Faculty Bibliography

Background/UNASSIGNED:Asymptomatic Plasmodium falciparum infections are common in Malawi, however, the implications of these infections for the burden of malaria illness are unknown. Whether asymptomatic infections eventually progress to malaria illness, persist without causing symptoms, or clear spontaneously remains undetermined. We identified asymptomatic infections and evaluated the associations between persistent asymptomatic infections and malaria illness. Methods/UNASSIGNED:Children and adults (N = 120) who presented at a health facility with uncomplicated malaria were followed monthly for two years. During follow-up visits, participants with malaria symptoms were tested and treated if positive. Samples from all visits were tested for parasites using both microscopy and PCR, and all malaria infections underwent genotyping. Cox frailty models were used to estimate the temporal association between asymptomatic infections and malaria illness episodes. Mixed models were used to estimate the odds of clinical symptoms associated with new versus persistent infections. Results/UNASSIGNED:Participants had a median follow-up time of 720 days. Asymptomatic infections were detected during 23% of visits. Persistent asymptomatic infections were associated with decreased risk of malaria illness in all ages (HR 0.50, p < 0.001). When asymptomatic infections preceded malaria illness, newly acquired infections were detected at 92% of subsequent clinical episodes, independent of presence of persistent infections. Malaria illness among children was more likely due to newly acquired infections (OR 1.4, 95%CI 1.3-1.5) than to persistent infections. Conclusions/UNASSIGNED:Asymptomatic P. falciparum infections are associated with decreased incidence of malaria illness but do not protect against disease when new infection occurs.

Few data exist on the incidence or duration of natural Plasmodium falciparum infections in high transmission settings. School-aged children (SAC) carry a disproportionate burden of infections, suggesting either increased incidence or duration. We estimated the incidence and duration of unique infections by age groups. The Mfera Cohort Study (2012-2017) had two years of follow-up with 120 participants tested monthly and during sick visits. Blood samples were collected to detect P. falciparum by microscopy and polymerase chain reaction. Positive samples underwent genotyping. Simulation was used to account for high non-detection of infection among low parasitemia infections, which increase in frequency with age. Adults had significantly fewer unique infections per person per year (median, 2.5) compared to SAC and under-five children (6.3 and 6.6, respectively). Over half of all genotypes were persistent. Infections lasted significantly longer in adults (median, 180 days) and SAC (median, 163 days) compared to under-five children (median, 97 days), after accounting for age-dependent, non-detection of infection. SAC acquired new infections at the same rate as under-five children, but maintained these infections for longer periods of time, similar to adults. This study provides new insights into P. falciparum infection dynamics that should be considered when designing malaria control strategies.

Background. The multiplex polymerase chain reaction respiratory pathogen panel (RPP) is used frequently in emergency departments (EDs) for the rapid identification of viruses and atypical bacteria of the respiratory tract. Its clinical value is unclear, as numerous studies have demonstrated that its use has a limited impact on antibiotic prescribing. We aimed to describe the relationship between RPP results and antibiotic prescribing rates for ED patients in our large academic medical center. Methods. We retrospectively analyzed the charts of 1,061 patients aged 18-90 who were treated and released from two EDs from January 1, 2015 to January 31, 2018 and underwent RPP testing. Patients with evidence of bacterial infection were excluded based on RPP detection of atypical bacteria and microbiological analysis of blood, urine, wound, and sputum specimens. The results of the RPP and the rates of subsequent respiratory pathogen-directed antibiotic prescribing (including ED and outpatient pharmacy orders) were compared. Results. Antibiotic prescription rates were 21.5% in patients who tested negative for any respiratory virus, compared with 14.5% in patients who tested positive (OR 0.70, P < 0.01). When positive RPPs were subdivided based on virus type (influenza and non-influenza) and compared with negative RPPs, only influenza-detection was associated with a significant reduction in antibiotic prescriptions (Table 1). Conclusion. In our study population, the presence of a respiratory virus detected by the RPP was correlated with a significant decrease in antibiotic prescribing. This effect was largely driven by influenza detection. This demonstrates that at our institution, the RPP may have a role in reducing unnecessary antibiotic utilization, but providers need further guidance in the interpretation of non-influenza respiratory virus positivity. (Table Presented)

Recent World Health Organization (WHO) guidelines recommend antiretroviral therapy (ART) for all HIV-infected people; previously CD4+ T lymphocyte quantification (CD4 count) or clinical staging determined eligibility for children >/= 5 years old in low- and middle-income countries. We examined positive predictive value (PPV) of a rapid diagnostic test (RDT) algorithm and ART eligibility for hospitalized children with newly diagnosed HIV infection. We enrolled 363 hospitalized Malawian children age 2 months to 16 years with two serial positive HIV RDT from 2013 to 2015. Children aged /= 5 years, 8.9% were ineligible for ART under previous WHO guidelines. Improved HIV testing algorithms are needed for accurate diagnosis of HIV infection in children as prevalence of pediatric HIV declines. Universal treatment will significantly increase the numbers of older children who qualify for ART.

Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRalpha1.7 domains. Furthermore, a recombinant CIDRalpha1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRalpha1 domains in brain swelling.

Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P < 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV+) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV+ and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly (>9 times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly (>2-fold) greater in HIV+ children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV+ children exacerbates the pathological features associated with CM. IMPORTANCE : There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV+) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV+ than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV+ children. Our findings raise the possibility that HIV+ children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.

HIV infection is widespread throughout the world and is especially prevalent in sub-Saharan Africa and Asia. Similarly, Plasmodium falciparum, the most common cause of severe malaria, affects large areas of sub-Saharan Africa, the Indian subcontinent, and Southeast Asia. Although initial studies suggested that HIV and malaria had independent impact upon patient outcomes, recent studies have indicated a more significant interaction. Clinical studies have shown that people infected with HIV have more frequent and severe episodes of malaria, and parameters of HIV disease progression worsen in individuals during acute malaria episodes. However, the effect of HIV on development of cerebral malaria, a manifestation of P. falciparum infection that is frequently fatal, has not been characterized. We review clinical and basic science studies pertaining to HIV and malaria coinfection and cerebral malaria in particular in order to highlight the likely role HIV plays in exacerbating cerebral malaria pathogenesis.