Modulation of Airway Inflammation by Haemophilus influenzae Isolates Associated with Chronic Obstructive Pulmonary Disease Exacerbation

Abstract

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...

Haemophilus influenzae Infection Drives IL-17-Mediated Neutrophilic Allergic Airways Disease

“…NTHi is commonly isolated from the nasopharynx of healthy individuals, but is also associated with chronic airway diseases such as bronchiectasis [37] , COPD [38] , and chronic bronchitis [39] . NTHi is the bacterium most commonly isolated during COPD exacerbations, and NTHi strains isolated during these exacerbations induce higher levels of IL-8, and subsequent neutrophil recruitment to the airways, than colonizing strains [40] . Simpson and colleagues have recently demonstrated that a large proportion of neutrophilic asthmatics are colonized with H. influenzae , have increased innate immune activation, and 6-8 fold higher endotoxin levels compared to other asthma subtypes and healthy controls [12] .…”

Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD

“…Chronic bacterial colonization of the airways contribute to the inflammatory response of COPD [ 13 ] and to disease progression [ 14 – 16 ]. Airway infection is also a key pathogenic mechanism of COPD exacerbations [ 13 , 15 , 17 – 19 ] which, are characterized by a flare-up of airway inflammation [ 20 – 22 ]. Non-typeable Haemophilus influenzae (NTHi) is frequently isolated from COPD patients both when clinically stable and during exacerbations [ 17 , 19 ].…”

Haemophilus influenzae protein E recognizes the C‐terminal domain of vitronectin and modulates the membrane attack complex

“…Among the typeable strains, H. influenzae type b (Hib) is considered to be most virulent causing bacteraemia, pneumonia and acute bacterial meningitis or occasionally, osteomyelitis, epiglottitis and joint infections (Watt et al ., 2009). Non‐typeable H. influenzae (NTHi) is most commonly associated with otitis media, sinusitis and chronic obstructive pulmonary disease (COPD) (Murphy, 2003; Sethi et al ., 2004, Look et al ., 2006). A crucial factor in the H. influenzae pathogenesis involves the initial adherence to the respiratory mucosa.…”