From silent infection to symptomatic malaria: host phenomic determinants of Plasmodium falciparum outcomes in Fanteakwa South District, Ghana

Asymptomatic Plasmodium falciparum infections sustain malaria transmission in endemic areas, yet progression to symptomatic disease varies among individuals. This study examined asymptomatic infection in Fanteakwa South District, Ghana, focusing on how demographic and host phenomic factors influence progression to symptomatic malaria. This study employed a prospective cohort design nested within a cross-sectional survey. Participants of all ages were recruited from four communities using stratified random sampling and screened for malaria using mRDT and PCR. ABO blood group, Rhesus D factor, and haemoglobin phenotype were determined. Individuals with asymptomatic P. falciparum infection were followed weekly for 28 days with repeat mRDT, microscopy, and temperature measurements. Statistical analyses evaluated associations between demographic, phenomic, and infection outcomes. Among 353 participants, females constituted 59.8%, and adults aged 18–65 years were the largest age group (42.5%). Blood group O (55.8%), HbAA (85.3%), and Rhesus D positivity (91.8%) predominated. PCR detected more P. falciparum infections (52.1%) than mRDT (42.8%), indicating a substantial burden of submicroscopic asymptomatic malaria. PCR positivity varied across communities and was highest among children (61.9%) and adolescents (68.6%). During follow-up, 131 participants (37.1%) converted to mRDT and microscopy positivity, with 43.5% converting in the first week. Early conversion was most frequent among children (54.5%, p < 0.001), followed by adolescents, while adults and older adults showed fewer early conversions. Individuals with blood groups A and AB progressed earlier, whereas blood group O showed delayed conversion. All conversions occurred among HbAA individuals, with no progression among HbAS carriers. The Rhesus D factor had no significant effect, while gender differences emerged later, with higher conversion among males in Week 3 ( p = 0.015). Progression from asymptomatic to symptomatic P. falciparum infection is strongly shaped by age and host erythrocyte phenomic traits. Blood groups A and AB and the HbAA phenotype favour early conversion, whereas blood group O and HbAS delay or prevent progression. These findings underscore the importance of molecular surveillance and phenome-informed risk stratification for targeted malaria control in endemic communities.