A Systematic Review: Performance of Rapid Diagnostic Tests for the Detection of Plasmodium knowlesi, Plasmodium malariae, and Plasmodium ovale Monoinfections in Human Blood

Abstract

Background: Despite the increased use and worldwide distribution of malaria rapid diagnostic tests (RDTs) that distinguish between Plasmodium falciparum and non-falciparum species, little is known about their performance detecting Plasmodium knowlesi (Pk), Plasmodium malariae (Pm), and Plasmodium ovale (Po). This review seeks to analyze the results of published studies evaluating the diagnostic accuracy of malaria RDTs in detecting Pk, Pm, and Po monoinfections.

Methods: MEDLINE, EMBASE, Web of Science, and CENTRAL databases were systematically searched to identify studies that reported the performance of RDTs in detecting Pk, Pm, and Po monoinfections.

Results: Among 40 studies included in the review, 3 reported on Pk, 8 on Pm, 5 on Po, 1 on Pk and Pm, and 23 on Pm and Po infections. In the meta-analysis, estimates of sensitivities of RDTs in detecting Pk infections ranged 2%-48%. Test performances for Pm and Po infections were less accurate and highly heterogeneous, mainly because of the small number of samples tested.

Conclusions: Limited data available suggest that malaria RDTs show suboptimal performance for detecting Pk, Pm, and Po infections. New improved RDTs and appropriately designed cross-sectional studies to demonstrate the usefulness of RDTs in the detection of neglected Plasmodium species are urgently needed.

Figure 1.

Antigens targeted by rapid diagnostic test (RDT) types included in the review. Only type 2, 3, 4, and 6 RDTs are able to distinguish between Plasmodium falciparum (Pf) and non-falciparum infections. Type 2 tests detect Pf-specific histidine-rich protein-2 (HRP2) antigen and panmalarial aldolase, which is expressed by all species. Type 3 tests detect a pan-specific LDH in addition to Pf-specific HRP2 antigen. Type 4 RDTs target Pf-specific and pan-specific lactate dehydrogenase (LDH) antigens as two separate lines, allowing distinction between Pf and non-falciparum infections. Type 6 RDTs are 4-band tests that target Pf-specific HRP2, Pv-specific LDH, and pan-specific LDH [7, 8]. Abbreviations: HRP2, Histidine-rich protein-2; Pf, Plasmodium falciparum; pLDH, Plasmodium lactate dehydrogenase; Pv, Plasmodium vivax; RDT, rapid diagnostic test.

Figure 2.

Flow chart of the selection procedure. Forty articles were included in the review. Abbreviations: Pf, Plasmodium falciparum; Pv, Plasmodium vivax; RDT, rapid diagnostic test.

Figure 3.

Methodological quality assessment of 40 studies included in the review. Reviewers’ assessment of four key domains—patient selection, index test, reference standard, and flow and timing—of the Quality Assessment of Diagnostic Accuracy Score 2 tool is presented in stack bars as the proportion of studies with high/unclear/low risk of bias and with high/clear/low concerns regarding applicability [13].

Figure 4.

Performance of malaria rapid diagnostic tests (RDTs) for the detection of Plasmodium knowlesi mono-infections in human blood. A, Forest plot of sensitivity and specificity of RDT types for detection of Plasmodium knowlesi (Pk) infections. Studies are ordered by sample source site and study ID. B, Plot of sensitivity versus specificity as estimated in studies that report on both. Abbreviations: APD, average parasite density of Pk cases (° median parasite density); CI, confidence interval; NA, not available; NR, not reported; RDT, rapid diagnostic test.

Figure 5.

Performance of malaria rapid diagnostic tests (RDTs) for the detection of Plasmodium malariae mono-infections in human blood. A, Forest plot of sensitivity and specificity of RDT types for detection of Plasmodium malariae (PM) infections. Studies are ordered by RDT type, sample source site, study design, and study ID. Studies listed have cross-sectional design unless marked with * for case–control design or with ** for unclear design. B, Plot of sensitivity versus specificity as estimated in studies that report on both. Size of symbols corresponds to the number of cases evaluated in each study. Abbreviations: APD, average parasite density of Pk cases (° median parasite density); CI, confidence interval; NA, not available; NR, not reported; RDT, rapid diagnostic test.

Figure 6.

Performance of malaria rapid diagnostic tests (RDTs) for the detection of Plasmodium ovale mono-infections in human blood. A, Forest plot of sensitivity and specificity of RDT types for detection of Plasmodium ovale (Po) infections. Studies are ordered by sample source site, study design, and study ID. Studies listed have cross-sectional design unless marked with * for case–control design or with ** for unclear design. Eibach et al [27] has been designated as 2013a and 2013b to distinguish between the first part of the study (2013a), which was conducted in a nonendemic setting, and the second part of the study (2013b), which was conducted in an endemic setting. B, Plot of sensitivity versus specificity as estimated in studies that report on both. Size of symbols corresponds to the number of cases evaluated in each study. Abbreviations: APD, average parasite density of Pk cases (° median parasite density); CI, confidence interval; NA, not available; NR, not reported; RDT, rapid diagnostic test.