Lung Disease May Evade Diagnosis in Half of Heavy Smokers, Ex-Smokers

Standard Testing May Fail to Recognize Key Subset of Patients, UCSF-Led Study Shows

By Suzanne Leigh

Approximately 50 percent of current and ex-smokers with normal lung function have chronic breathing symptoms and flare-ups that are similar to patients with a disease that is the nation’s third most common killer, according to a multisite study led by UCSF. The research, involving 2,736 current and ex-smokers, as well as never-smokers, suggests the disease’s diagnostic criteria should be reviewed.

Chronic obstructive pulmonary disease (COPD) is a progressive lung condition that typically occurs in smokers and ex-smokers and is characterized by shortness of breath. Diagnosis is made with a spirometer, an instrument that measures how much air a person can exhale during a forced breath in one second and the total amount of air exhaled during testing. COPD is diagnosed if the ratio of these two figures is below the normal level of 0.70.

But research headed by Prescott Woodruff, MD, MPH, of the Cardiovascular Research Institute at UCSF, questions the use of spirometer for making a definitive COPD diagnosis.

Woodruff and researchers from 12 institutions assessed patient data from 2010 through 2015, which included current and ex-smokers whose lung function was normal according to spirometry. They found that approximately half of this group had chronic breathing symptoms. Additionally they were significantly more likely than the never-smokers to suffer from “exacerbations” or flare-ups, the authors reported in the study published May 12, 2016, in the New England Journal of Medicine.

Among the never-smokers, 2 percent had chronic symptoms of bronchitis versus 33 percent of symptomatic current and ex-smokers with normal lung function. Among the never-smokers 5 percent had been diagnosed with asthma and 14 percent suffered from wheezing, compared with 27 percent and 69 percent respectively among the symptomatic current and ex-smokers with normal lung function.

Of note, the researchers found that the incidence of symptoms in the current and ex-smokers with normal lung function was at a similar level as those symptomatic current and ex-smokers whose spirometry placed them in the mild-to-moderate COPD category.

‘Normal’ Patients More Likely to Have Thickening of Airways

The researchers also discovered that symptomatic current and ex-smokers were less active than their non-symptomatic counterparts and had spirometry readings that were normal, but closer to meeting the COPD threshold. High-resolution CT scans revealed thickening of the walls of the airways indicating disease that can cause airflow limitation.

Some 42 percent of this group had treated their symptoms with bronchodilators and 23 percent used inhaled steroids in the three months before study enrollment.

“What these results tell us is that there is a large group of individuals who have symptoms that resemble COPD although they do not meet COPD diagnostic criteria,” said Woodruff, a UCSF professor of medicine in the Division of Pulmonary Critical Care, Sleep and Allergy. “They receive the same treatment as COPD patients, but we don’t know about the efficacy of these treatments because these patients are not represented in clinical trials.

“These findings suggest that symptomatic smokers and ex-smokers may have ‘pre-COPD’ or ‘early-stage COPD’ and that research needs to be done to find optimal therapies for these patients and ultimately to develop a treatment that stalls disease progression,” he said.

Participants in the study were aged 40 to 80. Eligibility for current and ex-smokers was consumption of the equivalent of at least one pack of cigarettes daily for a minimum of 20 years; never-smokers had to have healthy lung function and to have consumed less than the equivalent of one pack of cigarettes daily over one year.

‘Stage 0’ Dropped by Global COPD Group

The Global Initiative for Chronic Obstructive Lung Disease, an organization set up to increase awareness of COPD and decrease morbidity and mortality, dropped its ‘stage 0’ category for patients with normal spirometry, who had sputum production and a chronic cough, after concluding that there was “incomplete evidence that the individuals who meet the definition of at risk necessarily progress to Stage I.”

“These data suggest that the ‘stage 0’ category should be reinstituted to promote recognition of this condition and research into appropriate treatments,” said Woodruff.

More than 3 million people died of COPD in 2012, equivalent to 6 percent of all deaths globally, according to the World Health Organization. COPD is incurable but preventable due to its strong association with smoking, the primary cause of the disease.

The study was supported by funding from the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health and by the Foundation for the National Institutes of Health, whose external advisory board includes members from some pharmaceutical companies. UCSF researchers disclose that UCSF is one of the sites that comprise the NHLBI-funded SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). First author Woodruff reports personal fees and grants from pharmaceutical companies Genentech, Johnson & Johnson, Roche, Neostem, AstraZeneca, Novartis and from the National Institutes of Health. Further disclosure information is available at

Co-authors are Stephen Lazarus, MD, and Stephanie Christenson, MD, of UCSF; R. Graham Barr, MD, DrPH, of Columbia University Medical Center, N.Y.; Fernando Martinez, MD, of Weill-Cornell Medical College, N.Y.; Eugene Bleecker, MD, Wake Forest University, Winston-Salem, N.C.; David Couper, PhD, and Natalia Gouskova, PhD, of University of North Carolina at Chapel Hill; Jeffrey Curtis, MD, of Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor; MeiLan Han, MD, of University of Michigan, Ann Arbor; Nadia Hansel, MD, of Johns Hopkins University School of Medicine, Baltimore; Eric Hoffman, PhD, of University of Iowa Carver School of Medicine, Iowa City; Richard Kanner, MD, and Robert Paine III, MD, of  University of Utah Hospitals and Clinics, Salt Lake City; Eric Kleerup, MD, and Donald Tashkin, MD, of David Geffen School of Medicine, UCLA; and Stephen Rennard, MD, of University of Nebraska Medical Center, Omaha, and AstraZeneca, Cambridge, U.K.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.