Correspondence
New Strains of Bacteria and Exacerbations of COPD
N Engl J Med 2002; 347:2077-2079December 19, 2002
- Article
To the Editor:
I find the choice of denominators by Sethi et al. (Aug. 15 issue)1 curious, in that they compare patients with new strains during exacerbations with stable patients without new strains. This appears to be comparing apples and oranges, particularly given the wide range of base-line characteristics in the study population. For example, the forced expiratory volume in one second (FEV1) at base line ranged from 0.47 liter to 4.07 liters, and the FEV1 as a percentage of the predicted value ranged from 15 percent to 99 percent. Furthermore, over the 56-month study period, the number of patient visits to the clinic ranged from 2 to 65. Therefore, it seems feasible that a healthier population of patients with more stable chronic obstructive pulmonary disease (COPD) was serving as the control group. A more appropriate comparison would have been between patients who had exacerbations with new strains and those who had exacerbations without new strains.
The safest conclusions to be drawn from the study are that new strains occasionally appear in the sputum of patients with COPD both during stable periods (181 instances in the study) and during exacerbations (89 instances), and that new strains may be causally related to exacerbations in a minority of cases. In this carefully conducted longitudinal study that used advanced molecular techniques, it is unfortunate that no attempts were made to identify, characterize, and elucidate the emerging role of viruses in acute exacerbations of chronic bronchitis.2
2 ReferencesAmar Kureishi, M.D.
Am Oberen Werth 27, D-40489 Dusseldorf, Germany
akureishi@hotmail.com 1
Sethi S ,Evans N ,Grant BJB ,Murphy TF . New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347:465-471
Full Text | Web of Science | Medline2
Seemungal T ,Harper-Owen R ,Bhowmik A , et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1618-1623
Web of Science | Medline
To the Editor:
Sethi et al. diagnosed exacerbations of COPD more commonly when certain new bacterial strains appeared in the sputum than when they were absent, suggesting that they caused the attacks. The new strains were unassociated with exacerbations of COPD in most cases (66 percent), so an alternative explanation is that they are not pathogens but, rather, that they more readily colonize inflamed bronchi during exacerbations (precipitated by other causes) than they do the airways of stable patients. The evidence offered by Sethi et al. supporting a strain-specific immune response in exacerbations rests on old, contradictory serologic investigations1 and an unsatisfactory study involving only two patients and no controls.2
The accompanying editorial by Anthonisen3 misinterprets the article's confusing, incomplete tables, thereby exaggerating the frequency of bacterial “pathogens” during exacerbations of COPD. The percentage of samples without these organisms was 62 percent, not 18 percent — a proportion that is consistent with other studies, in which 50 to 70 percent of cultures were negative, whether they were of expectorated or bronchoscopic specimens.1
3 ReferencesJan V. Hirschmann, M.D.
Veterans Affairs Medical Center, Seattle, WA 98108
pepsi@u.washington. edu 1
Hirschmann JV . Do bacteria cause exacerbations of COPD? Chest 2000;118:193-203
CrossRef | Web of Science | Medline2
Yi K ,Sethi S ,Murphy TF . Human immune response to nontypeable Haemophilus influenzae in chronic bronchitis. J Infect Dis 1997;176:1247-1252
CrossRef | Web of Science | Medline3
Anthonisen NR . Bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347:526-527
Full Text | Web of Science | Medline
To the Editor:
In their prospective study with 81 patients with chronic bronchitis, 91 percent of whom had moderate-to-severe airway obstruction, Sethi and colleagues showed an association between exacerbation of the disease and acquisition of new strains of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Recently, we completed a prospective, longitudinal study in which strains of H. influenzae were cultured and analyzed phenotypically and genotypically (with analyses of major outer-membrane proteins1 and random amplified polymorphic DNA2) from 105 of 142 sputum samples (74 percent) collected at four-week intervals for six months from 19 patients with mild-to-moderate chronic obstructive bronchitis and chronic H. influenzae infections. We observed persistence, simultaneous persistence, and reinfection with related and unrelated strains. Forty-four strains with distinct patterns of major outer-membrane proteins were cultured; 22 (50 percent) were newly acquired strains, whereas only 3 of these were associated with an exacerbation. Thus, 86 percent of newly acquired strains were not associated with an exacerbation, whereas 67 percent of exacerbations occurred when no new strain was acquired.
Our findings appear to refute the theory that newly acquired strains of H. influenzae have a causative role in many acute exacerbations of chronic bronchitis, as suggested by Sethi et al. — and, indeed, by us in an earlier study involving patients with chronic bronchitis who were not chronically infected.3 Possibly, the contribution of newly acquired strains to the inflammatory process is obscured by an already marked inflammation of the airway, especially in chronically infected patients with chronic bronchitis,4 and therefore they do not lead to an exacerbation of the disease.
4 ReferencesPaul Bresser, M.D., Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the NetherlandsLoek van Alphen, Ph.D.
National Institute for Public Health and Environment, 3720 BA Bilthoven, the NetherlandsRené Lutter, Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands
r.lutter@amc. uva. nl 1
van Alphen L ,Riemens T ,Poolman J ,Zanen HC . Characteristics of major outer membrane proteins of Haemophilus influenzae. J Bacteriol 1983;155:878-885
Web of Science | Medline2
van Belkum A ,Duim B ,Regelink A ,Moller L ,Quint W ,van Alphen L . Genomic DNA fingerprinting of clinical Haemophilus influenzae isolates by polymerase chain reaction (PCR) amplification: comparison with major outer-membrane protein and restriction fragment length analysis. J Med Microbiol 1994;41:63-68
CrossRef | Web of Science | Medline3
Groeneveld K ,van Alphen L ,Eijk PP ,Visschers G ,Jansen HM ,Zanen 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
CrossRef | Web of Science | Medline4
Bresser P ,Out TA ,van Alphen L ,Jansen HM ,Lutter R . Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic Haemophilus influenzae airway infection: comparison with noninfected patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:947-952
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Kureishi has expressed concern that the patients with new strains during exacerbations are different from patients without new strains. The longitudinal design of our study allowed us to sample the same patients repeatedly. The unit of analysis was not the patient but the clinic visit. Therefore, patients with exacerbations associated with new strains are often the same patients as those who do not have new strains at other visits. Specifically, 88 percent of the patients who had exacerbations associated with new strains also had exacerbations without new strains. Therefore, the severity of the underlying COPD was not a confounding variable in our analysis.
Dr. Hirschmann implies that since new strains were not always associated with exacerbations, alternative explanations need to be considered. Because children and adults continuously acquire and clear strains of H. influenzae and other bacterial pathogens from the respiratory tract, to expect that every acquisition of a new strain will result in an exacerbation is too simplistic. A complex host–pathogen interaction most likely determines the outcome of the acquisition of a new strain by a patient; the determinants include the virulence of the pathogen, the host inflammatory response, preexisting immunity, the perception of symptoms, and others.
We agree with Dr. Hirschmann that definitive conclusions regarding strain-specific immune responses to bacterial pathogens in COPD cannot be drawn on the basis of available published data. Serologic investigations that use laboratory strains, rather than homologous isolates, are not capable of showing strain-specific immune responses, which accounts for the contradictory results of older serologic studies. However, a growing number of studies that use the homologous infecting isolates have demonstrated strain-specific immune responses in animal models, adults with COPD, and children with otitis media.1-5 We are currently analyzing the results of immunoassays using homologous isolates from the patients from our longitudinal study.
The interesting observations of Bresser et al. appear to reflect a subgroup of patients with COPD who have chronic H. influenzae infection. The frequency of positive sputum cultures for H. influenzae in their patients was 74 percent, whereas the frequency of positive cultures for H. influenzae in our samples from unselected patients with COPD was 21 percent. Indeed, we have observed a similar subgroup of patients with high levels of colonization and infection within our study population. These observations emphasize the heterogeneity of patients with COPD with regard to the role of bacteria in the course and pathogenesis of disease.
5 ReferencesSanjay Sethi, M.D.
Timothy F. Murphy, M.D.
State University of New York at Buffalo, Buffalo, NY 14215
ssethi@buffalo.edu 1
Groeneveld K ,van Alphen L ,Voorter C ,Eijk PP ,Jansen HM ,Zanen HC . Antigenic drift of Haemophilus influenzae in patients with chronic obstructive pulmonary disease. Infect Immun 1989;57:3038-3044
Web of Science | Medline2
Duim B ,Vogel L ,Puijk W , et al. Fine mapping of outer membrane protein P2 antigenic sites which vary during persistent infection by Haemophilus influenzae. Infect Immun 1996;64:4673-4679
Web of Science | Medline3
Yi K ,Sethi S ,Murphy TF . Human immune response to nontypeable Haemophilus influenzae in chronic bronchitis. J Infect Dis 1997;176:1247-1252
CrossRef | Web of Science | Medline4
Yi K ,Murphy TF . Importance of an immunodominant surface-exposed loop on outer membrane protein P2 of nontypeable Haemophilus influenzae. Infect Immun 1997;65:150-155
Web of Science | Medline5
Faden H ,Bernstein J ,Brodsky L , et al. Otitis media in children. I. The systemic immune response to nontypable Haemophilus influenzae. J Infect Dis 1989;160:999-1004
CrossRef | Web of Science | Medline
Author/Editor Response
The editorialist replies:
To the Editor: Dr. Hirschmann is correct; I did some bad math in analyzing Table 3 of the paper of Sethi et al. In more than 60 percent of sputum samples obtained during exacerbations, no bacterial pathogens were isolated. This fact does not change the findings of Sethi et al. that the risk of an exacerbation was increased when pathogens were isolated and that this risk was further increased when a new strain of bacteria was detected. The correction tends to emphasize the point made in the editorial that bacterial infection is very likely not the only cause of exacerbations.
Nick R. Anthonisen, M.D., Ph.D.
Respiratory Hospital, Winnipeg, MB R3A 1R8, Canada
nanthonisen@exchange.hsc. mb. ca
