Defining Resilience to Smoking-related Lung Disease: A Modified Delphi Approach from SPIROMICS

Abstract

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease who have minimal or no airflow obstruction. Objectives: To develop a multidimensional definition of a lung-related "resilient smoker" that is useful in research studies and then identify a resilient smoker subgroup in the SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort using this definition. Methods: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ⩾80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD. Results: Consensus was achieved on 6 of 12 diagnostic items, which include cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in forced expiratory volume in 1 second. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of CRP (C-reactive protein) and sTNFRSF1A (soluble tumor necrosis receptor factor1A) was lower in resilient than nonresilient smokers (P = 0.02 and P = 0.03). Conclusions: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "nonresilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from nonresilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344).

Keywords: biomarkers; chronic obstructive pulmonary disease; consensus development; smoking; spirometry.

Figures

Figure 1.

Results of Delphi rounds 1 and 2. *Indicates domain achieved consensus (⩾80% panel members with vote of “strongly agree” or “agree”). The vertical hashed bar represents 80% cutoff. FEV 25–75% = forced expiratory volume at 25–75% of pulmonary volume; FEV1 = forced expiratory volume in 1 second; fSAD = functional small airway disease; RV = residual volume; SGRQ = St. George’s Respiratory Questionnaire; TLC = total lung capacity.

Figure 2.

Application of the Delphi definition to SPIROMICS to identify resilient smokers. Out of the 2,973 participants, 892 smokers had preserved spirometry. In an iterative fashion, those with symptoms measured by CAT and mMRC scores were excluded. Next, those with COPD exacerbations, followed by those with abnormal computed tomography radiographic findings, and then abnormal rate of FEV1 decline, were removed. This resulted in 149 resilient smokers. CAT = COPD Assessment Test; FVC = forced vital capacity; LLN = lower limit of normal; mMRC = Modified Medical Research Council Dyspnea Scale; Post-BD FEV1 = post-bronchodilator forced expiratory volume in 1 second; PRMfSAD = functional small airway disease measured by parametric response mapping.

Figure 3.

In the 892 smokers with preserved spirometry, representation and overlap of those subjects with symptoms, exacerbations, radiographic abnormalities, and abnormal FEV1 decline, which we defined as nonresilient smokers. N = 294 participants were excluded because of missing data. Symptoms, measured by abnormal COPD Assessment Test or Modified Medical Research Council Dyspnea scale, are represented by the green circle. Exacerbations, both retrospective and prospective, are represented by the blue circle. Radiographic abnormalities measured by emphysema or functional small airway disease measured by parametric response mapping are represented by the yellow circle. Abnormal FEV1 decline is represented by the pink circle. The white background indicates those who did not have abnormalities in any of the above domains and are classified as resilient smokers. FEV1 = forced expiratory volume in 1 second.