| Summary: | Sickle cell disease (SCD) is one of the commonest inherited disorders worldwide. Acute chest syndrome (ACS) is the commonest cause of death in young adults and pulmonary dysfunction is a major contributor to morbidity in aging adults with SCD, but the aetiology is poorly understood. The first four studies presented in this thesis test the hypothesis that pulmonary vascular abnormalities are involved in the pathogenesis of SCD-related lung disease. Significant associations were found between small vessel pulmonary vascular dimensions, lung function abnormalities and echocardiographic estimates of ventricular function and cardiac output in adults with SCD; the decline in lung function observed in a subset of patients with longitudinal measurements correlated with changes in vascular dimension. Increased pulmonary capillary blood volume was shown to be related to the airways obstruction seen in SCD children. Respiratory system resistance and pulmonary capillary blood volume were significantly correlated in the SCD children, but not in the controls, suggesting the raised respiratory system resistance in the SCD children was, at least partly, explained by their increased pulmonary capillary blood volume. Additionally, fluid loading by means of blood transfusion in SCD children was found to acutely increase pulmonary capillary blood volume resulting in an increase in respiratory system resistance and worsening lung function. Furthermore, alveolar nitric oxide production was elevated in SCD children compared to controls and in the SCD children was correlated with pulmonary blood flow, but airway nitric oxide flux was similar to that of the controls and did not correlate with biomarkers of airways obstruction. Lung function appears to deteriorate over time in children with SCD, but prospective longitudinal data with appropriate control groups were lacking. The study presented in chapter five tested the hypothesis that lung function in SCD children, assessed longitudinally, would decline relative to controls and was related to ACS, and that restrictive abnormalities would increase in prevalence. In SCD children, but not controls, lung function declined significantly, and was significantly associated with ACS. Restrictive abnormalities were significantly more common at follow up.
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