Intercurrent flaviviral viremia and Plasmodium ovale infection in ill returned travelers to Ontario

Abstract

Purpose: Similar epidemiology and clinical presentations of arboviral infections and malaria along with the typically sequential approach to diagnostic testing, with malaria excluded urgently in febrile returned travelers, may mask the true epidemiology of such dual infections. Flaviviruses have been reported to trigger relapsing forms of malaria, including Plasmodium ovale, long after primary malarial infection, and this may delay the diagnosis of malaria. We aim to understand the incidence of intercurrent flaviviral infection in cases of confirmed Plasmodium ovale infection, where the flavivirus may have triggered relapse. Methods & Materials: DNA and RNA from biobanked isolates of P. ovale detected in whole blood at the Public Health Ontario Laboratory between 2006 and 2018 will be extracted and screened for intercurrent flaviviral infections using previously validated real-time PCR (qPCR) assays targeting multiple flaviviruses (pan-FLAV) and specifically dengue virus types 1–4 (DEN1, DEN2, DEN3, DEN4). Results: One-hundred fifteen unique isolates of P. ovale were identified over the reporting period, of which 62 had sufficient specimen for further molecular analysis. Among analyzed cases, over half occurred in males (36/62 [58%]), over a third occurred in females (23/36 [37%]), and 5% (3/62) had unassigned sex. Median age of P. ovale cases was 28.8 years (range 22 mos - 72 years; IQR 18.8–40.1 years). Median parasitemia was < 0.01% (range < 0.01% - 0.8%). Thirty (48%) P. ovale cases had documented travel history exclusively to Africa, with Nigeria as the most common source country (22/54 [40.1%]). Pan-FLAV assay yielded a 1.6% (1/62) positivity rate. DEN1-4 assay results are pending. Conclusion: P. ovale infections are most commonly imported to Ontario from West Africa, and Nigeria, specifically. Intercurrent flaviviral viremia was noted in at least 1.6%, which may suggest that primary flaviviral infection triggered a relapse of P. ovale. Alternatively, such co-occurrence may suggest primary infection with both organisms known to cause fever in returning travelers. Consideration of flaviviral co-infection should be given to the P. ovale patient with deep thrombocytopenia, lymphopenia, and high-yield arboviral symptomatology such as rash and retro-orbital headache. The influence of flaviviruses on the clinical course of P. ovale should be examined prospectively.