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.

Figure 1.

Selection of study subjects. Abbreviations: Pf, Plasmodium falciparum; PfHRP2, P. falciparum histidine-rich protein 2; pLDH, parasite lactate dehydrogenase; RDT, rapid diagnostic test.

Figure 2.

Frequency distributions of peripheral blood parasitemia, plasma Plasmodium falciparum histidine-rich protein 2 (PfHRP2) concentrations, and modeled fitted PfHRP2, according to malaria clinical group (1 = healthy rapid diagnostic test [RDT]–negative controls, 2 = asymptomatic carriers, 3 = uncomplicated malaria, 4 = severe malaria, 5 = severe malaria). The fitted PfHRP2 distributions (right column) show the modeled PfHRP2 distributions with the underlying contributing PfHRP2 distributions of different diagnostic groups (dotted lines), composed of RDT-negative controls (light green), asymptomatic carriers (green), and patients with uncomplicated malaria (blue turquoise) or severe malaria (bright blue and purple).

Figure 3.

Malaria-attributable proportion (left axis) and sensitivity (median, 95% credible interval; right axis) for severe disease, according to log₁₀ plasma Plasmodium falciparum histidine-rich protein 2 (PfHRP2) concentration. The malaria-attributable proportion was derived from the predicted PfHRP2 distributions from the median (95% credible interval) values of the m_ij distributions of individuals in each malaria diagnostic group (see Supplementary Materials).

Figure 4.

Blood culture positivity, according to plasma Plasmodium falciparum histidine-rich protein 2 (PfHRP2) quintile, in patients with severe malaria. Gram-positive bacteria included Streptococcus pneumonia, Staphylococcus aureus, β-hemolytic Streptococcus. Other gram-negative bacteria included Haemophilus influenza (type b), unspecified gram-negative rods, Salmonella typhi, Acinetobacter baumannii, Burkholderia cepacia, Kingella kingae, Neisseria species, Pseudomonas oryzihabitans, and Pasteurella species. Gram-negative bacteria included Salmonella species, Escherichia coli, Enterobacter cloacae, and Klebsiella species. Contaminants included Micrococcus species, Bacillus species, coagulase-negative Staphylococcus, yeast, Corynebacterium species (diphtheroids), unspecified gram-positive rods, mixed bacterial species, Ralstonia pickettii, α-hemolytic Streptococcus viridans, Sphingomonas paucimobilis, Pseudomonas stutzeri, Chryseomonas luteola, and Stenotrophomonas maltophilia.