Malaria may influence the transmission of Kaposi sarcoma associated herpesvirus in endemic areas.

To the Editors: Wakeham et al reported an association between asymptomatic malaria parasitemia and Kaposi sarcoma associated herpesvirus (KSHV) seropositivity among children born to women enrolled in the Entebbe Mother and Baby Study (EMABS). The EMABS is a cohort study established to investigate the effect of antihelminthic treatment given to pregnant women and their children on immune response to vaccination in early childhood. Wakeham et al had previously reported that pregnant women enrolled in the EMABS were at higher risk for KSHV seropositivity if they had asymptomatic malaria parasitemia or infection with hookworm, reinforcing the role of certain parasites in the high prevalence of KSHV in endemic areas. Other studies have reported that infection with Schistosoma mansoni increases the risk of KSHV seropositivity in Egypt and China. These cross-sectional studies support the hypothesis that parasites may influence KSHV immune control resulting in increased KSHV susceptibility and its persistence in KSHV endemic areas where coinfections with helminths and malaria are also highly prevalent. This hypothesis is supported by immunological studies showing that parasite infections modulate the host immune response toward a Th2 immune profile with decreased production of the Th1 cytokines responsible for the clearance of viral infections. This unbalanced immune response toward Th2 predominance provides a better host cell profile for the survival of KSHV. KSHV genome encodes immunomodulatory cytokines that interfere with both innate and adaptive host immune responses, including suppressing interferon (IFN) response to viral proteins. This negative immune modulation of IFN peaks during KSHV lytic viral cycle, whereas only a handful of immunomodulatory genes are expressed during latency. It is plausible that, if acquired earlier than KSHV primary infection, immune modulation of IFN response by helminth and Plasmodia species favors KSHV lytic replication and persistence soon after primary infection in KSHV endemic areas, a hypothesis that cannot be tested in crosssectional studies. Arguably, KSHV, Plasmodia species, and soil transmitted helminths are solely able to trigger potent host immunomodulation. Moreover, it is possible that increased antibodies to KSHV in the presence of malaria parasitemia are due to new infection, reactivation of infection, or nonspecific polyclonal activation, being difficult to interpret findings of studies investigating viral and parasitic coinfections in the context of immunomodulatory drug intervention and/or pregnancy. The EMABS children included in Wakeham et al study were enrolled in a randomized control trial, and those found to have helminth infections in the intervention arm were treated with antihelminthic drugs resulting in at least 50% reduction in the prevalence of hookworm and Ascaris lumbricoides. In addition, regardless of allocation group (intervention or placebo), more than 80% of all children in the EMABS randomized control trial had received antihelminthic treatment elsewhere up to the age they had been selected for inclusion in the study of Wakeham et al. As the authors acknowledged, it is likely that their results were biased, possibly either by the altered immune response or by the very low prevalence of helminth infections, both triggered by the antihelminthic treatment given to study subjects. The low prevalence of malaria and helminth infections they found could be related to the use of insensitive diagnostic methods, which did not include molecular tests to define asymptomatic malaria parasitemia. In addition, coprocological tests for helminth infections were performed only once a year in the EMABS cohort. The use of tests of limited sensitivity to define malaria and helminth infections may have introduced nondifferential misclassification bias in the findings of Wakeham et al, leading to null association between helminth infection and KSHV seropositivity and underestimation of the true effect of the association between malaria and KSHV seropositivity. The authors did not mention the climate season at time of sample collection, and the cross-sectional design did not allow adjustment for malaria seasonality, which might, alternatively, have overestimated the magnitude of the association between malaria and KSHV seropositivity. As the authors mention, it is likely that KSHV is transmitted through saliva between family members as it has been reported in several KSHV cross-sectional surveys, but studies conducted by our group and others suggest that mother and older siblings are more likely to transmit KSHV to a younger child, whereas the father’s serostatus is not associated with the KSHV serostatus of their offspring, and KSHV seropositivity is not correlated between spouses in endemic areas, suggesting an interplay between environment and genetic factors. Studies conducted among African descendants living in French Guiana suggested that a major recessive gene may confer susceptibility or resistance to KSHV infection paving the way for the identification of candidate genes that might be associated with susceptibility to KSHV. Study of Wakeham et al was conducted among a large number of mother– child pairs in Uganda, a KSHV endemic area. Their results confirm previous reports of an association of KSHV seropositivity with increasing age, individual HIV infection, and KSHV mother’s serostatus. Supported by the Conselho Nacional de Desenvolvimento Científico e Technológico, an agency of the Brazilian Ministry of Science and Technology (Grants 304879/2003-7, 305258/2006-0, and 473867/2006-0). The study among Mapuera populations was supported by grants from the Welcome Trust (Grant 075454/B/04/Z), CNPq 300317/97-2, and Fundação Faculdade de Medicina, University of São Paulo, São Paulo, Brazil. Additional financial support was provided by the UK Department for International Development– funded Research Programme Consortium on Research and Capacity Building on Sexual and Reproductive Health and HIV in Developing Countries of the LSHTM. The author has no funding or conflicts of interest to disclose.