Abstract
SummaryBackgroundAdoption 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.MethodsIn 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.FindingsOf 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.InterpretationSignificant 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.FundingBill & Melinda Gates Foundation, The Royal Society, and the UK Medical Research Council.
Highlights
The ability to accurately detect malaria infection during population surveys is a cornerstone of effective survei llance and control of the Plasmodium parasite
Our results show that submicroscopic infections predominate in low-transmission settings across all regions, and reveal marked geographical variation, with the proportion of infections that are submicroscopic being highest in South American surveys and lowest in west African surveys
Current transmission levels partly explain these results, we find that historical transmission intensity represents a crucial determinant of the size of the submicroscopic reservoir, as does the demographic structure of the infected population and the PCR or microscopy methodology used
Summary
The ability to accurately detect malaria infection during population surveys is a cornerstone of effective survei llance and control of the Plasmodium parasite. Malaria detection is undertaken using microscopy of blood films or rapid diagnostic tests, in recent years there has been an increase in the use of more sensitive molecular methods in research contexts These techniques (typically PCR based)[1] have revealed the widespread presence of infections with parasite densities lower than the threshold of detection by routine methods such as microscopy.[2,3,4] Such submicroscopic infections are present across a range of different settings and populations.[5,6] rarely causative of severe symptoms, these infections have been associated with some adverse outcomes during pregnancy[7] and in children younger than 10 years.[8].
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