Among 330 adolescent and adult patients presenting with acute undifferentiated fever at two health facilities in Hoima, Uganda, leptospirosis prevalence reached 27–33% depending on diagnostic criteria — statistically comparable to malaria at 30.3%. Co-infection occurred in 8.8% of cases. The dominant strain, Leptospira interrogans serovar Bataviae, was documented in Uganda for the first time. Skinning animals carried a fivefold elevated odds of infection (aOR 5.19), while mosquito exposure doubled risk — possibly a proxy for outdoor environmental contact. qPCR and serology showed poor concordance, confirming that neither test alone suffices for accurate diagnosis.
This finding challenges a deeply entrenched clinical assumption across sub-Saharan Africa: that fever equals malaria until proven otherwise. Leptospirosis, a bacterial zoonosis transmitted via animal urine contaminating water or soil, is treatable with doxycycline or penicillin — yet it is rarely tested for, and patients likely receive empirical broad-spectrum antibiotics or antimalarials unnecessarily. The antimicrobial resistance implications are significant. For adults living or working near livestock, water sources, or wildlife, this adds urgency to broadening differential diagnosis protocols. Limitations are notable: the study is facility-based and regional, covering only one Ugandan district, so generalizability remains uncertain. The combined diagnostic requirement (PCR plus serology) is also resource-intensive for low-income settings. Critically, this is a preprint posted on medRxiv and has not yet undergone peer review — findings should be interpreted with appropriate caution until independently validated. If confirmed, Uganda's national febrile illness guidelines warrant significant revision.