INFLAMMATORY MARKERS IN BACTERIAL EXACERBATIONS OF COPD

To the Editor :

Aaron and colleagues (1) recently showed convincingly that inflammatory markers in the sputum of adults with COPD are elevated during exacerbation compared with clinically stable periods. However, their data do not support their conclusion that the inflammatory response observed during exacerbation "appears to occur independently of a demonstrable viral or bacterial infection." In their study, viral infection was established in just two exacerbations and bacteria in a single sputum sample at the time of exacerbation. Based on these numbers, one cannot draw meaningful conclusions regarding the role of viral or bacterial infection in the elevated inflammatory markers seen during exacerbations.

The definition of an acute exacerbation due to bacteria as "demonstration of a new pathogenic organism cultured from sputum on the day of exacerbation, but not cultured at baseline" is problematic. Adults with COPD are colonized by potential pulmonary bacterial pathogens during clinically stable periods. Such a definition does not account for this observation, nor does the definition take into account the dynamic turnover of bacterial strains observed in COPD (2). It would be important to know the results of sputum cultures in the patients studied. The single patient whom the authors concluded experienced a bacterial exacerbation had Klebsiella pneumoniae in the sputum, an organism that many authors would question being a cause of exacerbation. Finally, the observation that only 14 exacerbations occurred in 50 patients over a 9 to 15 month period, differs substantially from other prospective studies that show a rate of 1 to 1.5 exacerbations per patient annually (3). Do the authors have an explanation for this difference?

A recent study of 81 exacerbations of COPD showed that inflammatory markers were significantly increased in sputum samples that contained Haemophilus influenzae and Moraxella catarrhalis compared with sputum samples that contained no bacterial pathogens at the time of exacerbation (4). Another study involving 121 patients with COPD showed that bacterial pathogens in sputum are associated with neutrophil influx (5). In addition, Hill and colleagues (6) demonstrated that the degree of inflammation was dependent upon the number of bacteria in sputum. These pivotal studies with larger numbers of samples show that increased airway inflammation is associated with isolation of bacteria from sputum in COPD. These observations form the basis of ongoing work to elucidate the role of bacteria more precisely in the course and pathogenesis of COPD.

University at Buffalo, SUNY and VA Western New York, Healthcare System, Buffalo, New York

Susan L. Hill, and Robert A. Stockley

Queen Elizabeth Hospital, Birmingham, United Kingdom

1. Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, et al . . Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 349-355 [Abstract/Free Full Text].

2. Groeneveld K, van Alphen L, Eijk PP, Visschers G, Jansen HM, Zenen HC. Endogenous and exogenous reinfections by Haemophilus influenzae in patients with chronic obstructive pulmonary disease: the effect of antibiotic treatment on persistence. J Infect Dis 1990; 161: 512-517 [Medline].

3. Murphy TF, Sethi S. Bacterial infection in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 146: 1067-1083 [Medline].

4. Sethi S, Muscarella K, Evans N, Klingman KL, Grant BJB, Murphy TF. Airway inflammation and etiology of acute exacerbations of chronic bronchitis. Chest 2000; 118: 1557-1565 [Abstract/Free Full Text].

5. Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000; 117: 1638-1645 [Abstract/Free Full Text].

6. Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med 2000; 109: 288-295 [Medline].

From the Authors:

We appreciate the comments of Dr. Murphy and his colleagues and we would like to reply to the important issues that they mention in their letter. Our study (1) included a thorough microbiologic assessment (including quantitative bacterial cultures from induced sputum and PCR assays for respiratory viruses) of each patient with COPD at three time points: (1) at baseline when they were well, (2) during the time of an actual COPD exacerbation, and (3) one month post-exacerbation. Of the fourteen patients who experienced an exacerbation, a potentially pathogenic bacteria was cultured from the induced sputum sampled at the time of exacerbation from only one of the patients. Cultures from the other 13 patients exhibited only Neisseria species, non-pneumococcal alpha-hemolytic streptopcoccus, or Diptheroids at the time of exacerbation. These bacteria are normal respiratory tract flora and are not respiratory pathogens, therefore they were not judged to be responsible for exacerbation in these patients.

Our study was able to demonstrate that sputum markers of granulocytic inflammation increased, relative to the stable state, in those patients in whom no acute bacterial or viral infection could be demonstrated. However, as Dr. Murphy correctly points out, the number of patients in our study in whom infection was definitively established was small. Therefore we were careful not to make any conclusion about the magnitude of change seen in inflammatory markers in infected patients. We simply concluded that patients with clinical exacerbations of COPD, in whom airway infection cannot be demonstrated, appear to have significantly increased sputum levels of granulocytic inflammatory markers relative to their stable state.

A recently published study by Sethi and colleagues (2) does suggest that COPD exacerbations in which H. influenzae or M. catarrhalis is cultured from sputum are characterized by higher sputum levels of TNF- and neutrophil elastase than COPD exacerbations in which these bacteria are not cultured. This study did not compare sputum markers within individual patients at times of clinical stability relative to times of exacerbation. Therefore the Sethi study presents complementary data that do not conflict with the results of our study. We agree with Dr. Murphy's comments that further studies, using longitudinal assessment of patients, at times of clinical stability and at times of exacerbation, are necessary to elucidate the role of bacteria more precisely in the pathogenesis of COPD exacerbation.

The Ottawa Hospital, Ottawa, Ontario, Canada

1. Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, et al . . Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 349-355 .

2. Sethi S, Muscarella K, Evans N, Klingman KL, Grant BJB, Murphy TF. Airway inflammation and etiology of acute exacerbations of chronic bronchitis. Chest 2000; 118: 1557-1565 .