Clinicopathological Correlations in Chronic Sickle Cell Lung Disease.

Chronic lung injury is a major cause of morbidity and mortality in sickle cell disease. Although this pulmonary injury appears to be progressive and the etiology is multifactorial, the pathogenesis is incompletely understood. Study of the histopathologic changes can be useful as evidence of the underlying pathophysiology, especially if correlated with the clinical stage of the disease.

HYPOTHESIS: The histopathology of the lung in sickle cell disease varies with the clinical stage of chronic lung disease.

METHODS: Medical records and autopsy reports from 324 archived autopsies of homozygous sickle cell disease were reviewed and each case was assigned a clinical severity score that ranged from 0 (no pulmonary dysfunction) to 3 (severe pulmonary dysfunction). Histologic sections from these cases were then studied in a masked manner and findings were subjectively graded on a scale of 0 (absent) to 4+ (severe). The histopathologic findings were then correlated with the clinical stage of the lung disease, using Pearson’s correlation coefficients and coefficient of determinations.

RESULTS: The frequency of some histopathologic findings showed a positive correlation with the increasing severity of the clinical stage of the disease, including age (r = 0.92; R² = 0.85), vascular intimal hyperplasia (r = 0.74; R² = 0.55), vascular medial hyperplasia (r = 0.87; R² = 0.76), dilation of capillary plexi (r = 0.98; R² = 0.96) and interstitial fibrosis (r = 0.78; R² = 0.61). Scoring of the severity of the histopathologic findings suggested a pattern of progression of the morphologic injury. The earliest evidence of injury seen during infancy consisted of focal disruption of alveolar septae with hemorrhages and interstitial fibrosis (1+). These findings were more pronounced during childhood (2+) when asymptomatic restrictive defects were reported, but capillary diffusion capacity remained normal. During adolescence, these findings were well defined (3+) along with increased tortuosity of capillaries, dilation of capillary plexi and intimal hyperplasia of medium-size vessels. In adulthood, these findings were most pronounced (4+) and were accompanied by episodic dyspnea. Obliterative vasculopathy was seen almost exclusively in cases with clinical pulmonary hypertension. At end stage there appeared to be less intra-alveolar hemorrhage and edema.

DISCUSSION: These findings strongly suggest that the earliest evidence of chronic sickle lung disease is injury to capillaries and to pre- and post-capillary vessels. This early injury appears to be followed by increased tortuosity of capillaries, dilation of collateral vessels and then changes in larger arterial vessels. Interstitial fibrosis was seen in cases with restrictive defects. Increased capillary surface area secondary to tortuosity of capillaries probably accounts for the clinical evidence of normal diffusion capacity. These findings support the clinical evidence that sickle cell chronic lung disease is progressive. Furthermoore, this study strongly suggests that sickle chronic lung disease follows a pattern of injury and remains asymptomatic until the pulmonary architecture has undergone considerable remodeling. These findings help explain the stealthy way in which sickle cell disease steals the pulmonary reserve.