Serum Immunoglobulin G Levels Are Associated with Risk for Exacerbations: An Analysis of SPIROMICS

Rationale: Serum IgG deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD), but it is unclear whether concentrations in the lower end of the normal range still confer risk. Objectives: To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD. Methods: Former and current smokers in SPIROMICS (the Subpopulations and Intermediate Outcome Measures of COPD study) (n = 1,497) were studied: 1,026 with COPD and 471 at risk for COPD. In a subset (n = 1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographic characteristics, current smoking, smoking history, FEV₁ percent predicted, inhaled corticosteroids, and serum IgA. Measurements and Main Results: The 35th percentile (1,225 mg/dl in this cohort) of IgG was the best cutoff by Akaike information criterion. Below this, there was increased exacerbation risk (incidence rate ratio [IRR], 1.28; 95% confidence interval [CI], 1.08-1.51). Among subclasses, IgG1 and IgG2 below the 35th percentile (354 and 105 mg/dl, respectively) were associated with increased risks of severe exacerbation (IgG1, IRR, 1.39; 95% CI, 1.06-1.84; IgG2, IRR, 1.50; 95% CI, 1.14-1.1.97). These associations remained significant when additionally adjusting for a history of exacerbations. Conclusions: Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting that subtle impairment of humoral immunity may be associated with exacerbations.