The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density

Hannah Slater ,Mwinyi Msellem,Anders Björkman,Cécile Nabet,Bronner P Gonçalves,Melissa Kapulu,Eleanor M Riley ,Ogobara K Doumbo ,Chris Drakeley,André Lin Ouédraogo ,Alfred B Tiono ,Seth Owusu‐Agyei ,Natalie Hofmann ,Roly Gosling,Fitsum G Tadesse ,Teun Bousema,Venkatachalam Udhayakumar,François Nosten ,Ivo Müeller ,Leanne J Robinson ,Endalamaw Gadisa,Paul Rácz ,Jacklin F Mosha ,Robert W Sauerwein ,Janet Midega,Naomi W Lucchi ,Gonzalo J Domingo ,Nicholas J White ,Amanda Ross,Ulrika Morris,Renaud Piarroux,Safiatou Doumbo ,Jackie Cook,Daniel Chandramohan,Mallika Imwong,Ingrid Felger,Kwadwo A Koram ,Felista Mwingira,Cristian Koepfli,Suradip Das ,Lucy Okell

doi:10.1038/s41467-019-09441-1

Abstract

Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.

Highlights

For clarity, we outline the terminology used throughout this article: a submicroscopic infection is defined as an infection which is detectable by molecular methods, but not by microscopy
In this article we analyse a series of datasets, harnessing the increasing quantities of molecular data generated in recent years, to investigate the density, temporal dynamics and infectiousness of low-density P. falciparum infections
Individuals in each dataset were split into two groups: those with infections that were detectable by PCR and microscopy or RDT, and those with infections that were detectable by PCR only (Fig. 1b)

Summary

Introduction

For clarity, we outline the terminology used throughout this article: a submicroscopic infection is defined as an infection which is detectable by molecular methods, but not by microscopy. The proportion of all PCR-detected malaria-infected individuals that are detected by microscopy/RDT is significantly lower in lower transmission settings This indicates a lower average parasite density in these settings, contrary to what might be expected given the lower antiparasite immunity to malaria in these populations. Induced malariatherapy infections showed clear declines in average parasite density and detectability over time even when no treatment was given1,14,15 In these infections, low-density periods occurred early in infection, with more than 60% of untreated patients experiencing a subpatent period lasting for 1–34 days directly after the initial peak in parasitaemia. We examine the parasite density distributions of asymptomatically infected populations in a range of transmission settings measured by quantitative molecular methods, with implications for the required sensitivity of new diagnostics. We use studies where mosquito were fed on asymptomatically infected individuals to estimate the relative infectivity of individuals with subpatent parasitaemia and their contribution to the infectious reservoir

Methods

Results

Conclusion