Sickle cell disease (SCD) is associated with a myriad of complications and great heterogeneity of phenotypic expression between patients and in the same patient over his or her lifetime. Several decades ago, many authors observed that no infection was found in a majority of adult patients with SCD hospitalized with a clinical presentation suggestive of community-acquired pneumonia.1,2 Thus, they suspected other mechanisms (including vaso-occlusion–driven pulmonary infarction) and the generic term acute chest syndrome (ACS) was proposed to account for acute pulmonary complications of SCD.
Estimates show that half of SCD patients will experience ACS during their lifetime, with an overall incidence >10 per 100 patient-years.3 ACS is the most common reason for critical care need in SCD, accounting for up to three-quarters of admissions of adults with SCD in intensive care units.4-6 In fact, ACS may be associated with a need for acute organ support, especially mechanical ventilation, which is required in 5% to 13% of patients with ACS in observational cohorts.7-9
The risk of hospital death during ACS also varies across series, ranging from 1.6% to 13%.6-9 Age may influence the clinical picture of ACS, with a milder disease in children and a more severe disease in adults.10 ACS is considered one of the leading causes of death from SCD, especially in adulthood.11-13 Adults with a higher ACS rate also have a higher rate of mortality (from all causes) than those with low ACS rates.3,11
Adults are particularly at risk for severe, rapidly progressive ACS, resulting in respiratory failure accompanied by multiorgan dysfunction within 24 hours of onset of pulmonary symptoms. This severe form of ACS may be causally linked to sudden death.14
Figure 12-1 summarizes the pathophysiology of ACS. Sickling in the pulmonary circulation may be triggered by the polymerization of sickle hemoglobin (HbS) under conditions of hypoxia. The adhesion of sickled red blood cells (RBCs) to the pulmonary vessel endothelium is boosted by inflammation and endothelial dysfunction, notably via the expression of adhesion molecules on the surface of endothelial cells (eg, vascular cell adhesion molecule 1 [VCAM1] endothelial receptor) and RBCs (eg, α4β1 integrin), as well as the alteration of nitric oxide metabolism and lipoprotein oxidation by free hemoglobin and free heme.15,16 Some experimental studies suggest the relevance of neutrophil-platelet aggregate formation in lung arterioles in promoting lung vaso-occlusion.17 An enhanced response to inflammatory insults could play a role in the increased susceptibility to pulmonary dysfunction that has been observed clinically in SCD.18 The dehydration of RBCs (which alters their rheology)19 and acidosis (which shifts the dissociation curve of hemoglobin to the right, thus promoting its deoxygenation) also play a role in vaso-occlusion.20 A vicious cycle has been suggested in the ...