Performance of Antigen Concentration Thresholds for Attributing Fever to Malaria among Outpatients in Angola

Abstract

The density of malaria parasites is a key determinant of whether an infected individual develops fever. While the pyrogenic threshold for malaria parasite density has been well studied, there are no analogous data on the antigen levels associated with fever during infection. Samples from 797 afebrile and 457 febrile outpatients from two provinces in Angola with known concentrations of histidine-rich protein 2 (HRP2), aldolase, and lactate dehydrogenase (LDH) antigens were analyzed by Bayesian latent class modeling to attribute malarial etiology to the fevers and to estimate the sensitivity and specificity of different antigen thresholds for detection of malaria fevers. Among patients with aldolase or LDH levels detectable with a bead-based assay, the concentrations of these two antigens did not differ between afebrile and febrile patients. In contrast, the concentrations of HRP2 were substantially higher in febrile HRP2-positive patients than in afebrile HRP2-positive patients. When HRP2 concentrations were considered, the malaria-attributable fractions of fever cases were 0.092 in Huambo Province and 0.39 in Uíge Province. Diagnostic tests detecting HRP2 with limits of detection (LODs) in the range of 3,000 to 10,000 pg/µl would provide ideal sensitivity and specificity for determination of malarial etiology among febrile persons.

Keywords: Plasmodium falciparum; pyrogenic threshold.

FIG 1

Estimates of θ, the estimated distributions of antigen concentrations in patients without malarial etiology but with detectable antigen levels. Shaded envelopes correspond to 95% CIs (blue, Uíge Province; red, Huambo Province). The vertical lines in the HRP2 panel correspond to the nominal LODs of the different types of RDTs (ultrasensitive RDT, 200 pg/ml; standard RDT, 3,000 pg/ml).

FIG 2

Estimates of ϕ, the distribution of HRP2 antigen levels in febrile patients with true malarial etiology. Shaded envelopes correspond to 95% CIs (blue, Uíge Province; red, Huambo Province). Vertical lines are as in Fig. 1.

FIG 3

Estimates of $\lambda \prime$, the probability that cases are malaria attributable, according to antigen concentrations. Shaded envelopes correspond to 95% CIs (blue, Uíge Province; red, Huambo Province). Vertical lines are as in Fig. 1.

FIG 4

Sensitivities and specificities of different antigen concentration thresholds for diagnosis of malaria fever. Blue indicates Uíge Province, and red indicates Huambo Province. The values are log₁₀ antigen concentrations. Triangles, LOD of the ultrasensitive HRP2 RDT; circles, LOD of the standard HRP2 RDT.