Which Clinical Factors Predict Lung Function Decline in Pediatric Asthma?

Children with severe and nonsevere asthma are at risk for poor lung function trajectories into adulthood, with several clinically relevant factors predictive of changes in forced expiratory volume in 1 second (FEV₁) over time, according study findings published in The Journal of Allergy and Clinical Immunology.

The clinical predictors of lifelong poor lung function in children with asthma are not fully understood.  Investigators therefore sought to establish phenotypic factors associated with FEV₁ throughout childhood, using data from the Severe Asthma Research Program (SARP) 3 pediatric cohort study (ClinicalTrials.gov identifier: NCT01606826).

SARP3, which enrolled children between November 2012 and January 2015, aimed to better understand phenotypic and natural history outcomes of pediatric asthma by disease severity. The trial enrolled a group of carefully characterized, longitudinally reassessed children and adults with severe asthma, as well as a comparator group with nonsevere asthma. Definitions of severe and nonsevere asthma were based on American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria.

For the current analysis, investigators measured lung function at baseline and annually.

The primary outcome was the absolute value FEV₁ at each evaluation for up to
6 years, which was adjusted for several time-varying factors associated with lung growth, including age, sex, race, height, and predicted FEV₁ by Global Lung Function Initiative reference equations. Secondary outcomes included postbronchodilator FEV₁ and prebronchodilator FEV₁/forced vital capacity (FVC).

Overall, the analysis included 188 participants (average age, 11.5±2.8 years; 62.2% male; 53% Black) who underwent 862 spirometry evaluations. Of those, 111 had severe asthma and 77 had nonsevere asthma. The mean pre-bronchodilator FEV₁ was 89.7± (standard deviation [SD]=16.6); post-bronchodilator FEV₁ was 104.3 (SD=16.0) percent predicted. At enrollment, 31% reported no exacerbations, 42.2% reported moderate (1-2 per year) exacerbation frequency, and 26.7% reported high (≥3 per year) exacerbation frequency in the prior 12 months.

To characterize baseline corticosteroid responsiveness, all participants received a standard intramuscular dose of triamcinolone acetonide (TA) 1 mg/kg, up to a maximum dose of 40 mg, with repeat evaluations occurring 18±3 days later. Simple subtraction was used to calculate triamcinolone-induced difference from baseline FEV₁ (tdFEV₁).

After analysis, factors identified as relating to FEV₁ included baseline fractional exhaled nitric oxide (FeNO; 95% CI, -92 to -6; P <.05), response to a characterizing dose of TA (95% CI, -12.3 to -4.5; P <.001), and maximal bronchodilator reversibility (95% CI, -37 to -16; P <.001). Annually evaluated time factors, such as age, obesity, and frequency of exacerbations, were also predictive of FEV₁ changes over time.

Notably, the investigators found a significant age and sex interaction with respect to FEV₁. In boys, a moderate exacerbation frequency (ie, 1 to 2) in the past 12 months was associated with -20 mL (95% CI, -39 mL to -2 mL) FEV₁ at each successive year. A high frequency of exacerbations (ie, ≥3) at 12 to 24 months prior to evaluation was associated with -34 mL (95% CI, -61 mL to -7 mL) FEV₁ at each successive year. Notably, no such exacerbation-related associations were reported among girls. The investigators also found that in all participants, FEV₁ showed an age interaction with obesity and maximum bronchodilator reversibility.

Study limitations include incomplete data on participants’ pubertal development as well as some interpretation issues, including the fact that low FVC in itself may be a sign of poor lung growth or a reflection of poor airflow or airway closure, which would then lead to an overestimation of pulmonary function.

Overall, said investigators, “We identified post-bronchodilator tdFEV₁, FeNO, maximum bronchodilator reversibility, and obesity predict lower FEV₁ in a highly phenotyped cohort of children and adolescents with severe and non-severe asthma and also describe a novel sex-specific risk of exacerbations on lower lung function in boys.”

These findings may offer a framework of clinically available measures “that can identify children with asthma who are at risk of lung function impairment over time,” said study authors.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Gaffin JM, Petty CR, Sorkness RL, et al; National Heart, Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators. Determinants of lung function across childhood in the Severe Asthma Research Program (SARP) 3. J Allergy Clin Immunol. Published online August 27, 2022. doi:10.1016/j.jaci.2022.08.014