Defining Falciparum-Malaria-Attributable Severe Febrile Illness in Moderate-to-High Transmission Settings on the Basis of Plasma PfHRP2 Concentration

Abstract

Background. In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations.Methods. Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6−60 months in communities and a nearby hospital in northeastern Tanzania. The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests. The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease.Results. The plasma PfHRP2 concentration showed a close correlation with the severity of infection. PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%–100%), with a sensitivity of 74% (95% CI, 72%–77%), whereas a concentration of <200 ng/mL denoted severe febrile illness of an alternative diagnosis in >10% (95% CI, 3%–27%) of patients. Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles.Conclusions. The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.

Hemozoin-generated vapor nanobubbles for transdermal reagent- and needle-free detection of malaria

“…Thus, the quantitative H-VNB diagnostics of malaria will require additional calibration. Parasitemia level as currently measured also does not always correlate with disease severity (22,23). Therefore, after a detailed preclinical study, the H-VNBs may reveal unique diagnostic and prognostic metrics.…”

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

“…Thus, restoration of EPCR functions may be a key target for adjunctive malaria drug treatments. protein 2 (PfHRP2), a surrogate of parasite biomass, can predict disease severity and fatality rates in both children and adults (31,32), the probability of disease deterioration (33), retinopathy-positive cerebral malaria (34), and whether a fever is caused by malaria (35). Nevertheless, a recent longitudinal study in Tanzanian children showed that high PfHRP2 levels did not necessitate severe disease (36), suggesting severe disease requires additional factors.…”

Quantification of Plasmodium falciparum Histidine-Rich Protein-2 in Cerebrospinal Spinal Fluid from Cerebral Malaria Patients

“…Levels of PfHRP-2 in plasma most often do not correlate with parasitemia. 23,24 Here, we identified PfHRP-2 by both an RDT using a minimum volume of 10 μL and by immuno-PCR using an average volume of 5 μL because of limited volume in archival samples. The non-repetitive protein aldolase was mostly absent from CSF by RDT, either from lack of sensitivity of the RDT for aldolase compared with PfHRP-2 in CSF (as is described in whole blood) 25 or because proteolysis between capture and detection epitopes for the RDT makes aldolase in CSF not detectable in the RDT format.…”

“…The PfHRP2 levels in uncomplicated malaria are about 100 to 300 ng/mL. 17,24,27 The PfHRP-2 could enter the CSF by the choroid plexus with its fenestrated endothelium and specialized epitheloid cells that generate a 200-fold reduction in protein as they produce CSF from plasma. 26 Additionally, 50% of CSF is made from interstitial fluid in brain parenchyma, which drains directly into ventricles.…”