The results indicate that H. influenzae strains isolated from patients during COPD exacerbations often induce more airway inflammation and likely have differences in virulence compared with colonizing strains. These findings support the concept that bacteria infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function.

Introduction: Chronic obstructive pulmonary disease (COPD) has been associated with lower airway, systemic, and, more recently, upper airway inflammation. The systemic component may be important through an association with increased cardiovascular comorbidity. While it is known that lower airway and systemic inflammation are increased at exacerbation of COPD (Ex)-COPD, it is not known whether the upper airway is involved at this time, nor how the upper airway, lower airway, and systemic compartments relate during such events. We investigated the relationships between systemic, upper airway, and lower airway inflammation at ExCOPD. Method: Serum, nasal wash, and sputum samples were obtained at 41 Ex in 41 subjects with COPD (mean [SD] age, 69.0 [7.7] yr; FEV 1 , 1.00 [0.43] L). We assayed leukocytes, IL-6, IL-8, myeloperoxidase (MPO), and CRP. Pre-Ex baseline samples were available in 21 patients. Results: In addition to increases in systemic and lower airway inflammation, Ex were associated with greater upper airway inflammation (nasal leukocytes and IL-6, stable vs. Ex: 4.08 vs. 4.41 log 10 cells/ml, p ϭ 0.04; 0.40 vs. 0.89 log 10 pg/ml, p ϭ 0.09). There were significant correlations between the lower airway and systemic, and lower and upper airway inflammation, but not between the upper airway and systemic compartments: sputum leukocytes with serum IL-6 and CRP (r ϭ 0.38, p ϭ 0.01; r ϭ 0.39, p ϭ 0.02) and sputum IL-8 with serum IL-6 (r ϭ 0.37, p ϭ 0.02). Sputum MPO correlated with nasal leukocytes, IL-6, IL-8, and MPO: (all r Ͼ 0.43, p Ͻ 0.01), and sputum leukocytes with nasal IL-6 (r ϭ 0.38, p ϭ 0.02). Similar relationships were observed in paired data for changes in sputum leukocytes with changes in serum IL-6 and CRP. Conclusion: ExCOPD are associated with pan-airway inflammation, but the systemic inflammatory response is related to the magnitude of the lower rather than upper airway inflammation. Conflict of Interest Statement : J.R.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.R.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.M.A.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.C.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.A.W. has received honoraria for lectures at meetings or attendance at Advisory Boards from the following companies: GlaxoSmithKline (GSK), Boehringer Ingelheim, Astra Zeneca, Bayer, and Aventis Pasteur. She has received research grants totaling approximately $600,000 from GSK for studies of COPD questionnaires, studies of COPD exacerbation time course, flow cytometric studies of the interaction of the upper and lower airway in COPD, study of time course of inflammatory markers at COPD exacerbation, analysis of long-term changes in airway and systemic inflammatory markers, clinical...

Infection by nontypable Haemophilus influenzae in the airway causes inflammation, and newly isolated strains of these bacteria are associated with an increased risk of disease exacerbation in patients with chronic obstructive pulmonary disease (COPD). In this study we questioned whether strains of H. influenzae associated with exacerbations cause greater inflammation than strains colonizing airways of COPD patients. Bacterial strains were obtained from COPD patients that underwent serial assessment of clinical status, sputum microbiology, and serum antibacterial antibody production. Exacerbation strains were defined as new isolates cultured during exacerbation of clinical symptoms with subsequent development of a homologous bactericidal antibody response. These strains were compared to colonization strains that were not associated with an increase in symptoms or new antibody production. We found that strains of H. influenzae associated with exacerbations caused more airway neutrophil recruitment than colonizer strains in an in vivo mouse model of airway infection. Experiments using an in vitro model of human primary airway epithelial cells revealed that exacerbation strains adhered significantly more to epithelial cells than colonizing strains. Exacerbating strains also induced greater release of interleukin-8 after interaction with airway epithelial cells, a response likely mediated by increased activation of both the nuclear factor-kappaB and p38 mitogen-activated protein kinase signaling pathways. The results indicate that H. influenzae isolated from patients with exacerbations of COPD induce more airway inflammation and likely have differences in virulence compared to colonizing strains. These findings support the concept that H. influenzae infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function.