Feasibility and Safety of Immunoglobulin (Ig) Treatment in COPD Outpatients With Frequent Exacerbations: Pilot Study 1
Feasibility and Safety of Immunoglobulin (Ig) Treatment in COPD Outpatients With Frequent Exacerbations: Pilot Study 1
Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the
 airways, associated with poor health status, functional disability, significant morbidity,
 and increased risk of death. In Ontario, COPD is the leading cause of hospital admission and
 readmission, and costs the health system approximately 3 billion dollars annually.
 Individuals with COPD experience increased 'flare-up's' (acute exacerbations) as their
 disease worsens, characterized by periods of increased shortness of breath, cough, phlegm
 production, and weakness. Acute exacerbations of COPD (AECOPD) are most commonly caused by
 viral or bacterial infections, and often require patients to seek attention at the emergency
 room or hospital for treatment. Current treatments to prevent COPD exacerbations are only
 modestly effective. New therapies are needed to improve the quality of life and clinical
 outcomes for individuals living with COPD.

 Previous research at our center has shown a favourable effect of an antibody treatment
 (immunoglobulin) on the frequency of AECOPD, doctor visits, treatments, and hospitalizations
 for COPD patients. However, rigorous studies with more patients are required to confirm this
 effect.

 The investigators propose a clinical trial to evaluate immunoglobulin treatment in
 outpatients with frequent exacerbations. In this study the investigators will determine if
 immunoglobulin treatment is feasible, safe, tolerable, and potentially effective in reducing
 the frequency of acute exacerbations. If this study is feasible and potentially effective, it
 will inform larger studies to confirm the therapeutic effect of immunoglobulin treatment, and
 would be a major advance in care of COPD.
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.
Inclusion Criteria:

 -  Adult patients with frequent exacerbations of COPD (clinically dominant COPD in the
 case of multiple co-morbidities eg. bronchiectasis, interstitial lung disease,
 congestive heart failure)

 -  Confirmed diagnosis of COPD (bronchodilator FEV1/FVC ratio <0.7 on spirometry within
 previous 12 months)

 -  Age >40 years

 -  >10 pack year smoking history

 -  Frequent COPD exacerbations in the previous 12 months before enrollment, defined by
 one or both of the following:

 -  Treatment as an outpatient with antibiotics or prednisone (physician diagnosed COPD
 exacerbation) on 2 previous occasions OR

 -  One hospitalization for COPD exacerbation (as defined by 2/3 of increased dyspnea,
 sputum volume, or sputum purulence in patients with known airflow limitation)

 -  Expected to live > 12 months

 Exclusion Criteria:

 -  Known severe hypersensitivity to immunoglobulin or its components (anaphylaxis)

 -  Active or metastatic malignancy (including chronic lymphocytic leukemia) excluding
 local skin cancers

 -  History of hematopoietic stem cell transplant or solid organ transplant

 -  Current treatment with a biological therapy for other conditions

 -  Concomitant significant immunodeficiency or use of immunosuppressive treatment (other
 than for COPD)

 -  Alpha-1 antitrypsin deficiency (based on enzyme level from bloodwork)

 -  Significant proteinuria (dipstick proteinuria ≥ 3+ AND known urinary protein loss ≥ 2
 g/day or nephrotic syndrome) and/or has a history of acute renal failure and/or severe
 renal impairment (creatinine more than 2.5 times the upper limit of normal and/or on
 dialysis)

 -  IgA deficiency (IgA <0.1 g/L)

 -  Immunoglobulin therapy in the last 12 months or on current Ig therapy or have a
 clinical indication for Ig replacement therapy
 (www.nacblood.ca/resources/guidelines/IVIG.html)

 -  Pregnancy