Correspondence
Chronic Obstructive Pulmonary Disease
N Engl J Med 2000; 343:1969-1971December 28, 2000
- Article
To the Editor:
In his otherwise excellent review (July 27 issue),1 Dr. Barnes did not adequately address the role of bacterial infection in the pathogenesis and clinical course of chronic obstructive pulmonary disease (COPD). Four studies have demonstrated the presence of substantial concentrations of potential respiratory bacterial pathogens in distal airway secretions in samples obtained through a bronchoscope in approximately half of all patients during an acute exacerbation.2 Immunologic studies using homologous strains and immunoassays specific for surface-exposed epitopes have demonstrated the development of specific antibodies to bacterial pathogens that were isolated during an acute exacerbation.2 We have recently demonstrated that neutrophilic airway inflammation is greater during exacerbations associated with the isolation of bacteria from sputum cultures than during exacerbations in which the sputum cultures are sterile.3 These investigations, which Barnes did not include in his review, support the role of bacteria as a cause in 50 percent of acute exacerbations, making them the most common cause.
Barnes infers that because treatment with antibiotics during acute exacerbations had only a small benefit in placebo-controlled trials, a bacterial cause of exacerbations of COPD is unlikely. Alternative explanations need to be considered. In these trials, the usual end point was the resolution of symptoms at two to three weeks. Since the predominant benefit of antibiotics in an acute exacerbation is to hasten the resolution of symptoms and prevent complications, many of these trials did not adequately measure these effects.
Though the precise role of bacterial infection in COPD is not understood, ignoring bacterial infection as a mere epiphenomenon in this disease is not appropriate. We think that, given the availability of modern investigative tools, a more vigorous exploration of the role of bacterial infection is required and may produce surprising results.
3 ReferencesSanjay Sethi, M.D.
Timothy F. Murphy, M.D.
State University of New York at Buffalo, Buffalo, NY 142151
Barnes PJ . Chronic obstructive pulmonary disease. N Engl J Med 2000;343:269-280
Full Text | Web of Science | Medline2
Sethi S . Infectious etiology of acute exacerbations of chronic bronchitis. Chest 2000;117:380S-385S
CrossRef | Web of Science | Medline3
Sethi S, Muscarella K, Evans N, Klingman KL, Grant BJB, Murphy TF. Airway inflammation and etiology of acute exacerbations of chronic bronchitis. Chest (in press).
To the Editor:
Barnes's excellent review of COPD omitted mention of important secondary prevention measures. Influenza vaccination and pneumococcal vaccination are recommended by the Advisory Committee on Immunization Practices for persons with COPD.1,2 Such vaccinations can yield substantial health benefits to persons at high risk, such as those with chronic lung disease, while also saving money. In a cohort study of 1898 elderly persons with chronic lung disease, for example, influenza vaccinations over a period of three influenza seasons were associated with a 52 percent reduction in the rate of hospitalization because of pneumonia or influenza (95 percent confidence interval, 18 to 72 percent) and a 70 percent reduction in the rate of death (95 percent confidence interval, 57 to 79 percent). Influenza vaccination was also associated with a reduction in the number of outpatient visits.3 In addition, pneumococcal vaccination of elderly people was associated with a reduction of 43 percent in the rate of hospitalization because of pneumonia (95 percent confidence interval, 16 to 62 percent) and a reduction of 29 percent in the rate of death (95 percent confidence interval, 9 to 44 percent).4 In a serotype-prevalence study that was based on data from a program of national surveillance for pneumococcal disease by the Centers for Disease Control and Prevention, pneumococcal vaccination was shown to reduce the incidence of invasive pneumococcal disease among persons with chronic pulmonary disease.2 Finally, both types of vaccination have been found to reduce costs.4,5
(Within the past 18 months I have received research funding from Aventis Pasteur and Aviron.)
5 ReferencesKristin L. Nichol, M.D., M.P.H.
Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 554171
Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP)
Medline2
Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997;46(RR-8):1-24
3
Nichol KL ,Baken L ,Nelson A . Relation between influenza vaccination and outpatient visits, hospitalization, and mortality in elderly persons with chronic lung disease. Ann Intern Med 1999;130:397-403
Web of Science | Medline4
Nichol KL ,Baken L ,Wuorenma J ,Nelson A . The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease. Arch Intern Med 1999;159:2437-2442
CrossRef | Web of Science | Medline5
Nichol KL ,Wuorenma J ,Von Sternberg T . Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens. Arch Intern Med 1998;158:1769-1776
CrossRef | Web of Science | Medline
To the Editor:
We do not agree with Barnes's assertion that recent studies have demonstrated that long-term oxygen therapy does not increase survival among patients with chronic obstructive pulmonary disease and hypoxemia. Two landmark studies, the Nocturnal Oxygen Therapy Trial1 and the British Medical Research Council study,2 found impressive reductions in the relative risks of death (relative risk, 0.52 and 0.67, respectively) with the use of supplemental oxygen in patients with partial pressures of arterial oxygen of less than 55 mm Hg. The more recent trial, by Gorecka et al., that was cited by Barnes included 135 patients with partial pressures of arterial oxygen between 56 and 65 mm Hg.3 Although these investigators did not observe even a trend toward a reduction in mortality in the oxygen-treated group, they also did not demonstrate that oxygen does not increase survival in such patients.
According to the method of Collett,4 it can be calculated that the study by Gorecka et al.3 had a power of 80 percent, with a two-tailed alpha of 0.05, to detect a hazard ratio for death of 0.44 in the oxygen-treated group. This ratio is lower than that reported in the previous studies1,2 and excessively optimistic, given that the cohort of patients had less severe hypoxemia than those in the earlier studies. The most optimistic, yet still plausible, assumption is that the effect would be equivalent to that in previous studies. This can be approximated by the use of a hazard ratio of 0.6, the average of the results from the previous studies. Using the death rate reported by Gorecka et al.,3 we calculated that 234 patients would have been required for the study to have the power to detect such an effect with a power of 80 percent and a two-tailed alpha of 0.05. Repeating this calculation with more realistic hazard ratios of 0.7 to 0.9 yields required sample sizes as large as 5500 patients.
Although it is true that supplemental oxygen has not been proved to improve outcomes in patients with COPD who have mild hypoxemia, a lack of efficacy has not been conclusively demonstrated. We should not be too hasty in discarding the notion that the only clearly proven lifesaving intervention for patients with stable COPD may also be helpful in those with less severe disease.
4 ReferencesTheodore K. Marras, M.D.
L. Constance Marras, M.D.
University of Toronto, Toronto, ON M5G 2C4, Canada1
Nocturnal Oxygen Therapy Trial Group
Web of Science | Medline2
Medical Research Council Working Party
Web of Science | Medline3
Gorecka D ,Gorzelak K ,Sliwinski P ,Tobiasz M ,Zielinski J . Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia. Thorax 1997;52:674-679
CrossRef | Web of Science | Medline4
Collett D. Modelling survival data in medical research. London: Chapman & Hall, 1994.
Author/Editor Response
Dr. Barnes replies:
To the Editor: I agree with Drs. Sethi and Murphy about the importance of bacterial infections in exacerbations of COPD, although the proportion of exacerbations that is due to bacterial infections is not certain; I was not able to cite their articles, which had not yet been published. A recent study correlated the bacterial-colony count in sputum samples from patients with COPD with the intensity of inflammation, indicating the potential importance of bacterial colonization.1 However, it has not been clearly shown that the colony counts increase during exacerbations. In one study, approximately half the patients with exacerbations had significant growth of bacteria in sputum cultures, and this finding was more likely in patients with severe obstruction.2 However, it is also important to recognize the role of upper respiratory viral infections, particularly rhinovirus,3 and of noninfectious causes of exacerbations of COPD and to develop techniques that can discriminate among the various causes so that antibiotics can be used more selectively in the future. It is likely that there is an interaction between viral and bacterial infections, and this possibility deserves further study. Unfortunately, prophylactic antibiotics are not beneficial in patients with COPD, and broad-spectrum antibiotics appear to have relatively little clinical benefit in patients with acute exacerbations.
Influenza and pneumococcal vaccinations are important preventive measures in patients with COPD and are routinely given in many countries, although the evidence that vaccination is effective in these patients has only recently become available. I thank Dr. Nichol for providing the relevant supporting references, which also highlight the health care–related savings associated with the use of these vaccines.
In my review I emphasized the benefits of long-term oxygen therapy in patients with COPD who have severe hypoxemia (defined as a partial pressure of arterial oxygen of less than 55 mm Hg), but I also questioned whether this finding can be extrapolated to patients with less severe hypoxemia. I agree with Drs. Marras and Marras that the study by Gorecka et al. of patients with partial pressures of oxygen in the range of 56 to 65 mm Hg4 may not have had adequate statistical power to determine whether supplemental oxygen reduces mortality, since mortality is already low in this group of patients. Supplemental oxygen is often recommended for patients with partial pressures of oxygen in the range of 56 to 60 mm Hg if they also have evidence of pulmonary hypertension and polycythemia, although there is no evidence that this approach is beneficial — a finding confirmed by a recent systematic review.5 Patients with COPD who had arterial oxygen tensions in the range of 56 to 69 mm Hg did not benefit from nocturnal supplemental oxygen in terms of reductions in pulmonary hypertension or increases in survival.6 Since supplemental oxygen is an expensive treatment that is currently widely used, larger trials should be conducted to determine whether it provides any benefit in patients with COPD who have moderate hypoxemia.
6 ReferencesPeter J. Barnes, D.M., F.R.C.P.
National Heart and Lung Institute, London SW3 6LY, United Kingdom1
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
CrossRef | Web of Science | Medline2
Miravitlles M ,Espinosa C ,Fernandez-Laso E ,Martos JA ,Maldonado JA ,Gallego M . Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Chest 1999;116:40-46
CrossRef | Web of Science | Medline3
Seemungal T ,Harper-Owen R ,Bhowmik A ,Jeffries DJ ,Wedzicha JA . Detection of rhinoviruses in induced sputum at exacerbations of chronic obstructive pulmonary disease. Eur Respir J 2000;16:677-683
CrossRef | Web of Science | Medline4
Gorecka D ,Gorzelak K ,Sliwinski P ,Tobiasz M ,Zielinski J . Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia. Thorax 1997;52:674-679
CrossRef | Web of Science | Medline5
Crockett AJ ,Cranston JM ,Moss JR ,Alpers JH . Domicilary oxygen for COPD (Cochrane Review). Cochrane Database Syst Rev 2000;4:CD001744-CD001744
Medline6
Chaouat A ,Weitzenblum E ,Kessler R , et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J 1999;14:1002-1008
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Yuxian Huang, Fumi Mikami, Hirofumi Jono, Wenhong Zhang, Xinhua Weng, Tomoaki Koga, Haidong Xu, Chen Yan, Hirofumi Kai, Jian-Dong Li. (2007) Opposing roles of PAK2 and PAK4 in synergistic induction of MUC5AC mucin by bacterium NTHi and EGF. Biochemical and Biophysical Research Communications 359:3, 691-696
CrossRef2
Ran Chen, Jae Hyang Lim, Hirofumi Jono, Xin-Xing Gu, Young S. Kim, Carol B. Basbaum, Timothy F. Murphy, Jian-Dong Li. (2004) Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2–TAK1-dependent p38 MAPK-AP1 and IKKβ-IκBα-NF-κB signaling pathways. Biochemical and Biophysical Research Communications 324:3, 1087-1094
CrossRef3
Sanjay Sethi, Thomas M. File. (2004) Managing patients with recurrent acute exacerbations of chronic bronchitis: a common clinical problem. Current Medical Research and Opinion 20:10, 1511-1521
CrossRef
