Novel insights into the aetiology and pathophysiology of increased airway inflammation during COPD exacerbations

Bacterial infections are generally considered to be the most common causes of COPD exacerbations. It is estimated that more than 40% of all exacerbations are of bacterial origin[9, 11, 12]. Accordingly, antibiotics should be administered in inpatients and outpatients with acute COPD exacerbation and changes in sputum characteristics suggestive of bacterial infection[8].

The most common bacteria connected to COPD exacerbations are non-typable H. Influenzae, S. Pneumoniae, and M. Cattarhalis[9, 11, 12]. The same bacteria often colonize the nasal mucosa and pharynx of healthy individuals, but in smokers and in patients with COPD impaired mucocilliary clearance and innate immunity allow these pathogens to colonize the lower airways[13]. COPD exacerbations may be triggered by the acquisition of a new bacterial species or by an increase in the absolute number of the same bacteria that colonize the airways or by the acquisition of a different strain from the same bacterial species [14‐16].

Airway bacteria initiate airway inflammation through several interconnecting mechanisms. The surface of bacteria allows the complement system to be activated through the alternative pathway, while specific surface molecules of the bacteria, called Pathogen-Associated Molecular Patterns (PAMPs), bind to pattern recognition receptors on a variety of leukocytes and initiate signalling pathways that lead to the activation of NF-κB and production of proinflammatory cytokines[17]. Once activated, innate immunity can trigger both cell-mediated and antibody-mediated adaptive immune responses. This cascade of events leads to increased blood flow to tissue, increased temperature, redness and swelling which characterize inflammation.

A significant number of studies in stable COPD patients suggest that airway bacterial infections are associated with increased airway inflammation(18–21). Finding a relationship between bacteria and inflammation on stable COPD adds weight to the argument that bacteria may play a causative role in airway inflammation during COPD exacerbations.

Soler et al used protected specimen brush and bronchoalveolar lavage sampling to determine inflammatory cell counts, levels of cytokines concentrations and microbial patterns in stable COPD patients and found that increased neutrophils and tumour necrosis factor-alpha (TNF-alpha) levels may be related to bronchial colonization[18]. Increased TNF-alpha, as well as myeloperoxidase (MPO) and interleukin-8 (IL-8) levels have been specifically related with H. Influenzae infection, as shown by Bresser et al[19]. However, in that study all mediators were measured in frozen sputum and MPO and IL-8 levels were only retrospectively compared to non-infected patients. In fresh sputum samples from COPD patients R. Stockley and his group demonstrated that MPO, neutrophil elastase (NE) activity, IL-8 and LTB4 levels are positively related to sputum bacterial load[20]. Moreover, the type of organism affected sputum MPO levels and NE activity; MPO levels were relatively increased in the presence of Ps. Aeruginosa compared to H. Influenzae and to M. Catarrhalis. There have been also reports for decreased secretory leukocyte protease inhibitor (SLPI) in sputum samples from COPD patients colonised with bacteria[20, 21]. Upper airways inflammation in COPD is also increased when there is bacterial colonization[22]. All these results taken together suggest that bacteria are actively involved in the mechanisms of increased inflammation in stable COPD. It would be logical to assume a similar association for COPD exacerbations.

A large prospective longitudinal study by Sethi et al addressed the hypothesis that patients with bacterial-positive exacerbations show increased inflammation compared to bacterial-negative exacerbations[23]. Among H. Influenzae, H. Parainfluenzae and M. Catarrhalis positive exacerbations, H. Influenzae and M. Catarrhalis demonstrated higher sputum TNF-alpha and NE levels compared to bacterial-negative exacerbations. Moreover, increased NE levels above a certain level could distinguish bacterial from non-bacterial exacerbations with 71% sensitivity and 84% specificity. Others have failed to report any difference in sputum NE levels and other fluid-phase mediators between patients with H. Influenzae exacerbations or bacterial-negative exacerbations[24]. This discrepancy may be due to differences in sputum induction time or in sputum processing or in the assays used for the detection of fluid-phase mediators. Another intriguing hypothesis is that different strains of the same pathogens may induce different levels of inflammation and subjects taking part in different studies might have been infected by different strains of H. Influenzae. It was recently shown that H. Influenzae strains isolated from COPD patients during exacerbation induce more inflammation than strains of the same pathogen isolated from colonizers[16]. The close association between airway infections and increased inflammation during COPD exacerbations has been further confirmed by a report of increased systemic inflammation in infected patients during exacerbation[25].

Consistent with these observations, airway inflammation can be decreased with treatment of the infection. Early evidence came from a relatively small study, which showed that neutrophilic mediators' levels may decrease after treatment of bacterial exacerbations[26]. Gompertz et al confirmed that there are significant decreases in neutrophilic inflammatory mediators after treatment of purulent exacerbations[27]. Most importantly, White et al studied patients with bacterial exacerbations and demonstrated a significant fall in sputum leukotriene B4 (LTB4) levels and an increase in SLPI levels in patients in whom bacteria were eradicated, but not in those in whom bacteria persisted on stable state[24]. Moreover, MPO and LTB4 levels were significantly lower and SLPI levels significantly higher in patients with treated compared to patients with untreated bacterial infections on stable state.

In conclusion, three major findings support the hypothesis that bacterial infections are actively implicated in the mechanisms of increased airway inflammation during COPD exacerbations: 1) bacterial infections increase airway inflammation in colonized stable COPD patients 2) bacterial-positive exacerbations show increased inflammation (particularly of neutrophilic type) compared to bacterial-negative exacerbations and 3) eradication of bacteria after a bacterial exacerbation is accompanied by a significant decrease in airway inflammation. A summary of these findings is presented in table 2.

Respiratory viruses are important triggers of COPD exacerbations. Initial studies using serology and cell cultures for detecting viral infections suggested that 30% of COPD exacerbations are related to viral infections [28‐30]. Later studies using the more sensitive method of reverse transcriptase polymerase chain reaction showed that 40%–50% of COPD exacerbations may be secondary to viral infection[31, 32]. Rhinoviruses, picornaviruses, respiratory syncytial virus, influenza A and B and coronaviruses are more frequently detected[31, 32].

Possible mechanisms of viral-induced inflammation have been described. The airway epithelial cell is the principal host cell for most respiratory viruses[33]. Viral replication in the epithelial cell triggers intracellular signalling pathways, including activation of NFκB, which leads to increases in the secretion of multiple cytokines and recruitment of multiple leukocytes to the airways[33]. Antigen presenting cells are of particular importance, because binding of viruses to these cells induces innate and adaptive immune responses and T lymphocyte activation[34].

There is convincing data that viruses induce inflammation in asthma[35]. In animal models of emphysema, latent adenoviral infection amplifies the emphysematous destruction and increases the inflammatory response[36]. In stable COPD latent adenoviral infection has been associated with severe emphysema and increased inflammation[37]. The group of J Wedzicha showed that viral infections might be implicated in the mechanisms of increased airway and possibly systemic inflammation during COPD exacerbations. Plasma IL-6 and fibrinogen levels were higher during viral than non-viral exacerbations, although the difference just failed to reach statistical significance[31]. However, in that study viruses were detected in nasal samples and it has been shown that in COPD patients respiratory viruses are detected more frequently in induced sputum than in nasal lavage[32, 38]. When rhinovirus infection was detected in induced sputum samples a significant correlation was demonstrated between rhinovirus infection and increased sputum IL-6 levels on COPD exacerbations[38].

Further to these observations, two recent studies showed that viral airway infections during COPD exacerbations are related to airway eosinophilia[39, 40]. This new finding may be of particular clinical importance as airway eosinophilia could be used as an indicator of viral infection during an exacerbation. The important role of eosinophils in the pathogenesis of COPD exacerbations is further supported by studies in bronchial biopsies and sputum samples, which show increased eosinophil numbers and eosinophil mediators in COPD patients during exacerbations [41‐46]. Eosinophils may be actively involved in the pathogenesis of viral-induced COPD exacerbations through the release of destructive enzymes, reactive oxygen species and inflammatory mediators.

Atypical pathogens with potential importance in acute exacerbations include M. Pneumoniae, C. Pneumoniae and Legionella spp. Considerable confusion exists in the literature regarding the significance of these potential pathogens in acute exacerbations of COPD[47]. This is partly due to differences in the techniques used to detect the presence of atypical infections. When a fourfold increase in antibody titter or a positive culture or RT-PCR is used, M. Pneumoniae and Legionella are rare and C. Pneumoniae infection may be involved in up to 9% of COPD exacerbations[30, 48‐50]. Moreover, chronic colonization with C. Pneumoniae may be associated with a higher rate of COPD exacerbations[51]. C. Pneumonia infection can amplify inflammation in the airways of COPD patients by stimulating the production and expression of cytokines, chemokines and adhesion molecules[52]. However, clear evidence showing a direct relationship between increased inflammation and C. Pneumoniae infection during COPD exacerbations is yet lacking[50].