The impact of emerging Plasmodium knowlesi on accurate diagnosis by light microscopy: a systematic review and modelling analysis

Abstract

ABSTRACTBackgroundThe five Plasmodium spp. that cause human malaria appear similar under light microscopy, which raises the possibility that misdiagnosis could routinely occur in clinical settings. Assessing the extent of misdiagnosis is of particular importance for monitoring P. knowlesi, which co-circulates with the other Plasmodium spp.MethodsWe performed a systematic review and meta-analysis of studies comparing the performance of microscopy and PCR for diagnosing malaria in settings with co-circulation of the five Plasmodium spp. We assessed the extent to which co-circulation of Plasmodium parasites affects diagnostic outcomes. We fit a Bayesian hierarchical latent class model to estimate variation in microscopy sensitivity and specificity.ResultsMean sensitivity of microscopy was low, yet highly variable across Plasmodium spp., ranging from 41.7% (95% CI: 22.8 – 64.1%) for P. falciparum and 40.3% (22.0 – 61.5%) for P. vivax to 0.119% (0.0121 – 0.640%) for P. knowlesi, 7.57% (2.66 – 22.0%) for P. malariae, and 0.180% (0.00491 – 1.21%) for P. ovale. Observed PCR prevalence was positively correlated with estimated microscopic sensitivity and negatively correlated with estimated microscopic specificity, though the strength of the associations varied by species.ConclusionsOur analysis suggests that co-circulation of Plasmodium spp. undermines the accuracy of microscopy. Sensitivity was considerably lower for P. knowlesi, P. malariae, and P. ovale. The negative association between specificity and PCR prevalence imply that less frequently encountered species may be misdiagnosed as more frequently encountered species. Together, these results suggest that the burden of P. knowlesi, P. malariae, and P. ovale may be underappreciated in a clinical setting.SummaryCo-circulation of Plasmodium species parasites may limit the accuracy of malaria diagnosis by light microscopy. Variation in performance of light microscopy is highly correlated with the prevalence of the parasites in the epidemiological setting.