Subclinical malaria in sickle cell disease in Northern Uganda: prevalence, predictors, and hematologic impact

Abstract Objectives Sickle Cell Disease (SCD), characterized by persistently low hemoglobin (Hb) and hematocrit levels, is among the leading causes of under-five mortality in high prevalence countries. Sub-Saharan Africa bears the highest burden of both sickle cell disease (SCD) and malaria. Subclinical malaria (SCM), defined as parasitemia without overt clinical symptoms, may worsen anemia in SCD, but its clinical significance remains uncertain. We evaluated the prevalence, predictors, and clinical associations of SCM using a hierarchical diagnostic framework. Methods We conducted a cross-sectional study (June–August 2025) at the SCD clinic of Gulu Regional Referral Hospital in Northern Uganda by surveying patients on SCD management, Malaria exposure, and related variables as well as collecting blood samples for analysis. SCM was defined using five hierarchical criteria: blood smear (BS)-confirmed parasitemia, rapid diagnostic test (RDT) positivity, any positive test (BS or RDTPositive), an adjusted RDT definition excluding malaria within the preceding 30 days, and a combined definition of smear-confirmed or adjusted RDT. Modified Poisson regression evaluated predictors of SCM, and linear regression assessed associations with hemoglobin concentration and normalized symptom severity scores. Results Among 274 participants (median age 12 years; 54.4% male), overall SCM prevalence was 23.4% by either BS or RDT, with RDT positivity 22.3% and smear positivity 11.7%. Rural residence was the only independent predictor of SCM. Mean hemoglobin was lower among smear-positive participants compared with smear-negative participants (6.87 vs 7.82 g/dL, p=0.0027). Broader RDT-based definitions were not associated with hemoglobin differences, and SCM across categories were not associated with symptom scores. Median Hb with Hydroxyurea (HU) use was higher but not statistically significant (p = 0.107). Conclusions SCM was common among SCD patients (23.4%) in Northern Uganda, but only microscopy-confirmed parasitemia (11.7%) was associated with ∼1g/dL lower hemoglobin. HU use was associated with increased Hb overall but did not moderate malaria-related Hb changes or presence of SCD symptoms. RDTs had limited clinical utility for identifying clinically significant SCM in this population as positivity may reflect antigen persistence, rather than true infection.