Rationale and design of a screening study to detect schistosomiasis-associated pulmonary hypertension in Ethiopia and Zambia

Abstract

Schistosomiasis is a major cause of pulmonary arterial hypertension (PAH) worldwide, but the prevalence and risk factors for schistosomiasis-associated PAH (SchPAH) development are not well understood. Schistosomiasis-associated hepatosplenic disease (SchHSD) is thought to be a major risk factor for PAH development. Herein, we describe our plans for prospectively screening SchHSD subjects for clinical evidence of PAH at two major academic medical centers and national referral hospitals in Addis Ababa, Ethiopia and Lusaka, Zambia. The screening study will primarily be conducted by echocardiography, in addition to clinical assessments. Plasma samples will be drawn and banked for subsequent analysis based on preclinical animal model rationale. If successful, this study will demonstrate feasibility of conducting prospective cohort studies of SchPAH screening in schistosomiasis-endemic regions of Africa, and provide initial data on clinic-based disease prevalence and potential mechanistic biomarkers underlying disease pathogenesis.

Keywords: pulmonary hypertension; schistosomiasis; study design.

Figure 1

Preclinical model of schistosomiasis‐PH, and mechanism of schistosomiasis‐PH pathogenesis as indicated by preclinical studies. (a) The Schistosoma‐PH mouse model uses intraperitoneal egg sensitization/intravenous egg challenge, followed by right heart catheterization and tissue analysis. (b) Live Schistosoma eggs in the lungs release glycoproteins such as omega‐1, which is taken up by host dendritic and other antigen presenting cells (APCs). The APCs present the antigen to CD4 T cells, which become activated to a Th2 phenotype secreting proteins IL‐4 and IL‐13. This causes recruitment of Ly6c⁺ (classical) monocytes, which express the protein thrombospondin‐1 (TSP‐1) in a HIF2α‐dependent manner. TSP‐1 activates TGF‐β (likely the isoform TGF‐β1), resulting in pulmonary vascular disease