First malaria vaccine slashes childhood deaths.

Final evaluation brings good news from RTS,S rollout.

Impact of Oxidative Stress on Risk of Death and Readmission in African Children With Severe Malaria: A Prospective Observational Study.

BACKGROUND: We hypothesized that oxidative stress in Ugandan children with severe malaria is associated with mortality. METHODS: We evaluated biomarkers of oxidative stress in children with cerebral malaria (CM, n = 77) or severe malarial anemia (SMA, n = 79), who were enrolled in a randomized clinical trial of immediate vs delayed iron therapy, compared with community children (CC, n = 83). Associations between admission biomarkers and risk of death during hospitalization or risk of readmission within 6 months were analyzed. RESULTS: Nine children with CM and none with SMA died during hospitalization. Children with CM or SMA had higher levels of heme oxygenase-1 (HO-1) (P < .001) and lower superoxide dismutase (SOD) activity than CC (P < .02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio [OR], 6.07 [95% confidence interval {CI}, 1.17-31.31]; P = .03) but a lower risk of death with increasing SOD activity (OR, 0.02 [95% CI, .001-.70]; P = .03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrollment. CONCLUSIONS: Children with CM or SMA develop oxidative stress in response to severe malaria. Oxidative stress is associated with higher mortality in children with CM but not with SMA. CLINICAL TRIALS REGISTRATION: NCT01093989.

A newly characterized malaria antigen on erythrocyte and merozoite surfaces induces parasite inhibitory antibodies.

We previously identified a Plasmodium falciparum (Pf) protein of unknown function encoded by a single-copy gene, PF3D7_1134300, as a target of antibodies in plasma of Tanzanian children in a whole-proteome differential screen. Here we characterize this protein as a blood-stage antigen that localizes to the surface membranes of both parasitized erythrocytes and merozoites, hence its designation as Pf erythrocyte membrane and merozoite antigen 1 (PfEMMA1). Mouse anti-PfEMMA1 antisera and affinity-purified human anti-PfEMMA1 antibodies inhibited growth of P. falciparum strains by up to 68% in growth inhibition assays. Following challenge with uniformly fatal Plasmodium berghei (Pb) ANKA, up to 40% of mice immunized with recombinant PbEMMA1 self-cured, and median survival of lethally infected mice was up to 2.6-fold longer than controls (21 vs. 8 d, P = 0.005). Furthermore, high levels of naturally acquired human anti-PfEMMA1 antibodies were associated with a 46% decrease in parasitemia over 2.5 yr of follow-up of Tanzanian children. Together, these findings suggest that antibodies to PfEMMA1 mediate protection against malaria.

Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention.

BACKGROUND: Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa. METHODS: We conducted an individually randomized, controlled trial to assess whether seasonal vaccination with RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria and whether the two interventions combined were superior to either one alone in preventing uncomplicated malaria and severe malaria-related outcomes. RESULTS: We randomly assigned 6861 children 5 to 17 months of age to receive sulfadoxine-pyrimethamine and amodiaquine (2287 children [chemoprevention-alone group]), RTS,S/AS01E (2288 children [vaccine-alone group]), or chemoprevention and RTS,S/AS01E (2286 children [combination group]). Of these, 1965, 1988, and 1967 children in the three groups, respectively, received the first dose of the assigned intervention and were followed for 3 years. Febrile seizure developed in 5 children the day after receipt of the vaccine, but the children recovered and had no sequelae. There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01E as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively. CONCLUSIONS: Administration of RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria. The combination of these interventions resulted in a substantially lower incidence of uncomplicated malaria, severe malaria, and death from malaria than either intervention alone. (Funded by the Joint Global Health Trials and PATH; ClinicalTrials.gov number, NCT03143218.).

Post-Malaria Anemia Is Rare in Malawian Children with Cerebral Malaria.

Artesunate therapy for severe malaria syndromes has been associated with post-treatment hemolysis and anemia. We defined post-malaria anemia as any decrease in hematocrit between the index hospitalization for severe malaria and 1 month after. We determined the incidence and severity of post-malaria anemia in Malawian children surviving cerebral malaria (CM) by analyzing hospital and follow-up data from a long-standing study of CM pathogenesis. Children enrolled before 2014 and treated with quinine (N = 258) were compared with those admitted in 2014 and after, and treated with artesunate (N = 235). The last hematocrit value obtained during hospitalization was compared with the 1-month post-hospitalization hematocrit value. The overall rate of a post-hospitalization decrease in hematocrit in children surviving CM was 5.3% (11 of 235 or 4.7% for quinine, 15 of 258 or 5.8% for artesunate; odds ratio, 3.23 [0.88, 18.38]); no patients with a decrease in hematocrit were symptomatic, and none required transfusion after hospitalization. Of the 26 children who had a decrease in hematocrit 1 month after hospitalization, 23.1% had evidence of a new malaria infection. When children treated with quinine and artesunate were combined, a higher hematocrit level on admission, lower quantitative histidine-rich protein level, and splenomegaly were associated independently with post-malaria anemia. In African survivors of CM, post-malaria anemia is rare, mild, and unassociated with the anti-malarial treatment received.

Variation in Calculating and Reporting Antimalarial Efficacy against Plasmodium falciparum in Sub-Saharan Africa: A Systematic Review of Published Reports.

Antimalarials, in particular artemisinin-based combination therapies (ACTs), are critical tools in reducing the global burden of malaria, which is concentrated in sub-Saharan Africa. Performing and reporting antimalarial efficacy studies in a transparent and standardized fashion permit comparison of efficacy outcomes across countries and time periods. This systematic review summarizes study compliance with WHO laboratory and reporting guidance pertaining to antimalarial therapeutic efficacy studies and evaluates how well studies from sub-Saharan Africa adhered to these guidelines. We included all published studies (January 2020 or before) performed in sub-Saharan Africa where ACT efficacy for treatment of uncomplicated Plasmodium falciparum infection was reported. The primary outcome was a composite indicator for study methodology consistent with WHO guidelines for statistical analysis of corrected efficacy, defined as an article presenting a Kaplan-Meier survival analysis of corrected efficacy or reporting a per-protocol analysis where new infections were excluded from the numerator and denominator. Of 581 articles screened, we identified 279 for the review. Molecular correction was used in 83% (232/279) to distinguish new infections from recrudescences in subjects experiencing recurrent parasitemia. Only 45% (99/221) of articles with therapeutic efficacy as a primary outcome and performing molecular correction reported corrected efficacy outcomes calculated in a way consistent with WHO recommendations. These results indicate a widespread lack of compliance with WHO-recommended methods of analysis, which may result in biases in how antimalarial effectiveness is being measured and reported from sub-Saharan Africa.

The effect of blood transfusion on outcomes among African children admitted to hospital with Plasmodium falciparum malaria: a prospective, multicentre observational study.

BACKGROUND: Infection with Plasmodium falciparum leads to severe malaria and death in approximately 400 000 children each year in sub-Saharan Africa. Blood transfusion might benefit some patients with malaria but could potentially harm others. The aim of this study was to estimate the association between transfusion and death among children admitted to hospital with P falciparum malaria. METHODS: In this prospective, multicentre observational study, we analysed admissions to six tertiary care hospitals in The Gambia, Malawi, Gabon, Kenya, and Ghana that participated in the Severe Malaria in African Children network. Patients were enrolled if they were younger than 180 months and had a Giemsa-stained thick blood smear that was positive for P falciparum. Blood transfusion (whole blood at a target volume of 20 mL per kg) was administered at the discretion of the responsible physicians who were aware of local and international transfusion guidelines. The primary endpoint was death associated with transfusion, which was estimated using models adjusted for site and disease severity. We also aimed to identify factors associated with the decision to transfuse. The exploratory objective was to estimate optimal haemoglobin transfusion thresholds using generalised additive models. FINDINGS: Between Dec 19, 2000, and March 8, 2005, 26 106 patients were enrolled in the study, 25 893 of whom had their transfusion status recorded and were included in the primary analysis. 8513 (32·8%) patients received a blood transfusion. Patients were followed-up until discharge from hospital for a median of 2 days (IQR 1-4). 405 (4·8%) of 8513 patients who received a transfusion died compared with 689 (4·0%) of 17 380 patients who did not receive a transfusion. Transfusion was associated with decreased odds of death in site-adjusted analysis (odds ratio [OR] 0·82 [95% CI 0·71-0·94]) and after adjusting for the increased disease severity of patients who received a transfusion (0·50 [0·42-0·60]). Severe anaemia, elevated lactate concentration, respiratory distress, and parasite density were associated with greater odds of receiving a transfusion. Among all study participants, transfusion was associated with improved survival when the admission haemoglobin concentration was up to 77 g/L (95% CI 65-110). Among those with impaired consciousness (Blantyre Coma Score ≤4), transfusion was associated with improved survival at haemoglobin concentrations up to 105 g/L (95% CI 71-115). Among those with hyperlactataemia (blood lactate ≥5·0 mmol/L), transfusion was not significantly associated with harm at any haemoglobin concentration-ie, the OR of death comparing transfused versus not transfused was less than 1 at all haemoglobin concentrations (lower bound of the 95% CI for the haemoglobin concentration at which the OR of death equals 1: 90 g/L; no upper bound). INTERPRETATION: Our findings suggest that whole blood transfusion was associated with improved survival among children hospitalised with P falciparum malaria. Among those with impaired consciousness or hyperlactataemia, transfusion was associated with improved survival at haemoglobin concentrations above the currently recommended transfusion threshold. These findings highlight the need to do randomised controlled trials to test higher transfusion thresholds among African children with severe malaria complicated by these factors. FUNDING: US National Institute of Allergy and Infectious Diseases.

The clinical spectrum of severe childhood malaria in Eastern Uganda.

BACKGROUND: Few recent descriptions of severe childhood malaria have been published from high-transmission regions. In the current study, the clinical epidemiology of severe malaria in Mbale, Eastern Uganda, is described, where the entomological inoculation rate exceeds 100 infective bites per year. METHODS: A prospective descriptive study was conducted to determine the prevalence, clinical spectrum and outcome of severe Plasmodium falciparum malaria at Mbale Regional Referral Hospital in Eastern Uganda. All children aged 2 months-12 years who presented on Mondays to Fridays between 8.00 am and 5.00 pm from 5th May 2011 until 30th April 2012 were screened for parasitaemia. Clinical and laboratory data were then collected from all P. falciparum positive children with features of WHO-defined severe malaria by use of a standardized proforma. RESULTS: A total of 10 208 children were screened of which 6582 (64%) had a positive blood film. Of these children, 662 (10%) had clinical features of severe malaria and were consented for the current study. Respiratory distress was the most common severity feature (554; 83.7%), while 365/585 (62.4%) had hyperparasitaemia, 177/662 (26.7%) had clinical jaundice, 169 (25.5%) had severe anaemia, 134/660 (20.2%) had hyperlactataemia (lactate ≥ 5 mmol/L), 93 (14.0%) had passed dark red or black urine, 52 (7.9%) had impaired consciousness and 49/662 (7.4%) had hypoxaemia (oxygen saturations < 90%). In-hospital mortality was 63/662 (9.5%) overall but was higher in children with either cerebral malaria (33.3%) or severe anaemia (19.5%). Factors that were independently associated with mortality on multivariate analysis included severe anaemia [odds ratio (OR) 5.36; 2.16-1.32; P = 0.0002], hyperlactataemia (OR 3.66; 1.72-7.80; P = 0.001), hypoxaemia (OR) 3.64 (95% CI 1.39-9.52; P = 0.008), and hepatomegaly (OR 2.29; 1.29-4.06; P = 0.004). No independent association was found between mortality and either coma or hyperparasitaemia. CONCLUSIONS: Severe childhood malaria remains common in Eastern Uganda where it continues to be associated with high mortality. An unusually high proportion of children with severe malaria had jaundice or gave a history of having recently passed dark red or black urine, an issue worthy of further investigation.

Decreased Mortality of falciparum Malaria in Anemic Prisoners of War?

Modern clinical trials have suggested that anemia protects against malaria mortality. Military records of the Second World War in Asia were examined to see if there was support for this hypothesis. When relatively well-nourished Imperial Japanese Navy sailors captured on Nauru (n = 799) were imprisoned on the Fauro Islands, 26% died from falciparum malaria. Similarly treated but very malnourished colocated Imperial Army soldiers experienced low stable malaria mortality. One-fifth of previously healthy Australian Army soldiers (n = 252) retreating from New Britain died largely because of malaria in April 1942. Malnourished prisoners of war, who were as a group very anemic, both Australian Army soldiers in Thailand and Japanese Army soldiers in Papua New Guinea, had high malaria rates but very low (< 3%) mortality rates. Malaria immunity does not adequately explain this dichotomy, suggesting that severe nutritional deprivation may be protective against malaria mortality possibly because of iron-deficiency anemia.

Graphing and reporting heterogeneous treatment effects through reference classes.

BACKGROUND: Exploration and modelling of heterogeneous treatment effects as a function of baseline covariates is an important aspect of precision medicine in randomised controlled trials (RCTs). Randomisation generally guarantees the internal validity of an RCT, but heterogeneity in treatment effect can reduce external validity. Estimation of heterogeneous treatment effects is usually done via a predictive model for individual outcomes, where one searches for interactions between treatment allocation and important patient baseline covariates. However, such models are prone to overfitting and multiple testing and typically demand a transformation of the outcome measurement, for example, from the absolute risk in the original RCT to log-odds of risk in the predictive model. METHODS: We show how reference classes derived from baseline covariates can be used to explore heterogeneous treatment effects via a two-stage approach. We first estimate a risk score which captures on a single dimension some of the heterogeneity in outcomes of the trial population. Heterogeneity in the treatment effect can then be explored via reweighting schemes along this axis of variation. This two-stage approach bypasses the search for interactions with multiple covariates, thus protecting against multiple testing. It also allows for exploration of heterogeneous treatment effects on the original outcome scale of the RCT. This approach would typically be applied to multivariable models of baseline risk to assess the stability of average treatment effects with respect to the distribution of risk in the population studied. CASE STUDY: We illustrate this approach using the single largest randomised treatment trial in severe falciparum malaria and demonstrate how the estimated treatment effect in terms of absolute mortality risk reduction increases considerably in higher risk strata. CONCLUSIONS: 'Local' and 'tilting' reweighting schemes based on ranking patients by baseline risk can be used as a general approach for exploring, graphing and reporting heterogeneity of treatment effect in RCTs. TRIAL REGISTRATION: ISRCTN clinical trials registry: ISRCTN50258054. Prospectively registered on 22 July 2005.

Is Malaria an Important Cause of Death among Adults?

A long-held assumption has been that nearly all malaria deaths in high-transmission areas are of children younger than 5 years and pregnant women. Most global malaria mortality estimates incorporate this assumption in their calculations. In 2010, the Indian Million Death Study, which assigns cause of death by verbal autopsy (VA), challenged the reigning perception, producing a U-shaped mortality age curve, with rates rising after age 45 years in areas of India with substantial malaria transmission. Similar patterns are seen in Africa in the International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) network, also relying on VA. Whether these results are accurate or are misidentified deaths can be resolved by improving the evidence for assigning causes for adult acute infectious deaths in high malaria transmission areas. The options for doing so include improving the accuracy of VA and adding postmortem biological evidence, steps we believe should be initiated without delay.

Predictors of outcome in childhood Plasmodium falciparum malaria.

Plasmodium falciparum malaria is classified as either uncomplicated or severe, determining clinical management and providing a framework for understanding pathogenesis. Severe malaria in children is defined by the presence of one or more features associated with adverse outcome, but there is wide variation in the predictive value of these features. Here we review the evidence for the usefulness of these features, alone and in combination, to predict death and other adverse outcomes, and we consider the role that molecular biomarkers may play in augmenting this prediction. We also examine whether a more personalized approach to predicting outcome for specific presenting syndromes of severe malaria, particularly cerebral malaria, has the potential to be more accurate. We note a general need for better external validation in studies of outcome predictors and for the demonstration that predictors can be used to guide clinical management in a way that improves survival and long-term health.

Malaria in patients with sickle cell anaemia: burden, risk factors and outcome at the Laquintinie hospital, Cameroon.

BACKGROUND: It is believed that the current prevalence of malaria in endemic areas reflects selection for the carrier form of sickle cell trait through a survival advantage. Malaria has been incriminated as a great cause of mortality in people with sickle cell disease (SCD). However, people with SCD, a high-risk group, do not benefit from free or subsisized malaria prevention and treatment in Cameroon unlike other vulnerable groups which may be due to insufficient evidence to guide policy makers. This study aimed at describing clinical and socio-demographic characteristics of patients with malaria, determining the prevalence of malaria in hospitalized children and in those with SCD and without, compare frequency of presentation of malaria related complications (using clinical and laboratory elements that define severe malaria) between children admitted for malaria with SCD and those without and finally, determing the risk factors for death in children admitted for malaria. METHODS: This was a retrospective analysis of admission records of children age 1 to 18 years with a confirmed malaria diagnosis admitted at the Laquintinie Hospital during January 2015 through December 2018. Clinical features, laboratory characteristics and outcome of malarial infections, stratified by SCD status were studied. Patients with HIV infection, malnutrition, renal failure and discharged against medical advice were excluded from the study. Data were analysed using Epi-info 7 software and analysis done. Chi square test, Odds ratios, CI and student's t test were used to determine association between variables. Statistical significance was set at p-value ≤0.05. RESULTS: The prevalence of malaria was lower among children with SCD than it was among children without SCD (23.5% vs 44.9%). Similarly, among those with a positive microscopy, the mean parasite density was significantly lower among children with SCD than it was among children without SCD (22,875.6 vs 57,053.6 parasites/ µl with t-value - 3.2, p-value 0.002). The mean hemoglobin concentration was lower in SCD as compared to non SCD (5.7 g/l vs 7.4 g/l, t-value - 12.5, p-value < 0.001). Overall mortality in SCD was 3.4% and malaria was reponsible for 20.4% of these deaths as compared to the 35.4% in non SCD patients. Convulsion and impaired consciousness were significantly lower in SCD group (OR:0.1, CI: 0.1-0.3, p value < 0.01 and OR:0.1, CI:0.1-0.2, p-value < 0.001 respectively). Death was significantly higher in SCD patients with malaria as compared to SCD patients admitted for other pathologies (3.2% vs 1.5%., OR:2.2, CI:1-5, p-value 0.050). CONCLUSION: The SCD population has a lower mortality related to malaria compared to the non-SCD population. Meanwhile, within the SCD population, those admitted with malaria are twice more likely to die than those admitted for other pathologies. Jaundice, hepatomegaly and splenomegaly were common in SCD with malaria, however no risk factors for malaria severity or malaria related death was identified.

Associations Between Restrictive Fluid Management and Renal Function and Tissue Perfusion in Adults With Severe Falciparum Malaria: A Prospective Observational Study.

BACKGROUND: Liberal fluid resuscitation has proved harmful in adults with severe malaria, but the level of restriction has not been defined. METHODS: In a prospective observational study in adults with severe falciparum malaria, restrictive fluid management was provided at the discretion of the treating physician. The relationships between the volume of fluid and changes in renal function or tissue perfusion were evaluated. RESULTS: A total of 154 patients were studied, 41 (26.6%) of whom died. Median total fluid intake during the first 6 and 24 hours from enrollment was 3.3 (interquartile range [IQR], 1.8-5.1) mL/kg per hour and 2.2 (IQR, 1.6-3.2) mL/kg per hour, respectively. Total fluid intake at 6 hours was not correlated with changes in plasma creatinine at 24 hours (n = 116; rs = 0.16; P = .089) or lactate at 6 hours (n = 94; rs = -0.05; P = .660). Development of hypotensive shock or pulmonary edema within 24 hours after enrollment were not related to the volume of fluid administration. CONCLUSIONS: Restrictive fluid management did not worsen kidney function and tissue perfusion in adult patients with severe falciparum malaria. We suggest crystalloid administration of 2-3 mL/kg per hour during the first 24 hours without bolus therapy, unless the patient is hypotensive.

Acute Kidney Injury in Children with Severe Malaria Is Common and Associated with Adverse Hospital Outcomes.

BACKGROUND: The prevalence of acute kidney injury (AKI) in children with severe malaria in sub-Saharan African may have been underestimated. The study aimed to determine the prevalence of AKI in children with severe malaria and its association with adverse hospital outcomes. METHODS: At presentation, we measured complete blood count, serum bilirubin, and serum electrolytes, urea and creatinine in children with severe malaria. At 24 h after hospitalization, we repeated serum creatinine measurement. Urine passed in the first 24 h of hospitalization was also measured. We defined AKI and its severity using the Kidney Disease: Improving Global Outcome AKI guidelines. RESULTS: The study involved 244 children (53.3% males) with a median age of 3.5 (1.9-7.0) years. One hundred and forty-four (59%) children had AKI, and it reached maximum Stages 1, 2 and 3 in 56 (23%), 45 (18.4%) and 43 (17.6%) children, respectively. The majority (86.1%) with AKI had only elevated serum creatinine. Mortality increased with increasing severity of AKI on univariate analysis but weakened on multiple logistic regression. Mortality was also higher in those with both oliguria and elevated serum creatinine than in those with elevated serum creatinine only (50% vs. 4.8%, p < 0.001). Furthermore, children with AKI spent three days more in hospital than those without AKI (p < 0.001). CONCLUSIONS: Acute kidney injury complicates severe malaria in 6 out of every 10 children and is commonly identified using elevated serum creatinine. It is also associated with adverse hospital outcome.

Cyclooxygenase-2 haplotypes influence the longitudinal risk of malaria and severe malarial anemia in Kenyan children from a holoendemic transmission region.

Cyclooxygenase-2 [(COX-2) or prostaglandin endoperoxide H2 synthase-2 (PTGS-2)] induces the production of prostaglandins as part of the host-immune response to infections. Although a number of studies have demonstrated the effects of COX-2 promoter variants on autoimmune and inflammatory diseases, their role in malaria remains undefined. As such, we investigated the relationship between four COX-2 promoter variants (COX-2 -512 C > T, -608 T > C, -765 G > C, and -1195 A > G) and susceptibility to malaria and severe malarial anemia (SMA) upon enrollment and longitudinally over a 36-month follow-up period. All-cause mortality was also explored. The investigation was carried out in children (n = 1081, age; 2-70 months) residing in a holoendemic Plasmodium falciparum transmission region of western Kenya. At enrollment, genotypes/haplotypes (controlling for anemia-promoting covariates) did not reveal any strong effects on susceptibility to either malaria or SMA. Longitudinal analyses showed decreased malaria episodes in children who inherited the -608 CC mutant allele (RR = 0.746, P = 1.811 × 10-4) and -512C/-608T/-765G/-1195G (CTGG) haplotype (RR = 0.856, P = 0.011), and increased risk in TTCA haplotype carriers (RR = 1.115, P = 0.026). Over the follow-up period, inheritance of the rare TTCG haplotype was associated with enhanced susceptibility to both malaria (RR = 1.608, P = 0.016) and SMA (RR = 5.714, P = 0.004), while carriage of the rare TTGG haplotype increased the risk of malaria (RR = 1.755, P = 0.007), SMA (RR = 8.706, P = 3.97 × 10-4), and all-cause mortality (HR = 110.000, P = 0.001). Collectively, these results show that SNP variations in the COX-2 promoter, and their inherited combinations, are associated with the longitudinal risk of malaria, SMA, and all-cause mortality among children living in a high transmission area for P. falciparum.

Exposure to Ebola Virus and Risk for Infection with Malaria Parasites, Rural Gabon.

An association between malaria and risk for death among patients with Ebola virus disease has suggested within-host interactions between Plasmodium falciparum parasites and Ebola virus. To determine whether such an interaction might also influence the probability of acquiring either infection, we used a large snapshot surveillance study from rural Gabon to test if past exposure to Ebola virus is associated with current infection with Plasmodium spp. during nonepidemic conditions. We found a strong positive association, on population and individual levels, between seropositivity for antibodies against Ebola virus and the presence of Plasmodium parasites in the blood. According to a multiple regression model accounting for other key variables, antibodies against Ebola virus emerged as the strongest individual-level risk factor for acquiring malaria. Our results suggest that within-host interactions between malaria parasites and Ebola virus may underlie epidemiologic associations.

Reduced Cardiac Index Reserve and Hypovolemia in Severe Falciparum Malaria.

BACKGROUND: Impaired microvascular perfusion is central to the development of coma and lactic acidosis in severe falciparum malaria. Refractory hypotension is rare on admission but develops frequently in fatal cases. We assessed cardiac function and volume status in severe falciparum malaria and its prognostic significance. METHODS: Patients with severe (N = 101) or acute uncomplicated falciparum malaria (N = 83) were recruited from 2 hospitals in India and Bangladesh, and healthy participants (N = 44) underwent echocardiography. RESULTS: Patients with severe malaria had 38% shorter left ventricular (LV) filling times and 25% shorter LV ejection times than healthy participants because of tachycardia; however, stroke volume, LV internal diameter in diastole (LVIDd), and LV internal diameter in systole (LVIDs) indices were similar. A low endocardial fraction shortening (eFS) was present in 17% (9 of 52) of severe malaria patients. Adjusting for preload and afterload, eFS was similar in health and severe malaria. Fatal cases had smaller baseline LVIDd and LVIDs indices, more collapsible inferior vena cavae (IVC), and higher heart rates than survivors. The LVIDs and IVC collapsibility were independent predictors for mortality, together with base excess and Glasgow Coma Scale. CONCLUSIONS: Patients with severe malaria have rapid ejection of a normal stroke volume. Fatal cases had features of relative hypovolemia and reduced cardiac index reserve.

Changes in monocyte subsets are associated with clinical outcomes in severe malarial anaemia and cerebral malaria.

Monocytes are plastic heterogeneous immune cells involved in host-parasite interactions critical for malaria pathogenesis. Human monocytes have been subdivided into three populations based on surface expression of CD14 and CD16. We hypothesised that proportions and phenotypes of circulating monocyte subsets can be markers of severity or fatality in children with malaria. To address this question, we compared monocytes sampled in children with uncomplicated malaria, severe malarial anaemia, or cerebral malaria. Flow cytometry was used to distinguish and phenotype monocyte subsets through CD14, CD16, CD36 and TLR2 expression. Data were first analysed by univariate analysis to evaluate their link to severity and death. Second, multinomial logistic regression was used to measure the specific effect of monocyte proportions and phenotypes on severity and death, after adjustments for other variables unrelated to monocytes. Multivariate analysis demonstrated that decreased percentages of non-classical monocytes were associated with death, suggesting that this monocyte subset has a role in resolving malaria. Using univariate analysis, we also showed that the role of non-classical monocytes involves a mostly anti-inflammatory profile and the expression of CD16. Further studies are needed to decipher the functions of this sub-population during severe malaria episodes, and understand the underlying mechanisms.

Early and late mortality after malaria in young children in Papua, Indonesia.

BACKGROUND: In southern Papua, Indonesia, malaria is highly prevalent in young children and is a significant cause of morbidity and early mortality. The association between malaria and delayed mortality is unknown. METHODS: Routinely-collected hospital surveillance data from southern Papua, Indonesia, were used to assess the risk of recurrent malaria and mortality within 12 months of an initial presentation with malaria in all children younger than 5 years old attending the local hospital. Analysis was primarily by Kaplan Meier and Cox regression methods. RESULTS: In total 15,716 children presenting with malaria between April 2004 and December 2013 were included in the analysis; 6184 (39.3%) with Plasmodium falciparum, 7499 (47.7%) with P. vivax, 203 (1.3%) with P. malariae, 3 with P. ovale and 1827 (11.6%) with mixed infections. Within 1 year, 48.4% (7620/15,716) of children represented a total of 16,957 times with malaria (range 1 to 11 episodes), with the incidence of malaria being greater in patients initially presenting with P. vivax infection (1334 [95%CI 1307-1361] per 1000 patient years) compared to those with P. falciparum infection (920 [896-944]). In total 266 (1.7%) children died within 1 year of their initial presentation, 129 (48.5%) within 30 days and 137 (51.5%) between 31 and 365 days. There was no significant difference in the mortality risk in patients infected with P. vivax versus P. falciparum either before 30 days (Hazard Ratio (HR) 1.02 [0.69,1.49]) or between 31 and 365 days (HR = 1.30 [0.90,1.88]). Children who died had a greater incidence of malaria, 2280 [95%CI 1946-2671] per 1000 patient years preceding their death, compared to 1141 [95%CI 1124-1158] per 1000 patient years in those surviving. CONCLUSIONS: Children under-5 years old with P. vivax malaria, are at significant risk of multiple representations with malaria and of dying within 1 year of their initial presentation. Preventing recurrent malaria must be a public health priority in this vulnerable population.