Juliet Mwanga-Amumpaire

Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial.

Summary Background Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria. Methods This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054. Findings 5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63–0·90; relative reduction 22·5%, 95% CI 8·1–36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49–0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66–0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64–0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43–0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects. Interpretation Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide. Funding The Wellcome Trust.

Predicting the Clinical Outcome of Severe Falciparum Malaria in African Children: Findings From a Large Randomized Trial

Four predictors were independently associated with an increased risk of death: acidosis, cerebral manifestations of malaria, elevated blood urea nitrogen, or signs of chronic illness. The standard base deficit was found to be the single most relevant predictor of death.

Sequence variation does not confound the measurement of plasma PfHRP2 concentration in African children presenting with severe malaria

BackgroundPlasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria. The Pfhrp2 gene is highly polymorphic, with deletion of the entire gene reported in both laboratory and field isolates. These issues potentially confound the interpretation of PFHRP2 measurements.MethodsStudies designed to detect deletion of Pfhrp2 and its paralog Pfhrp3 were undertaken with samples from patients in seven countries contributing to the largest hospital-based severe malaria trial (AQUAMAT). The quantitative relationship between sequence polymorphism and PFHRP2 plasma concentration was examined in samples from selected sites in Mozambique and Tanzania.ResultsThere was no evidence for deletion of either Pfhrp2 or Pfhrp3 in the 77 samples with lowest PFHRP2 plasma concentrations across the seven countries. Pfhrp2 sequence diversity was very high with no haplotypes shared among 66 samples sequenced. There was no correlation between Pfhrp2 sequence length or repeat type and PFHRP2 plasma concentration.ConclusionsThese findings indicate that sequence polymorphism is not a significant cause of variation in PFHRP2 concentration in plasma samples from African children. This justifies the further development of plasma PFHRP2 concentration as a method for assessing African children who may have severe falciparum malaria. The data also add to the existing evidence base supporting the use of rapid diagnostic tests based on PFHRP2 detection.

Asymptomatic Plasmodium Infections in Children in Low Malaria Transmission Setting, Southwestern Uganda

A survey of asymptomatic children in Uganda showed Plasmodium malariae and P. falciparum parasites in 45% and 55% of microscopy-positive samples, respectively. Although 36% of microscopy-positive samples were negative by rapid diagnostic test, 75% showed P. malariae or P. ovale parasites by PCR, indicating that routine diagnostic testing misses many non–P. falciparum malarial infections.

Malaria is an uncommon cause of adult sepsis in south-western Uganda

BackgroundMalaria is often considered a cause of adult sepsis in malaria endemic areas. However, diagnostic limitations can make distinction between malaria and other infections challenging. Therefore, the objective of this study was to determine the relative contribution of malaria to adult sepsis in south-western Uganda.MethodsAdult patients with sepsis were enrolled at the Mbarara Regional Referral Hospital between February and May 2012. Sepsis was defined as infection plus ≥2 of the following: axillary temperature >37.5°C or <35.5°C, heart rate >90 or respiratory rate >20. Severe sepsis was defined as sepsis plus organ dysfunction (blood lactate >4 mmol/L, confusion, or a systolic blood pressure <90 mmHg). Sociodemographic, clinical and laboratory data, including malaria PCR and rapid diagnostic tests, as well as acid fast bacteria sputum smears and blood cultures were collected. Patients were followed until in-patient death or discharge. The primary outcome of interest was the cause of sepsis. Multivariable logistic regression was performed to assess predictors of mortality.ResultsEnrollment included 216 participants who were 51% female with a median age of 32 years (IQR 27–43 years). Of these, 122 (56%) subjects were HIV-seropositive of whom 75 (66%) had a CD4+ T cell count <100 cells/μL. The prevalence of malaria was 4% (six with Plasmodium falciparum, two with Plasmodium vivax). Bacteraemia was identified in 41 (19%) patients. In-hospital mortality was 19% (n = 42). In multivariable regression analysis, Glasgow Coma Score <9 (IRR 4.81, 95% CI 1.80-12.8) and severe sepsis (IRR, 2.07, 95% CI 1.03-4.14), but no specific diagnoses were statistically associated with in-hospital mortality.ConclusionMalaria was an uncommon cause of adult sepsis in a regional referral hospital in south-western Uganda. In this setting, a thorough evaluation for alternate causes of disease in patients presenting with sepsis is recommended.

Inhaled nitric oxide and cerebral malaria: basis of a strategy for buying time for pharmacotherapy.

There are approximately 225–600 million new malaria infections worldwide annually, with severe and cerebral malaria representing major causes of death internationally. The role of nitric oxide (NO) in the host response in cerebral malaria continues to be elucidated, with numerous known functions relating to the cytokine, endovascular and cellular responses to infection with Plasmodium falciparum. Evidence from diverse modes of inquiry suggests NO to be critical in modulating the immune response and promoting survival in patients with cerebral malaria. This line of investigation has culminated in the approval of 2 phase II randomized prospective clinical trials in Uganda studying the use of inhaled NO as adjuvant therapy in children with severe malaria. The strategy underlying both trials is to use the sytemic antiinflammatory properties of inhaled NO to “buy time” for chemical antiparasite therapy to lower the parasite load. This article reviews the nexus of malaria and NO biology with a primary focus on cerebral malaria in humans.

Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial

Treatment with inhaled nitric oxide as an adjuvant therapy for pediatric patients with cerebral malaria for 48 hours did not result in a significant difference in plasma Angiopoietin-1 levels when compared with placebo in a phase II open-label clinical trial.

Male Gender is independently associated with pulmonary tuberculosis among sputum and non-sputum producers people with presumptive tuberculosis in Southwestern Uganda

BackgroundLittle is known about the association between gender and risk of TB infection. We sought to assess the impact of gender on TB prevalence among people with presumptive tuberculosis at a regional referral hospital in a high TB and HIV prevalence setting.MethodsWe analyzed data from two diagnostic TB studies conducted in rural, southwestern Uganda. People with presumptive tuberculosis were evaluated by chest X-ray, fluorescence microscopy, TB culture, and HIV testing. Our primary outcome of interest was TB infection, as defined by a positive TB culture. Our primary explanatory variable of interest was gender. We fit univariable and multivariable logistic regression models to investigate associations between TB infection and gender, before and after adjusting or possible confounding factors, including ability to produce sputum, age and residence.ResultsBetween April 2010 and September 2012, 863 people with presumptive tuberculosis (PWPTB) were enrolled in the two studies at Mbarara Regional Referral Hospital (MRRH) in Uganda. Among them 664 (76.9%) were able to produce sputum. X-ray was suggestive of TB for 258 (66.5%) of males and 175 (44.8%) of female (p < 0.001). using microscopy 84 (20%) of males and 48 (10.9%) of females were diagnosed with TB (p < 0.001) while 122 (30.3%) of males and 76 (18.4%) of females were diagnosed with TB (p < 0.001) using TB culture.In multivariable logistic regression models, the odds of having TB was higher in males than females (AOR 2.2 (1.56-3.18 95% CI°, P < 0.001), after adjustment for age, HIV status, ability to produce sputum, and residence.ConclusionIn Southwestern Uganda, TB prevalence is higher among male than female people with presumptive TB. The increased risk of TB among males is independent of other TB risk factors. These findings emphasize the need for gender-focused interventions aimed at reducing TB transmission.

Sociocultural and Structural Factors Contributing to Delays in Treatment for Children with Severe Malaria: A Qualitative Study in Southwestern Uganda

Malaria is a leading cause of pediatric mortality, and Uganda has among the highest incidences in the world. Increased morbidity and mortality are associated with delays to care. This qualitative study sought to characterize barriers to prompt allopathic care for children hospitalized with severe malaria in the endemic region of southwestern Uganda. Minimally structured, qualitative interviews were conducted with guardians of children admitted to a regional hospital with severe malaria. Using an inductive and content analytic approach, transcripts were analyzed to identify and define categories that explain delayed care. These categories represented two broad themes: sociocultural and structural factors. Sociocultural factors were 1) interviewees distinctions of “traditional” versus “hospital” illnesses, which were mutually exclusive and 2) generational conflict, where deference to ones elders, who recommended traditional medicine, was expected. Structural factors were 1) inadequate distribution of health-care resources, 2) impoverishment limiting escalation of care, and 3) financial impact of illness on household economies. These factors perpetuate a cycle of illness, debt, and poverty consistent with a model of structural violence. Our findings inform a number of potential interventions that could alleviate the burden of this preventable, but often fatal, illness. Such interventions could be beneficial in similarly endemic, low-resource settings.

Antimicrobial-resistant infections among postpartum women at a Ugandan referral hospital

Introduction Puerperal sepsis causes 10% of maternal deaths in Africa, but prospective studies on incidence, microbiology and antimicrobial resistance are lacking. Methods We performed a prospective cohort study of 4,231 Ugandan women presenting to a regional referral hospital for delivery or postpartum care, measured vital signs after delivery, performed structured physical exam, symptom questionnaire, and microbiologic evaluation of febrile and hypothermic women. Malaria rapid diagnostic testing, blood and urine cultures were performed aseptically and processed at Epicentre Mbarara Research Centre. Antimicrobial susceptibility and breakpoints were determined using disk diffusion per EUCAST standards. Hospital diagnoses, treatments and outcomes were abstracted from patient charts. Results Mean age was 25 years, 12% were HIV-infected, and 50% had cesarean deliveries. Approximately 5% (205/4176) with ≥1 temperature measurement recorded developed postpartum fever or hypothermia; blood and urine samples were collected from 174 (85%), and 17 others were evaluated clinically. Eighty-four (48%) had at least one confirmed source of infection: 39% (76/193) clinical postpartum endometritis, 14% (25/174) urinary tract infection (UTI), 3% (5/174) bloodstream infection. Another 3% (5/174) had malaria. Overall, 30/174 (17%) had positive blood or urine cultures, and Acinetobacter species were the most common bacteria isolated. Of 25 Gram-negatives isolated, 20 (80%) were multidrug-resistant and cefepime non-susceptible. Conclusions For women in rural Uganda with postpartum fever, we found a high rate of antibiotic resistance among cultured urinary and bloodstream infections, including cephalosporin-resistant Acinetobacter species. Increasing availability of microbiology testing to inform appropriate antibiotic use, development of antimicrobial stewardship programs, and strengthening infection control practices should be high priorities.