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Turkish Respiratory Journal
April 2005, Volume 6, Number 1, Page(s) 022-027
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The Role of Atypical Bacteria in Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Özen Kaçmaz Başoğlu, MD1; Ayça Arzu Sayıner, MD2; Ayşın Zeytinoğlu, MD2; Abdullah Sayıner, MD1
1Department of Chest Diseases, Ege University Faculty of Medicine, Izmir, Turkey 2Department of Microbiology, Ege University Faculty of Medicine, Izmir, Turkey
Keywords: chronic obstructive pulmonary disease, antibiotics, Mycoplasma pneumoniae, Chlamydia pneumoniae, acute bacterial exacerbation
Summary
Objectives: To determine the prevalence of Chlamydia and Mycoplasma infections in outpatients with acute exacerbations of chronic obstructive pulmonary disease (COPD) and to compare the efficacy of amoxicillin-clavulanic acid vs clarithromycin in order to observe whether these atypical bacterial infections alter the course of the disease. Methods: Fifty consecutive patients with COPD exacerbations (mean age 64.1±8.8 yrs, 46 males, FEV1 47.7±16.5%) were randomised to receive either oral clarithromycin or oral amoxicillin-clavulanic acid. Gram stain and bacteriologic culture of the sputum were done and paired serum samples were obtained for serological studies. Results: Thirteen patients were (26%) found to have serologic evidence of acute C. pneumoniae (7 patients) or M. pneumoniae (6 patients) infection. There was no difference between patients with Chlamydia and Mycoplasma infection and the others with regard to age, gender, concomitant disease, duration and severity of COPD and symptoms. Six of 13 (46%) patients with atypical bacterial infections vs 8 (22%) of 37 patients without such infections had another bacteria isolated from sputum (p<0.01). Six patients with atypical infections received clarithromycin and all were cured or improved; the remaining 7 patients received amoxicillin-clavulanic acid and there was one failure. The treatment success was similar in the overall patient population. Similar recurrence rates were observed in patients with and without evidence of atypical bacterial infection during the 6-month follow-up. The recurrence rate was also independent of the antibiotic given. Conclusions: We conclude that, although frequently detected, acute infections due to Chlamydia and Mycoplasma do not alter the course and outcome of COPD exacerbations.	Top Summary Introduction Methods Results Disscussion References
Introduction
Bacterial infections are the causative events in nearly half of exacerbations of chronic obstructive pulmonary disease (COPD); the other half is believed to be due to viral infections, inhalation of environmental irritants and other causes [1]. Several studies have shown that there are three bacteria which are responsible for the majority of infective exacerbations; namely, Hemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis [2,3]. Recent studies which investigated the role of atypical bacteria have provided serologic evidence that exacerbations were associated with Mycoplasma pneumoniae infection in 1-4% and with Chlamydia pneumoniae infection in 4-22% of the patients [4-7]. Co-infection with other pathogenic bacteria is documented by sputum culture in a significant part of these patients, and thus, the significance of the atypical bacteria in the pathogenesis and outcome of COPD exacerbations is questioned [8,9]. It has been reported that Chlamydia infection may lead to prolonged exacerbations of asthma and that these are relieved with appropriate antibiotic treatment [10,11]. Subsequent controlled studies, however, have not found any significant association between serologic evidence of Chlamydia infection and asthma [12,13]. The role of chronic Chlamydia infection in the development of COPD is being investigated and debated [14,15]. It has been demonstrated that lung cells and macrophages of COPD patients are more frequently infected with C. pneumoniae [16]; however, there is no firm data yet as to the significance of this microorganism in stable disease and exacerbations. Determination of the role of these atypical bacteria in COPD exacerbations is of particular importance for the practicing physicians, as the antimicrobial treatment is frequently empirical. The aims of this study were, firstly, to determine the frequency of infections due to M. pneumoniae and C. Pneumoniae in COPD exacerbations, as detected serologically and secondly, to examine whether infections with these bacteria are associated with any particular clinical feature. The patients were also randomised to receive either clarithromycin or amoxicillin-clavulanic acid so as to find out whether treatment covering atypical agents would have any significant effect on the course and outcome of the exacerbations.	Top Summary Introduction Methods Results Disscussion References
Methods
Study population Fifty consecutive patients with COPD presenting to the outpatient clinic and diagnosed according to the American Thoracic Society definitions [17], were included in the study. The inclusion criteria were age older than 40 years, presence of a smoking history of more than 10 pack-years and having the signs and symptoms of an exacerbation, possibly of an infectious origin. An exacerbation was defined as an acute episode of worsening respiratory symptoms with at least two of the following: increased shortness of breath, increased sputum volume, and purulent sputum. Patients were excluded if they had pneumonia and/or respiratory failure and/or cor pulmonale necessitating hospitalization and treatment with parenteral antibiotics. All patients gave written informed consent. Initial assessment and treatment Upon inclusion to the study, a detailed initial examination was done and the age, duration of COPD, smoking history, presence of co-morbidities, and duration of symptoms were recorded. Apart from the physical examination, a chest x-ray was obtained; complete blood count and a pulmonary function test (using a water-sealed spirometer, Sensormedics 2400, USA) were performed. The patients were randomized to receive either oral clarithromycin, 500 mg b.i.d. or oral amoxicillin-clavulanic acid, 625 mg t.i.d., both for ten days. The randomization list and sealed envelopes were prepared prior to the initiation of the study and consecutive envelopes were opened with the inclusion of new patients so as to determine the study medication. All patients received appropriate bronchodilator therapy including inhaled â2 agonists, ipratropium bromide and oral theophylline; but none were initially given systemic glucocorticoids. Microbiologic examinations Gram stain and bacteriologic culture of the sputum were done in all patients who could produce sputum of adequate quality. Cultures were made from Gram stained sputum samples which revealed more than 25 leukocytes and less than 10 epithelial cells per low-power field. Paired serum samples were obtained in all patients, one at inclusion in the study and the other during the convalescent period (at 28-35 days of treatment), for serologic studies. Microimmunofluorescence (MIF) method was used to detect antibodies of IgG, IgA and IgM type to Chlamydia pneumoniae (MRL Diagnostics, USA) and indirect fluorescent antibody test for IgG and IgM antibodies to Mycoplasma pneumoniae (Zeus Scientific, USA). The physicians treating and following the patients (OKB and AS) remained uninformed about the serology results until after the study ended. Interpretation of serology results [18]: A. C. pneumoniae infection: 1. No evidence of infection: All antibodies negative in both samples. 2. Acute infection: IgM positive and/or four-fold rise in IgG titer. An IgG titer equal to or higher than 1/512 was interpreted as possible acute infection. 3. Past infection: IgG positivity of <1/512 with no significant increase. B. M. pneumoniae infection: 1. No evidence of infection: All antibodies negative. 2. Acute infection: IgM positive and/or four-fold rise in IgG titer. 3. Past infection: IgG positivity of <1/512 with no significant increase. Follow-up The patients were followed up on three occasions. The first was a telephone call made on day 15, when the patients were questioned with regard to their symptoms. They were asked to present to the outpatient clinic if they had not improved clinically. The second was about a month from the first visit (days 28-35), when the patients were re-assessed at the outpatient clinic. At this visit their symptoms were scored, a sputum sample was collected for bacteriologic examination, a serum sample was obtained for serology, a chest xray was performed and they were questioned for adverse events. According to the evolution of symptoms and clinical findings, the outcome of the exacerbation was evaluated as “cure”, “improvement” or “failure”. Cure was defined as resolution of signs and symptoms related to the acute exacerbation; improvement, as incomplete resolution of symptoms but improvement in other clinical findings; and failure as the lack of resolution of any of the initial signs and symptoms. All patients were advised to contact and/or present to the outpatient clinic if they experienced a worsening of symptoms or any adverse events. Any such contact was recorded in the patients’ files. The final assessment was done by telephone contact again at six months to account for any exacerbation which might have not been reported. Statistical analysis The primary end point was the clinical response of the patients with acute Mycoplasma pneumoniae and/or Chlamydia pneumoniae infection to the two antibiotic regimens. The secondary end points were the rates and clinical features of acute infections due to Mycoplasma and Chlamydia in COPD. Thus, comparisons were made between the findings of the patients with and without atypical examinations, and of the responses of the patients with atypical infections to beta-lactam and macrolide treatments. Statistical analysis was done using Student’s t-test for parametric variables. Analysis of categorical variables was done using Chi-Square Test and Fisher’s Exact Test. A value of p<0.05 was considered significant for all statistical analysis. All data were expressed as means ± standard deviations (SD).	Top Summary Introduction Methods Results Disscussion References
Results
Demographic findings Fifty patients (mean age 64.1±8.8 yrs, 46 males) with a COPD exacerbation not necessitating hospitalization were included in the study. The mean smoking history was 44.8±27.6 pack-years and the duration of COPD was 16.1±13.3 years. The disease was of Stage 1 in 19 patients (38%), of Stage 2 in 18 (36%) and of Stage 3 in 13 patients (26%). Twenty-five patients had a concomitant disease; namely, ischemic heart disease in 15 (30%), hypertension in six (12%), and diabetes mellitus, chronic hepatitis and cerebrovascular disease in one patient each (Table 1). Click to Enlarge Table 1: Demographic features of the patients Microbiologic findings Bacteriologic examinations revealed a pathogen in 14 (28%) of the patients: Haemophilus influenzae in eight; Streptococcus pneumoniae, Moraxella catarrhalis and Pseudomonas aeruginosa in two patients each. The results of serologic studies are shown in Figure 1. In short, seven (14%) and six (12%) of the patients were found to have evidence of acute infection due to C. pneumoniae and M. pneumoniae, respectively. The number of cases with acute C. pneumoniae infection rises to 13 (26%) if a single high titre (>1/512) of IgG for C. Pneumoniae is included in the diagnostic criteria, indicating possible acute infection. Of the pathogenic bacteria isolated in bacteriologic cultures, six were found in patients with evidence of atypical bacterial infection (6/13, 46%) and eight in the remaining patients (8/37, 22%) (p<0.01). Click to Enlarge Figure 1: Serology results of the study population. The serologic evidence of acute C. pneumoniae and M. pneumoniae infection was demonstrated in 13 patients (26%). There was no difference between patients with and without evidence of atypical bacterial infection with regard to age, gender, smoking history, duration and stage of COPD, presence of comorbidity, duration and severity of respiratory symptoms, and leukocyte count (Table 2). Click to Enlarge Table 2: Characteristics of the patients with and without evidence of atypical bacterial infection Antibiotic treatment Twenty-five patients were randomized to receive clarithromycin and another 25 were treated with amoxicillin-clavulanic acid. Three patients (two in amoxicillin-clavulanic acid group, one in clarithromycin group) came back to the outpatient clinic on days 3, 5, and 8 of treatment because of lack of improvement in their symptoms. In two of these, Pseudomonas aeruginosa was found to have grown in the sputum culture, both patients were hospitalized, appropriate change was made in their antibiotic treatment and were thus considered to be treatment failures. Oral glucocorticoid treatment had to be started in the third patient, after which he improved. On the telephone contact at two weeks, two other patients in the clarithromycin group and two in the amoxicillinclavulanic acid group reported that they still had breathlessness and necessary adjustments were made in their bronchodilator doses without any additional treatment. All the remaining patients were assessed at the visit on day 30 (days 28-35). Of the 13 patients with evidence of Chlamydia and Mycoplasma infection, six were found to have been randomized to clarithromycin treatment. At the one-month follow-up visit, four (67%) were cured and the remaining two had improvement of symptoms. The remaining seven patients with atypical infection had been given amoxicillin-clavulanic acid, of whom four (57%) were cured, two (29%) improved and one had treatment failure. The patient who failed had no other bacteria isolated at sputum culture. Overall, there was no difference as to the clinical efficacy of the two study drugs. Besides, outcome was similar in patients with and without evidence of atypical infection (Figure 2). Similar results were obtained in patients with possible acute C. pneumoniae infection who were also included in the study group. Click to Enlarge Figure 2: Outcome in patients with atypical infection (n=13) and patients without atypical infection (n=37) according to the antibiotic treatment. The outcome was similar in both groups (p>0.05). Follow-up All patients except for six (five treated with clarithromycin and one with amoxicillin-clavulanic acid) were followed for six months. During the follow-up period, out of the 20 patients who had received clarithromycin, 11 (55%) had one, two (10%) had two, and one had three exacerbations. Of the 24 patients receiving amoxicillin-clavulanic acid, 15 (62.5%) had one and three (12.5%) had two exacerbations. The difference between the two treatment groups with regard to recurrent exacerbations was not significant. Similar recurrence rates were also noted in patients with Chlamydia and Mycoplasma infections (15 recurrences in 11 of 12 patients) and in those without such infections (24 recurrences in 21 of 32 patients) (p>0.05).	Top Summary Introduction Methods Results Disscussion References
Discussion
The results of this study confirmed the previous reports on the high prevalence of Chlamydia and Mycoplasma infections in COPD exacerbations, as detected serologically. The most important finding, however, was that these bacteria did not play any significant role in the clinical course of the disease, in that evidence of acute infection was not associated with any difference in the clinical presentation or course of the exacerbation, nor was it associated with a worse outcome or more frequent recurrences. Moreover, macrolide treatment did not have any effect superior to that of amoxicillin-clavulanic acid, which has no activity against atypical pathogens. The fact that specific antimicrobial therapy directed against atypical pathogens does not confer any significant advantage on the clinical outcome is important from the practicing physician’s standpoint. Antibiotic treatment is recommended for exacerbations with at least two of three cardinal symptoms: increased shortness of breath, increased sputum volume and purulent sputum [19] and the choice of antibiotics are mostly empirical. Several recent studies have suggested that exacerbations are caused by different bacteria in patients with different degrees of severity of airflow obstruction [20,21]. The choice of antibiotics based on the severity of functional impairment, and thus, on the spectrum of bacteria that are prevalent in related subsets of patients is reported to result in improved outcomes [22,23]. Recent studies which found high prevalence of infection with atypical pathogens in COPD [5,6,24] suggested that these bacteria be taken into account when the treatment is planned. The significance of these serologically documented infections, however, has been unclear and there is no data on whether they have an impact on the course of the disease. In fact, there is evidence from studies on community-acquired pneumonia and acute bronchitis that similar clinical response rates were achieved in patients with positive Chlamydia serology, who were treated with macrolides or quinolones and those who were given beta-lactam antibiotics [25,26]. Moreover, bacteriologic eradication of C. pneumoniae was reported following azithromycin as well as amoxicillin-clavulanic acid therapy [27]. To our knowledge, this study is the first one to investigate the clinical significance of the atypical bacteria in COPD exacerbations. The prevalence of serologically documented acute infections due to Chlamydia and Mycoplasma were 14% and 12%, respectively, rates similar to those previously reported from Turkey [6,24]. These infections, however, had no impact on the clinical presentation and outcome of the exacerbations, were not associated with a protracted course or increase in recurrence rates and antibiotic coverage of these bacteria did not change the clinical response; all of which argue against any significant role. Interestingly, on the other hand, there was a significant trend for more frequent isolation of other pyogenic bacteria from patients infected with these pathogens; an observation already reported in several studies [15,24,26]. They may, therefore, enable other pathogens to cause bronchial infection, for which, one possible mechanism is reduction in ciliary motility [28]. Another recent study also provided important information on the significance of C. pneumoniae infection in stable COPD patients. Strachan et al [14] screened patients with obstructive airway disease for serologic evidence of C. Pneumoniae infection (IgG and IgA positivity) and then followed them up for a period of five years. No association was found between C. pneumoniae antibody titres and lung function decline, subsequent need for bronchodilator treatment and mortality. Blasi et al [15], on the other hand, found a higher frequency of exacerbations in patients with chronic C. pneumoniae infection (as assessed by polymerase chain reaction on peripheral blood monocytes) who were longitudinally followed; but the data was not controlled for FEV1 levels. Thus, the significance of the finding is not very clear, as the frequency of exacerbations has also been shown to be related with the degree of functional impairment [29]. Besides, no data was provided, regarding the etiology, treatment and outcome of the exacerbations. One limitation of this study could be the relative insensitivity of the serologic methods used for detecting evidence of acute infection due to Mycoplama or Chlamydia. However, serology is the most commonly used tool for the diagnosis of these infections and the microimmunofluorescence test is generally accepted as the gold standard for the serologic detection of C. pneumoniae infection [9,18]. Paired sera were obtained from all patients in this study so as to increase the diagnostic accuracy. Besides, all other techniques also have their own limitations. Cultures of both agents are time-consuming, laborintensive and relatively insensitive. Polymerase chain reaction offers the possibility for improved detection of these agents; however, the method is not standardized and has the disadvantages of false positivity and not being able to distinguish acute infection from a carriage state [18,30]. The study may also be criticized for being open in that the patients and the physicians in charge were not blind to the antibiotic given. This was mainly because there is no independent company in this country which could provide adequately prepared study medications and placebo tablets and also because the investigators were reluctant to receive any support from the pharmaceutical industry. The clinicians in charge of following the patients and collecting the clinical data remained uninformed about serology results, however, so as to minimize any bias with regard to the significance of Mycoplasma and Chlamydia infections, which this study mainly addressed. In conclusion, Chlamydia and Mycoplasma do not appear to be microorganisms directly responsible for acute exacerbations of COPD, and they do not appear to alter the outcome or the course. Thus, antibiotic coverage for these bacteria is not warranted in exacerbations.	Top Summary Introduction Methods Results Discussion References
References
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