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Wilson L Mandala,1–3 Esther N Gondwe,1,† Tonney S Nyirenda,1,4 Mark Drayson,5 Malcolm E Molyneux,1,6 Calman A MacLennan1,7 1Malawi Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi; 2Biomedical Sciences Department, College of Medicine, Blantyre, Malawi; 3Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo, Malawi; 4Pathology Department, College of Medicine, Blantyre, Malawi; 5Institute of Immunology and Immunotherapy, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, UK; 6Liverpool School of Tropical Medicine, Liverpool, UK; 7Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK †Esther N Gondwe passed away on April 5, 2018 Aim: Cerebral malaria (CM), unlike severe malarial anemia (SMA), has previously been characterized by pan-lymphopenia that normalizes in convalescence, while HIV infection is associated with depletion of CD4+ T cells. In this study, we investigate whether HIV infection in Malawian children exacerbates the pan-lymphopenia associated with CM. Methods: We investigated the absolute and percentage lymphocyte-subset counts and their activation and memory status in Malawian children presenting with either CM who were HIV-uninfected (n=29), HIV-infected (n=9), or SMA who were HIV-uninfected (n=30) and HIV-infected (n=5) in comparison with HIV-uninfected children without malaria (n=42) and HIV-infected children without malaria (n=4). Results: HIV-infected CM cases had significantly lower absolute counts of T cells (P=0.006), CD4+ T cells (P=0.0008), and B cells (P=0.0014) than HIV-uninfected CM cases, and significantly lower percentages of CD4+ T cells than HIV-uninfected CM cases (P=0.005). HIV-infected SMA cases had significantly lower percentages of CD4+ T cells (P=0.001) and higher CD8+ T cells (P=0.003) in comparison with HIV-uninfected SMA cases. HIV-infected SMA cases had higher proportions of activated T cells (P=0.003) expressing CD69 than HIV-uninfected SMA cases. Conclusion: HIV infection compounds the perturbation of acute CM and SMA on lymphocytes, exacerbating subset-specific lymphopenia in CM and increasing activation status in SMA, potentially exacerbating host immunocompromise. Keywords: HIV, cerebral malaria, severe malarial anemia, Malawian children

In malaria-endemic areas, Plasmodium falciparum parasitemia is common in apparently healthy children and severe malaria is commonly misdiagnosed in patients with incidental parasitemia. We assessed whether the plasma Plasmodium falciparum DNA concentration is a useful datum for distinguishing uncomplicated from severe malaria in African children and Asian adults. P. falciparum DNA concentrations were measured by real-time polymerase chain reaction (PCR) in 224 African children (111 with uncomplicated malaria and 113 with severe malaria) and 211 Asian adults (100 with uncomplicated malaria and 111 with severe malaria) presenting with acute falciparum malaria. The diagnostic accuracy of plasma P. falciparum DNA concentrations in identifying severe malaria was 0.834 for children and 0.788 for adults, similar to that of plasma P. falciparum HRP2 levels and substantially superior to that of parasite densities (P < .0001). The diagnostic accuracy of plasma P. falciparum DNA concentrations plus plasma P. falciparum HRP2 concentrations was significantly greater than that of plasma P. falciparum HRP2 concentrations alone (0.904 for children [P = .004] and 0.847 for adults [P = .003]). Quantitative real-time PCR measurement of parasite DNA in plasma is a useful method for diagnosing severe falciparum malaria on fresh or archived plasma samples.

Background\ud Children with severe malaria are at increased risk of invasive bacterial disease particularly infection with enteric gram-negative organisms. These organisms are likely to originate from the gut, however, how and why they breach the intestinal interface in the context of malaria infection remains unclear. One explanation is that accumulation of infected red blood cells (iRBCs) in the intestinal microvasculature contributes to tissue damage and subsequent microbial translocation which can be addressed through investigation of the impact of cytoadhesion in patients with malaria and intestinal damage.\ud \ud Methods\ud Using a static adhesion assay, cytoadhesion of iRBCs was quantified in 48 children with malaria to recombinant proteins constitutively expressed on endothelial cell surfaces. Cytoadhesive phenotypes between children with and without biochemical evidence of intestinal damage [defined as endotoxemia or elevated plasma intestinal fatty acid binding protein (I-FABP)] was compared.\ud \ud Results\ud The majority of parasites demonstrated binding to the endothelial receptors CD36 and to a lesser extent to ICAM-1. Reduced adhesion to CD36 but not adhesion to ICAM-1 or rosetting was associated with malarial anaemia (p = 0.004). Increased adhesion of iRBCs to ICAM-1 in children who had evidence of elevated I-FABP (p = 0.022), a marker of intestinal ischaemia was observed. There was no correlation between the presence of endotoxemia and increased adhesion to any of the recombinant proteins.\ud \ud Conclusion\ud Increased parasite adhesion to ICAM-1 in children with evidence of intestinal ischaemia lends further evidence to a link between the cytoadherence of iRBCs in gut microvasculature and intestinal damage.

Background: Multicultural comparative studies have recently increased scientific knowledge base regarding the mental health of diverse populations. This cross-cultural study was cross-sectionally designed to assess differences in the prevalence and predictors of clinically significant depressive symptoms between Chinese and Malawian children. Methods: A total of 478 children (237 Chinese and 241 Malawians) were randomly recruited in the study. The participants completed a Children Depression Inventory in the dimensions of Negative Mood, Interpersonal Problems, Ineffectiveness, Anhedonia, and Negative Self- Esteem. They further provided demographic and family structure information. Data were analyzed by Student’s t-test, Chi-square test, and logistic regression. Results: The prevalence of clinically significant depressive symptoms was 16% and 12.4% for Chinese and Malawian study participants, respectively. Multivariate logistic regression analysis showed that fighting among siblings (adjusted odds ratio [aOR] = 4.1, 95% CI, 3.5–5.9), fighting among children and parents (aOR = 7.7, 95% CI, 4.6–9.8) and living with father only (aOR = 4.1, 95% CI, 3.4–6.7) were significant predictors of clinically significant depressive symptoms among Chinese study participants. On the other hand, clinically significant depressive symptoms were predicted by employment status of a mom only among Malawian study participants (aOR = 3.0, 95% CI, 2.3–5.9). Conclusions: We conclude that diverse cultures affect children’s mental health differently and this cluster of children has a noticeable amount of depressive symptoms that in the least requires further diagnosis and preventive measures.

Background: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy. Methods: In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention. Results: Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone - insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth. Conclusions: Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust. Trial registration: Registered at Clinicaltrials.gov NCT01841099.

Background: In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations. Methods: Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6−60 months in communities and a nearby hospital in northeastern Tanzania. The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests. The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease. Results:The plasma PfHRP2 concentration showed a close correlation with the severity of infection. PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%–100%), with a sensitivity of 74% (95% CI, 72%–77%), whereas a concentration of 10% (95% CI, 3%–27%) of patients. Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles. Conclusions: The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.

Schoolchildren in developing countries often have inadequate intakes of iron, due primarily to poor bioavailability. Increasing meat in the diet could improve both the amount of iron consumed and its availability. The effect of increases in intakes of meat and ascorbic acid on absorbed iron was investigated by theoretically modifying the habitual diet of rural Kenyan schoolchildren. The projected changes in the amount of absorbed iron and prevalence of inadequate iron intakes were calculated for 78 children (6–9 years of age). The prevalence of inadequate iron intakes decreased from 77% to 54% through the theoretical addition of 50 g beef or 100 mg ascorbic acid and to 23% through the addition of both to dinner each day. To reduce the prevalence of inadequate iron intake to 5%, the addition of 100 g meat plus 150 mg ascorbic acid would be necessary. The combined addition of meat and ascorbic acid to a meal has the potential to reduce the projected prevalence of inadequate iron intakes among these schoolchildren.