Are Colonial Haemophilus influenzae Responsible for Exacerbations of Chronic Obstructive Pulmonary Disease After All?/From the Authors

To the Editor:

The study by Murphy and colleagues (1) reignites the debate on whether colonizing bacteria are to blame for periods of exacerbations in patients with chronic obstructive pulmonary disease. The authors speculate that the presence of Haemophilus influenzae in the respiratory tract, even in the setting of a negative sputum culture, raises the question of whether bacteria cause a greater proportion of exacerbations than is revealed by sputum culture. However, one could argue to the contrary. If the same strains of H. influenzae are continuously present in the airway, why should the colonial bacteria be responsible for exacerbations after all? Current data are contradictory. Although Sethi and colleagues (2), together with Patel and colleagues (3), have demonstrated that exacerbations are related to acquisition of new strains and colonization of H. influenzae, Bresser and colleagues (4) have shown otherwise.

Murphy and colleagues also mentioned that a patient with clinical evidence of an exacerbation with a negative sputum culture would cause most clinicians to conclude that the exacerbation had a nonbacterial etiology. We would like to refute this comment, because clinicians do not merely base their judgement on sputum culture alone in deciding whether an exacerbation is infective or noninfective in nature. Other factors are taken into account, such as radiologic findings, inflammatory markers, and the presence or absence of pyrexia, together with color and consistency of sputum. Finally, and most importantly, the findings of Murphy and colleagues (1) highlight a potentially serious flaw in previous studies in which negative sputum cultures have been taken to indicate the absence of bacteria. Conversely, these may have simply represented periods of negative sputum culture in persistently colonized individuals.

Conflict of Interest Statement: D.K.C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; K.C.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; A.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; G.P.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter.

DANIEL K. C. LEE

Ipswich Hospital

Ipswich, United Kingdom

KEAN C. KHOO

Llandough Hospital

Penarth, Wales, United Kingdom

AHILANANDAN DUSHIANTHAN

Gloucestershire Royal Hospital

Gloucester, United Kingdom

GRAEME P. CURRIE

Aberdeen Royal Infirmary

Aberdeen, Scotland, United Kingdom

References

1. Murphy TF, Brauer AL, Schiffmacher AT, Sethi S. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170:266-272.

2. Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347:465-471.

3. Patel IS, Seemungal TA, Wilks M, Lloyd-Owen SJ, Donaldson GC, Wedzicha JA. Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations. Thorax 2002; 57:759-764.

4. Bresser P, van Alphen L, Lutter R. New strains of bacteria and exacerbations of COPD. N Engl J Med 2002;347:2077-2079.

From the Authors:

The more we learn more about the dynamics of colonization and infection of the respiratory tract in adults with chronic obstructive pulmonary disease (COPD) by Haemophilus influenzae, the more complex the story becomes. When a new strain acquisition of H. influenzae occurs, multiple outcomes are possible, including the presence or absence of clinical symptoms of exacerbation (1), the presence or absence of mucosal and systemic antibody responses (2), the presence or absence of T-cell responses (3), rapid clearance of the organism, persistent colonization (4, 5), and combinations of these scenarios. Indeed, the process of new strain acquisition and persistent colonization coexist in these patients. Our prospective data indicate that a primary mechanism of bacterial exacerbation is acquisition of a new strain (1). Our current study (4) establishes that patients may be persistently colonized by H. influenzae despite negative sputum cultures. Thus, we agree with Dr. Lee and colleagues that studies which rely on sputum cultures to indicate absence of H. influenzae must be interpreted with caution.

The interesting observations of Bresser and colleagues (6) are derived from a selected group of 19 patients who were heavily colonized by H. influenzae. The frequency of positive cultures for H. influenzae in their patients was 74%, whereas the frequency of positive cultures for H. influenzae in our unselected patients with COPD was 21%. We observed a similar subgroup of patients with high levels of colonization and infection within our study population as well. These observations emphasize the heterogeneity of patients with COPD with regard to the role of bacteria in the disease.

We fully agree with Dr. Lee and colleagues that the result of a sputum culture alone does not reliably identify the etiology of an exacerbation. However, the reality is that a negative sputum culture would cause most clinicians to conclude that the exacerbation was not bacterial in etiology.

The observation that H. influenzae persistently colonizes the respiratory tract has important implications beyond a consideration of the etiology of exacerbations. It will be most interesting to assess the effect of persistent colonization on airway inflammation, on daily symptoms of COPD, and on the susceptibility of superimposed infection by viruses and other bacteria. Such studies will help to elucidate more subtle but potentially important effects of H. influenzae colonization on the course and pathogenesis of COPD.

Conflict of Interest Statement: T.F.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter.

TIMOTHY F. MURPHY

SANJAY SETHI

University at Buffalo, State University of New York

Buffalo, New York

References

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.

2. Sethi J, Wrona C, Grant BJB, Murphy TF. Strain-specific immune response to Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;169:448-453.

3. Abe Y, Murphy TF, Sethi S, Faden HS, Dmochowski J, Harabuchi Y, Thanavala YM. Lymphocyte proliferative response to P6 of Haemophilus influenzae is associated with relative protection from exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;165:967-971.

4. Murphy TF, Bruer AL, Schiffmacher AT, Sethi S. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170:266-272.

5. Bresser P, Out TA, van Alphen L, Jansen M, 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.

6. Bresser P, van Alphen L, Lutter R. New strains of bacteria and exacerbations of COPD. N Engl J Med 2002;347:2077-2079.

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