinal barrier disruption and translocation, 2) structural intestinal barrier disruption and inflammation and 3) systemic inflammation. Principle components pathway analyses also showed that L/M with %L, I-FABP and MPO associate with impaired growth, while also (like MPO) associating with a systemic inflammation cluster of kynurenine, LBP, sCD14, SAA and K/T. Systemic evidence of LPS translocation associated with stunting, while markers of barrier disruption or repair (A1AT and Reg1 with low zonulin) associated with fecal MPO and neopterin. We conclude that key noninvasive biomarkers of intestinal barrier disruption, LPS translocation and of intestinal and systemic inflammation can help elucidate how we recognize, understand, and assess effective interventions for enteropathy and its growth and developmental consequences in children in impoverished settings.