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N Engl J Med. 2016 May 12;374(19):1811-21. doi: 10.1056/NEJMoa1505971.

Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function.

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From the Cardiovascular Research Institute (P.G.W., S.C.L.) and the Department of Medicine, Division of Pulmonary, Critical Care, Sleep, and Allergy (P.G.W., S.A.C., S.C.L.), University of California at San Francisco, San Francisco; the Departments of Medicine and Epidemiology, Columbia University Medical Center (R.G.B.), and the Department of Medicine, Weill-Cornell Medical College (F.J.M.) - both in New York; the Department of Medicine, Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem (E.B.), and the Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill (D.C., N.A.G.) - both in North Carolina; the Section of Pulmonary and Critical Care Medicine, Medical Service, Veterans Affairs Ann Arbor Healthcare System (J.L.C.), and the Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan (J.L.C., M.K.H.) - both in Ann Arbor; the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore (N.N.H.); the Department of Radiology, University of Iowa Carver College of Medicine, Iowa City (E.A.H.); the Department of Medicine, University of Utah Hospitals and Clinics, Salt Lake City (R.E.K., R.P.); the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles (E.K., D.P.T.); the Department of Medicine, University of Nebraska Medical Center, Omaha (S.R.); and the Clinical Discovery Unit, AstraZeneca, Cambridge, United Kingdom (S.R.).



Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms.


We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest.


Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids.


Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base. (Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS number, NCT01969344.).

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