Background: Sickle cell anemia (SCA) is a life threatening monogenic disorder associated with early death. Platt et al. reported median ages of death (42 years males; 48 years females) from the Cooperative Study of Sickle Cell Disease (CSSCD). Forced expiratory volume in one second (FEV1) on pulmonary function testing (PFT), is commonly used to monitor disease severity in individuals with asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease. FEV1 (% predicted) has been shown to predict mortality in the general population, but no PFT result has predicted earlier death in SCA. We tested the hypothesis that abnormal pulmonary function was associated with earlier death.

Methods: A prospective cohort study using the CSSCD data was constructed. We evaluated a total of 430 participants from the CSSCD study who had evaluable PFT, using data from the first PFT at age 21 years and older, and reviewed centrally for quality. Predicted values were determined for each subject based on age, gender, height, and race for FEV1, forced vital capacity (FVC), and the FEV1/FVC ratio using the Global Lung Function 2012 equations. Abnormal results for FEV1, FEV1/FVC, and FVC were determined by comparison to their lower limits of normal. Predicted values for total lung capacity (TLC) were obtained utilizing the prediction equations published, and adjusted by 12% to account for the effect of race on these values; a value <80% predicted was considered abnormal. Values of FEV1, FEV1/FVC, FVC, and TLC were used to categorize PFT patterns as normal, obstructive, or restrictive based on American Thoracic Society/European Respiratory Society guidelines according to a modified algorithm based on Pellegrino (2005). Assessment of the association between PFT and mortality was investigated using Kaplan-Meier product limit estimation and Cox proportional hazards regression. The full regression models were adjusted for factors known to be associated with mortality. Multivariable Cox regression models were constructed, and only covariates that were nominally significant predictors (p<0.20) were used for the final model. FEV1% was reverse-coded so that lower values are associated with hazard ratios above 1.

Results: Median age was 31.4 years at time of first PFT and median follow-up was 5.5 years. In the cohort, 47% had normal, 29% restrictive, 8% obstructive, 2% mixed, and 14% non-specific pulmonary function patterns. There were no differences in SCA severity between groups (PFT vs no PFT). During follow-up, 63 (15%) participants died. Those who died had significantly higher WBC, lower hemoglobin levels, and lower FEV1% predicted, but not lower FEV1/FVC ratio. Pulmonary function patterns were not associated with earlier death- obstructive (p= 0.97), restrictive (p=0.41), and non-specific (p= 0.609). In the final multi-variable model, lower FEV1% predicted is associated with increased hazard of death [HR per %-predicted 1.02 (95% CI 1.00 – 1.04; p =0.037)], as did older age [HR 1.07 (95% CI 1.04-1.10; p<0.001)], male sex [HR 2.09 (95% CI 1.20-3.65; p=0.010)], higher ACS incidence rate [HR per event/yr 10.4 (95% CI 3.11-34.8; p <0.001)], LDH [HR per mg/dl 1.002 (95% CI 1.00-1.003; p = 0.015)] Table. A threshold of <70 FEV1 % predicted was associated with earlier death (Log rank test (p =0.002) Figure.

Conclusion: For the first time, we have demonstrated that spirometry evaluation with FEV1% predicted identifies adults with sickle cell anemia who have increased hazard of death. Routine spirometry testing should become standard care in individuals with SCA, enabling early intervention for those at risk.

Table:

Final Cox Regression Model for death after lung function testing with reduced set of covariates (N=404)

Covariate BHazard Ratio (95% CI)P
Age at PFT# 0.07 1.07 (1.04, 1.10) <0.001 
Male 0.74 2.09 (1.20, 3.65) 0.010 
White blood cell count (109/L) 0.08 1.09 (0.98, 1.20) 0.096 
ACS rate post-PFT (# per year) 2.34 10.39 (3.11, 34.78) <0.001 
Pain rate post-PFT (# per year) 0.14 1.15 (0.98, 1.36) 0.095 
Lactic dehydrogenase (mg/dL) 0.002 1.002 (1.00, 1.003) 0.015 
FEV1 percent predicted** 0.021 1.02 (1.00, 1.04) 0.037 
Covariate BHazard Ratio (95% CI)P
Age at PFT# 0.07 1.07 (1.04, 1.10) <0.001 
Male 0.74 2.09 (1.20, 3.65) 0.010 
White blood cell count (109/L) 0.08 1.09 (0.98, 1.20) 0.096 
ACS rate post-PFT (# per year) 2.34 10.39 (3.11, 34.78) <0.001 
Pain rate post-PFT (# per year) 0.14 1.15 (0.98, 1.36) 0.095 
Lactic dehydrogenase (mg/dL) 0.002 1.002 (1.00, 1.003) 0.015 
FEV1 percent predicted** 0.021 1.02 (1.00, 1.04) 0.037 
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# PFT = Pulmonary function test

** FEV1% is reverse-coded so that lower values are associated with hazard ratios above 1.

Figure:
Figure:. Kaplan-Meier survival curves stratified by FEV1 above and below 70% predicted in 430 adults with sickle cell anemia followed for a median of 5.5 years (p = 0.002; Log rank test).
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Kaplan-Meier survival curves stratified by FEV1 above and below 70% predicted in 430 adults with sickle cell anemia followed for a median of 5.5 years (p = 0.002; Log rank test).

Figure:
Figure:. Kaplan-Meier survival curves stratified by FEV1 above and below 70% predicted in 430 adults with sickle cell anemia followed for a median of 5.5 years (p = 0.002; Log rank test).
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Kaplan-Meier survival curves stratified by FEV1 above and below 70% predicted in 430 adults with sickle cell anemia followed for a median of 5.5 years (p = 0.002; Log rank test).

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Disclosures

No relevant conflicts of interest to declare.

Topics:
forced expiratory volume function, sickle cell anemia, pulmonary function tests, cystic fibrosis, follow-up, spirometry, abnormal test results, asthma, chronic obstructive airway disease, forced vital capacity

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2014 by The American Society of Hematology
2014
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