Abstract
Background Adoption of molecular techniques to detect Plasmodium falciparum infection has revealed many previously undetected (yet transmissible) low-density infections in areas of low malaria transmission. In a world where numerous countries are approaching elimination, additional data from low transmission areas are required to better understand the determinants of submicroscopic infection and their potential relevance in these settings.
Methods We updated a systematic review of studies assessing asexual P. falciparum prevalence by microscopy and PCR in the same population. PubMed and Web of Science databases were searched up to July 2017. Bayesian regression modelling was used to explore determinants of the size of the submicroscopic reservoir across endemic populations and define when and where submicroscopic infections are likely to be most relevant to malaria control efforts.
Findings A total of 105 references containing 387 microscopy/PCR prevalence pairs were included. Our results highlight marked geographical variation in the proportion of submicroscopically infected individuals across settings, with the submicroscopic reservoir largest in regions with historically low levels of transmission and smaller in areas that have only more recently reduced transmission. Age was also a significant determinant, with submicroscopic infection more likely in adults than infants (0-5 years) and older children (5-15 years), although we did not observe a statistically significant influence of seasonality. Integrating these results with estimates of infectivity in relation to parasite density suggests the contribution of this 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 sub-group in the approach to elimination.
Funding None
Evidence before this study Cross-sectional studies of malaria prevalence in endemic populations have revealed the widespread presence of infections with parasite densities lower than the threshold of detection by microscopy. Previous systematic reviews of these surveys have highlighted that the fraction of P.falciparum infections missed by microscopy can be substantial (∼45% of all infections detected by PCR on average), that submicroscopic infection is more likely in adults than in children (a phenomenon attributed to increased levels of immunity), and that this missed fraction (the “submicroscopic reservoir”) is typically highest in areas with low transmission intensity. Although further work is required, a number of studies have also demonstrated the capacity of these submicroscopic, low density infections to infect mosquitoes and therefore contribute to onwards transmission.
Added value of this study Although previous studies have found that infections in older, more immune individuals are more likely to be submicroscopic, in lower transmission settings where individuals generally develop less immunity, a larger proportion of infections are also typically submicroscopic. Here we present an updated systematic review to explore this apparent paradox across a range of transmission settings and define contexts in which submicroscopic infections are likely to be most relevant to malaria control efforts. Leveraging the substantial increase in the availability of malaria cross-sectional surveys reporting prevalence by molecular methods, we explore the association of submicroscopic infection with a number of novel factors – these include age (at a finer resolution than has previously been possible), seasonality, geography and historical transmission patterns. Our findings highlight striking geographical variation in the size of the submicroscopic reservoir - this variation can be explained in-part by the historical patterns of transmission characterising each area, with the submicroscopic reservoir largest in areas with historically low levels of transmission. Integrating this information with estimates of the infectivity of submicroscopic and microscopically-detectable infections allows us to better define when and where submicroscopic malaria infections may be relevant to control efforts and highlights that the contribution of these low-density infections to transmission is likely to vary substantially across different settings.
Implications of all the available evidence Our work highlights important and material differences in submicroscopic malaria epidemiology across settings and suggests the absence of a one-size-fits-all solution for malaria control efforts targeting this infected sub-group. Whether or not the submicroscopic reservoir requires targeting in the approach to elimination will depend on the particular setting, and likely warrant different approaches if the infection is to be controlled most effectively in the approach to elimination.