Beatrice Amadi

Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial

BACKGROUND Cryptosporidiosis in children in developing countries causes persistent diarrhoea and malnutrition and is associated with increased mortality, but there is no effective treatment. We aimed to assess the effect of nitazoxanide-a new broad-spectrum antiparasitic drug-on morbidity and mortality in Zambian children with diarrhoea due to Cryptosporidium parvum. METHODS Children with cryptosporidial diarrhoea who were admitted to the University Teaching Hospital, Lusaka, Zambia, between November, 2000, and July, 2001, and whose parents consented to their having an HIV test were randomly assigned nitazoxanide (100 mg twice daily orally for 3 days) or placebo. The primary endpoint was clinical response on day 7 after the start of treatment. Secondary endpoints included parasitological response by day 10 and mortality at day 8. Analysis was by intention to treat, with exclusion of patients subsequently found to be negative for C parvum or co-infected at baseline. The trial was stratified by HIV serology. FINDINGS 50 HIV-seropositive and 50 HIV-seronegative children were recruited for the study, four of whom were subsequently excluded. In HIV-seronegative children, diarrhoea resolved in 14 (56%) of 25 receiving nitazoxanide and 5 (23%) of 22 receiving placebo (difference 33%, 95% CI 7-59; p=0.037). C parvum was eradicated from stool in 13 (52%) of 25 receiving nitazoxanide and three (14%) of 22 receiving placebo (38%, 95% CI 14-63; p=0.007). Four children (18%) of 22 in the placebo group had died by day 8, compared with none of 25 in the nitazoxanide group (-18%, -34 to 2; p=0.041). HIV-seropositive children did not benefit from nitazoxanide. Nitazoxanide was not significantly associated with adverse events in either stratum. INTERPRETATION A 3-day course of nitazoxanide significantly improved the resolution of diarrhoea, parasitological eradication, and mortality in HIV-seronegative, but not HIV-seropositive, children.

Intestinal and systemic infection, HIV, and mortality in Zambian children with persistent diarrhea and malnutrition.

Background Persistent diarrhea–malnutrition syndrome is a complex of infection and immune failure that involves protein, calorie and micronutrient depletion, and metabolic disturbances. We report an analysis of the impact of HIV infection on infectious disease, clinical presentation, and mortality in Zambian children with persistent diarrhea and malnutrition. Methods Two hundred children (94 boys and 106 girls, 6–24 months old) were examined on admission to the malnutrition ward of University Teaching Hospital in Lusaka, Zambia. There was then 1 month of follow-up. Results Antibodies to HIV were found in 108 of the children (54%). The common intestinal infections (Cryptosporidium parvum [26%] and nontyphoid Salmonella spp [18%]), septicemia (17%), and pulmonary tuberculosis confirmed by gastric lavage (13.5%) were not significantly more common in HIV-seropositive than in HIV-seronegative children. HIV-seropositive children were more likely to have marasmus whereas HIV-seronegative children were more likely to have kwashiorkor. Weight-for-age z scores at nadir (postedema) were lower in HIV-seropositive children (median, -4.4; interquartile range [IQR], −5.0 to −3.8) than in HIV-seronegative children (median, −3.7; IQR, -4.2 to -3.1;P < 0.0001). Height-for-age and weight-for-height z scores and mid-upper arm circumference showed a similar difference. Of the 200 children, 39 (19.5%) died within 28 days; cryptosporidiosis and marasmus were the only independent predictors of death. Conclusions Although intestinal and systemic infections did not differ for HIV-seropositive and HIV-seronegative children, HIV influenced nutritional states of all children. Cryptosporidiosis and marasmus were associated with higher mortality.

Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence

In the ideal situation, use of WHO therapeutic guidelines for management of severe malnutrition 5 and a continuum of care for malnourished children 6 through community therapeutic care pro grammes would successfully improve survival in children without HIV infection. An alarming consequence of the HIV epidemic is an increase in the need by severely malnourished, seriously ill children for facility-based treatment. Ready-to-use therapeutic foods that facilitate eff ective home-based therapy have resulted in recovery rates for uncomplicated severe malnutrition of more than 90%, with reported case-fatality rates of less than 5%; 7

Randomised study of skin-to-skin versus incubator care for rewarming low-risk hypothermic neonates

In neonates, an admission temperature of less than 36 O C is associated with or contributes to increased morbidity and mortality. 1 Skin-to-skin (STS) care prevents neonatal hypothermia 2 but has not been investigated for treatment of hypothermia. We compared STS with incubator care for rewarming low-risk infants with hypothermia. 80 consecutive low-risk hypothermic infants (clinically stable with admission weight of � 1500 g, absence of respiratory distress, no cyanosis or overt sepsis, not requiring oxygen or intravenous fluids, and no major congenital malformations), admitted to the Neonatal Intensive Care unit, at the University Teaching Hospital, Lusaka, Zambia were randomly assigned treatment with STS care by the mother (n=41) or in an incubator (n=39). The study was explained to the mother or parents and we obtained her or their consent before assignment to study groups. Incubator temperature was 35 O

Dendritic Cell Anergy Results from Endotoxemia in Severe Malnutrition

Malnutrition predicts an increased risk of morbidity and mortality from infection. Defects in cell-mediated immunity, such as thymic atrophy, impaired cutaneous tuberculin responses, and reduced T cell mitogenesis in vitro, are well characterized. There has been no convincing mechanism proposed for these T cell defects. However, as T cell responses rely on signals received from APCs, this study evaluates dendritic cell (DC) function in children with severe malnutrition. Repeated sampling of peripheral blood from 81 severely malnourished children at the University Teaching Hospital, Lusaka, Zambia, demonstrated for the first time a defect in DC numbers in children with malnutrition (28 per microliter) and a recovery in cell number (48 per microliter; p < 0.01) with standard treatment. We describe normal DC maturation in the majority of malnourished children. However, in 17% of our study patients, in association with endotoxemia we describe the novel finding of DC maturation failure (down-regulation rather than up-regulation of HLA-DR). There was a strong correlation between the strength of HLA-DR up or down-regulation and the generation of IL-10 (r = −0.481; p = 0.003). These “anergic” DCs failed to support T cell proliferation. Defects in DC number and the immunosuppressive phenotype of DCs from severely malnourished children with endotoxemia provide a rational basis for the anergy found in severe malnutrition.

Morbidity and nutritional impairment in relation to CD4 count in a Zambian population with high HIV prevalence

The HIV epidemic has greatly increased morbidity in many African cities and severe undernutrition is a prominent feature of the clinical presentation. However, there is little information about the relationship of morbidity or nutritional status to immune damage at a population level. We report a cross-sectional study of morbidity and nutritional status in relation to CD4 count in an impoverished urban community in Lusaka, Zambia, at enrollment into a longitudinal study. Over a 2 month period in 1999, 261 (52%) of 506 adults resident in one area were interviewed and examined. Of 186 adults who consented to testing, 33 (51%) of 65 who were HIV seropositive reported symptoms of disease compared to 39 (32%) of 121 who were HIV seronegative (OR 2.2, 95%CI 1.1-4.2; P=0.02). Peripheral blood CD4 counts in HIV seronegative individuals were broadly similar to norms in developed countries, but 8 (7%) had CD4 counts below 500 cells/microl. Morbidity in HIV seropositive adults was dominated by tuberculosis (n=11), other respiratory infections (5) or persistent diarrhoea (4), and affected individuals had a wide range of CD4 counts. Nutritional impairment was evident in HIV seropositive adults with clinical evidence of opportunistic infection (OI), not those with asymptomatic HIV infection. Unexpectedly, we also noted that systolic blood pressure was reduced progressively in HIV infection and in those with OI. In conclusion, HIV-related morbidity was dominated by a small number of treatable infectious diseases occurring over a wide range of CD4 count. Nutritional impairment was associated with OI.

Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus

BACKGROUND Kwashiorkor, a form of severe malnutrition with high mortality, is characterized by edema and systemic abnormalities. Although extremely common, its pathophysiology remains poorly understood, and its characteristic physical signs are unexplained. OBJECTIVE Because kwashiorkor can develop in protein-losing enteropathy, which is caused by a loss of enterocyte heparan sulfate proteoglycan (HSPG), and previous observations suggest abnormal sulfated glycosaminoglycan (GAG) metabolism, we examined whether intestinal GAG and HSPG are abnormal in children with kwashiorkor. DESIGN Duodenal biopsy samples collected from Zambian children with marasmus (n = 18), marasmic kwashiorkor (n = 8), and kwashiorkor (n = 15) were examined for expression of HSPG, GAGs, and immunologic markers and compared against reference samples from healthy UK control children. GAG and HSPG expression density and inflammatory cell populations were quantitated by computerized analysis. RESULTS The kwashiorkor group was less wasted and had a lower HIV incidence than did the other groups. All duodenal biopsy samples showed inflammation compared with the histologically uninflamed control samples. Biopsy samples from marasmic children had greater inflammation and greater CD3+ and HLA-DR (human leukocyte antigen DR)-positive cell densities than did samples from children with kwashiorkor. Expression of both HSPG and GAGs was similar between marasmic and well-nourished UK children but was markedly lower in children with kwashiorkor in both the epithelium and lamina propria. Although underglycosylated and undersulfated, epithelial syndecan-1 protein was normally expressed in kwashiorkor, which confirmed that abnormalities arise after core protein synthesis. CONCLUSIONS Intestinal HSPG loss occurs in kwashiorkor, which may precipitate protein-losing enteropathy to cause edema. If occurring systemically, impaired HSPG expression could cause several previously unexplained features of kwashiorkor. We speculate that a genetic predisposition to reduced HSPG biosynthesis may offer a contrasting selective advantage, by both diminishing protein catabolism during transient undernutrition and protecting against specific infectious diseases.

CD4 Counts Decline Despite Nutritional Recovery in HIV-Infected Zambian Children With Severe Malnutrition

OBJECTIVE. The objective of this study was to establish the contribution that severe malnutrition makes to CD4 lymphopenia in HIV-infected and uninfected children and to determine the changes in CD4 count during nutritional rehabilitation. METHODS. Fifty-six children with severe malnutrition and with and without HIV infection were recruited from a pediatric ward in Lusaka for measurement of CD4 counts on admission, on discharge, and at final nutritional recovery. RESULTS. HIV-uninfected children with severe malnutrition had normal CD4 counts. In contrast, CD4 counts in HIV-infected children with severe malnutrition were reduced, more so in those without edema compared with those with edema. Mean CD4 count of HIV-infected SM children fell despite nutritional recovery so that at the time of full nutritional recovery, >85% of HIV-infected children required antiretroviral therapy. CONCLUSIONS. Severe malnutrition did not reduce the CD4 counts of children without HIV. HIV-infected children with severe malnutrition may respond well to nutritional rehabilitation, despite low CD4 counts, but nearly all require early antiretroviral therapy to prevent disease progression.

Nutrition interventions need improved operational capacity

The Lancet’s Child Survival Series was a galvanising manifesto: it focused action plans to improve the wellbeing of children worldwide. However, the authors did not address in detail the importance of nutrition in child survival, and thus the current Undernutrition Series was born. This welcome new Series focuses on micronutrient interventions and stunting as manifestations of a poor diet, and comprehensively catalogues the topic from a multiplicity of datasets and viewpoints. Undernutrition results from a complex web of interactions, from the molecular and microbiological level of the individual to the cultural and socioeconomic characteristics of societies. The intricacy of undernutrition as a global problem seems to defy simple, directed, and uniform programmes. However, we will not eff ectively improve child survival unless we untangle this web, because over 50% of child deaths result from undernutrition. Working in southern Africa, we are convinced the key will be to translate the understanding of undernutrition into practical interventions. We are faced with an over whelming burden of HIV, and the treatment of ser iously ill children with chronic infections leading to undernourishment is challenging. Old guidelines do not suffi ce because the clinical presentation, pathophysiology, and prognosis have changed because of HIV. Additionally, further investigation of the clinical and pathophysiological complexities and treatment of malnourished children with HIV in the context of health systems is needed if interventions are to be eff ective. Two large-scale interventions in South African services have infl uenced international policies. First, a strong child-health system that supports exclusive breastfeeding in HIV-infected women can increase the survival of infants exposed to and infected with HIV. Second, community-based management of uncomplicated severe malnutrition without HIV infection, which was for years treated in facilities according to the WHO standard protocol, has dramatically improved recovery rates that were formerly almost equivalent to case-fatality rates. Many of the factors that the authors of the Undernutrition Series identify conspired to create this failure in treatment: the lack of doctors and nurses to administer care; use of foods that were easily contaminated; overcrowded and understaff ed hospitals; the absence of accessible early interventions in vulnerable communities; and the lack of coherent and adequately funded national strategies. Community-based care with ready-to-use therapeutic food for children with uncomplicated severe malnutrition has transformed understaff ed child-health services. Home-based therapy with locally developed scientifi c breakthroughs, new-found resources, political resolve, and moral indignation—can work in cohort. Together, we can make major advances in short periods of time if we give the challenge of hunger the priority it deserves.

Endomicroscopic and Transcriptomic Analysis of Impaired Barrier Function and Malabsorption in Environmental Enteropathy.

Introduction Environmental enteropathy (EE) is associated with growth failure, micronutrient malabsorption and impaired responses to oral vaccines. We set out to define cellular mechanisms of impaired barrier function in EE and explore protective mechanisms. Methods We studied 49 adults with environmental enteropathy in Lusaka, Zambia using confocal laser endomicroscopy (CLE); histology, immunohistochemistry and mRNA sequencing of small intestinal biopsies; and correlated these with plasma lipopolysaccharide (LPS) and a zinc uptake test. Results CLE images (median 134 for each study) showed virtually ubiquitous small intestinal damage. Epithelial defects, imaged by histology and claudin 4 immunostaining, were predominantly seen at the tips of villi and corresponded with leakage imaged in vivo by CLE. In multivariate analysis, circulating log-transformed LPS was correlated with cell shedding events (β = 0.83; P = 0.035) and with serum glucagon-like peptide-2 (β = -0.13; P = 0.007). Zinc uptake from a test dose of 25mg was attenuated in 30/47 (64%) individuals and in multivariate analysis was reduced by HIV, but positively correlated with GLP-2 (β = 2.72; P = 0.03). There was a U-shaped relationship between circulating LPS and villus surface area. Transcriptomic analysis identified 23 differentially expressed genes in severe enteropathy, including protective peptides and proteins. Conclusions Confocal endomicroscopy, claudin 4 immunostaining and histology identify epithelial defects which are probably sites of bacterial translocation, in the presence of which increased epithelial surface area increases the burden of translocation. GLP 2 and other protective peptides may play an important role in mucosal protection in EE.