LONDON—Physicians have known for years that patients with chronic obstructive pulmonary disease (COPD) may have lower airway colonization with Haemophilus influenzae, Streptococcus pneumoniae, or other bacteria. However, what role such pathogens play in COPD exacerbations has been controversial.

“Our data show that these bacteria probably are not just along for the ride,” said Irem S. Patel, MD, in a recent interview. Dr. Patel, a clinical research fellow in respiratory medicine at St. Bartholomew’s Hospital in London, was the lead investigator in a study associating lower airway bacterial colonization in stable COPD patients with more frequent exacerbations, more symptoms, and increased sputum purulence during exacerbations.[1]

In addition, another new study suggests that it may not only be the presence of bacteria in the lower airways that contributes to COPD exacerbations but also the acquisition of new bacterial strains.[2] In that study, a new strain more than doubled the risk of an exacerbation.

“If bacteria do play a role, then it may be right to treat COPD exacerbations with antibiotics, as many practitioners do,” remarked lead study author Sanjay Sethi, MD. “We will need more research on these bacteria to develop other treatments for them, such as vaccines,” added Dr. Sethi, Associate Professor of Pulmonary and Critical Care Medicine at the State University of New York in Buffalo.

ANALYSIS OF DIARY CARDS

For Dr. Patel’s study, 29 patients with moderate to severe stable COPD used diary cards for 18 months to record their indoor peak flows and presence of or increases in dyspnea, sputum purulence, wheeze, or other symptoms. While clinically stable, they provided sputum samples for baseline bacterial culture and measurement of interleukin 6 (IL-6) and IL-8.

The patients, whose mean age was 66, had a mean forced expiratory volume in one second (FEV1) of 1.06 L—only 38.7% of predicted. Their FEV1:forced vital capacity ratio was 43.7 and their daily inhaled corticosteroid dose averaged 1.20 mg.

Diary card data documented 94 exacerbations during a median follow-up of 529 days; each case was confirmed clinically within 48 hours of onset. The median exacerbation rate was 2.58 episodes per patient annually.

Of the sputum samples, 51.7% were positive for at least one potential pathogen, including H influenzae, Haemophilus parainfluenzae, S pneumoniae, Pseudomonas aeruginosa, and Branhamella catarrhalis. The presence of any possible pathogen multiplied the odds of a COPD exacerbation 6.25 times; it was also associated with a trend toward daily dyspnea that just missed statistical significance (P = .058).

Colonization with H influenzae in particular was associated with increased symptoms and sputum purulence during exacerbations. This pathogen also appeared to increase cough and the amount of time needed to recover peak flow during exacerbations, although these findings did not reach statistical significance.

The sputum level of IL-8, but not of IL-6, was significantly correlated with the total sputum bacterial count. This supports the belief that COPD patients with frequent exacerbations have increased airway inflammation even when clinically stable because of bacterial colonization, the study authors suggested.

In these patients, IL-8 causes neutrophils to transmigrate to the airway epithelium, where they bind to intercellular adhesion molecule 1 (ICAM-1). A rise in tumor necrosis factor alpha (related to bacterial colonization) or increased interferon-gamma levels (due to viral infection) may compound this effect. Both chemokines enhance neutrophil accumulation in the airways by increasing epithelial ICAM-1 expression.

A clearer picture of these mechanisms may change the path of treatment. For example, new drugs could be developed to break the cycle of airway inflammation associated with bacterial colonization of the lower airways.[3]

THE INFLUENCE OF NEW STRAINS

To assess the effect of new bacterial strains on COPD exacerbations, Dr. Sethi and colleagues collected sputum samples from 81 COPD outpatients (mean age, 66.5) monthly and during exacerbations. An exacerbation was defined as a major worsening of at least one COPD symptom or a minor worsening of at least two of those symptoms in the absence of other causes, such as pneumonia, upper respiratory infection, and congestive heart failure.

Bacteria isolated from sputum samples were categorized as new or old based on molecular typing. A new strain was one that had not been isolated previously from a patient’s sputum.

The patients made 1,975 clinic visits to provide sputum samples within 56 months. Of the visits, 374 occurred during COPD exacerbations, for a mean exacerbation rate of 2.1 per patient annually.

Analysis of the association between bacterial colonization and exacerbations was derived from only 1,827 visits because of either incomplete data or failure to obtain a sputum sample. Bacterial pathogens were isolated from 33% of the samples; the relative risk (RR) of an exacerbation among patients with these pathogens was 1.44 (95% confidence interval [CI], 1.24 to 1.68).

Dr. Sethi and colleagues were able to analyze the relationship between strain acquisition and COPD exacerbations in 1,655 of the clinic visits, 302 of which occurred during exacerbations. Eighty-nine of the 270 visits (33%) in which a new strain was isolated involved an exacerbation, compared with only 213 of 1,385 visits (15.4%) in which no new strain was isolated.

The overall RR of exacerbations among patients with a new bacterial strain was 2.15 (95% CI, 1.83 to 2.53). For those with a new strain of H influenzae, Moraxella catarrhalis, or S pneumoniae, the RRs were 1.69 (95% CI, 1.37 to 2.09), 2.96 (95% CI, 2.39 to 3.67), and 1.77 (95% CI, 1.14 to 2.75), respectively. The results for H influenzae particularly highlight the need for strain analysis in COPD because only new strains of that pathogen raised the exacerbation risk, the investigators pointed out.

Should the study findings change clinical practice? Probably not, asserts Nicholas R. Anthonisen, MD, PhD.[4] The findings support the current empirical use of antibiotics to treat COPD exacerbations, explains Dr. Anthonisen, Professor of Internal Medicine at the University of Manitoba in Winnipeg. “The [Sethi] study does, however, point to a major gap in our knowledge—namely, which antibiotics should be used,” he acknowledges.

—Timothy Begany