Multi-Level Factors Contributing to Painful Vaso-Occlusive Crisis in Patients Taking Hydroxyurea for Sickle Cell Disease in Kalangala, Uganda

Abstract

ABSTRACTBackground:Sickle cell disease (SCD) is a life-threatening non-communicable disease (NCD) and a major global public health concern. About 300,000 babies are born annually with the genetic disorder, 75% in Sub-Saharan Africa. In Uganda, the burden of SCD is about 20,000 births annually, and nearly 80% of these children do not live past five years of age. In contrast, the survival rate in high-income countries is 99%. Therefore, SCD is not just a public health concern but a global health equity crisis. The complications from SCD include hemolysis and vaso-occlusive crisis. Hydroxyurea (HU) has become standard of care therapy due to its reduction in the frequency and severity of these complications. Hydroxyurea increases fetal hemoglobin (HbF), decreasing the sickling process and ultimately, reducing the number of sickled cells. This reduction prolongs the lifespan of red blood cells (RBCs), reduces hemolysis, and adhesion to vascular endothelium. Patients prescribed HU have fewer painful VOCs and a reduced need for medical attention. Patient, clinical, and community-level factors, such as lack of routine monitoring, poor adherence, and HU stockouts, are associated with reduced HU effectiveness in Uganda. Purpose:Vaso-occlusive crisis can mask impending irreversible complications such as infarction or tissue ischemia, which could lead to mortality. Despite the high efficacy of HU in SCD patients, barriers to HU’s effectiveness remain, and little is known about them specifically in low-resource settings. Studies have shown that reduced HU effectiveness contributes to recurrent VOCs, but have not identified the contributing factors. This study poses the question: why do SCD patients in Kalangala, Uganda, experience persistent painful vaso-occlusive crises despite taking HU? Methods:We conducted a convergent mixed-method study of patients attending the SCD clinic at Kalangala Health Center IV (KHCIV) in Kalangala District, Uganda. Kalangala is an island in the northwestern region of Lake Victoria. The Government of Uganda has designated this district as a low-resource, “hard to reach” and “hard to stay” region. This is due to the costly multi-modal transportation patients have to endure to access care, not to mention the chronic understaffing in government facilities. The study population was SCD patients attending the KHCIV sickle cell clinic who were on HU therapy. Data collection included standardized surveys, interviews, and the extraction of clinical data. The study was conducted over 24 months (01-2024 to 12-2025). Results:Among surveyed patients, 13.2% experienced recurrent VOCs (≥3 VOCs per year), while medical records showed a prevalence ranging from 12% in 2024 to 19% in 2025. Moderate protein diversity intake was significantly associated with recurrent VOCs in crude and adjusted models (PR = 4.75, 95% CI: 1.38 – 16.29). HbF Category, HU duration, age, and traditional medicine were not significantly associated with recurrent VOCs. A higher number of clinic visits was significantly associated with recurrent VOCs, indicating higher healthcare utilization among patients with severe disease. Qualitative findings demonstrated financial strain to adequate nutrition, caregiver burden, transport challenges, weather exposure, school absenteeism, stigma, and health system monitoring constraints contributing to recurrent VOCs. DiscussionThis study highlighted that recurrent VOCs among SCD patients on HU in rural Uganda are shaped by multilevel biological, nutritional, social, and structural determinants. Optimizing HUs’ effectiveness in a “hard-to-reach” setting requires integrated interventions that extend beyond pharmacotherapy. Nutrition-sensitive programming, improved documentation of outcomes, strengthened monitoring systems, and structural support for patients and families managing SCD are some of the recommendations that emerged as critical. These findings highlight the need for embedded SCD care within broader rural health system-strengthening frameworks in rural Uganda and sub-Saharan Africa.