Lung Function Decline in Smokers with Normal Spirometry: The Devastating Impact of Lung Attacks

Exacerbations are common complications of chronic obstructive pulmonary disease (COPD), characterized by an acute worsening of symptoms that often necessitates additional therapy (1–3). These exacerbations can vary in severity, ranging from mild cases that can be managed with reliever therapy at home to more severe instances requiring hospitalization and intensive treatment. An important treatment goal, as highlighted by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in their recommendations, is to reduce the risk and severity of future exacerbations (4).

Exacerbations not only seem to impact health quality in patients with COPD but also are associated with disease progression (5). Indeed, exacerbations have been associated with accelerated lung function decline and increased morbidity and mortality (6–10). It therefore seems only logical to refer to an exacerbation as a “lung attack” to clarify the seriousness of such an event, drawing a necessary analogy to referring to myocardial infarction as a “heart attack,” which (surprisingly) tends to attract more attention in both public health and political discussions because of its widespread recognition and urgency. The main difference, which always seems to create a heated debate, is the fact that exacerbations only involve patients with chronic lung disease, whereas myocardial infarction can also affect individuals without any prior history of heart disease. Nonetheless, exacerbations—or rather, lung attacks—have been described in individuals with normal lung function before (11–13), indicating that they are not confined to those with chronic lung disease but are a broader health concern impacting all individuals. Consequently, more research is needed to address lung attacks as acute events affecting the entire population, not only those with chronic conditions.

In this issue of the Journal, Fortis and colleagues (pp. 957–965) tested the hypothesis that respiratory exacerbations in individuals with cigarette smoking history but normal lung function are associated with lung function decline and increased mortality (14). For this purpose, the investigators have used COPDGene (Genetic Epidemiology for Chronic Obstructive Pulmonary Disease Study), which is a multicenter cohort from the United States including individuals aged 45–80 years with a smoking history of ⩾10 pack-years. Normal spirometry included those with post-bronchodilator FEV₁/ FVC ⩾ 0.70 and FEV₁ ⩾ 80% predicted, meaning that those with preserved ratio impaired spirometry (PRISm) (i.e., FEV₁/FVC ⩾ 0.70 and FEV₁ < 80% predicted) were excluded, which is important to clarify. Approximately 3,000 individuals were included and followed for 5 years to assess lung function decline. The attentive reader has probably noticed that the investigators follow up on a previous study in the COPDGene study with a more updated cohort, but this time only focusing on those with normal lung function (corresponds to GOLD 0 in their previous study) (7). Previously, the investigators found that exacerbations lead to excess lung function loss in individuals with established COPD (i.e., GOLD 1–4) but not in those with GOLD 0 or PRISm (although one might argue that there was a weak signal in these groups). It is important to acknowledge that their previous investigation has consistently been referenced and remains a valuable contribution to our field. In the present study, the investigators now demonstrate that exacerbations are associated with accelerated lung function decline in those with normal lung function. Average FEV₁ decline increased progressively with the number and severity of exacerbation: from 50.6 ml/yr in those with no exacerbations, to 50.9 ml/yr in those with one to two moderate exacerbations but no severe ones, 60.8 ml/yr in those with more than two moderate exacerbations but no severe ones, 64.2 ml/yr in those with at least one severe exacerbation but no moderate ones, and 65.5 ml/yr in those with both severe and moderate exacerbations. Interestingly, two turning points were identified in the association between the number of exacerbations and FEV₁ decline: up to 10 exacerbations, there seems to be an inverse linear relationship, with each additional exacerbation associated with a 3-ml/yr average FEV₁ decline, whereas from 10 to 20 exacerbations, a positive association was found, likely representing some form of recall bias, as experiencing 20 exacerbations in a year seems unlikely, and some of these may actually be the same exacerbation with a prolonged duration. The investigators also demonstrated that exacerbations were associated with progression to COPD over the 5 years of follow-up, which could be seen as a form of validation. Another important finding was that there was no interaction with asthma or smoking status, meaning that individuals with asthma did not experience greater FEV₁ decline than those without asthma, and the FEV₁ decline in former smokers was not significantly different from that in current smokers.

Strengths of the present study include a well-defined cohort of high-risk individuals, specifically middle-aged and older adult smokers with ⩾10 pack-year smoking history, together with relevant clinical information that is often not available in other cohorts. As with all types of studies, there are limitations that need to be considered. One limitation is that exacerbations were ascertained over periods of time, inhibiting the precise identification of the exact date of these events. In addition, severe exacerbations were defined by including both emergency department visits and hospitalizations, which may have led to the categorization of mild to moderate exacerbations as severe, as some patients were likely not admitted for further treatment. Another limitation is the high rate of loss to follow-up, particularly given the high-risk nature of the cohort, which is often attributed to deaths or dropouts, potentially impacting the generalizability of the findings (15). These limitations do not diminish the validity of the positive findings in the present study, however, which remain robust and meaningful in understanding the relationship between exacerbations and lung function decline.

Based on the growing body of evidence, exacerbations—or, more accurately, lung attacks—should be recognized as acute events in all patients, not just those with chronic lung disease, requiring urgent attention in both clinical practice and research. Lung attacks seem to affect lung function in a manner similar to how heart attacks affect heart pump function. Just as monitoring heart pump function after a heart attack is essential, following up on lung function after a lung attack should be equally logical and critical. This shift in focus would not only improve patient management in clinical settings but also expand the research agenda to encompass lung attacks across all populations, rather than limiting attention to those with COPD. With the present study, Fortis and colleagues deserve congratulations once again for their excellent contribution to the field, which will undoubtedly be frequently referenced. As they suggest at the end of their study, future research should investigate whether therapeutic interventions in high-risk individuals with normal spirometry can improve clinical outcomes and potentially prevent lung function decline and progression to COPD.