Plasmodium falciparum Malaria Is Associated With Increased Kaposi Sarcoma-Associated Herpesvirus (KSHV) Seropositivity and Higher KSHV Antibody Breadth and Magnitude: Results of a Case-Control Study From Rural Uganda

Background Previously, we showed that children with asymptomatic Plasmodium falciparum (Pf) malaria infection had higher Kaposi sarcoma-associated herpesvirus (KSHV) viral load, increased risk of KSHV seropositivity, and higher KSHV antibody levels. We hypothesize that clinical malaria has an even larger association with KSHV seropositivity. In the current study, we investigated the association between clinical malaria and KSHV seropositivity and antibody levels. Methods Between December 2020 and March 2022, sick children (aged 5-10 years) presenting at a clinic in Uganda were enrolled in a case-control study. Pf was detected using malaria rapid diagnostic tests (RDTs) and subsequently with quantitative real-time polymerase chain reaction (qPCR). Children with malaria were categorized into 2 groups: RDT+/PfPCR(+) and RDT-/PfPCR(+). Results The seropositivity of KSHV was 60% (47/78) among Pf-uninfected children, 79% (61/77) among children who were RDT-/PfPCR(+) (odds ratio [OR], 2.41 [95% confidence interval {CI}, 1.15-5.02]), and 95% (141/149) in children who were RDT+/PfPCR(+) (OR, 10.52 [95% CI, 4.17-26.58]; P-trend < .001). Furthermore, RDT+/PfPCR(+) children followed by RDT-/PfPCR(+) children had higher KSHV IgG and IgM antibody levels and reacted to more KSHV antigens compared to uninfected children. Conclusions Clinical malaria is associated with both increased KSHV seropositivity and antibody magnitude, suggesting that Pf is affecting KSHV immunity. Plasmodium falciparum (Pf) malaria is associated with increased Kaposi sarcoma-associated herpesvirus (KSHV) seropositivity and higher KSHV antibody breadth and magnitude. Pf association with KSHV is highest in children with clinical malaria (rapid diagnostic test/polymerase chain reaction positive) compared to children without malaria.