Evaluation of the Sensitivity of a pLDH-Based and an Aldolase-Based Rapid Diagnostic Test for Diagnosis of Uncomplicated and Severe Malaria Caused by PCR-Confirmed Plasmodium knowlesi, Plasmodium falciparum, and Plasmodium vivax

Abstract

dPlasmodium knowlesi can cause severe and fatal human malaria in Southeast Asia. Rapid diagnosis of all Plasmodium species is essential for initiation of effective treatment. Rapid diagnostic tests (RDTs) are sensitive for detection of uncomplicated and severe falciparum malaria but have not been systematically evaluated in knowlesi malaria. At a tertiary referral hospital in Sabah, Malaysia, we prospectively evaluated the sensitivity of two combination RDTs for the diagnosis of uncomplicated and severe malaria from all three potentially fatal Plasmodium species, using a pan-Plasmodium lactate dehydrogenase (pLDH)-P. falciparum histidine-rich protein 2 (PfHRP2) RDT (First Response) and a pan-Plasmodium aldolase-PfHRP2 RDT (ParaHIT). Among 293 hospitalized adults with PCR-confirmed Plasmodium monoinfection, the sensitivity of the pLDH component of the pLDHPfHRP2 RDT was 74% (95/129; 95% confidence interval [CI], 65 to 80%), 91% (110/121; 95% CI, 84 to 95%), and 95% (41/43; 95% CI, 85 to 99%) for PCR-confirmed P. knowlesi, P. falciparum, and P. vivax infections, respectively, and 88% (30/34; 95% CI, 73 to 95%), 90% (38/42; 95% CI, 78 to 96%), and 100% (12/12; 95% CI, 76 to 100%) among patients tested before antimalarial treatment was begun. Sensitivity in severe malaria was 95% (36/38; 95% CI, 83 to 99), 100% (13/13; 95% CI, 77 to 100), and 100% (7/7; 95% CI, 65 to 100%), respectively. The aldolase component of the aldolase-PfHRP2 RDT performed poorly in all Plasmodium species. The pLDH-based RDT was highly sensitive for the diagnosis of severe malaria from all species; however, neither the pLDH-nor aldolase-based RDT demonstrated sufficiently high overall sensitivity for P. knowlesi. More sensitive RDTs are needed in regions of P. knowlesi endemicity.

Combining Parasite Lactate Dehydrogenase-Based and Histidine-Rich Protein 2-Based Rapid Tests To Improve Specificity for Diagnosis of Malaria Due to Plasmodium knowlesi and Other Plasmodium Species in Sabah, Malaysia

“…These include tests incorporating the follow- (33), and pan-Plasmodium aldolase (ParaHit, 23% sensitivity with fresh isolates [25]; BinaxNOW, 29% sensitivity with fresh isolates [33]). …”

“…In a previous prospective evaluation of RDTs for P. knowlesi malaria, a pan-pLDHbased RDT demonstrated a moderate overall sensitivity for P. knowlesi of 74% (95/129; 95% confidence interval [CI], 65 to 80%), which improved for pretreatment samples (88%; 30/34; CI, 73 to 95%) and for severe disease (95%; 36/38; CI, 83 to 99%) (25). Neither this test nor a more poorly performing aldolase-based RDT also evaluated in that study approached a sensitivity of 100% for parasitemias of Ͼ100/l, which was previously defined as necessary for use as a clinically sufficient malaria diagnostic tool (26,27).…”

A Sensitive, Colorimetric, High-Throughput Loop-Mediated Isothermal Amplification Assay for the Detection of Plasmodium knowlesi

“…Ring and trophozoite stages of P. knowlesi appear morphologically very similar to both Plasmodium falciparum and Plasmodium malariae. 1 Microscopy has been found to be unreliable for diagnosing P. knowlesi in regions where it coexists with P. falciparum and Plasmodium vivax, 3,4 resulting in inappropriate or delayed administration of antimalarial treatment. Although high parasitemia has been found to predict severe disease, symptomatic disease frequently occurs at low parasitemia.…”

Plasmodium knowlesi infection imported to Germany, January 2013

“…P. knowlesi is morphologically very similar to P. malariae but can also be confused with P. falciparum in microscopy. As illustrated by the two cases described above, P. knowlesi infection causes variable results with commercially available rapid diagnostic tests, which do not seem to be reliable for diagnosis of P. knowlesi [3,4]. Although rapid diagnostic tests can complement microscopic diagnosis, they cannot replace microscopy, especially in patients with low parasite loads.…”