Bacteria within the lower respiratory tract plays a critical role in the clinical course and pathogenesis of chronic obstructive pulmonary disease (COPD). Evidence suggests that acute exacerbations are attributable to bacteria, and these exacerbations have a significant impact on a patient's health status and health services utilization. New bacterial strains play a central role in the pathogenesis of exacerbations, and acquisition of a new strain of potentially pathogenic bacteria (e.g., Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Pseudomonas aeruginosa) is strongly associated with the occurrence of an exacerbation.

The first part of this dissertation investigates the clinical impact of P. aeruginosa isolation in an outpatient COPD cohort. P. aeruginosa is an important pathogen in choric airway diseases including cystic fibrosis and bronchiectasis, significantly contributing to both morbidity and mortality. The relationship between P. aeruginosa and COPD mortality has been primarily investigated in hospitalized patients and is associated with higher mortality. Whether this extends to an outpatient sample is unknown, however a greater understanding of this relationship would help guide specific therapies and help inform eradication strategies.

Therefore, this aim investigated the association of P. aeruginosa isolation with long-term mortality and patient outcomes (exacerbations and hospitalizations) in a sample of U.S. veterans with COPD (n=181). After adjustment for age and pulmonary status, there was a positive association between the P. aeruginosa culture-positivity and mortality. Moreover, the rate of exacerbations and hospitalizations were higher for P. aeruginosa positive patients. Interestingly, we found an upward trend in exacerbation and hospitalization rates prior to isolation of P. aeruginosa in sputum culture, indicating that patients may be acquiring this organism prior to its isolation. As colonization by P. aeruginosa has adverse consequences, early eradication as practiced with cystic fibrosis may be applicable to COPD and should be considered.

The second part of the dissertation investigated bacterial colonization patterns and interactions among the four primary bacterial pathogens. Interspecies bacterial interactions can alter the composition of a microbial community and potentially influence disease incidence and severity. To date, our knowledge on respiratory bacterial interactions is limited to the nasopharynx in young children and has not yet been extended to longitudinal studies of lower respiratory tract colonization or to adults with COPD.

This aim evaluated the prevalence of bacterial colonization and determined species-specific interactions using sputum cultures collected at monthly visits in a sample of veterans with COPD over a 20 year period (n=8,843 clinic visits). Our findings indicate a positive association between S. pneumoniae and H. influenzae colonization as well as negative associations between P. aeruginosa and H. influenzae , and P. aeruginosa and M. catarrhalis. These findings were similar during both stable and exacerbation visits. Our work presents novel insight into interspecies synergy and competition between common pathogenic bacteria in patients with COPD. These interactions may offer novel therapeutic opportunities to alter the characteristics of the airway microbiota and further study of the mechanistic and clinical implications of these interactions is warranted.

For our third aim, we shifted to a health-services focus in order to further understand the causes and factors related to 30-day readmission for an acute exacerbation of COPD. This was prompted based on the recent inclusion of COPD discharges as one of the targeted diagnoses in the Hospital Readmission Reduction Program. As hospitals implement interventions to reduce COPD readmissions, we believe it is necessary to recognize the causes and reasons for early readmission and which patient, clinical, and hospital factors raise readmission risk. We conducted an analysis of the National Readmission Database from 2013-2014 and defined index admissions and readmission for a COPD exacerbation consistent with HRRP guidelines. Our findings indicate that respiratory-based diseases were the most common reasons for readmission with COPD as the most common diagnosis. Early readmission was associated with patient level factors (Medicaid payer status, lower household income, and higher comorbidity burden) and clinical factors (longer length of stay and discharge to a skilled nursing facility). Early readmission for AECOPD remains a burden to the healthcare system, with the majority readmitted for respiratory-based diagnoses. Multiple patient and clinical factors were associated with readmission including those related to low socioeconomic status and post-acute care discharge to a skilled nursing facility. Further work is needed to develop a risk stratification algorithm based on these factors to better predict AECOPD patients at high risk of early readmission during the index hospitalization.