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Background Mortality among children with acute illness in low-income and middle-income settings remains unacceptably high and the importance of post-discharge mortality is increasingly recognised. We aimed to explore the epidemiology of deaths among young children with acute illness across sub-Saharan Africa and south Asia to inform the development of interventions and improved guidelines. Methods In this prospective cohort study, we enrolled children aged 2–23 months with acute illness, stratified by nutritional status defined by anthropometry (ie, no wasting, moderate wasting, or severe wasting or kwashiorkor), who were admitted to one of nine hospitals in six countries across sub-Saharan Africa and south Asia between Nov 20, 2016, and Jan 31, 2019. We assisted sites to comply with national guidelines. Co-primary outcomes were mortality within 30 days of hospital admission and post-discharge mortality within 180 days of hospital discharge. A priori exposure domains, including demographic, clinical, and anthropometric characteristics at hospital admission and discharge, as well as child, caregiver, and household-level characteristics, were examined in regression and survival structural equation models. Findings Of 3101 children (median age 11 months [IQR 7–16]), 1120 (36·1%) had no wasting, 763 (24·6%) had moderate wasting, and 1218 (39·3%) had severe wasting or kwashiorkor. Of 350 (11·3%) deaths overall, 234 (66·9%) occurred within 30 days of hospital admission and 168 (48·0%) within 180 days of hospital discharge. 90 (53·6%) post-discharge deaths occurred at home. The proportion of children who died following discharge was relatively preserved across nutritional strata. Numerically large high-risk and low-risk groups could be disaggregated for early mortality and post-discharge mortality. Structural equation models identified direct pathways to mortality and multiple socioeconomic, clinical, and nutritional domains acting indirectly through anthropometric status. Interpretation Among diverse sites in Africa and south Asia, almost half of mortality occurs following hospital discharge. Despite being highly predictable, these deaths are not addressed in current guidelines. A fundamental shift to a child-centred, risk-based approach to inpatient and post-discharge management is needed to further reduce childhood mortality, and clinical trials of these approaches with outcomes of mortality, readmission, and cost are warranted.

Objectives: To assess whether viral, bacterial, metabolic, and autoimmune diseases are missed by conventional diagnostics among children with severe acute encephalopathy in sub-Saharan Africa. Study design: One hundred thirty-four children (6 months to 18 years) presenting with nontraumatic coma or convulsive status epilepticus to 1 of 4 medical referral centers in Uganda, Malawi, and Rwanda were enrolled between 2015 and 2016. Locally available diagnostic tests could be supplemented in 117 patients by viral, bacterial, and 16s quantitative polymerase chain reaction testing, metagenomics, untargeted metabolomics, and autoimmune immunohistochemistry screening. Results: Fourteen (12%) cases of viral encephalopathies, 8 (7%) cases of bacterial central nervous system (CNS) infections, and 4 (4%) cases of inherited metabolic disorders (IMDs) were newly identified by additional diagnostic testing as the most likely cause of encephalopathy. No confirmed cases of autoimmune encephalitis were found. Patients for whom additional diagnostic testing aided causal evaluation (aOR 3.59, 90% CI 1.57-8.36), patients with a viral CNS infection (aOR 7.91, 90% CI 2.49-30.07), and patients with an IMD (aOR 9.10, 90% CI 1.37-110.45) were at increased risk for poor outcome of disease. Conclusions: Viral and bacterial CNS infections and IMDs are prevalent causes of severe acute encephalopathy in children in Uganda, Malawi, and Rwanda that are missed by conventional diagnostics and are associated with poor outcome of disease. Improved diagnostic capacity may increase diagnostic yield and might improve outcome of disease.

Background Severe anaemia (haemoglobin Methods Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. Results Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63–3.78), p p p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21–1.69), p p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47–0.76), p p p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross splenomegaly and enlarged spleen increased risk by 1.73(1.23–2.44) and 1.46(1.18–1.82) respectively compared to no splenomegaly. Clustering identified four groups of children with readmission rates from 14 to 20%. The cluster with the highest readmission rate was characterised by very low haemoglobin (mean 3.6 g/dL). Sickle Cell Disease (SCD) predominated in two clusters associated with chronic repeated admissions or severe, acute presentations in largely undiagnosed SCD. The final cluster had high rates of malaria (78%), severity signs and very low platelet count, consistent with acute severe malaria. Conclusions Younger age, HIV infection and history of previous hospital admissions predicted increased risk of readmission. However, no obvious clinical factors for intervention were identified. As missing medication doses was highly predictive, attention to care related factors may be important. Trial registration ISRCTN ISRCTN84086586.

Background:Micronutrient deficiencies due to malabsorption, gut infections, and altered gut barrier function are common in children living with HIV (CLHIV) and may worsen with severe acute malnutrition (SAM).Methods:This secondary analysis of IMPAACT P1092, a Phase IV, multicenter, open label, non-randomized study of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) pharmacokinetics, safety, and tolerability enrolled SAM and non-SAM CLHIV age 6 to ResultsFifty-two participants, 25 SAM and 27 non-SAM, of median (Q1,Q3) age 19 (13,25) and 18 (12,25) months respectively, were enrolled. Zinc deficiency was present at entry in 2/27 (8%) from the SAM cohort. Mean (SD) baseline zinc levels for the SAM and non-SAM cohort [52.2(15.3), 54.7(12.2) µg/dL] and selenium [92.9(25.0), 84.3(29.2) µg/L] were similar, and there was no difference in change from study entry to week 48 for both: mean (95% CI) difference SAM minus non-SAM of -0.3 (-11.2,10.5) µg/dL and -5.1 (-20.1,9.8) µg/L for zinc and selenium respectively. Mean (SD) baseline total protein levels [75.2(13.2), 77.3(9.4) g/L] and mean change from entry to 48 weeks were similar between cohorts (mean difference (95% CI) (4.6 (-2.4,11.6). The SAM cohort had significantly lower serum albumin levels at entry compared to the non-SAM cohort (mean difference (95% CI) 6.2 (-10.1, -2.4) g/L) and levels were similar after 48 weeks (mean difference (95% CI) 0.4 (-2.2, 2.9) g/L). Mean increase in albumin at 48 weeks was greater in the SAM cohort (mean difference (95% CI) 6.3 (1.9, 10.7) g/L). ConclusionsThese children who were on highly active combination antiretroviral therapy and had malnutrition showed normal levels of selenium and zinc after 10-18 days of nutritional rehabilitation. Entry albumin levels were lower in SAM compared to non-SAM, with normalization to non-SAM levels by 48 weeks. Total protein levels were similar at entry and week 48.Trial RegistrationThe study was registered with ClinicalTrials.gov Identifier NCT01818258 26/03/2013

ObjectivesMortality during acute illness among children in low- and middle-income settings remain unacceptably high and there is increasing recognition of the importance of post-discharge mortality. A comprehensive understanding of pathways underlying mortality among acutely ill children is needed to develop interventions and improve guidelines. We aimed to determine the incidence, timing and contributions of proximal and underlying exposures for mortality among acutely ill young children from admission to hospital until 6 months after discharge in sub-Saharan Africa and South Asia in the context of guideline-based care.DesignA prospective stratified cohort study recruiting acutely ill children at admission to hospital with follow up until 180 days after discharge from hospital (November 2016-July 2019).SettingNine urban and rural hospitals in sub-Saharan Africa and South Asia across a range of facility levels, and local prevalences of HIV and malaria.ParticipantsInclusion criteria were age 2-23 months, admission to hospital with acute, non-traumatic medical illness and stratified into three groups by anthropometry. Children were excluded if currently receiving pulmonary resuscitation, had a known condition requiring surgery within 6 months or known terminal illness with death expected within 6 months.Main outcome measuresAcute mortality occurring within 30-days from admission; post-discharge mortality within 180-days from discharge; characteristics with direct and indirect associations with mortality within a multi-level a priori framework including demographic, clinical, anthropometric characteristics at admission and discharge from hospital, and pre-existing child-, caregiver- and household-level characteristics.ResultsOf 3101 participants (median age 11 months), 1218 were severely wasted/kwashiorkor, 763 moderately wasted and 1120 were not wasted. Of 350 deaths, 182 (52%) occurred during index admission, 234 (67%) within 30-days of admission and 168 (48%) within 180-days post-discharge. Ninety (54%) post-discharge deaths occurred at home. The ratio of inpatient to post-discharge mortality was consistent across anthropometric strata and sites. Large high and low risk groups could be disaggregated for both early and post-discharge mortality. Structural equation models identified direct pathways to mortality and multiple socioeconomic, clinical and nutritional domains acting indirectly through anthropometric status.ConclusionsAmong diverse sites in Africa and South Asia, almost half of mortality occurs post-discharge. Despite being highly predictable, these deaths are not addressed in current guidelines. A fundamental shift to a risk-based approach to inpatient and post-discharge management is needed to further reduce childhood mortality and clinical trials of these approaches with outcomes of mortality, readmission and cost are warranted.Trial RegistrationClinicalTrials.gov: NCT03208725

Summary Background Antiretroviral medication during pregnancy and breastfeeding substantially decreases the risk of HIV transmission from mothers to infants, but its effects on the child's neurodevelopment are unknown. This study compared neurodevelopmental outcomes of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children with HIV-unexposed and uninfected children at ages 12, 24, 48, and 60 months. Methods For this study, a prospective cohort of HIV-exposed and uninfected children was identified from two research sites in the PROMISE-BF trial (at Blantyre, Malawi, and Kampala, Uganda), in which pregnant HIV-infected mothers were randomly assigned to triple antiretroviral prophylaxis (lopinavir–ritonavir plus either lamivudine and zidovudine or emtricitabine and tenofovir), versus zidovudine alone. Post partum, the mother–infant pairs were randomly assigned to maternal triple antiretroviral treatment or infant nevirapine during breastfeeding. HIV-unexposed and uninfected children matched for age, sex, and socioeconomic background were enrolled at vaccination and well-child clinics at the study sites. We included only children without a history of documented brain infection or injury or substantial malnutrition, and whose mothers were randomly assigned and maintained within their assigned ante-partum and post-partum phases throughout their treatment arm periods. Primary outcomes were the Mullen Scales of Early Learning (MSEL) cognitive composite score at age 12 months, 24 months, and 48 months; and the mental processing index for the Kaufman Assessment Battery for Children, second edition (KABC-II) global score at 48 months and 60 months. Repeated measures were analysed using a linear mixed-effects model controlling for data collection site. Findings Between Aug 23, 2013, and Dec 17, 2014, we co-enrolled 861 children. For MSEL assessments, 738 were eligible for inclusion at age 12 months, 790 at age 24 months, and 692 at age 48 months. For KABC-II assessments, 685 were eligible for inclusion at age 48 months and 445 at age 60 months. There were no differences in MSEL cognitive composite scores according to exposure at age 12 and 24 months (p=0·19 and 0·24, respectively, for comparison of all groups). At 48 months, MSEL cognitive composite scores were worse for children of mothers who did not remain on triple antiretroviral treatment throughout both the ante-partum and post-partum treatment phases (adjusted means 80·64 [95% CI 77·74–83·54] and 81·34 [78·19–84·48], respectively), compared with those who did remain on triple treatment (adjusted mean 85·93, 95% CI 83·05–88·80; p=0·0486 for the comparison of all groups). The KABC-II composite scores (mental processing index) did not differ at 48 or 60 months according to exposure (p=0·81 and 0·89, respectively, for comparison of all groups). Scores for MSEL and KABC-II for children of mothers on triple antiretrovirals in both the ante-partum and post-partum treatment phases were similar to those for children in the HIV-unexposed and uninfected reference group at all timepoints. Interpretation Maternal triple antiretroviral exposure during both the ante-partum and post-partum phases did not result in greater developmental risks for the mothers' HIV-exposed and uninfected children through age 60 months, compared with children who were HIV-unexposed and uninfected. This might be because ante-partum triple antiretroviral protection of the health of mothers with HIV during pregnancy might be neuroprotective for the child, and when continued post partum, could enhance the quality of caregiving for the child through better clinical care for the mother. Funding National Institutes of Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BACKGROUND: The World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes.METHODS: In this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole.RESULTS: A total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P = 0.19) and by 180 days in 35 (4.5%) and 47 (6.0%), respectively (hazard ratio, 0.75; 95% CI, 0.48 to 1.15), without evidence of interaction with other randomizations (P>0.20) or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The mean length of hospital stay was 0.9 days longer in the control group.CONCLUSIONS: There was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not. The triggered-transfusion strategy in the control group resulted in lower blood use; however, the length of hospital stay was longer, and this strategy required clinical and hemoglobin monitoring. (Funded by the Medical Research Council and Department for International Development; TRACT Current Controlled Trials number, ISRCTN84086586.).

BACKGROUND. Adverse pregnancy outcomes such as preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) remain major global problems. We compared pregnancy outcomes among HIV-infected women receiving antiretroviral treatment (ART) and with CD4 ≥350 cells, and HIV-uninfected women to assess if disparities associated with HIV infection have been eliminated through use of ART. SETTING: Observational study conducted at five health facilities in Blantyre, Malawi during 2016–2017. METHODS. HIV-infected women receiving the national ART regimen (efavirenz+lamuvidine+tenfovir) and HIV-uninfected women were consented and enrolled at delivery. Data collected included sociodemographic and clinical; gestational age (GA); birth weight (BW); infant/maternal anthropometry; and laboratory results. We defined PTB as GA0·05). Of 231 SGA infants, 78·8% were proportionate and 21% were disproportionate. Of the 614 HIV-infected women on ART, 75% had undetectable virus at delivery. CONCLUSION. ART use has reduced the high rates of adverse pregnancy outcomes among HIV-infected women. However, the rates remain high irrespective of HIV infection and require appropriate interventions.

A comprehensive evidence-based framework is needed to guide policies and programmes that enable children and adolescents to accrue the human capital required to meet the Sustainable Development Goals (SDGs). This paper proposes a comprehensive, multisectoral, multilevel life-course conceptualisation of human capital development by building on the Nurturing Care Framework (NCF), originally developed for the foundational period of growth and development through the age 3 years. Nurturing care (NC) comprises stable environments that promote children’s health and nutrition, protect from threats, and provide opportunities for learning and responsive, emotionally supportive and developmentally enriching relationships. NC is fostered by families, communities, services, national policies and beyond. The principles apply across the life course, endorse equity and human rights, and promote long-term human capital. This paper presents an evidence-based argument for the extension of the NCF from preconception through adolescence (0–20 years), organised into six developmental periods: preconception/prenatal, newborn/birth, infancy/toddlerhood, preschool, middle childhood and adolescence. The proposed framework advances human capital within each developmental period by promoting resilience and adaptive developmental trajectories while mitigating negative consequences of adversities. Attaining the SDGs depends on strengthening human capital formation, extending throughout childhood and adolescence and supported by NC. Embedded in enabling laws, policies and services, the dynamic NCF components can mitigate adversities, enhance resilience and promote the well-being of marginalised groups. The life-course extension of the NCF is strategically positioned to enhance human capital, to attain the SDGs and to ensure that children or adolescents are not left behind in reaching their developmental potential.

BackgroundWe sought to identify perceptions of neurorehabilitation challenges for paediatric cerebral malaria (CM) survivors post-hospital discharge at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi.MethodsAn exploratory approach was used to qualitatively investigate the perceived neurorehabilitation challenges for paediatric CM survivors. Data were collected through semi-structured in-depth interviews (IDIs) and focus group discussions (FGDs). Eighteen data-gathering sessions were conducted with 38 total participants, including 3 FGDs with 23 primary caregivers, 11 IDIs with healthcare workers at QECH, and 4 IDIs with community-based rehabilitation workers (CRWs).ResultsFGDs revealed that caregivers lack important knowledge about CM and fear recurrence of CM in their children. Post-CM children and families experience substantial stigma and sociocultural barriers to integrating into their community and accessing neurorehabilitative care. At a community-level, rehabilitation infrastructure, including trained staff, equipment, and programmes, is extremely limited. Rehabilitation services are inequitably accessible, and community-based rehabilitation remains largely unavailable.ConclusionsThere is an urgent need to establish further training of rehabilitation personnel at all levels and to build accessible rehabilitation infrastructure in Malawi for post-CM patients. Additional work is required to expand this study across multiple regions for a holistic understanding of neurorehabilitation needs.

IntroductionSevere acute malnutrition (SAM) and disability are major global health issues. Although they can cause and influence each other, data on their co-existence are sparse. We aimed to describe the prevalence and patterns of disability among a cohort of children with SAM.MethodsA longitudinal cohort study in Malawi followed SAM survivors up to 7 years postdischarge. Clinical and anthropometric profiles were compared with sibling and community controls. Disability at original admission was identified clinically; at 7-year follow-up a standardised screening tool called ‘the Washington Group Questionnaire’ was used.Results60/938 (6.4%) of admissions to SAM treatment had clinically obvious disability at admission. Post-treatment mortality was high, with only 11/60 (18%) surviving till 7-year follow-up. SAM children with a disability at admission had 6.99 (95% CI 3.49 to 14.02; pThe Washington Group Questionnaire confirmed disability in all who had been identified clinically, and identified many who had not been previously flagged.ConclusionDisability is common among children affected by SAM. Those with disability-associated SAM have greatly increased risk of dying even if they survive the initial episode of malnutrition. Survivors have poorer growth, physical strength and school achievement. To enable all children to survive and thrive post-SAM, it is vital to focus more on those with disabilities. SAM treatment programmes should consider using not just clinical assessment but structured assessments to better identify at-risk individuals as well as understand the population of children for which they are developing services.

Background: We sought to identify perceptions of neurorehabilitation needs and challenges for paediatric cerebral malaria (CM) survivors post-hospital discharge at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. Methods: An exploratory approach was used to qualitatively investigate current available neurorehabilitation services; investigate the needs of caregivers, CM survivors, providers, and the community; and identify challenges and methods to accessing neurorehabilitation services. Data were collected through semi-structured in-depth interviews (IDIs) and focus group discussions (FGDs).Results: Eighteen data-gathering sessions were conducted with 38 total participants, including 3 FGDs with 23 primary caregivers, 11 IDIs with healthcare workers at QECH, and 4 IDIs with community-based rehabilitation workers (CRWs). FGDs revealed that caregivers lack important knowledge about CM and fear recurrence of CM in their children. Post-CM children and families experience substantial stigma and sociocultural barriers to integrating into their community and accessing neurorehabilitative care. At a community-level, rehabilitation infrastructure, including trained staff, equipment, and programmes, is extremely limited. Rehabilitation services are inequitably accessible, and community-based rehabilitation remains largely unavailable.Conclusions: There is an urgent need to establish further training of rehabilitation personnel at all levels and to build accessible rehabilitation infrastructure in Malawi for post-CM patients. Additional work is required to expand this study across multiple regions for a holistic understanding of neurorehabilitation needs.

GBS is a leading cause of mortality in newborn babies in high- and low-income countries worldwide. Different strains of GBS are characterized by different degrees of virulence, where some are harmlessly carried by humans or animals and others are much more likely to cause disease. The genome sequences of almost 2,000 GBS samples isolated from both animals and humans in high- and low- income countries were analyzed using a pan-genome-wide association study approach. This allowed us to identify 279 genes which are associated with different lineages of GBS, characterized by a different virulence and preferred host. Additionally, we propose that the GBS now carried in humans may have first evolved in animals before expanding clonally once adapted to the human host. These findings are essential to help understand what is causing GBS disease and how the bacteria have evolved and are transmitted., Streptococcus agalactiae (group B streptococcus; GBS) is a colonizer of the gastrointestinal and urogenital tracts, and an opportunistic pathogen of infants and adults. The worldwide population of GBS is characterized by clonal complexes (CCs) with different invasive potentials. CC17, for example, is a hypervirulent lineage commonly associated with neonatal sepsis and meningitis, while CC1 is less invasive in neonates and more commonly causes invasive disease in adults with comorbidities. The genetic basis of GBS virulence and the extent to which different CCs have adapted to different host environments remain uncertain. We have therefore applied a pan-genome-wide association study (GWAS) approach to 1,988 GBS strains isolated from different hosts and countries. Our analysis identified 279 CC-specific genes associated with virulence, disease, metabolism, and regulation of cellular mechanisms that may explain the differential virulence potential of particular CCs. In CC17 and CC23, for example, we have identified genes encoding pilus, quorum-sensing proteins, and proteins for the uptake of ions and micronutrients which are absent in less invasive lineages. Moreover, in CC17, carriage and disease strains were distinguished by the allelic variants of 21 of these CC-specific genes. Together our data highlight the lineage-specific basis of GBS niche adaptation and virulence. The genome sequences of almost 2,000 GBS samples isolated from both animals and humans in high- and low- income countries were analyzed using a pan-genome-wide association study approach. This allowed us to identify 279 genes which are associated with different lineages of GBS, characterized by a different virulence and preferred host. Additionally, we propose that the GBS now carried in humans may have first evolved in animals before expanding clonally once adapted to the human host. These findings are essential to help understand what is causing GBS disease and how the bacteria have evolved and are transmitted.

Background In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. Methods We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. Results Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21–33.78 and OR = 8.58, 95% CI = 2.56–29.08, respectively) and brain swelling (P Conclusions Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.

We aimed to identify the contribution of central nervous system (CNS) viral coinfection to illness in African children with retinopathy-negative or retinopathy-positive cerebral malaria (CM). We collected cerebrospinal fluid (CSF) from 272 children with retinopathy-negative or retinopathy-positive CM and selected CSF from 111 of these children (38 retinopathy positive, 71 retinopathy negative, 2 retinopathy unknown) for analysis by metagenomic next-generation sequencing. We found CSF viral coinfections in 7/38 (18.4%) retinopathy-positive children and in 18/71 (25.4%) retinopathy-negative children. Excluding HIV-1, human herpesviruses (HHV) represented 61% of viruses identified. Excluding HIV-1, CNS viral coinfection was equally likely in children who were retinopathy positive and retinopathy negative (P = 0.1431). Neither mortality nor neurological morbidity was associated with the presence of virus (odds ratio [OR] = 0.276, 95% CI: 0.056-1.363). Retinopathy-negative children with a higher temperature, lower white blood cell count, or being dehydrated were more likely to have viral coinfection. Level of consciousness at admission was not associated with CNS viral coinfection in retinopathy-negative children. Viral CNS coinfection is unlikely to contribute to coma in children with CM. The herpesviruses other than herpes simplex virus may represent incidental bystanders in CM, reactivating during acute malaria infection.

Background - The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment of infants with sepsis in low income settings (LICs), and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 LICs, Staphylococcus aureus, Klebsiella spp. and E.coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was >50% of all isolates, and 44% of Gram-negative isolates were gentamicin resistant. However, ceftriaxone may cause neonatal jaundice and gentamicin may cause deafness. Therefore, we compared parenteral benzylpenicillin plus gentamicin to ceftriaxone as first line treatment, assessing outcome and adverse events.\ud \ud Methods - This was an open randomized trial carried out in the Queen Elizabeth Central Hospital, Blantyre, Malawi from 2010 to 2013. Infants < 60 days of age with possible severe sepsis received either benzylpenicillin and gentamicin or ceftriaxone. Adverse events and outcomes were recorded until 6 months post discharge.\ud \ud Results - 348 infants were included in analyses. Outcome in the benzylpenicillin and gentamicin or ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae 14.5% and 11.2% respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% v 5%, p=0.03. Thirteen (6%) survivors had bilateral hearing loss. There was no difference between the treatment groups. By 6 months post discharge 11 more infants had died and 17 more children were found to have sequelae.\ud \ud Conclusions - Ceftriaxone and gentamicin are safe for infants in our setting. Infants should receive long term follow up as many poor outcomes occurred after hospital discharge.

OBJECTIVE To compare growth among antiretroviral drug and maternal HIV-exposed uninfected (AHEU) versus age-matched and sex-matched HIV-unexposed uninfected (HUU) children. DESIGN Prospective cohort of AHEU children identified from the PROMISE trial (NCT01061151: clinicaltrials.gov registry) and age-matched and sex-matched HUU controls from child-wellness clinics, enrolled (September 2013 to October 2014) in Malawi and Uganda. METHODS Weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head-circumference-for-age (HCAZ) z-scores were derived at 12 months and 24 months of age. Wilcoxon Rank-Sum and Fisher's exact tests were used for unadjusted exposure group comparisons. Generalized Estimating Equations models estimated adjusted relative risks (aRR) for poor growth outcomes. RESULTS Overall, 471 (50.5%) AHEU and 462 (49.5%) HUU children were assessed. Ugandan AHEU compared with HUU children had significantly lower mean LAZ (P

Streptococcus agalactiae (Group B streptococcus, GBS) is a coloniser of the gastrointestinal and urogenital tracts, and an opportunistic pathogen of infants and adults. The worldwide population of GBS is characterised by Clonal Complexes (CCs) with different invasive potentials. CC17 for example, is a hypervirulent lineage commonly associated with neonatal sepsis and meningitis, while CC1 is less invasive in neonates and more commonly causes invasive disease in adults with co-morbidities. The genetic basis of GBS virulence and to what extent different CCs have adapted to different host environments remain uncertain. We have therefore applied a pan-genome wide association study approach to 1988 GBS strains isolated from different hosts and countries. Our analysis identified 279 CC-specific genes associated with virulence, disease, metabolism and regulation of cellular mechanisms that may explain the differential virulence potential of particular CCs. In CC17 and CC23 for example, we have identified genes encoding for pilus, quorum sensing proteins, and proteins for the uptake of ions and micronutrients which are absent in less invasive lineages. Moreover, in CC17, carriage and disease strains were distinguished by the allelic variants of 21 of these CC-specific genes. Together our data highlight the lineage-specific basis of GBS niche adaptation and virulence, and suggest that human-associated GBS CCs have largely evolved in animal hosts before crossing to the humans and then spreading clonally.

Background: Antiretroviral drug and HIV exposed uninfected (AHEU) children were associated with growth deficits in some but not all previous studies which had considerable limitations. Objective: To compare anthropometric outcomes among AHEU, and HIV unexposed uninfected (HUU) children at 12 and 24-months-of-age. Design: Prospective cohort of AHEU children co-enrolled from the PROMISE randomized clinical trial (NCT01061151: clinicaltrials.gov registry); and age-and-sex-matched HUU controls enrolled from child-wellness clinics, between 09/2013-10/2014 in Malawi and Uganda. Methods: Standardized anthropometric and clinical data were collected at 12 and 24-months-of-age. We used WHO-population (2006) growth-standards to derive weight-for-age (WAZ); length-for-age (LAZ); weight-for-length (WLZ); and head-circumference-for-age (HCAZ) z-scores. Wilcoxon Rank-Sum/Fischer's exact tests were used for AHEU and HUU comparisons; and Generalized-Estimating-Equations models controlling for maternal-age, tap-water, electricity/gas, and breastfeeding status were used to estimate adjusted relative risk (aRR). Findings: Overall, 472 (50.5%) AHEU and 462 (49.5%) HUU children were assessed. Ugandan AHEU compared to HUU children had significantly lower mean-Z-scores: LAZ (p 0.05). The risk of stunting (more than two standard deviations below the WHO-population LAZ median) was increased among AHEU compared to HUU children: aRR=2.13 (95% confidence interval (CI): 1.36, 3.33), p=0.001, at 12-months, and aRR=1.67 (95% CI: 1.16, 2.41), p=0.006, at 24-months-of-age, in Uganda; and aRR=1.32 (95% CI: 1.10, 1.66), p=0.018, at 24-months-of-age, in Malawi. Relative-risk of HCAZ below WHO median was increased among AHEU children at 24-months-of-age, aRR = 1.35 (95% CI: 1.02, 1.79), p=0.038, in Uganda; and in similar direction but not significant, aRR=1.35 (95% CI: 0.91, 2.02), p=0.139, in Malawi. Interpretation: Perinatal maternal-HIV and ARV exposures were associated with lower LAZ (including stunting), WAZ and HCAZ at 24 months-of-age compared to sex and age-matched HUU children from similar socioeconomic backgrounds. Funding Statement: The study was funded by the US National Institute of Child Health and Human Development (HD 073296). Declaration of Interests: The authors do not have financial, consultant, institutional or other relationships that might lead to a bias or conflict of interest. Ethics Approval Statement: Regulatory oversight was provided by Institutional Review Boards in Malawi and Uganda, and the Johns Hopkins Medical Institute.

Objective To assess differences in cognition functions and gross brain structure in children seven years after an episode of severe acute malnutrition (SAM), compared with other Malawian children. Design Prospective longitudinal cohort assessing school grade achieved and results of five computer-based (CANTAB) tests, covering three cognitive domains. A subset underwent brain MRI scans which were reviewed using a standardized checklist of gross abnormalities and compared with a reference population of Malawian children. Setting Blantyre, Malawi. Participants Children discharged from SAM treatment in 2006 and 2007 (n 320; median age 9·3 years) were compared with controls: siblings closest in age to the SAM survivors and age/sex-matched community children. Results SAM survivors were significantly more likely to be in a lower grade at school than controls (adjusted OR = 0·4; 95 % CI 0·3, 0·6; P < 0·0001) and had consistently poorer scores in all CANTAB cognitive tests. Adjusting for HIV and socio-economic status diminished statistically significant differences. There were no significant differences in odds of brain abnormalities and sinusitis between SAM survivors (n 49) and reference children (OR = 1·11; 95 % CI 0·61, 2·03; P = 0·73). Conclusions Despite apparent preservation in gross brain structure, persistent impaired school achievement is likely to be detrimental to individual attainment and economic well-being. Understanding the multifactorial causes of lower school achievement is therefore needed to design interventions for SAM survivors to thrive in adulthood. The cognitive and potential economic implications of SAM need further emphasis to better advocate for SAM prevention and early treatment.

Summary Background Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia. Methods We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection. Findings Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p

Cerebral malaria, defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia, affects up to 1 million people per year, the vast majority of them being children living in sub-Saharan Africa. Despite optimal treatment, this condition kills 15% of those affected and leaves 30% of survivors with neurologic sequelae. The clinical diagnosis is hampered by its poor specificity, but the presence or absence of a malarial retinopathy in cerebral malaria has proven to be important in the differentiation of underlying coma etiology. Both antimalarials and intense supportive care are necessary for optimal treatment. As of yet, clinical trials of adjunctive therapies have not improved the high rates of mortality and morbidity. Survivors are at high risk of neurologic sequelae including epilepsy, neurodisabilities and cognitive–behavioral problems. The neuroanatomic and functional bases of these sequelae are being elucidated. Although adjunctive therapy trials continue, the best hope for African children may lie in disease prevention. Strategies include bednets, chemoprophylaxis and vaccine development.

Purpose\ud \ud We looked for herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively), varicella zoster virus (VZV), Epstein–Barr virus (EBV) and cytomegalovirus (CMV) DNA in Malawian adults with clinically suspected meningitis.\ud \ud Methods\ud \ud We collected cerebrospinal fluid (CSF) from consecutive adults admitted with clinically suspected meningitis to Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi, for a period of 3 months. Those with proven bacterial or fungal meningitis were excluded. Real-time polymerase chain reaction (PCR) was performed on the CSF for HSV-1 and HSV-2, VZV, EBV and CMV DNA.\ud \ud Results\ud \ud A total of 183 patients presented with clinically suspected meningitis. Of these, 59 (32 %) had proven meningitis (bacterial, tuberculous or cryptococcal), 39 (21 %) had normal CSF and 14 (8 %) had aseptic meningitis. For the latter group, a herpes virus was detected in 9 (64 %): 7 (50 %) had EBV and 2 (14 %) had CMV, all were human immunodeficiency virus (HIV)-positive. HSV-2 and VZV were not detected. Amongst those with a normal CSF, 8 (21 %) had a detectable herpes virus, of which 7 (88 %) were HIV-positive.\ud \ud Conclusions\ud \ud The spectrum of causes of herpes viral meningitis in this African population is different to that in Western industrialised settings, with EBV being frequently detected in the CSF. The significance of this needs further investigation.

Background Salmonella enterica serovar Typhi causes an estimated 22 million cases of typhoid fever and 216 000 deaths annually worldwide. We investigated an outbreak of unexplained febrile illnesses with neurologic findings, determined to be typhoid fever, along the Malawi-Mozambique border. Methods The investigation included active surveillance, interviews, examinations of ill and convalescent persons, medical chart reviews, and laboratory testing. Classification as a suspected case required fever and ≥1 other finding (eg, headache or abdominal pain); a probable case required fever and a positive rapid immunoglobulin M antibody test for typhoid (TUBEX TF); a confirmed case required isolation of Salmonella Typhi from blood or stool. Isolates underwent antimicrobial susceptibility testing and subtyping by pulsed-field gel electrophoresis (PFGE). Results We identified 303 cases from 18 villages with onset during March-November 2009; 214 were suspected, 43 were probable, and 46 were confirmed cases. Forty patients presented with focal neurologic abnormalities, including a constellation of upper motor neuron signs (n = 19), ataxia (n = 22), and parkinsonism (n = 8). Eleven patients died. All 42 isolates tested were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole; 4 were also resistant to nalidixic acid. Thirty-five of 42 isolates were indistinguishable by PFGE. Conclusions The unusual neurologic manifestations posed a diagnostic challenge that was resolved through rapid typhoid antibody testing in the field and subsequent blood culture confirmation in the Malawi national reference laboratory. Extending laboratory diagnostic capacity, including blood culture, to populations at risk for typhoid fever in Africa will improve outbreak detection, response, and clinical treatment.

The first African Child Neurology Association meeting identified key challenges that the continent faces to improve the health of children with neurology disorders. The capacity to diagnose common neurologic conditions and rare disorders is lacking. The burden of neurologic disease on the continent is not known, and this lack of knowledge limits the ability to lobby for better health care provision. Inability to practice in resource-limited settings has led to the migration of skilled professionals away from Africa. Referral systems from primary to tertiary are often unpredictable and chaotic. There is a lack of access to reliable supplies of basic neurology treatments such as antiepileptic drugs. Few countries have nationally accepted guidelines either for the management of epilepsy or status epilepticus. There is a great need to develop better training capacity across Africa in the recognition and management of neurologic conditions in children, from primary health care to the subspecialist level.

Plasmodium falciparum and other human malaria parasites can cause a variety of life-threatening syndromes. Diagnosis is difficult because none of these syndromes is unique to malaria, and parasitemia may be incidental rather than responsible for the illness. Malaria must be considered in the differential diagnosis of each of the severe syndromes it can cause – severe anemia, coma and convulsions, acidosis, hypoglycemia, shock, acute renal failure, intravascular hemolysis, acute respiratory distress syndrome and disseminated intravascular coagulation. The possibility of an alternative or additional infection must be considered and, in many circumstances, covered by initial emergency treatment. In the comatose patient the presence of a distinctive retinopathy is suggestive that malaria is the cause of the disease. Management must begin with emergency measures to ensure vital functions, followed by prompt provision of supportive measures (airway protection, glucose, fluids, oxygen, blood, antipyresis and ant...

Background. The Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW) has routinely collected specimens for blood culture from febrile patients, and cerebrospinal fluid from patients with suspected meningitis, presenting to Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi, since 1998. Methods. We present bloodstream infection (BSI) and meningitis surveillance data from 1998 to 2014. Automated blood culture, manual speciation, serotyping, and antimicrobial susceptibility testing were performed at MLW. Population data for minimum-incidence estimates in urban Blantyre were drawn from published estimates. Results. Between 1998 and 2014, 167 028 blood cultures were taken from adult and pediatric medical patients presenting to QECH; Salmonella Typhi was isolated on 2054 occasions (1.2%) and nontyphoidal Salmonella (NTS) serovars were isolated 10 139 times (6.1%), of which 8017 (79.1%) were Salmonella Typhimurium and 1608 (15.8%) were Salmonella Enteritidis. There were 392 cases of NTS meningitis and 9 cases of Salmonella Typhi meningitis. There have been 3 epidemics of Salmonella BSI in Blantyre; Salmonella Enteritidis from 1999 to 2002, Salmonella Typhimurium from 2002 to 2008, and Salmonella Typhi, which began in 2011 and was ongoing in 2014. Multidrug resistance has emerged in all 3 serovars and is seen in the overwhelming majority of isolates, while resistance to third-generation cephalosporins and fluoroquinolones is currently uncommon but has been identified. Conclusions. Invasive Salmonella disease in Malawi is dynamic and not clearly attributable to a single risk factor, although all 3 epidemics were associated with multidrug resistance. To inform nonvaccine and vaccine interventions, reservoirs of disease and modes of transmission require further investigation.

In 1891, Winter1 described the first 4 cases of tuberculous meningitis (TBM), in which “paracenteses of the theca vertebralis was performed to relieve cerebrospinal fluid (CSF) fluid pressure.” Since this original description of the lumbar puncture (LP) procedure, neurologists worldwide have relied on LPs for both diagnostic and therapeutic purposes. In resource-limited settings, LPs are often the only neurologic test available to aid the clinician in neurologic diagnosis. In sub-Saharan Africa, a large number of patients present to hospitals with acute neurologic symptoms, including those who are HIV-infected and have opportunistic infections such as cryptococcal meningitis and TBM. In these clinical scenarios, LPs are an essential point-of-care diagnostic and therapeutic procedure.2 The benefits of the LP as a diagnostic tool are well-known, but it is important to emphasize that therapeutic LPs are a low-cost measure to monitor and treat intracranial pressure (ICP) due to nonobstructive hydrocephalus in regions of the world where more sophisticated testing and treatment are unavailable due to limitations of medical equipment, medication supplies, and clinical personnel, including specialized neurologists and neurosurgeons.

HIV-1 is typically CCR5 using (R5) and T cell tropic (T-tropic), targeting memory CD4 + T cells throughout acute and chronic infections. However, viruses can expand into alternative cells types. Macrophage-tropic (M-tropic) HIV-1 variants have evolved to infect macrophages, which have only low levels of surface CD4. Most M-tropic variants have been isolated from the central nervous system during late-stage chronic infection. We used the HIV-1 env genes of well-defined, subject-matched M-tropic and T-tropic viruses to characterize the phenotypic features of the M-tropic Env protein. We found that, compared to T-tropic viruses, M-tropic viruses infect monocyte-derived macrophages (MDMs) on average 28-fold more efficiently, use low-density CD4 more efficiently, have increased sensitivity to soluble CD4 (sCD4), and show trends toward sensitivity to some CD4 binding site antibodies but no difference in sensitivity to antibodies targeting the CD4-bound conformation. M-tropic viruses also displayed a trend toward resistance to neutralization by monoclonal antibodies targeting the V1/V2 region of Env, suggesting subtle changes in Env protein conformation. The paired M- and T-tropic viruses did not differ in autologous serum neutralization, temperature sensitivity, entry kinetics, intrinsic infectivity, or Env protein incorporation. We also examined viruses with modestly increased CD4 usage. These variants have significant sensitivity to sCD4 and may represent evolutionary intermediates. CD4 usage is strongly correlated with infectivity of MDMs over a wide range of CD4 entry phenotypes. These data suggest that emergence of M-tropic HIV-1 includes multiple steps in which a phenotype of increased sensitivity to sCD4 and enhanced CD4 usage accompany subtle changes in Env conformation. IMPORTANCE HIV-1 typically replicates in CD4 + T cells. However, HIV-1 can evolve to infect macrophages, especially within the brain. Understanding how CCR5-using macrophage-tropic viruses evolve and differ from CCR5-using T cell-tropic viruses may provide insights into viral evolution and pathogenesis within the central nervous system. We characterized the HIV-1 env viral entry gene from subject-matched macrophage-tropic and T cell-tropic viruses to identify entry features of macrophage-tropic viruses. We observed several differences between T cell-tropic and macrophage-tropic Env proteins, including functional differences with host CD4 receptor engagement and possible changes in the CD4 binding site and V1/V2 region. We also identified viruses with phenotypes between that of “true” macrophage-tropic and T cell-tropic viruses, which may represent evolutionary intermediates in a multistep process to macrophage tropism.

Cerebral palsy is the most common cause of physical disability in children worldwide. However, little is reported on this condition in the African context. Doctors from 22 countries in Africa, and representatives from a further 5 countries outside Africa, met to discuss the challenges in the evaluation and management of children with cerebral palsy in Africa and to propose service needs and further research. Basic care is limited by the poor availability of diagnostic facilities or medical personnel with experience and expertise in managing cerebral palsy, exacerbated by lack of available interventions such as medications, surgical procedures, or even regular therapy input. Relevant guidelines are lacking. In order to guide services for children with existing disabilities, to effectively target the main etiologies and to develop preventive strategies for the continent, research priorities must include multicenter collaborative studies looking at the prevalence, risk factors, and treatment of cerebral palsy.

In addition to encountering most of the conditions treated by clinicians in the West, clinicians in the tropics are faced with unique tropical encephalopathies. These are largely but not entirely infectious in nature. Despite the relatively low cost of EEG technology, it remains unavailable in many low-income tropical settings even at the tertiary care level. Where available, the EEG recordings and interpretation are often of unacceptable quality. Nonetheless, there are existing data on the EEG patterns seen in malaria and a number of tropical viral, bacterial, and parasitic infestations.

This article presents key findings from the International Child Neurology Association/African Child Neurology Association Workshop. The viability of international guidelines for the management of children with epilepsy should be reviewed within each African country, and adapted to comply with the regional capacity. Such recommendations can be used to lobby for resources. More training centers should be developed in Africa, so that specialists can be trained within Africa, in skills relevant to the continent, in collaboration with “out of Africa” visiting-specialists to develop the concept of “train the trainers.” At least 1 child neurology specialist per 100 000 of the population is required. Specific to Africa are the challenges from stigma, prejudice, and misconceptions. “Epilepsy teams,” inclusive of the traditional healers, would enable management of increased numbers of children, and challenge policy such that it is the right of the child with epilepsy to have reliable access to appropriate antiepileptic drugs, support, and health care equity between the rural and urban settings.