Lower Airway Obstruction Is Associated with Increased Vaso-Occlusive Pain Episodes in Adults with Sickle Cell Anemia

Background: Vaso-occlusive pain episodes (VOE) are the most common complication and reason for hospital admission in individuals with Sickle Cell Anemia (SCA). Recently our team demonstrated that in adults with SCA followed prospectively for approximately 5 years, a lower baseline Forced Expiratory Volume in 1 second percent predicted (FEV₁%), which is associated with earlier mortality, but evidence of obstructive or restrictive lung function patterns is not (Blood 2015, in press). Based on the evidence that abnormal pulmonary function is associated with earlier mortality, we tested the hypothesis that baseline pulmonary function patterns were associated with SCA-related morbidity, including VOE and acute chest syndrome (ACS) events.

Procedure: A prospective cohort of adults with SCA followed in the Cooperative Study for Sickle Cell Disease (CSSCD) was constructed based on a planned secondary analysis. Data from the first PFT record at age 21 and older were used for this study. Percent predicted values were determined for each participant based on their age, gender, height, and race for FEV₁ and the ratio of FEV₁ to forced vital capacity (FEV₁/FVC) using the Global Lung Function 2012 equations (Eur Respir J, 2012; 40(6): 1324-1343). Assessment of lower airway obstruction was based on % predicted FEV₁/FVC. Percent predicted total lung capacity (TLC), a measure of restrictive lung disease, was determined using published equations and corrected based on race. All PFT evaluations were checked for quality. Negative binomial regression models were used to determine the association between future VOE, ACS events, and spirometry measurements after adjusting for age, sex, hemoglobin, and fetal hemoglobin levels.

Results: A total of 430 adults with SCA were evaluated. Ages of the study participants ranged from 21.7-66.4 years with a median age of 32.6 years at the time of first PFT and median follow-up was 5.5 years. Only FEV₁/FVC% predicted as a continuous covariate was a significant predictor of future VOE. Lower FEV₁/FVC% predicted was associated with higher future pain event rates with a rate ratio of 1.022 (95% CI 1.002 - 1.042; p=0.028). For every 10% decrease in FEV₁/FVC% predicted there is a 23% increase in the rate ratio. TLC% predicted did not predict future VOE (p=0.762). FEV₁/FVC% predicted or TLC% predicted did not predict future ACS events (p=0.618 and p=0.430 respectively). When FEV₁/FVC% predicted and TLC% predicted < 5^th percentile were used in the regression equation instead of continuous values, neither abnormal lung function parameter was associated with an increased incidence of VOE or ACS events.

Conclusions: For the first time, we have demonstrated that spirometry evaluation with FEV₁/FVC% predicted, as a measure of lower airway obstruction, identifies a group of adults with SCA at increased risk for future vaso-occlusive pain episode.