Non-linear effects of parasite density on symptom burden and hematologic indices in pediatric Plasmodium falciparum malaria

Abstract

Background The clinical and hematologic manifestations of pediatric Plasmodium falciparum malaria vary across transmission settings, and the extent to which parasite density predicts symptom burden and routine laboratory abnormalities at first presentation remains uncertain. This study aimed to characterize the non-linear associations between parasite density, clinical symptom burden, and hematologic indices among children with acute P. falciparum malaria using spline-based regression models. Methods We conducted a cross-sectional analysis of 357 Nigerian children aged 6 months to 10 years with microscopy-confirmed malaria at enrollment prior to treatment initiation. Twenty-one symptoms were recorded with graded severity, and parasite density was log-transformed for analysis. Non-linear associations were modeled using natural cubic splines within generalized regression frameworks, adjusting for axillary temperature and smear density unit where appropriate. Hemoglobin, platelet, and white blood cell counts were examined using spline-based linear models. Results Headache and vomiting were the most frequently reported symptoms, and most presentations were clinically mild. Parasite density demonstrated a non-linear positive association with overall symptom burden. Higher parasite densities were associated with greater symptom severity and an upward trend in total symptom count, with an increased likelihood of severe symptoms observed in the upper density range. No significant association was identified between parasite density and anemia severity or severe hematologic events. In contrast, thrombocytopenia showed a strong density-dependent association and moderate discriminatory performance. Hemoglobin and white blood cell counts demonstrated weak and non-significant relationships with parasite density. Conclusions At initial presentation, parasite density is non-linearly associated with increased clinical symptom burden, while thrombocytopenia emerges as a sensitive hematologic correlate of contemporary parasitemia. Hemoglobin and white blood cell counts appear to be poor real-time proxies of parasite load. Integrating structured symptom grading with platelet counts may enhance early triage and risk stratification in resource-limited endemic settings.