Parasitic, bacterial, viral, immune-mediated, metabolic and nutritional factors associated with nodding syndrome.

Nodding syndrome is a neglected, disabling and potentially fatal epileptic disorder of unknown aetiology affecting thousands of individuals mostly confined to Eastern sub-Saharan Africa. Previous studies have identified multiple associations-including Onchocerca volvulus, antileiomodin-1 antibodies, vitamin B6 deficiency and measles virus infection-yet, none is proven causal. We conducted a case-control study of children with early-stage nodding syndrome (symptom onset <1 year). Cases and controls were identified through a household survey in the Greater Mundri area in South Sudan. A wide range of parasitic, bacterial, viral, immune-mediated, metabolic and nutritional risk factors was investigated using conventional and state-of-the-art untargeted assays. Associations were examined by multiple logistic regression analysis, and a hypothetical causal model was constructed using structural equation modelling. Of 607 children with nodding syndrome, 72 with early-stage disease were included as cases and matched to 65 household- and 44 community controls. Mansonella perstans infection (odds ratio 7.04, 95% confidence interval 2.28-21.7), Necator americanus infection (odds ratio 2.33, 95% confidence interval 1.02-5.3), higher antimalarial seroreactivity (odds ratio 1.75, 95% confidence interval 1.20-2.57), higher vitamin E concentration (odds ratio 1.53 per standard deviation increase, 95% confidence interval 1.07-2.19) and lower vitamin B12 concentration (odds ratio 0.56 per standard deviation increase, 95% confidence interval 0.36-0.87) were associated with higher odds of nodding syndrome. In a structural equation model, we hypothesized that Mansonella perstans infection, higher vitamin E concentration and fewer viral exposures increased the risk of nodding syndrome while lower vitamin B12 concentration, Necator americanus and malaria infections resulted from having nodding syndrome. We found no evidence that Onchocerca volvulus, antileiomodin-1 antibodies, vitamin B6 and other factors were associated with nodding syndrome. Our results argue against several previous causal hypotheses including Onchocerca volvulus. Instead, nodding syndrome may be caused by a complex interplay between multiple pathogens and nutrient levels. Further studies need to confirm these associations and determine the direction of effect.

Viral, Bacterial, Metabolic, and Autoimmune Causes of Severe Acute Encephalopathy in Sub-Saharan Africa: A Multicenter Cohort Study.

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.

Divergent Rhabdovirus Discovered in a Patient with New-Onset Nodding Syndrome.

A divergent rhabdovirus was discovered in the bloodstream of a 15-year-old girl with Nodding syndrome from Mundri West County in South Sudan. Nodding syndrome is a progressive degenerative neuropathy of unknown cause affecting thousands of individuals in Sub-Saharan Africa. The index case was previously healthy until she developed head-nodding seizures four months prior to presentation. Virus discovery by VIDISCA-NGS on the patient's plasma detected multiple sequence reads belonging to a divergent rhabdovirus. The viral load was 3.85 × 103 copies/mL in the patient's plasma and undetectable in her cerebrospinal fluid. Further genome walking allowed for the characterization of full coding sequences of all the viral proteins (N, P, M, U1, U2, G, U3, and L). We tentatively named the virus "Mundri virus" (MUNV) and classified it as a novel virus species based on the high divergence from other known viruses (all proteins had less than 43% amino acid identity). Phylogenetic analysis revealed that MUNV forms a monophyletic clade with several human-infecting tibroviruses prevalent in Central Africa. A bioinformatic machine-learning algorithm predicted MUNV to be an arbovirus (bagged prediction strength (BPS) of 0.9) transmitted by midges (BPS 0.4) with an artiodactyl host reservoir (BPS 0.9). An association between MUNV infection and Nodding syndrome was evaluated in a case-control study of 72 patients with Nodding syndrome (including the index case) matched to 65 healthy households and 48 community controls. No subject, besides the index case, was positive for MUNV RNA in their plasma. A serological assay detecting MUNV anti-nucleocapsid found, respectively, in 28%, 22%, and 16% of cases, household controls and community controls to be seropositive with no significant differences between cases and either control group. This suggests that MUNV commonly infects children in South Sudan yet may not be causally associated with Nodding syndrome.

Premature Mortality, Risk Factors, and Causes of Death Following Childhood-Onset Neurological Impairments: A Systematic Review.

Background: Neurological impairment (NI) and disability are associated with reduced life expectancy, but the risk and magnitude of premature mortality in children vary considerably across study settings. We conducted a systematic review to estimate the magnitude of premature mortality following childhood-onset NI worldwide and to summarize known risk factors and causes of death. Methods: We searched various databases for published studies from their inception up to 31st October 2020. We included all cohort studies that assessed the overall risk of mortality in individuals with childhood-onset epilepsy, intellectual disability (ID), and deficits in hearing, vision and motor functions. Comparative measures of mortality such as the standardized mortality ratio (SMR), risk factors and causes were synthesized quantitatively under each domain of impairment. This review is registered on the PROSPERO database (registration number CRD42019119239). Results: The search identified 2,159 studies, of which 24 studies were included in the final synthesis. Twenty-two (91.7%) studies originated from high-income countries (HICs). The median SMR was higher for epilepsy compared with ID (7.1 [range 3.1-22.4] vs. 2.9 [range 2.0-11.6]). In epilepsy, mortality was highest among younger age groups, comorbid neurological disorders, generalized seizures (at univariable levels), untreatable epilepsy, soon after diagnosis and among cases with structural/metabolic types, but there were no differences by sex. Most deaths (87.5%) were caused by non-epilepsy-related causes. For ID, mortality was highest in younger age groups and girls had a higher risk compared to the general population. Important risk factors for premature mortality were severe-to-profound severity, congenital disorders e.g., Down Syndrome, comorbid neurological disorders and adverse pregnancy and perinatal events. Respiratory infections and comorbid neurological disorders were the leading causes of death in ID. Mortality is infrequently examined in impairments of vision, hearing and motor functions. Summary: The risk of premature mortality is elevated in individuals with childhood-onset NI, particularly in epilepsy and lower in ID, with a need for more studies for vision, hearing, and motor impairments. Survival in NI could be improved through interventions targeting modifiable risk factors and underlying causes.

A cohort analysis of survival and outcomes in severely anaemic children with moderate to severe acute malnutrition in Malawi.

INTRODUCTION: Moderate to severe acute malnutrition (SAM/MAM) and severe anaemia are important and associated co-morbidities in children aged less than five years. Independently, these two morbidities are responsible for high risk of in-hospital and post-discharge deaths and hospital readmissions. The primary objective of this study is to investigate the risk of death among severely anaemic children with moderate to severe acute malnutrition compared to children with severe anaemia alone. METHODS: This was a retrospective analysis of data collected from a large prospective study that was investigating severe anaemia in children aged less than 5 years old. The study was conducted at Queen Elizabeth Central Hospital in Blantyre and Chikhwawa district hospital in southern Malawi. Children aged less than five years old; with severe anaemia were screened and enrolled. Each child was followed up for eighteen months at one, three, six, twelve and eighteen months after enrolment. Data were analysed using STATA 15. RESULTS: Between July 2002 and July 2004, 382 severely anaemic children were enrolled in the main study. A total of 52 children were excluded due to missing anthropometric data. Out of the 330 included, 53 children were moderately to severely malnourished and 277 were not. At the end of the 18-month follow period, 28.3% of children with MAM/SAM died compared to 13% of children without MAM/SAM (RR 2.1, CI 0.9-4.2, p = 0.03). Similarly, children with moderate to severe malnutrition reported a significantly higher number of malaria infection cases (33.9%) compared to children with severe anaemia alone (27.9%, p = 0.02). However, the number of hospitalizations and recurrence of severe anaemia was similar and not statistically significant between the two groups (RR 0.8 (0.4-1.4), p = 0.6 and RR 1.1 (0.3-2.8), p = 0.8). CONCLUSION: Among children with severe anaemia, those who also had moderate to severe malnutrition had a twofold higher risk of dying compared to those who did not. It is therefore crucial to investigate acute malnutrition among severely anaemic children, as this might be treatable factor associated with high mortality.

The clinical use of longitudinal bio-electrical impedance vector analysis in assessing stabilization of children with severe acute malnutrition.

BACKGROUND & AIMS: Severe Acute Malnutrition (SAM) in children is determined using anthropometry. However, bio-electrical impedance (BI) analysis could improve the estimation of altered body composition linked to edema and/or loss of lean body mass in children with SAM. We aimed to assess: 1) the changes in BI parameters during clinical stabilization and 2) whether BI parameters add prognostic value for clinical outcome beyond the use of anthropometry. METHODS: This prospective observational study enrolled children, aged 6-60 months, that were admitted at Queen Elizabeth Central Hospital in Blantyre, Malawi, for complicated SAM (i.e., having either severe wasting or edematous SAM with a complicating illness). Height, weight, mid-upper arm circumference (MUAC), and BI were measured on admission and after clinical stabilization. BI measures were derived from height-adjusted indices of resistance (R/H), reactance (Xc/H), and phase angle (PA) and considered to reflect body fluids and soft tissue in BI vector analysis (BIVA). RESULTS: We studied 183 children with SAM (55% edematous; age 23.0 ± 12.0 months; 54% male) and 42 community participants (age 20.1 ± 12.3 months; male 62%). Compared to community participants, the BIVA of children with edematous SAM were short with low PA and positioned low on the hydration axis which reflects severe fluid retention. In contrast, children with severe wasting had elongated vectors with a PA that was higher than children with edematous SAM but lower than community participants. Their BIVA position fell within the top right quadrant linked to leanness and dehydration. BIVA from severely wasted and edematous SAM patients differed between groups and from community children both at admission and after stabilization (p < 0.001). Vector position shifted during treatment only in children with edematous SAM (p < 0.001) and showed a upward translation suggestive of fluid loss. While PA was lower in children with SAM, PA did not contribute more than anthropometry alone towards explaining mortality, length of stay, or time-to-discharge or time-to-mortality. The variability and heterogeneity in BI measures was high and their overall added predictive value for prognosis of individual children was low. CONCLUSIONS: BIVA did not add prognostic value over using anthropometry alone to predict clinical outcome. Several implementation challenges need to be optimized. Thus, in low-resource settings, the routine use of BI in the management of pediatric malnutrition is questionable without improved implementation.

Clinical features to distinguish meningitis among young infants at a rural Kenyan hospital.

BACKGROUND: Detection of meningitis is essential to optimise the duration and choice of antimicrobial agents to limit mortality and sequelae. In low and middle-income countries most health facilities lack laboratory capacity and rely on clinical features to empirically treat meningitis. OBJECTIVE: We conducted a diagnostic validation study to investigate the performance of clinical features (fever, convulsions, irritability, bulging fontanel and temperature ≥39°C) and WHO-recommended signs (drowsiness, lethargy, unconsciousness, convulsions, bulging fontanel, irritability or a high-pitched cry) in discriminating meningitis in young infants. DESIGN: Retrospective cohort study. SETTING: Kilifi County Hospital. PATIENTS: Infants aged <60 days hospitalised between 2012 and 2016. MAIN OUTCOME MEASURE: Definite meningitis defined as positive cerebrospinal fluid (CSF) culture, microscopy or antigen test, or leucocytes ≥0.05 x 10∧9/L. RESULTS: Of 4809 infants aged <60 days included, 81 (1.7%) had definite meningitis. WHO-recommended signs had sensitivity of 58% (95% CI 47% to 69%) and specificity of 57% (95% CI 56% to 59%) for definite meningitis. Addition of history of fever improved sensitivity to 89% (95% CI 80% to 95%) but reduced specificity to 26% (95% CI 25% to 27%). Presence of ≥1 of 5 previously identified signs had sensitivity of 79% (95% CI 69% to 87%) and specificity of 51% (95% CI 50% to 53%). CONCLUSIONS: Despite a lower prevalence of definite meningitis, the performance of previously identified signs at admission in predicting meningitis was unchanged. Presence of history of fever improves the sensitivity of WHO-recommended signs but loses specificity. Careful evaluation, repeated assessment and capacity for lumbar puncture and CSF microscopy to exclude meningitis in most young infants with potential signs are essential to management in this age group.

Malaria Chemoprevention in the Postdischarge Management of Severe Anemia.

BACKGROUND: Children who have been hospitalized with severe anemia in areas of Africa in which malaria is endemic have a high risk of readmission and death within 6 months after discharge. No prevention strategy specifically addresses this period. METHODS: We conducted a multicenter, two-group, randomized, placebo-controlled trial in nine hospitals in Kenya and Uganda to determine whether 3 months of malaria chemoprevention could reduce morbidity and mortality after hospital discharge in children younger than 5 years of age who had been admitted with severe anemia. All children received standard in-hospital care for severe anemia and a 3-day course of artemether-lumefantrine at discharge. Two weeks after discharge, children were randomly assigned to receive dihydroartemisinin-piperaquine (chemoprevention group) or placebo, administered as 3-day courses at 2, 6, and 10 weeks after discharge. Children were followed for 26 weeks after discharge. The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. Conditional risk-set modeling for recurrent events was used to calculate hazard ratios with the use of the Prentice-Williams-Peterson total-time approach. RESULTS: From May 2016 through May 2018, a total of 1049 children underwent randomization; 524 were assigned to the chemoprevention group and 525 to the placebo group. From week 3 through week 26, a total of 184 events of readmission or death occurred in the chemoprevention group and 316 occurred in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.54 to 0.78; P<0.001). The lower incidence of readmission or death in the chemoprevention group than in the placebo group was restricted to the intervention period (week 3 through week 14) (hazard ratio, 0.30; 95% CI, 0.22 to 0.42) and was not sustained after that time (week 15 through week 26) (hazard ratio, 1.13; 95% CI, 0.87 to 1.47). No serious adverse events were attributed to dihydroartemisinin-piperaquine. CONCLUSIONS: In areas with intense malaria transmission, 3 months of postdischarge malaria chemoprevention with monthly dihydroartemisinin-piperaquine in children who had recently received treatment for severe anemia prevented more deaths or readmissions for any reason after discharge than placebo. (Funded by the Research Council of Norway and the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT02671175.).

A possible role for hepcidin in the detection of iron deficiency in severely anaemic HIV-infected patients in Malawi.

INTRODUCTION: Iron deficiency is a treatable cause of severe anaemia in low-and-middle-income-countries (LMIC). Diagnosing it remains challenging as peripheral blood markers poorly reflect bone-marrow iron deficiency (BM-ID), especially in the context of HIV-infection. METHODS: Severely anaemic (haemoglobin ≤70g/l) HIV-infected adults were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. BM-ID was evaluated. Accuracy of blood markers (including hepcidin, mean corpuscular volume, mean cellular haemoglobin concentration, serum iron, serum ferritin, soluble transferrin receptor (sTfR), sTfR index, sTfR-ratio) to detect BM-ID was evaluated by ROC area under the curve (AUCROC). RESULTS: Seventy-three patients were enrolled and 35 (48.0%) had BM-ID. Although hepcidin and MCV performed best (AUCROC of 0.593 and 0.545 respectively) all markers performed poorly in identifying BM-ID (ROC<0.6). The AUCROC of hepcidin in males was 0.767 (sensitivity 80%, specificity 78%) and in women 0.490 (sensitivity 60%, specificity 61%). CONCLUSION: BM-ID deficiency was common in severely anaemic HIV-infected patients. It is an important and potential treatable contributor to severe anaemia but lack of definitive biomarkers makes it difficult to accurately assess iron status in these patients. Further investigation of the potential of hepcidin is needed, including exploration of the differences in hepcidin results between males and females.

Severe anaemia complicating HIV in Malawi; Multiple co-existing aetiologies are associated with high mortality.

BACKGROUND: Severe anaemia is a major cause of morbidity and mortality in HIV-infected adults living in resource-limited countries. Comprehensive data on the aetiology are lacking but are needed to improve outcomes. METHODS: HIV-infected adults with severe (haemoglobin ≤70g/l) or very severe anaemia (haemoglobin ≤ 50 g/l) were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Fifteen potential causes and associations with anaemia severity and mortality were explored. RESULTS: 199 patients were enrolled: 42.2% had very severe anaemia and 45.7% were on ART. More than two potential causes for anaemia were present in 94% of the patients including iron deficiency (55.3%), underweight (BMI<20: 49.7%), TB infection (41.2%) and unsuppressed HIV infection (viral load >1000 copies/ml) (73.9%). EBV/CMV co-infection (16.5%) was associated with very severe anaemia (OR 2.8 95% CI 1.1-6.9). Overall mortality was high (53%; 100/199) with a median time to death of 17.5 days (IQR 6-55) days. Death was associated with folate deficiency (HR 2.2; 95% CI 1.2-3.8) and end stage renal disease (HR 3.2; 95% CI 1.6-6.2). CONCLUSION: Mortality among severely anaemic HIV-infected adults is strikingly high. Clinicians should be aware of the urgent need for a multifactorial approach including starting or optimising HIV treatment, considering TB treatment, nutritional support and optimising renal management.

Premature mortality in children aged 6-9 years with neurological impairments in rural Kenya: a cohort study.

BACKGROUND: Neurological impairments might significantly contribute to reduced life expectancy in low-income and middle-income countries (LMICs). There are no empirical studies of premature mortality in children with neurological impairments in Africa. This study estimated the risk of premature mortality in children with neurological impairments and identified risk factors and causes of death. METHODS: We did a cohort study based on a two-stage epidemiological survey in the Kilifi Health and Demographic Surveillance System (Kilifi, Kenya). Study participants were children aged 6-9 years. In the first stage, five trained field workers administered a low-cost screening tool to a random sample of households. In the second stage, we assessed for neurological impairments in five domains (epilepsy, cognitive impairments, vision impairments, hearing impairments, and motor impairments) using comprehensive clinical evaluation and extensive neuropsychological assessments. From the two-stage survey we identified a cohort of children with neurological impairment and a cohort of matched controls. We also enrolled an age-matched sample from the general population. The primary outcome was all-cause mortality. Mortality rates, standardised mortality ratio (SMR), and hazard ratios (HR) for risk factors were estimated and causes of death identified. FINDINGS: We enrolled 306 children with neurological impairment, 9912 survey controls, and 22 873 age-matched participants from the general population, and followed up the cohorts between June 1, 2001, and Aug 31, 2018. Median follow-up was 14·5 years (IQR 8·6-17·2). 11 (3·9%) of 284 children with neurological impairment, 92 (1·0%) of 9009 controls, and 272 (1·2%) of 22 873 participants in the general population sample died during the follow-up. Overall mortality rates were 309·8 per 100 000 person-years of observation (95% CI 126·7-492·9) in children with neurological impairment, 80·8 per 100 000 person-years of observation (64·3-97·3) in controls, and 98·8 per 100 000 person-years of observation (87·1-110·6) in the general population sample (mortality rate ratio 3·83, 95% CI 2·05-7·16, p<0·001, compared with controls; 3·13, 1·71-5·72, p<0·001, compared with the general population). Mortality risk in children with neurological impairment was not dependent on the severity of impairment (p=0·291) nor on a specific neurological impairment domain (p=0·205). The overall risk of death adjusted for age and sex was higher in children with neurological impairment compared with controls (HR 4·24, 95% CI 2·26-7·94, p=0·002). An SMR of 3·15 (95% CI 1·66-5·49) was obtained after using the general population sample as the reference for indirect standardisation. In multivariable risk factor analysis, developmental delay (adjusted HR 18·92, 95% CI 2·23-160·44, p=0·007) and severe malnutrition (20·92, 3·14-139·11, p=0·002) increased the risk of mortality in children with neurological impairment. Infections such as HIV/AIDS and accidents were common among all decedents. INTERPRETATION: The risk of premature mortality was higher in children diagnosed with neurological impairments compared with the general population and was increased by developmental delay and severe malnutrition. Child development and nutritional status should be assessed in all children in LMICs and tailored interventions started to improve outcomes. FUNDING: Wellcome Trust, DELTAS Africa Initiative.

Novel Orthobunyavirus Identified in the Cerebrospinal Fluid of a Ugandan Child With Severe Encephalopathy.

A Ugandan child with an unexplained encephalitis was investigated using viral metagenomics. Several sequences from all segments of a novel orthobunyavirus were found. The S-segment, used for typing, showed 41% amino acid diversity to its closest relative. The virus was named Ntwetwe virus, after the hometown of the patient.

Effect of Antibiotic-Mediated Microbiome Modulation on Rotavirus Vaccine Immunogenicity: A Human, Randomized-Control Proof-of-Concept Trial.

Rotavirus vaccines (RVV) protect against childhood gastroenteritis caused by rotavirus (RV) but have decreased effectiveness in low- and middle-income settings. This proof-of-concept, randomized-controlled, open-label trial tested if microbiome modulation can improve RVV immunogenicity. Healthy adults were randomized and administered broad-spectrum (oral vancomycin, ciprofloxacin, metronidazole), narrow-spectrum (vancomycin), or no antibiotics and then vaccinated with RVV, 21 per group per protocol. Baseline anti-RV IgA was high in all subjects. Although antibiotics did not alter absolute anti-RV IgA titers, RVV immunogenicity was boosted at 7 days in the narrow-spectrum group. Further, antibiotics increased fecal shedding of RV while also rapidly altering gut bacterial beta diversity. Beta diversity associated with RVV immunogenicity boosting at day 7 and specific bacterial taxa that distinguish RVV boosters and RV shedders were identified. Despite the negative primary endpoint, this study demonstrates that microbiota modification alters the immune response to RVV and supports further exploration of microbiome manipulation to improve RVV immunogenicity.

Multiplex Real-time PCR Detection of Intestinal Protozoa in HIV-infected Children in Malawi: Enterocytozoon Bieneusi Is Common and Associated With Gastrointestinal Complaints and May Delay BMI (Nutritional Status) Recovery.

BACKGROUND: Intestinal protozoa are common opportunistic infections in HIV patients. Longitudinal studies on either the clinical relevance or the effect of immune reconstitution by antiretroviral therapy on intestinal protozoan infections in children are lacking however. This study investigates prevalence and clinical relevance of intestinal protozoa in HIV-infected Malawian children before and during their first year of antiretroviral treatment (ART). METHODS: Stool samples collected at enrolment and during follow-up were tested for nonopportunistic (Giardia lamblia, Dientamoeba fragilis, Entamoeba histolytica) and opportunistic protozoa (Enterocytozoon bieneusi, Encephalitozoon spp., Cryptosporidium spp. and Cystoisospora belli) using multiplex real-time polymerase chain reaction. Associations between infections and clinical symptoms were evaluated using univariate methods. RESULTS: Nonopportunistic and opportunistic protozoa were detected in 40% (14/35) and 46% (16/35) of children at baseline, respectively. E. bieneusi was the most prevalent protozoa (37%, 13/35) and associated with gastrointestinal complaints (43% in positive (10/13) versus 18% (4/22) in E. bieneusi-negative children, P = 0.001. Body mass index recovery during 12 months of ART was more commonly delayed in E. bieneusi-positive children (+0.29 +standard deviation 0.83) than E. bieneusi-negative children (+1.03 +standard deviation 1.25; P = 0.05). E. bieneusi was not detected after 12 months of ART. CONCLUSIONS: E. bieneusi was the most prevalent opportunistic intestinal protozoa, present in over a third of study participants before initiation of ART. Although all children cleared E. bieneusi after 12 months of ART, E. bieneusi was associated with gastrointestinal complaints and may delay body mass index recovery. Trials to assess effect of treatment of E. bieneusi on nutritional status should be considered in HIV-infected African children.

Lyme Borreliosis in Children: A Tertiary Referral Hospital-Based Retrospective Analysis.

Lyme borreliosis (LB) is an endemic disease in adults in Western countries. Although children may also be infected, pediatric studies on LB are scarce. This study aims to estimate the incidence of LB among children with a clinical suspicion for Lyme in a tertiary referral center in the Netherlands. Patient chart data on medical history, clinical signs and symptoms, diagnostic test results and diagnoses were collected using standardized case record forms. Patients were categorized based on clinical and laboratory findings using a modified, previously published classification system. We included 325 children, with a median age of 11.9 years, of whom 61.8% were female. LB was diagnosed in 38 of the referred children (11.7%). However, of the 85 patients who were specifically referred to the Lyme clinic, 28 (32.9%) were diagnosed with LB. Of the specifically referred Lyme-positive patients, 11 (39.3%) had a definitive LB diagnosis. Twelve children had a posttreatment LB syndrome. In line with previous reports in adults, only a small proportion of children referred with a suspicion of LB were diagnosed with definite or probable LB, which illustrates the difficulty in diagnosing LB by the general practitioner or pediatrician in a district hospital.

The Relation Between Malnutrition and the Exocrine Pancreas: A Systematic Review.

OBJECTIVE: The relation between malnutrition and exocrine pancreatic insufficiency (EPI) has been described previously, but it is unclear if malnutrition leads to EPI or vice versa. We systematically synthesized current evidence evaluating the association between malnutrition and EPI in children. METHODS: Pubmed, Embase, and Cochrane databases were searched from inception until February 2017. We included cohort or case-controlled studies in children reporting on prevalence or incidence of EPI and malnutrition. Data generation was performed independently by 2 authors. Quality was assessed by using quality assessment tools from the National Heart, Lung, and Blood Institute. RESULTS: Nineteen studies were divided into 2 groups: 10 studies showing EPI leading to malnutrition, and 9 studies showing malnutrition leading to EPI. Because of heterogeneity in design, definitions, and outcome measures, pooling of results was impossible. Quality was good in 4 of 19 studies. Pancreatic insufficiency was linked to decreased nutritional status in 8 of 10 articles, although this link was not specified properly in most articles. In malnourished children, improvement was seen in pancreatic function in 7 of 9 articles after nutritional rehabilitation. The link between the 2 was not further specified. Heterogeneity exists with respect to definitions, outcome measures, and study design. CONCLUSIONS: There is sufficient evidence for an association between EPI and malnutrition. We could not confirm whether there is a correlation or causality between EPI or malnutrition. It was therefore not possible to draw firm conclusions from this systematic review on underlying pathophysiological mechanisms between EPI and malnutrition. More observational clinical trials are crucially needed.

Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition: A Randomized Controlled Trial.

OBJECTIVE: To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition. STUDY DESIGN: We conducted a randomized, controlled trial in 90 children aged 6-60 months with complicated severe acute malnutrition at the Queen Elizabeth Central Hospital in Malawi. All children received standard care; the intervention group also received PERT for 28 days. RESULTS: Children treated with PERT for 28 days did not gain more weight than controls (13.7 ± 9.0% in controls vs 15.3 ± 11.3% in PERT; P = .56). Exocrine pancreatic insufficiency was present in 83.1% of patients on admission and fecal elastase-1 levels increased during hospitalization mostly seen in children with nonedematous severe acute malnutrition (P <.01). Although the study was not powered to detect differences in mortality, mortality was significantly lower in the intervention group treated with pancreatic enzymes (18.6% vs 37.8%; P < .05). Children who died had low fecal fatty acid split ratios at admission. Exocrine pancreatic insufficiency was not improved by PERT, but children receiving PERT were more likely to be discharged with every passing day (P = .02) compared with controls. CONCLUSIONS: PERT does not improve weight gain in severely malnourished children but does increase the rate of hospital discharge. Mortality was lower in patients on PERT, a finding that needs to be investigated in a larger cohort with stratification for edematous and nonedematous malnutrition. Mortality in severe acute malnutrition is associated with markers of poor digestive function. TRIAL REGISTRATION: ISRCTN.com: 57423639.

The Intestinal Microbiome in Infectious Diseases: The Clinical Relevance of a Rapidly Emerging Field.

The field of infectious disease is undergoing a paradigm shift as the intestinal microbiome is becoming understood. The aim of this review is to inform infectious disease physicians of the potential relevance of the intestinal microbiome to their practice. We searched Medline using both index and text words relating to infectious diseases, microbiome, and probiotics. Relevant articles published up through 2017 were reviewed within Rayyan. The review illustrates pathophysiologic concepts linking the microbiome and infectious diseases; specifically, the intestinal microbiome's relevance to early immune development, the microbiome and enteric infections, the microbiome's relevance in compromised hosts, and antimicrobial resistance. Within each subject, there are specific examples of diseases and at-risk patient populations where a role for the microbiome has been strongly established. This provides an overview of the significance of the intestinal microbiome to microbiology, pediatric and adult infectious diseases with an underpinning of concepts useful for the practicing clinician.

Myocardial and haemodynamic responses to two fluid regimens in African children with severe malnutrition and hypovolaemic shock (AFRIM study).

BACKGROUND: Fluid therapy in severely malnourished children is hypothesized to be deleterious owing to compromised cardiac function. We evaluated World Health Organization (WHO) fluid resuscitation guidelines for hypovolaemic shock using myocardial and haemodynamic function and safety endpoints. METHODS: A prospective observational study of two sequential fluid management strategies was conducted at two East African hospitals. Eligible participants were severely malnourished children, aged 6-60 months, with hypovolaemic shock secondary to gastroenteritis. Group 1 received up to two boluses of 15 ml/kg/h of Ringer's lactate (RL) prior to rehydration as per WHO guidelines. Group 2 received rehydration only (10 ml/kg/h of RL) up to a maximum of 5 h. Comprehensive clinical, haemodynamic and echocardiographic data were collected from admission to day 28. RESULTS: Twenty children were enrolled (11 in group 1 and 9 in group 2), including 15 children (75%) with kwashiorkor, 8 (40%) with elevated brain natriuretic peptide >300 pg/ml, and 9 (45%) with markedly elevated median systemic vascular resistance index (SVRI) >1600 dscm-5/m2 indicative of severe hypovolaemia. Echocardiographic evidence of fluid-responsiveness (FR) was heterogeneous in group 1, with both increased and decreased stroke volume and myocardial fractional shortening. In group 2, these variables were more homogenous and typical of FR. Median SVRI marginally decreased post fluid administration (both groups) but remained high at 24 h. Mortality at 48 h and to day 28, respectively, was 36% (4 deaths) and 81.8% (9 deaths) in group 1 and 44% (4 deaths) and 55.6% (5 deaths) in group 2. We observed no pulmonary oedema or congestive cardiac failure on or during admission; most deaths were unrelated to fluid interventions or echocardiographic findings of response to fluids. CONCLUSION: Baseline and cardiac response to fluid resuscitation do not indicate an effect of compromised cardiac function on response to fluid loading or that fluid overload is common in severely malnourished children with hypovolaemic shock. Endocrine response to shock and persistently high SVRI post fluid-therapy resuscitation may indicate a need for further research investigating enhanced fluid volumes to adequately correct volume deficit. The adverse outcomes are concerning, but appear to be unrelated to immediate fluid management.