Predictors of recovery from complicated severe acute malnutrition among children 6-59 months admitted at Mbale Hospital, Uganda

Introduction: In Uganda, 300,000 children under 5 years are acutely malnourished with 1.3% suffering from Severe Acute Malnutrition (SAM). Mbale Regional Referral hospital (MRRH) nutrition unit admits SAM children with comorbidities into inpatient care striving to ensure recovery, reduce morbidity and mortality. We assessed the incidence and predictors of time to recovery among SAM children admitted as inpatients in MRRH nutrition unit. Methods: We reviewed records of children 6-59 months old managed at the inpatient unit for SAM at MRRH from 2013 to 2016. Data on patient demographics, comorbidities, medications administered, and treatment outcomes were collected from the integrated nutrition register and patient charts. Recovery incidence was determined using Kaplan Meier survival analysis. Cox proportional hazards regression competing risks model with death, default and transfer as competing risks was fit to identify predictors of time to recovery. Results: Overall, 322 patient records were reviewed of which 183 (56.8%) were males with median age of 19 months (IQR; 14-26 months). Of these, 246 (76.4%) recovered with recovery incidence of 31.3 per 1000 person days and a median recovery time of 27 days (IQR; 16-38 days). Children with SAM who were dewormed during treatment were 33% more likely to recover faster compared to their counterparts who were not dewormed (AHR= 1.33; C.I = 1.01-1.74). Conclusion: Recovery was in acceptable range of Sphere standards and deworming was a predictor of time to recovery. The Uganda Ministry of health should ensure nutritional rehabilitation units follow the stipulated guidelines for management of SAM. Findings were limited by missing data

Drug-resistant genotypes and multi-clonality in Plasmodium falciparum analysed by direct genome sequencing from peripheral blood of malaria patients.

Naturally acquired blood-stage infections of the malaria parasite Plasmodium falciparum typically harbour multiple haploid clones. The apparent number of clones observed in any single infection depends on the diversity of the polymorphic markers used for the analysis, and the relative abundance of rare clones, which frequently fail to be detected among PCR products derived from numerically dominant clones. However, minority clones are of clinical interest as they may harbour genes conferring drug resistance, leading to enhanced survival after treatment and the possibility of subsequent therapeutic failure. We deployed new generation sequencing to derive genome data for five non-propagated parasite isolates taken directly from 4 different patients treated for clinical malaria in a UK hospital. Analysis of depth of coverage and length of sequence intervals between paired reads identified both previously described and novel gene deletions and amplifications. Full-length sequence data was extracted for 6 loci considered to be under selection by antimalarial drugs, and both known and previously unknown amino acid substitutions were identified. Full mitochondrial genomes were extracted from the sequencing data for each isolate, and these are compared against a panel of polymorphic sites derived from published or unpublished but publicly available data. Finally, genome-wide analysis of clone multiplicity was performed, and the number of infecting parasite clones estimated for each isolate. Each patient harboured at least 3 clones of P. falciparum by this analysis, consistent with results obtained with conventional PCR analysis of polymorphic merozoite antigen loci. We conclude that genome sequencing of peripheral blood P. falciparum taken directly from malaria patients provides high quality data useful for drug resistance studies, genomic structural analyses and population genetics, and also robustly represents clonal multiplicity

The Safety of Adult Male Circumcision in HIV-Infected and Uninfected Men in Rakai, Uganda

Ron Gray and colleagues report on complications of circumcision in HIV-infected and HIV-uninfected men from two related trials in Uganda, finding increased risk with intercourse before wound healing

Deciphering the Complex Distribution of Human Immunodeficiency Virus Type 1 Subtypes among Different Cohorts in Northern Tanzania.

Increased understanding of the genetic diversity of HIV-1 is challenging but important in the development of an effective vaccine. We aimed to describe the distribution of HIV-1 subtypes in northern Tanzania among women enrolled in studies preparing for HIV-1 prevention trials (hospitality facility-worker cohorts), and among men and women in an open cohort demographic surveillance system (Kisesa cohort). The polymerase encompassing partial reverse transcriptase was sequenced and phylogenetic analysis performed and subtype determined. Questionnaires documented demographic data. We examined factors associated with subtype using multinomial logistic regression, adjusted for study, age, and sex. Among 140 individuals (125 women and 15 men), subtype A1 predominated (54, 39%), followed by C (46, 33%), D (25, 18%) and unique recombinant forms (URFs) (15, 11%). There was weak evidence to suggest different subtype frequencies by study (for example, 18% URFs in the Kisesa cohort versus 5-9% in the hospitality facility-worker cohorts; adjusted relative-risk ratio (aRR) = 2.35 [95% CI 0.59,9.32]; global p = 0.09). Compared to men, women were less likely to have subtype D versus A (aRR = 0.12 [95% CI 0.02,0.76]; global p = 0.05). There was a trend to suggest lower relative risk of subtype D compared to A with older age (aRR = 0.44 [95% CI 0.23,0.85] per 10 years; global p = 0.05). We observed multiple subtypes, confirming the complex genetic diversity of HIV-1 strains circulating in northern Tanzania, and found some differences between cohorts and by age and sex. This has important implications for vaccine design and development, providing opportunity to determine vaccine efficacy in diverse HIV-1 strains

B Cell Depletion in HIV-1 Subtype A Infected Ugandan Adults: Relationship to CD4 T Cell Count, Viral Load and Humoral Immune Responses

To better understand the nature of B cell dysfunctions in subjects infected with HIV-1 subtype A, a rural cohort of 50 treatment-naïve Ugandan patients chronically infected with HIV-1 subtype A was studied, and the relationship between B cell depletion and HIV disease was assessed. B cell absolute counts were found to be significantly lower in HIV-1+ patients, when compared to community matched negative controls (p<0.0001). HIV-1-infected patients displayed variable functional and binding antibody titers that showed no correlation with viral load or CD4+ T cell count. However, B cell absolute counts were found to correlate inversely with neutralizing antibody (NAb) titers against subtype A (p = 0.05) and subtype CRF02_AG (p = 0.02) viruses. A positive correlation was observed between subtype A gp120 binding antibody titers and NAb breadth (p = 0.02) and mean titer against the 10 viruses (p = 0.0002). In addition, HIV-1 subtype A sera showed preferential neutralization of the 5 subtype A or CRF02_AG pseudoviruses, as compared with 5 pseudoviruses from subtypes B, C or D (p<0.001). These data demonstrate that in patients with chronic HIV-1 subtype A infection, significant B cell depletion can be observed, the degree of which does not appear to be associated with a decrease in functional antibodies. These findings also highlight the potential importance of subtype in the specificity of cross-clade neutralization in HIV-1 infection

The Bacterial and Viral Complexity of Postinfectious Hydrocephalus in Uganda

Postinfectious hydrocephalus (PIH), often following neonatal sepsis, is the most common cause of pediatric hydrocephalus world-wide, yet the microbial pathogens remain uncharacterized. Characterization of the microbial agents causing PIH would lead to an emphasis shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention. We examined blood and CSF from 100 consecutive cases of PIH and control cases of non-postinfectious hydrocephalus (NPIH) in infants in Uganda. Genomic testing was undertaken for bacterial, fungal, and parasitic DNA, DNA and RNA sequencing for viral identification, and extensive bacterial culture recovery. We uncovered a major contribution to PIH from Paenibacillus , upon a background of frequent cytomegalovirus (CMV) infection. CMV was only found in CSF in PIH cases. A facultatively anaerobic isolate was recovered. Assembly of the genome revealed a strain of P. thiaminolyticus . In mice, this isolate designated strain Mbale , was lethal in contrast with the benign reference strain. These findings point to the value of an unbiased pan-microbial approach to characterize PIH in settings where the organisms remain unknown, and enables a pathway towards more optimal treatment and prevention of the proximate neonatal infections. One Sentence Summary We have discovered a novel strain of bacteria upon a frequent viral background underlying postinfectious hydrocephalus in Uganda

Paenibacillus infection with frequent viral coinfection contributes to postinfectious hydrocephalus in Ugandan infants

Postinfectious hydrocephalus (PIH), which often follows neonatal sepsis, is the most common cause of pediatric hydrocephalus worldwide, yet the microbial pathogens underlying this disease remain to be elucidated. Characterization of the microbial agents causing PIH would enable a shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention of the disease. Here, we examined blood and CSF samples collected from 100 consecutive infant cases of PIH and control cases comprising infants with non-postinfectious hydrocephalus in Uganda. Genomic sequencing of samples was undertaken to test for bacterial, fungal, and parasitic DNA; DNA and RNA sequencing was used to identify viruses; and bacterial culture recovery was used to identify potential causative organisms. We found that infection with the bacterium Paenibacillus, together with frequent cytomegalovirus (CMV) coinfection, was associated with PIH in our infant cohort. Assembly of the genome of a facultative anaerobic bacterial isolate recovered from cultures of CSF samples from PIH cases identified a strain of Paenibacillus thiaminolyticus. This strain, designated Mbale, was lethal when injected into mice in contrast to the benign reference Paenibacillus strain. These findings show that an unbiased pan-microbial approach enabled characterization of Paenibacillus in CSF samples from PIH cases, and point toward a pathway of more optimal treatment and prevention for PIH and other proximate neonatal infections