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The pathogenesis of acute infection in COPD

Educational aims To give an overview of the types of infectious agents involved in causing acute exacerbations of chronic obstructive pulmonary disease (COPD). To outline the mechanisms through which infectious agents drive exacerbations. To introduce the concept that mixed infections may increase the severity of exacerbations. Summary A number of virulence factors have been associated with bacterial pathogens' propensity to cause exacerbations, and the genetic basis for these has begun to be examined. In addition, the acquisition of new strains of some bacteria has been associated with exacerbations. Viral nucleic acids are detected in about half of exacerbations, and several viruses are implicated, in particular rhinovirus. The manner in which these and other pathogens, individually and collectively, interact with the host merits further scrutiny if the prevention and treatment of acute COPD exacerbations are to be improved.


Bacteria
The results of recent studies demonstrate that the acquisition of new bacterial strains, mainly nontypeable Haemophilus infl uenzae, Moraxella catarrhalis and Streptococcus pneumoniae, appears to be the predominant initiating event for an acute exacerbation of COPD (fi gure 2) [12,13]. The acquisition of new strains of Pseudomonas aeruginosa, however, is not related to acute exacerbations [13]. The balance between host defence and pathogen virulence determines the level of proliferation of the pathogen (the bacterial load), which in turn determines the increase in airway infl ammation. Large increases in airway infl ammation result in greater pathophysiological changes, which lead to symptoms intense enough for the patient to seek healthcare, and often to be diagnosed as experiencing an exacerbation. Conversely, if there is a limited increase in airway infl ammation, symptoms may not increase to such an intensity that an exacerbation is diagnosed. Furthermore, over time, the development of an adaptive immune response may limit the proliferation of the pathogen, or regulatory mechanisms may dampen the infl ammation, though the bacterial strain may persist. In these situations, the bacterial infection would be regarded as colonisation. To add to the complexity, patient perception, access to care and physician interpretation of symptoms are additional determinants of the diagnosis of exacerbations.
Putative pathogen virulence factors for respiratory bacterial pathogens include adhesion to and invasion of airway epithelial cells, inactivation of host defence mechanisms and elicitation of infl ammatory mediators from airway cells. Furthermore, exacerbation strains adhered in significantly higher numbers to and elicited more IL-8 from primary airway human airway epithelial cells Acute exacerbations of COPD are a significant cause of morbidity and mortality and are associated with frequent visits to physicians and hospitalisations. Thus, this condition results in signifi cant economic burden to healthcare systems. The causes of acute COPD exacerbations may be multi-factorial. Viral infections and/or levels of air pollution may exacerbate the existing infl ammation in the airways, which in turn, may pre dispose patients to secondary bacterial infections. Infectious agents, including bacteria, viruses and atypical pathogens, are currently implicated in up to 80% of acute exacerbations of COPD (fi gure 1) [1].
A considerable body of empirical evidence now supports the concept that exacerbations are acute infl ammatory events superimposed on the chronic infl ammation characteristic of COPD [2][3][4][5]. Several infl ammatory cells and molecules measured in exhaled breath, induced or expectorated sputum, bronchoalveolar lavage (BAL) or bronchial biopsy have been found to be elevated during acute exacerbations [6]. Furthermore, increased levels of plasma fi brinogen, interleukin (IL)-6, C-reactive protein and procalcitonin have been noted during exacerbations, demonstrating increased systemic infl ammation [7].
A normal tracheobronchial tree has innate defence mechanisms to maintain sterility. These are compromised in the airway of COPD patients, allowing the microbial pathogens to become established and proliferate in the lower airway. Infl ammatory and adaptive immune responses are recruited to deal with these proliferating microbial pathogens [8][9][10][11]. Increased levels of infl ammatory cells and cytokines induce airway secretions, bronchospasm and mucosal oedema, which in turn lead to worsening ventilation/ perfusion mismatch and hyperinfl ation, resulting in acute changes in the patient's symptoms. : new strain negative. data from [13].

Viruses
Previous investigations of the viral causation of exacerbations of COPD relied on serological studies and on viral cultures of upper airway samples. Now, investigators are using PCR-based detection of viral nucleic acids in sputum samples and are able to detect viral nucleic acids in 48-56% of exacerbations and 6-19% of controls. PAPI et al. [4] found that sputum eosinophilia was characteristic of exacerbations of viral aetiology. With widespread use of the infl uenza vaccine, rhino virus has become the predominant virus implicated in exacerbations [18,19]. Respiratory syncytial virus is also now recognised as capable of causing signifi cant illness in elderly adults with chronic lung and heart illness [20]. Other viruses associated with exacerbations include infl uenza, para infl uenza, adenovirus, coronavirus and human metapneumovirus.

Atypical pathogens and co-infection
The importance of Mycoplasma pneumoniae and Chlamydia pneumoniae infections in acute COPD exacerbations is not well defi ned [21][22][23][24]. The major limitation is related to the diagnostic methods used in studies to defi ne infection with these pathogens. These diagnostic methods include culture of respiratory secretions, PCR detection of microbial DNA and serology.
An antecedent viral infection is not essential for the development of bacterial acute exacerbations. Exacerbations may be attributed to virus alone, to both viral and bacterial infection or to bacterial infection alone [25]. Co-infection by in culture when compared with colonising strains (fi gure 3) [14]. Several investigators have recently published studies examining whether genetic differences underlie the pathogenic potential of H. infl uenzae strains isolated from the sputum of patients with COPD [15]. A specifi c combination of genes was found to be related to exacerbation, and inactivation of host defences appears to be an important determinant of disease expression among bacterial strains. These observations support pathogen virulence as an important determinant of clinical manifestations of new bacterial strain acquisition in COPD.
Exacerbations are infl ammatory events; however, this infl ammatory process is not uniform and is related to the aetiology of the exacerbation. Exacerbations associated with bacterial pathogens exhibit signifi cantly more neutrophilic infl ammation than nonbacterial episodes [16,17]. Resolution of symptoms of exacerbations associated with purulent sputum is associated with a consistent decrease in neutrophilic airway infl ammation.
P. aeruginosa has been isolated from sputum and bronchoscopic samples in COPD exacerbations, usually with underlying severe airfl ow obstruction. However, for P. aeruginosa, an association between exacerbations and new strain isolation was not identifi ed in COPD or in cystic fi brosis. This suggests that alternative mechanisms underlie exacerbations caused by this pathogen, such as biofi lm formation, increased bacterial load or reinfection because of a markedly impaired immune response in these sicker patients. Other Gram-negative Enterobacteriaecae and Staphylococcus aureus are often isolated from sputum during exacerbations and from bronchoscopy samples obtained during exacerbations of severe COPD.

Figure 3
Nontypeable H. infl uenzae from patients with acute COPD exacerbations (Exac) elicit greater infl ammation and epithelial cell adhesion than colonising (Col) strains. Reproduced from [14], with permission from the punlosher. virus and bacteria does seem to increase the severity of exacerbations, with greater decrement of lung function, higher bacterial loads and more systemic infl ammation (fi gure 4) [3,4]. Co-infection with C. pneumoniae and bacterial infection has also been described, however, without an impact on the clinical manifestations of exacerbation [22].

Conclusions
Though substantial progress has been made in the understanding of infectious exacerbations in COPD, much still needs to be learned. The complexity of the host-pathogen interaction that determines the onset and cause of exacerbations needs further exploration, including examination of host cellular and molecular mechanisms, the determinants of pathogen virulence and those pathogens' interaction with airway epithelial cells and macrophages. The interactions of the various causes of exacerbations need to be better understood, to facilitate the development of prevention strategies based on these interactions. Novel methods of treatment and prevention would undoubtedly emerge from such insights into the mechanisms and pathophysiology of exacerbations.