To the Editor:

We read with great interest the recent publication by Burnim and colleagues in the Journal, which investigates the association between serum IgG levels and the risk of exacerbations in current and former smokers with or at risk for chronic obstructive pulmonary disease (COPD) (1). In a robust prospective multicenter cohort study, the authors demonstrated that serum total IgG concentrations at the lower end of the normal range are prospectively associated with an increased risk of exacerbations, even among individuals with milder disease. Moreover, the study showed that concentrations of IgG subclasses, IgG1 and IgG2, at the lower end of the normal range are also linked to an increased risk of severe exacerbations (1). These novel observations suggest that the optimal IgG threshold for predicting exacerbation risk exceeds the traditionally accepted normal reference range, highlighting the critical role of even subtle impairments in humoral immunity in exacerbating risk among individuals with or at risk for COPD.

To substantiate these findings, the authors employed multivariable models rigorously adjusted for potential confounders, including demographic characteristics, education, smoking history, current smoking status, lung function (FEV₁ percent predicted), use of inhaled corticosteroids, serum IgA levels, and history of exacerbations (1). However, one notable limitation is the apparent exclusion of comorbidities as a confounder despite their established association with a higher risk of exacerbations and mortality in COPD (2, 3). COPD is frequently accompanied by extensive comorbidities, including diabetes mellitus, arterial hypertension, sleep disorders, and cardiovascular diseases (4, 5). A nationwide study in Scotland involving more than 1.2 million adults revealed that 86% of patients with COPD had at least one comorbidity, compared with 48.9% of individuals without COPD (5). Furthermore, 22.3% of patients with COPD had five or more comorbid conditions, in contrast to only 4.9% of those without COPD (5). Comorbidities may also influence the levels and activity of serum IgG. For instance, abnormal serum IgG concentrations and dysfunctional IgG due to nonenzymatic glycosylation have been reported in patients with diabetes (6). Considering the potential impact of comorbidities on IgG levels and their role as risk factors for exacerbation, we are keen to understand whether comorbidities affected IgG levels in the cohort analyzed by Burnim and colleagues. Providing this information could offer valuable insights into the interplay between comorbidities and humoral immunity, potentially refining our understanding of risk stratification and guiding more personalized therapeutic approaches for patients with COPD.