Bernard Chasekwa

Stunting is characterized by chronic inflammation in Zimbabwean infants.

Background Stunting affects one-third of children in developing countries, but the causes remain unclear. We hypothesized that enteropathy leads to low-grade inflammation, which suppresses the growth hormone-IGF axis and mediates stunting. Methods We conducted a case-control study of 202 HIV-unexposed Zimbabwean infants who were stunted (height-for-age Z-score (HAZ) <−2; cases) or non-stunted (HAZ >−0.5; controls) at 18 months. We measured biomarkers of intestinal damage (I-FABP), inflammation (CRP, AGP, IL-6) and growth hormone-IGF axis (IGF-1, IGFBP3) in infant plasma at 6 weeks and 3, 6, 12 and 18 months, and in paired maternal-infant plasma at birth. Adjusted mean differences between biomarkers were estimated using regression models. Multivariate odds ratios of stunting were estimated by logistic regression. Results At birth, cases were shorter (median (IQR) HAZ −1.00 (−1.53, −0.08) vs 0.03 (−0.57, 0.62,); P<0.001) than controls and their mothers had lower levels of IGF-1 (adjusted mean difference (95%CI) −21.4 (−39.8, −3.1) ng/mL). From 6 weeks to 12 months of age, levels of CRP and AGP were consistently higher and IGF-1 and IGFBP3 lower in cases versus controls; IGF-1 correlated inversely with inflammatory markers at all time-points. I-FABP increased between 3–12 months, indicating extensive intestinal damage during infancy, which was similar in cases and controls. In multivariate analysis, higher log10 levels of CRP (aOR 3.06 (95%CI 1.34, 6.99); P = 0.008) and AGP (aOR 7.87 (95%CI 0.74, 83.74); P = 0.087) during infancy were associated with stunting. There were no associations between levels of I-FABP, IL-6, sCD14 or EndoCAb and stunting. Conclusions Stunting began in utero and was associated with low maternal IGF-1 levels at birth. Inflammatory markers were higher in cases than controls from 6 weeks of age and were associated with lower levels of IGF-1 throughout infancy. Higher levels of CRP and AGP during infancy were associated with stunting. These findings suggest that an extensive enteropathy occurs during infancy and that low-grade chronic inflammation may impair infant growth.

Formative Research on Hygiene Behaviors and Geophagy among Infants and Young Children and Implications of Exposure to Fecal Bacteria

We conducted direct observation of 23 caregiver–infant pairs for 130 hours and recorded wash-related behaviors to identify pathways of fecal–oral transmission of bacteria among infants. In addition to testing fingers, food, and drinking water of infants, three infants actively ingested 11.3 ± 9.2 (mean ± SD) handfuls of soil and two ingested chicken feces 2 ± 1.4 times in 6 hours. Hand washing with soap was not common and drinking water was contaminated with Escherichia coli in half (12 of 22) of the households. A one-year-old infant ingesting 1 gram of chicken feces in a day and 20 grams of soil from a laundry area of the kitchen yard would consume 4,700,000–23,000,000 and 440–4,240 E. coli, respectively, from these sources. Besides standard wash and nutrition interventions, infants in low-income communities should be protected from exploratory ingestion of chicken feces, soil, and geophagia for optimal child health and growth.

Complementary feeding messages that target cultural barriers enhance both the use of lipid-based nutrient supplements and underlying feeding practices to improve infant diets in rural Zimbabwe.

Supplementation with lipid-based nutrient supplements (LiNS) is promoted as an approach to prevent child undernutrition and growth faltering. Previous LiNS studies have not tested the effects of improving the underlying diet prior to providing LiNS. Formative research was conducted in rural Zimbabwe to develop feeding messages to improve complementary feeding with and without LiNS. Two rounds of Trials of Improved Practices were conducted with mothers of infants aged 6-12 months to assess the feasibility of improving infant diets using (1) only locally available resources and (2) locally available resources plus 20 g of LiNS as Nutributter®/day. Common feeding problems were poor dietary diversity and low energy density. Popular improved practices were to process locally available foods so that infants could swallow them and add processed local foods to enrich porridges. Consumption of beans, fruits, green leafy vegetables, and peanut/seed butters increased after counselling (P < 0.05). Intakes of energy, protein, vitamin A, folate, calcium, iron and zinc from complementary foods increased significantly after counselling with or without the provision of Nutributter (P < 0.05). Intakes of fat, folate, iron, and zinc increased only (fat) or more so (folate, iron, and zinc) with the provision of Nutributter (P < 0.05). While provision of LiNS was crucial to ensure adequate intakes of iron and zinc, educational messages that were barrier-specific and delivered directly to mothers were crucial to improving the underlying diet.

Congenital and Postnatal CMV and EBV Acquisition in HIV-Infected Zimbabwean Infants

Background HIV-infected infants in sub-Saharan Africa have rapid disease progression. We hypothesized that co-infection with cytomegalovirus (CMV) or Epstein Barr virus (EBV) increases mortality in HIV-infected infants. Methods 257 antiretroviral therapy-naïve HIV-infected Zimbabwean infants were tested for CMV and EBV at 6 weeks of age by real-time PCR; if positive, birth samples were retrieved where available to distinguish congenital and postnatal infection. The impact of co-infection on mortality through 6 months was estimated using Kaplan-Meier and Cox proportional hazards methods. Results At 6 weeks, 203/257 (79%) HIV-infected infants were CMV-positive; 27 (11%) had congenital CMV, 108 (42%) postnatal CMV and 68 (26%) indeterminate timing of infection. By 6 months, 37/108 (34%) infants with postnatal CMV versus 16/54 (30%) CMV-negative infants died (adjusted hazard ratio (aHR) 1.1 [95%CI 0.6, 2.2]). At 6 weeks, 33/257 (13%) HIV-infected infants had EBV co-infection; 6 (2%) had congenital EBV, 18 (7%) postnatal EBV and 9 (4%) indeterminate timing of infection. By 6 months, 5/18 (28%) infants with postnatal EBV versus 72/224 (32%) EBV-negative infants died (aHR 0.8 [95%CI 0.3, 2.3]). Conclusions The vast majority of HIV-infants had acquired CMV by 6 weeks, and EBV co-infection occurred earlier than expected, with one in eight HIV-infected infants positive for EBV by 6 weeks. There was a high prevalence of congenital CMV infection and we identified 6 infants with congenital EBV infection, which has not previously been reported in Africa or in the context of HIV infection. Neither CMV nor EBV co-infection was associated with increased mortality.

Acute illness is associated with suppression of the growth hormone axis in Zimbabwean infants.

Frequent infections contribute to childhood stunting in developing countries but the causal pathways are uncertain. We tested the hypothesis that intercurrent illnesses suppress the growth hormone axis through reductions in insulin-like growth factor 1 (IGF-1). In a birth cohort of 202 HIV-unexposed Zimbabwean infants, we analyzed data on 7-day illness recall and measured plasma interleukin-6, C-reactive protein, alpha-1-acid glycoprotein, and IGF-1 by enzyme-linked immunosorbent assay, at age 6 weeks, and then 3, 6, 12, and 18 months. Children with recent acute illness had lower IGF-1 concentrations than healthy children and IGF-1 correlated inversely (P < 0.05) with inflammatory biomarkers at most time points between 3 and 18 months. Using path analysis, we showed that cough and fever had a predominantly indirect effect on suppressing IGF-1, through the acute-phase response, whereas diarrhea had a predominantly direct effect on IGF-1. Acute illness may therefore impact the growth hormone axis through both direct and indirect pathways.

Dosing of praziquantel by height in sub-Saharan African adults.

The cornerstone of schistosomiasis control is mass praziquantel treatment in high prevalence areas. Adults are an important target population, given increasing recognition of the burden of male and female genital schistosomiasis. However, use of weighing scales to calculate praziquantel dosing in rural areas can be challenging. For school-age children, the World Health Organization (WHO) has approved a dose pole to simplify praziquantel dosing based on height. We modified the pediatric dose pole by adding two height categories and incorporating a simple overweight/obesity adjustment, for simplified mass treatment of adults in sub-Saharan Africa. Using the rural Zimbabwean Demographic and Health Survey data, we show that the modified dose pole with body mass index adjustment would result in > 98% of adults receiving an acceptable dose (30-60 mg/kg), with only 1.4% and 0.3% receiving an inadequate dose (< 30 mg/kg) or high dose (> 60 mg/kg), respectively. An adult dose pole may provide a more feasible alternative to weighing scales in community-based praziquantel treatment programs.

Intestinal Damage and Inflammatory Biomarkers in Human Immunodeficiency Virus (HIV)-Exposed and HIV-Infected Zimbabwean Infants

Summary HIV-infected Zimbabwean infants had high levels of inflammation, but no biomarker was associated with mortality. HIV-exposed but uninfected infants had higher C-reactive protein than HIV-unexposed infants, but baseline levels of intestinal damage were not related to subsequent HIV acquisition through breastfeeding.

Cytomegalovirus acquisition and inflammation in human immunodeficiency virus-exposed uninfected Zimbabwean infants

Abstract Cytomegalovirus (CMV) acquisition and inflammation were evaluated in 231 human immunodeficiency virus (HIV)–exposed uninfected (HEU) and 100 HIV-unexposed Zimbabwean infants aged 6 weeks. The HEU and HIV-unexposed infants had a similarly high prevalence of CMV (81.4% vs 74.0%, respectively; P = .14), but HEU infants had higher CMV loads (P = .005) and >2-fold higher C-reactive protein (CRP) concentrations (P < .0001). The CMV-positive HEU infants had higher CRP than the CMV-negative HEU infants; this association disappeared after adjusting for maternal HIV load. Overall, CMV acquisition is high in early life, but HEU infants have higher CMV loads and a proinflammatory milieu, which may be driven partly by maternal HIV viremia.

Reply to Correspondence: is the strength of association between indicators of dietary quality and the nutritional status of children being underestimated?

To the Editors, We are grateful to Thorne-Lyman et al. (2014) for the insightful comments in response to the Jones et al. (2014) article. We largely agree with observations highlighting important limitations of dietary data drawn from 24-h recall methods and take the opportunity to augment the discussion of the important question posed regarding the potential underestimation of the associations between indicators of dietary quality and child nutritional status. Thorne-Lyman et al. (2014) suggest in particular that low statistical power resulting from random within-person error introduced through the use of single pass 24-h recall data may explain the statistically non-significant relationships observed between the World Health Organization (WHO) minimum dietary diversity (MDD) indicator and child stunting in the recent article by Jones et al. (2014). They further suggest that this within-person error could be corrected for in analyses if at least one additional day of data on the food group diversity of young child diets were collected. We agree with this assertion and suggest also that these challenges are not limited to random withinperson error associated with data derived from 24-h recalls. Taking the MDD indicator as an example, we highlight in the Jones et al. (2014) article that this indicator lacks specificity with respect to the micronutrient adequacy of diets (i.e. it may commonly misclassify adequate diets as inadequate). Therefore, even with sufficient statistical power, classifying the adequacy of diets using a binary categorical variable may not allow for sufficient accuracy when using regression analysis to examine the relationship between diet diversity and nutrition-related health outcomes (Royston et al. 2006). Investing the effort and expense to collect replicate measurements of child dietary diversity will reduce within-person error and can provide a more accurate exposure assessment. Having done this, however, it would be disadvantageous to limit the analysis by using an indicator that lacks specificity and therefore cannot take full advantage of the additional information collected from those replicate measurements. While the WHO indicators provide practitioners, researchers and decision-makers with easy-to-use metrics to draw attention to disparities in child feeding practices, they have specific limitations in assessing diet-health relationships. In highlighting the need to be clear about the use of data, Beaton (1994), in the article cited by Thorne-Lyman et al. (2014), points out that error in dietary assessment may have different consequences depending on the analytic question at hand. In regression analyses, for example, random error resulting from within-person variation may alter both the intercept of an observed relationship and the slope (Beaton 1994). However, if one is only interested in comparing group means (e.g. comparing dietary diversity across countries or subgroups within countries), random error will not bias the relationship, but will rather simply decrease statistical power to detect a difference (Beaton 1994). The WHO infant and young child feeding (IYCF) indicators are especially well suited for this latter purpose, in which case, the random within-person error introduced through single-day 24-h food group recall is not a serious concern in sufficiently large samples. In examining the relationship between diet and health on the other hand, random error is a threat to the actual observed relationship. It is not clear that the MDD indicator is the appropriate metric for representing dietary data collected using the replicate measurements needed for addressing this withinperson error. Indeed, future research efforts and discussions would be well directed towards identifying the most appropriate indicators, especially those that bs_bs_banner

Head circumferences of children born to HIV-infected and HIV-uninfected mothers in Zimbabwe during the preantiretroviral therapy era.

Objectives:To describe the head growth of children according to maternal and child HIV infection status. Design:Longitudinal analysis of head circumference data from 13 647 children followed from birth in the ZVITAMBO trial, undertaken in Harare, Zimbabwe, between 1997 and 2001, prior to availability of antiretroviral therapy (ART) or cotrimoxazole prophylaxis. Methods:Head circumference was measured at birth, then at regular intervals through 24 months of age. Mean head circumference-for-age Z-scores (HCZ) and prevalence of microcephaly (HCZ < −2) were compared between HIV-unexposed children, HIV-exposed uninfected (HEU) children and children infected with HIV in utero (IU), intrapartum (IP) and postnatally (PN). Results:Children infected with HIV in utero had head growth restriction at birth. Head circumference Z-scores remained low throughout follow-up in IP children, whereas they progressively declined in IU children. During the second year of life, HCZ in the PN group declined, reaching a similar mean as IP-infected children by 21 months of age. Microcephaly was more common among IU and IP children than HIV-uninfected children through 24 months. HEU children had significantly lower head circumferences than HIV-unexposed children through 12 months. Conclusion:HIV-infected children had lower head circumferences and more microcephaly than HIV-uninfected children. Timing of HIV acquisition; influenced HCZ, with those infected before birth having particularly poor head growth. HEU children had poorer head growth until 12 months of age. Correlations between head growth and neurodevelopment in the context of maternal/infant HIV infection, and further studies from the current ART era, will help determine the predictive value of routine head circumference measurement.