Exacerbations hasten emphysema progression in former smokers with COPD
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Former smokers with COPD who experienced exacerbations had larger lung density declines than those without exacerbations, according to a letter to the editor published in Annals of the American Thoracic Society.
“We found a stepwise greater loss of lung density with increasing exacerbation frequency, predominantly in former smokers who already had some preexisting emphysema,” Surya P. Bhatt, MD, MSPH, associate professor of medicine in the division of pulmonary, allergy and critical care medicine at the University of Alabama School of Medicine and medical director of the UAB Pulmonary Function and Exercise Physiology Lab, and colleagues wrote.
Using data from the COPDGene study, Bhatt and colleagues analyzed 3,874 adults (mean age, 63.4 years; 50.2% women; 25% African American) with COPD, either current (n = 1,522) or former persistent (n = 2,352) smokers, to find out if acute exacerbations are related to quicker emphysema progression.
Patients underwent spirometry and CT at study enrollment and after 5 years, and researchers tracked patients’ interval exacerbations every 3 to 6 months within the study period.
Of the total cohort, 1,829 patients had Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0, 357 had GOLD stage 1, 756 had GOLD stage 2, 365 had GOLD stage 3 and 87 had GOLD stage 4 disease at baseline.
Researchers characterized patients based on exacerbation frequency over 5 years: 2,590 (67%) patients had no exacerbations, 1,284 (33%) had at least one exacerbation, 864 (22%) had one to four exacerbations and 420 (11%) had at least five exacerbations.
Adjusting for variables such as age, sex, race and BMI, researchers found that a higher number of exacerbations was linked to larger adjusted lung density declines among patients who formally smoked.
Former smokers who had five or more exacerbations had a –5.22 g/L (95% CI, –6.23 to –4.21) change in lung density compared with a change of –4.16 g/L (95% CI, –4.91 to –3.41) among those who had one to four exacerbations and a change of –3.27 g/L (95% CI, –3.81 to –2.74) among those with no exacerbations (P < .0001 for all). Adjusted lung density estimates include aging effects, which researchers estimated to be 0.36 g/L per year.
Researchers reported similar findings when evaluating former smokers with at least 5% emphysema (5 exacerbations, –5.92 g/L, 95% CI, –7.13 to –4.71; 1-4 exacerbations, –4.68 g/L, 95% CI –5.67 to –3.69; no exacerbations, –3.73 g/L, 95% CI, –4.6 to –2.87), although this association did not occur for those with less than 5% emphysema at baseline regardless of smoking status.
On the other hand, patients who actively smoked had greater mean adjusted lung density changes than former smokers ( 5 exacerbations, –5.61 g/L, 95% CI, –7.39 to –3.83; 1-4 exacerbations, –5.58 g/L, 95% CI –6.84 to –4.32; no exacerbations, –4.89 g/L, 95% CI, –5.63 to –4.16), but researchers did not find the same effect modification that they found in the former smoker group.
“Exacerbations are related to emphysema progression in a dose-dependent manner,” Bhatt and colleagues wrote. “Even low exacerbation frequency is associated with a high risk of emphysema progression, especially once emphysema has already set in. As emphysema is irreversible, these results underscore the importance of preventing exacerbations.”
Perspective
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It is well established that COPD is characterized by progressive airflow limitation and chronic respiratory symptoms. Exacerbations of COPD involve episodes of worsening respiratory symptoms and are associated with increased health care utilization, reduced quality of life, substantial morbidity and mortality. Exacerbations can lead to a temporary or even permanent worsening of airflow limitation as well as quality of life. As a result, exacerbation prevention is of paramount importance in the care of patients with COPD.
Several defects in lung structure, including airway thickening, distal airway loss and emphysema, result in expiratory airflow obstruction in COPD. Emphysema, one important radiologic phenotype of COPD, is characterized by irreversible destruction of the alveolar spaces from continued ongoing inflammation. Emphysema is associated with worse outcomes in COPD and increase the risk for lung cancer, independent of smoking status or lung function. Because of the association of emphysema with exacerbations, medical providers are charged with reducing the development of emphysema as best as possible.
Previously, the COPDGene study confirmed what has long been suspected but never definitively shown, that COPD exacerbations worsen lung function decline. In this research letter, Bhatt and colleagues expand on prior findings by showing that COPD exacerbations increase the amount of emphysema over time. In this analysis of COPDGene, the investigators found that increasing numbers of COPD exacerbations during the 5-year interval studied were associated with greater amounts of emphysema on CT compared with others that had fewer or no COPD exacerbations.
Interestingly, these results were only significant among former smokers, as opposed to current smokers. The investigators hypothesized that the measures of emphysema used could have been altered by the presence of continued exposure to cigarette smoke and, in combination with lower numbers of participants classified as continued current smokers over the 5 years, the results may not be accurate.
Regardless, this analysis of the COPDGene study increases our understanding of how COPD exacerbations lead to worsening disease. Although not surprising, the results do corroborate that long-suspected notion seen in other studies in an extremely large and comprehensive analysis of current or former smokers at risk for COPD and with COPD. From a clinical standpoint, goals of care for patients with COPD would still include exacerbation prevention, independent of knowing how much emphysema was seen on CT scan. However, one could argue that the reasons for doing so are now one more: minimizing lung function decline and the development of and progression of emphysema. Additionally, this information can be used clinically to risk stratify patients for future morbidity and mortality.
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