Impact of Switching From Race-Based to Race-Neutral Spirometry Reference Equations in Children With Sickle Cell Anemia

Abstract

The American Thoracic Society now recommends race-neutral spirometry reference equations, as proposed by the Global Lung Initiative, which estimates lung function based solely on age, height, and sex [1]. However, the impact of this shift from race-based to race-neutral reference equations on the established relationship in children with sickle cell anemia between increasing age and decreasing FEV₁% predicted is unknown [2]. To address this knowledge gap in patient care management, we tested the following hypothesis: FEV1% predicted declines with age in children and adolescents with sickle cell anemia when using the new race-neutral pulmonary function test reference equations. All participants provided appropriate assent and parental written informed consent.

We re-analyzed the Sleep and Asthma Cohort (SAC) dataset, as previously done by our team [2]. The SAC cohort was a multi-center observational study comprising children and adolescents with sickle cell anemia, unselected for respiratory disease. The participants ranged from 4 to 18 years of age and were enrolled and followed between 2005 and 2011 at three clinical centers: Washington University School of Medicine in St. Louis, Missouri; Case Western Reserve University in Cleveland, Ohio; and UCL Great Ormond Street Institute of Child Health in London, UK.

Participants were either HbSS (N = 240) or HbSβ⁰ (N = 12). Children were not eligible for participation in the study if they received long-term blood transfusion therapy, received overnight oxygen or continuous positive airway pressure (CPAP) support, had chronic lung disease other than asthma, or were known to be HIV positive. We carefully screened all participants for asthma. Asthma classification was based on physician diagnosis and current prescription of asthma medication, consistent with previous methods [3]. After the start of the study, data from participants who initiated chronic blood transfusion therapy were censored from that point forward due to the known decrease in pain events following the initiation of chronic transfusion therapy.

Pulmonary function tests (PFTs) were obtained when participants were at least 4 weeks after discharge from the hospital for SCA complications and at baseline health without current illness, pain, or acute respiratory symptoms. Pulmonary function testing (spirometry and body plethysmography) was done at study enrollment and then at least annually during the study period. All PFTs were centrally adjudicated for acceptable quality as per the American Thoracic Society guidelines. Predicted values were determined for each participant using the previously recommended GLI 2012 Race-based reference equations and the newly recommended GLI 2023 Race-neutral reference equations. We used linear mixed-effects models to evaluate the association between age and pulmonary function.

A total of 223 participants were enrolled and had spirometry measurements; 197 participants met eligibility for analysis because they had at least three spirometry measurements over a minimum follow-up of 1 year (Table S1) [2]. The mean age of the final cohort at first testing was 11.0 years (range 4–19.3 years), 47.7% (n = 94) were male, 29.4% (n = 58) had asthma, and the mean hemoglobin was 8.2 g/dL.

When using the newly recommended race-neutral reference equations in the multivariable linear mixed regression, age was not a predictor of FEV₁% predicted (B = 0.03, 95% CI −0.20 to −0.26, p = 0.800) (Figure 1, Table S2). The race-neutral results contrast with the prior result of the race-based pulmonary function test reference equations, which demonstrated that children had a 0.3% decline per year in FEV₁% predicted (B = −0.30, 95% CI −0.56, −0.05, p = 0.02) (Figure 1) [2]. Additionally, the race-neutral pulmonary function reference equations produced FEV₁% predicted values that were systematically lower than those of the previously recommended race-based reference equations. The difference in race-neutral FEV₁% predicted versus race-based FEV₁% predicted values was greater for children between the ages of 5 to 15, narrowing after age 15 (Figure 2).

Our study has several limitations. As is the case for any negative result in a study, a false negative or true negative outcome is possible. We believe that our current result has a low likelihood of being a false negative because we previously found a statistically significant relationship in the same study population but using a different reference equation. Additionally, our narrow 95% confidence interval of the Beta coefficient (95% CI −0.20 to −0.26 for FEV₁% predicted and age) suggests that the estimate of the slope has sufficient precision and that our sample size was adequate. Furthermore, the race-neutral reference equation with no decrease in FEV1% predicted is inconsistent with the evidence that adults with SCD experience a decline in absolute FEV1 per increase in age [4]. There is also the possibility that our participants were too young and followed for too short a period to demonstrate a significant change in lung function during the study period, as was suggested previously by our team [2]. However, our data strongly suggest that using the race-neutral equation, compared to the race-based equation for children with SCD, will attenuate any decline in FEV1% predicted.

The importance of detecting a declining lung function in individuals with SCA is based on rigorously performed studies demonstrating a low FEV₁% predicted [5] is associated with early mortality in young adults with SCA. Thus, the race-neutral reference equation for pulmonary function, which attenuates an established marker for increased mortality in young adults with sickle cell anemia, may have limited clinical utility in this high-risk population for earlier death. The finding of no effective change in FEV₁% predicted among children with SCD may have no clinical significance. However, without evidence of the FEV1% predicted decline, the patient and their family may neglect opportunities to improve the FEV1% predicted by avoiding active and passive tobacco exposure, ambient air pollution, and achieving an average BMI for age.

In summary, based on our findings for race-neutral and race-based PFT equations in children with SCA, we recommend reporting both FEV₁% predicted values when performing PFTs in children with SCA until we have better knowledge about the clinical significance of either equation in this high-risk population for lung-related morbidity and mortality.

Study was approved by the Institutional Review Board and done in accordance with the Helsinki Declaration.

The authors declare no conflicts of interest.