Rationale

Serum Immunoglobulin G (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.

Measurements and main results

Former and current smokers in SPIROMICS (n=1,497) were studied, n=1,026 with and n=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 demographics, current smoking, smoking history, FEV₁% predicted, inhaled corticosteroids, and serum IgA.

Results

The 35th percentile (1225 mg/dL in this cohort) of IgG was the best cutoff by Akaike Information Criterion (AIC). Below this, there was increased exacerbation risk (IRR 1.28, 95% CI 1.08-1.51). Among subclasses, IgG1 and IgG2 below 35^th percentile (354 and 105 mg/dL, respectively) were both associated with increased risk 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 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 subtle impairment of humoral immunity may be associated with exacerbations.