Feasibility and Safety of Immunoglobulin (Ig) Treatment in COPD Outpatients With Frequent Exacerbations: Pilot Study 1

COPD is an incurable respiratory disease characterized by progressive decline in lung function, shortness of breath, exercise limitation, poor health status, and increased mortality. The World Health Organization cites Chronic Obstructive Pulmonary Disease (COPD) as the third leading cause of death worldwide, and estimates suggest it currently affects 65 million people. COPD is a leading cause for hospital admission and readmission in North America, and costs our health system 50 billion dollars annually. Patients with COPD experience episodic flares of their disease, known as acute exacerbations (AECOPD). AECOPD are characterized by increased cough, shortness of breath, sputum production, weakness, and worsening airflow obstruction. There is also a high degree of systemic inflammation and immune system activation during the exacerbation. As the severity of COPD increases, the frequency of exacerbations increases as well. However, a major predictor of recurrent exacerbations is a history of exacerbation. COPD exacerbations have a significant impact on the individual patient and the health system. Previous studies have shown that patients with exacerbations experience reductions in quality of life, such as ability to engage in activities of daily living, a worsening of lung function and an increased risk for mortality during and after the exacerbation period. Exacerbation events often cause the patient to seek acute medical attention and admission to hospital, which drives the high health care costs. History of hospital admission due to AECOPD is the strongest risk factor for readmission for recurrent AECOPD within one year. Hospitalization for AECOPD is also associated with lower 3-year survival (82.1%; 95% CI, 78.1% - 86.4%) as compared to COPD patients without history of hospitalization (92%; 95%CI, 90.8% - 93.3%) in the previous 3 years independent of the severity of airflow limitation. As a result, research has focused on methods to prevent or reduce the frequency of acute exacerbations, with expected positive impacts on patients and the health system. Unfortunately, there is no cure for COPD, and highly effective therapies are currently lacking. The current GOLD COPD guidelines recommend smoking cessation, exercise training, maximal bronchodilator therapy, and influenza and pneumococcal vaccinations to try and prevent exacerbations. In patients with frequent exacerbations, both chronic macrolide therapy with azithromycin, N-acetylcysteine and roflumilast (a PDE-4 inhibitor) have been shown to increase the time to next exacerbation. However, these therapies are only modestly effective, and patients continue to experience exacerbations while on maximal therapy. Further research into new therapeutics to prevent and reduce exacerbations is imperative. The development of newer immunomodulatory agents as adjuvant therapy to prevent AECOPD has become an area of intense investigation. Prolonged steroid use is associated with hypogammaglobulinemia in asthmatic patients. Patients with COPD have lower immunoglobulin G (IgG) levels compared to patients with other lung diseases, independent of oral steroid use and age. However, recurrent exacerbations still occur despite having normal baseline serum IgG (data not yet published). Intravenous and subcutaneous immunoglobulins (IVIG and SCIG, respectively) are prepared from pooled plasma from thousands of healthy blood donors. The large donor pool ensures a diversity of antibody specificities to a wide spectrum of antigens and microbial pathogens. IVIG or SCIG represents a privileged source of natural antibodies (NAb), which occur in the absence of autoimmune disease or immunization. NAb are not only an immune defense against pathogens but also have anti-inflammatory and immunomodulatory activities. Given the heightened systemic and airway inflammatory activity in patients with COPD, their propensity to infection-triggered exacerbations, and their suppressed mucosal or systemic immunity, the anti-inflammatory, anti-infective and immunomodulatory effects of Ig preparations could be beneficial for patients with COPD. The investigators recently reported a retrospective single center self-interval analysis of Ig treatment as adjunctive preventative treatment for AECOPD in 14 patients. Half (8 patients) had at least severe COPD by GOLD criteria. Ig treatment significantly reduced moderate and severe AECOPD from 4.7 ± 3.1 to 0.6 ± 1.0 per patient-year. Number of hospitalizations was markedly reduced from twelve in the year prior to one in the year following Ig treatment initiation. Even though the median baseline IgG level in this study cohort was 5.9 g/L (interquartile range 4.1 - 7.4), and 36% had IgG less than 5 g/L, the clinical effect of Ig treatment in reducing moderate and severe AECOPD was consistent across all cases. While this demonstrates some promise, prospective controlled studies are required to determine if Ig treatment could have any impact on the frequency of COPD exacerbations.