Heterogeneous mosquito exposure increases Plasmodium vivax and Plasmodium falciparum coinfections: a modelling study

In malaria-endemic regions, Plasmodium vivax and Plasmodium falciparum coexist and may interact. For instance, fevers induced by P. falciparum might activate dormant P. vivax parasites and concurrent radical cure of both species has been proposed to prevent relapses. Heterogeneous mosquito exposure may contribute to the dependence of both parasites. We conducted a literature review on their respective prevalence and that of coinfections. The data revealed a positive correlation between P. vivax and P. falciparum prevalence and coinfection prevalences exceeding expectations assuming infections occur independently. We used the review data to fit a compartmental model of coinfections that features heterogeneous mosquito exposure. The fit suggests that heterogeneous exposure sufficiently explains the observed departure from independence. Finally, we performed simulations under the model assessing the impact on P. vivax prevalence of the activation-by-fever hypothesis and the radical cure proposition. We demonstrated a moderate impact of allowing P. falciparum fevers to reactivate P. vivax and a substantial impact of treating P. falciparum cases with radical cure. Our model highlights the dependence between P. falciparum and P. vivax and emphasises the influence of heterogeneous mosquito exposure. This simple framework can inform the design of more complex models assessing integrated malaria control strategies in co-endemic regions.

Methods
We performed a literature review on PubMed to collect data from field epidemiology studies recording P. vivax, P. falciparum, and coinfection prevalence, among the general population. Specifically, we defined those studies as cross-sectional and active infection-detection studies performed in communities, unrestricted by age, sex, or symptomatic status. The keywords we used were:

Title: (Malaria OR Vivax OR Falciparum) NOT (Health-care facility OR Hospital OR Health centre OR Systematic Review OR Meta*)

Abstract: Prevalence OR Distribution OR Epidemiology OR Cross-section

Text: Vivax AND Falciparum

After title and abstract screening with “Rayyan”, we screened the main text and extracted the P. vivax, P. falciparum, and coinfection prevalence from each study, as well as the sample size and diagnostic method used to generate prevalence. We excluded studies that failed to report all those metrics or that did not screen the general population. A spreadsheet of the details of all the studies retained after title and abstract screening is available as a supplementary file.

We defined different metrics related to the coupled dynamics of P. vivax, P. falciparum, and coinfections. First, we introduced the notion of expected coinfection prevalence under the independence of P. vivax and P. falciparum. That is, we assumed that if P. vivax and P. falciparum transmission are independent, coinfection prevalence should be the product of P. falciparum and P. vivax prevalence. We then defined the proportional excess coinfection prevalence as the difference between observed and expected coinfection prevalence, normalized by different measures of local transmission intensity: P. vivax prevalence, P. falciparum prevalence, or overall malaria prevalence.