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

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.

Global & Temporal Patterns of Submicroscopic Plasmodium falciparum Malaria Infection

“…Whilst our results highlight that PCR 6 methodology does significantly influence the prevalence ratio (Supp Fig.7), systematic variation in 7 methodological quality across geographical (Supp Fig.5) and transmission archetypes (Supp Fig.6) 8 settings was not observed. Interestingly, our analyses revealed no influence of seasonal effects on 9 submicroscopic carriage, despite parasite densities having been shown to slightly rise during the rainy 10 season even when prevalence does not change significantly (possibly due to increased occurrence of 11 superinfection during these periods) 48,49 . This is consistent with other recent results which similarly 12 found no difference in the submicroscopic reservoir between seasons, when directly comparing the 13 wet and dry season submicroscopic prevalence across the same locations 20 .…”

“…Interestingly, our analyses revealed no influence of seasonal effects on 9 submicroscopic carriage, despite parasite densities having been shown to slightly rise during the rainy 10 season even when prevalence does not change significantly (possibly due to increased occurrence of 11 superinfection during these periods) 48,49 . This is consistent with other recent results which similarly 12 found no difference in the submicroscopic reservoir between seasons, when directly comparing the 13 wet and dry season submicroscopic prevalence across the same locations 20 . 14 Variation in the extent of parasite genetic diversity between settings could also explain the observed 15 results.…”

“…24 A number of hypotheses could explain these results, including systematic variation in asexual blood 1 stage multiplication rate of Plasmodium falciparum 46 or various haemoglobinopathies and human 2 genetic traits that have been linked to lower average parasite densities 41,47 . It is also not possible to 3 definitively preclude systematic variation in diagnostic quality across settings, although this is perhaps 4 unlikely: for example, a recent analysis found that whilst microscopy quality varies across settings, it 5 does not do so systematically with transmission intensity 48 . Whilst our results highlight that PCR 6 methodology does significantly influence the prevalence ratio (Supp Fig.7), systematic variation in 7 methodological quality across geographical (Supp Fig.5) and transmission archetypes (Supp Fig.6) 8 settings was not observed.…”

“…Our work suggests that the contribution of submicroscopic infections to onwards transmission is likely 6 highly variable across settings; however, this analysis is based on the detection of asexual parasites 7 and does not provide direct insight into gametocyte densities. The relationship between asexual 8 parasite and gametocyte density is highly non-linear 42 and the distributions of parasite densities in the 9 submicroscopic range can differ substantially between settings 48 . Therefore the proportion of 10 submicroscopic infections may not relate linearly to their contribution to onwards transmission.…”

“…Submicrosopically infected individuals 15 have been shown to contribute to transmission of the parasite across both areas of high 18 and low 19 16 transmission intensity, as well seasonal 16 and perennial 17 settings. Additionally, a recent meta-analysis 17 revealed the detection limit of microscopy to be higher than is typically assumed and estimated that 18 submicroscopic infections are on average only 3-fold less infectious to mosquitoes compared with 19 microscopy-positive individuals 20 , further underscoring the potential relevance of this infected sub-20 group to malaria control efforts. 21…”