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Pulmonary hypertension (PH) is associated with adverse outcomes in adults with sickle-cell disease (SCD), but its importance in children is less clear. The aim of this study was to define the incidence and causes of PH in pediatric patients with SCD. Children with SCD (n = 310) and matched controls (n = 54) were prospectively enrolled under basal conditions. Participants underwent echocardiography, pulse oximetry, 6-minute walk tests, and hematologic testing. Echocardiographic measures were compared between patients with SCD and control subjects before and after adjusting for hemoglobin. Correlations of echocardiographic and clinical parameters were determined. Tricuspid regurgitation velocity (TRV) was elevated compared to controls (2.28 vs 2.10 m/s, p0.0001). Increased TRV was associated with left ventricular diastolic diameter, hemoglobin, and estimated left atrial pressure. TRV remained elevated when controlling for left ventricular diameter and left atrial pressure. Echocardiographically derived pulmonary resistance was not significantly different between patients with SCD and controls, although it was elevated in the SCD subgroup with elevated TRV. When controlling for hemoglobin, TRV was no longer statistically different, but pulmonary insufficiency velocity, septal wall thickness, and estimated pulmonary resistance were statistically higher. TRV, pulmonary insufficiency end-diastolic velocity, and markers of increased cardiac output were correlated with indicators of adverse functional status, including history of acute chest syndrome, stroke, transfusions, and 6-minute walk distance. In conclusion, children with SCD had mildly increased TRV that was correlated with increased cardiac output and left ventricular filling pressures. Hemoglobin-adjusted analysis also suggested a contribution of primary vascular changes.

Death from malaria occurs from the complications of the infection: cerebral manifestations leading to coma and a severe and refractory anemia leading to hypoxia and cardiac decompensation. Several mechanisms have been identified to play a role in the pathogenesis of malarial anemia, such as erythrocyte lysis and phagocytosis, and sequestration of parasitized red blood cells, but recent data indicate that these mechanisms (singly or in combination) do not adequately explain the severity of this anemia. By contrast, hematologic studies have shown that bone marrow suppression and ineffective erythropoiesis contribute importantly to the severe anemia of malaria infection. The host mechanisms responsible for suppression of erythropoiesis may involve an excessive or sustained innate immune response or a pathologic skewing of the T-cell differentiation response with the attendant production of certain proinflammatory cytokines. Experimental data also indicate that severe malarial anemia is associated with the immunologic expression of a circulating inhibitor of erythropoiesis that functionally antagonizes the action of erythropoietin. We review the clinical and experimental basis for these concepts and discuss ongoing experimental and genetic studies aimed at unraveling the molecular basis of this malaria-induced bone marrow suppression.