Global patterns of submicroscopic Plasmodium falciparum malaria infection: insights from a systematic review and meta-analysis of population surveys

Abstract

Background Adoption of molecular techniques to detect Plasmodium falciparum infection has revealed many previously undetected (by microscopy) yet transmissible low-density infections. The proportion of these infections is typically highest in low transmission settings, but drivers of submicroscopic infection remain unclear. Here, we updated a previous systematic review of asexual P falciparum prevalence by microscopy PCR in the same population. We aimed to explore potential drivers of submicroscopic infection and to identify the locations where submicroscopic infections are most common.Methods In this systematic review and meta-analysis we searched PubMed and Web of Science from Jan 1, 2010, until Oct 11, 2020, for cross-sectional studies reporting data on asexual P falciparum prevalence by both microscopy and PCR. Surveys of pregnant women, surveys in which participants had been chosen based on symptoms or treatment, or surveys that did not involve a population from a defined location were excluded. Both the number of individuals tested and the number of individuals who tested positive by microscopy or PCR, or both, for P falciparum infection were extracted. Bayesian regression modelling was used to explore determinants of the size of the submicroscopic reservoir including geographical location, seasonality, age, methodology, and current or historical patterns of transmission.Findings Of 4893 identified studies, we retained 121 after screening and removal of duplicates. 45 studies from a previous systematic review were included giving 166 studies containing 551 cross-sectional survey microscopy and PCR prevalence pairs. Our results show that submicroscopic infections predominate in low-transmission settings across all regions, but also reveal marked geographical variation, with the proportion of infections that are submicroscopic being highest in South American surveys and lowest in west African surveys. Although current transmission levels partly explain these results, we find that historical transmission intensity also represents a crucial determinant of the size of the submicroscopic reservoir, as does the demographic structure of the infected population (with submicroscopic infection more likely to occur in adults than in children) and the PCR or microscopy methodology used. We also observed a small yet significant influence of seasonality, with fewer submicroscopic infections observed in the wet season than the dry season. Integrating these results with estimates of infectivity in relation to parasite density suggests the contribution of submicroscopic infections to transmission across different settings is likely to be highly variable.Interpretation Significant variation in the prevalence of submicroscopic infection exists even across settings characterised by similar current levels of transmission. These differences in submicroscopic epidemiology potentially warrant different approaches to targeting this infected subgroup across different settings to eliminate malaria.

Nationwide molecular surveillance of three Plasmodium species harboured by symptomatic malaria patients living in Ghana

“…Submicroscopic malaria parasites among febrile patients have been enumerated; however, due to overlapping symptoms between malaria and other febrile diseases, highly sensitive POC diagnostic tests must be used for diagnosis [ 40 ]. Although submicroscopic malaria infections rarely cause clinical disease, in some cases severe and acute symptoms, such as mild anaemia, coughing, vomiting and jaundice, may develop as the disease progresses without appropriate treatment [ 41 ]. Early detection of submicroscopic malaria parasites is very important as it ensures appropriate treatment and the accurate determination of the malaria reservoir size [ 42 , 43 ].…”

Infection submicroscopique à Plasmodium falciparum en zone d’endémie palustre : une revue de littérature

“…P. falciparum, en raison de son tropisme pour les érythrocytes, donne essentiellement une symptomatologie fébrile, souvent mortelle surtout chez l'enfant, les femmes enceintes et les sujets non immuns qui arrivent en zone d'endémie (1)(2). La grande létalité associée à certaines formes comme l'anémie sévère et le neuropaludisme amène à envisager devant tout patient avec fièvre un diagnostic du paludisme quels que soient les signes cliniques qui accompagnent cette fièvre surtout si le patient vit en zone endémique (1).…”

Limited Reliability of the Molecular Detection of Plasmodium spp. from Incubated Blood Culture Samples for Forensic Purposes

“…Further, molecular approaches such as PCR are more sensitive than antigen testing, including the recently introduced "ultrasensitive rapid diagnostic tests" [9,10]. Apart from the diagnostic needs in resource-rich non-endemic settings, the suitability of highly sensitive real-time PCR assays has also been suggested for malaria eradication programs [11][12][13][14][15][16].…”

“…• Plasmodium falciparum mono-infections were detected by SybrGreen-based screening PCR with low cycle threshold values(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and, thus, mixed plasmodial infections with severely dysbalanced parasitemia could not be excluded by melting curve analysis alone (n = 165).…”