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* From the Pneumology Department (Dr. Miravitlles), Hospital Vall d'Hebron, Barcelona, Spain; the RD Department (Dr. Espinosa), QF Bayer, Barcelona, Spain; the Pneumology Department, Hospital Magdalena, Castellon, Spain (Dr. Fernández-Laso); the Pneumology Unit, Hospital San Rafael (Dr. Martos), Barcelona, Spain; the Pneumology Department, Hospital Juan Ramón Jiménez, Huelva, Spain (Dr. Maldonado); and the Pneumology Unit (Dr. Gallego), Hospital Parc Taulí, Sabadell, Barcelona, Spain.
Correspondence to: Marc Miravitlles, MD, Rocafort 173–177, 3°1a, 08015 Barcelona, Spain; e-mail: marcm{at}separ.es
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Abstract |
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Design: Multicenter, cross-sectional, epidemiologic study.
Setting: Pneumology units in six secondary or tertiary hospitals in Spain.
Patients: Ninety-one patients with acute exacerbation of COPD were included.
Interventions: A quantitative sputum culture was performed, and bacterial growth was considered significant only when the germ was isolated at concentrations > 106 cfu (> 105 for Streptococcus pneumoniae) in samples with < 10 epithelial cells and > 25 leukocytes per low magnification field (x100).
Results: Germs isolated were the following: Haemophilus influenzae (20 cases; 22%), Pseudomonas aeruginosa (14 cases; 15%), S pneumoniae (9 cases; 10%), Moraxella catarrhalis (8 cases; 9%), other Gram-negative bacteria (7 cases; 7%), and non-potentially pathogenic microorganisms (non-PPMs; 33 cases; 36%). P aeruginosa and H influenzae were isolated more frequently among the patients with FEV1 < 50% than among those with FEV1 > 50% (p < 0.05). All patients with P aeruginosa in sputum had FEV1 < 1,700 mL. FEV1 < 50% was associated with a very high risk of P aeruginosa or H influenzae isolation: the odds ratios (ORs) are 6.62 (95% confidence interval [CI], 1.2 to 123.6) and 6.85 (95% CI, 1.6 to 52.6), respectively. Furthermore, active tobacco smoking was associated with a high risk of H influenzae isolation (OR, 8.1; 95% CI, 1.9 to 43.0).
Conclusions: Patients with the greatest degree of functional impairment, as measured by their FEV1, presented a higher probability of having an isolation of P aeruginosa or H influenzae in significant concentrations in sputum during an exacerbation. The diagnostic yield of sputum in patients with an FEV1 > 50% was low, with a predominance of non-PPMs. Low FEV1 and active tobacco smoking are data that should be considered when establishing an empiric antibiotic treatment for exacerbated COPD.
Key Words: antibiotics • bacterial resistance • COPD • etiology of exacerbations • exacerbations
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Introduction |
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Exacerbations, mostly of an infectious etiology, are a frequent cause of morbidity in COPD patients. A recent epidemiologic study observed that ambulatory patients with moderate-to-severe COPD suffered an average of two episodes per year, which required medical attention and engendered a widespread prescription of antibiotics.3 Furthermore, infection was the most common observable cause of death in prospectively followed-up COPD patients.4
Antibiotic treatment of COPD exacerbations is generally prescribed on an empiric basis. A European survey found that an analysis of the sputum of exacerbated patients is only requested in 10% of cases.5 The use of more specific, sensitive microbiological techniques is reserved for the hospital scenario in the context of clinical research.6 7 8
Given the importance and empiric nature of this issue, several scientific societies have published standards on the treatment of COPD exacerbations.9 10 11 Nevertheless, a recent survey conducted in several European countries revealed that these standards were barely implemented in the treatment of bronchial infection of COPD, with figures ranging from 4% in Spain to 28% in the United Kingdom.12 Equally noteworthy is the wide variability observed in the antibiotics used in these countries, which cannot be justified only on the basis of their differences in germ resistance patterns.12
In view of the above, it would be useful to define certain easy-to-obtain patient characteristics that might point to the possible etiology of COPD exacerbations, thereby facilitating the orientation of antibiotic treatment and reducing the high number of failures recorded with empiric treatment, which in some cases, is as high as 26%.13
This study focused on investigating whether the degree of functional impairment measured by the FEV1 in a cohort of ambulatory patients can provide an orientation as to the infectious etiology of COPD exacerbations.
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Materials and Methods |
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Study Population
Patients who were > 40 years old, attended one of the
seven participating centers, and had COPD and symptoms of acute
exacerbation were screened for participation. The study was
conducted between October 1996 and May 1997.
The Spanish Society of Pneumology and Thoracic Surgery 1996 definition was used to diagnose COPD11 , whereas the presence of at least two of the three following symptoms defined by Anthonisen et al14 was required to diagnose exacerbations: (1) increase in dyspnea; (2) increase in the production of sputum; and (3) increase in purulence of sputum. At least one sample of sputum that was considered analytically valid as per the criteria described below was required for a patient to be included in the study.
The following were the exclusion criteria: (1) previous diagnosis of bronchial asthma, cystic fibrosis, or bronchiectasis; (2) diagnosis of neoplasia; (3) clinical-radiologic evidence of pneumonia; and (4) any type of antibiotic treatment received over the 5 days prior to sampling the sputum for culture.
At least one sample of spontaneous sputum for microbiological analysis was obtained from all patients. The results of spirometry, performed in most cases within a period of 6 months prior to the exacerbation and in stable phase, were collected. If these data were not available, spirometry was conducted at least 1 month after the acute episode and always in stable phase, according to the criteria of the attending physician.
Microbiological Sputum Study
All patients were ambulatory, and sputum samples were obtained
at the first visit to the out-patient department or in the emergency
department. Samples were collected in a sterile vial and sent within
2 h to a central laboratory with headquarters near each of the
participating centers. All headquarters used the same standard action
protocol.
A Gram's stain of sputum in the area of maximal purulence was examined for polymorphonuclear leukocytes and epithelial cells. The following criteria, based on the criteria of Murray and Washington15 and Heineman et al,16 were applied in order for a sputum sample to be deemed acceptable for analysis: a microbiological study done by using a low-magnification lens (x 100) reveals < 10 epithelial cells and > 25 leukocytes per field. Sputum specimens not fulfilling these criteria (n = 49) were not cultured because they were not considered representative bronchial samples.
In cases with more than one sputum sample analyzed, the following criteria were used (in the order that is listed) to select a sample: quantity of bacterial growth (more was better than less) and quality of sputum (the greater the number of leukocytes and the fewer the number of epithelial cells the better).
Selected sputa were processed microbiologically for quantitative study following accepted laboratory methods.17 Using the microbiological loop, 0.01 mL sputa were seeded in the following culture media: blood agar, MacConkey agar, chocolate agar, and Sabouraud's agar plus chloramphenicol. Incubation was carried out at 35 ± 2°C in aerobic conditions. In the case of the chocolate agar, the atmosphere contained 5 to 7% CO2. A first reading was taken after 24 h, and a second final one was taken after 48 h of culture.
Bacterial agents were classified into potentially pathogenic microorganisms (PPMs) or non-PPMs, as described by Cabello et al.18 An arbitrary cutoff point was chosen to minimize the risk of dealing with contaminants. PPMs were only regarded as significant if they reached a growth of > 106 cfu, except for Streptococcus pneumoniae where growth of > 105 cfu was deemed sufficient. A PPM had to grow in significant concentrations irrespective of the presence of non-PPMs to be considered a potential causative agent of an exacerbation. No cases in which two or more PPMs grew in significant concentrations in a single sputum sample were observed. Similarly, no cases were found in which one PPM was alone but in low concentrations; thus, the presence of PPMs in low concentrations in sputum was always accompanied by other non-PPMs, and these samples were included in the group of non-PPMs of scant diagnostic value.
The sensitivity of bacteria identified as PPMs to antimicrobial agents was studied by the minimum inhibitory concentrations technique. Classifications as sensitive, intermediate, and resistant were made according to the criteria issued by the National Committee for Clinical Laboratory Standards.19 Antibiotics tested were the following: amoxicillin, amoxicillin/clavulanic acid, co-trimoxazole, cefixime, cefuroxime, erythromycin, and ciprofloxacin.
Statistical Analysis
Descriptive statistical analysis was made of the demographic
data of patients grouped according to the germs isolated in the sputum.
A logistic regression model was constructed for each isolated PPM. The dependent variable was the presence or absence of the germ in sputum, whereas the independent variables were the following: gender (0 = female; 1 = male), body mass index (0 = < 25; 1 = > 25), age (0 = < 70 years old; 1 = > 70 years old), years of COPD symptom evolution (0 = < 15 years; 1 = > 15 years), number of months since the last acute episode (0 = < 2 months; 1 = > 2 months), smoking (0 = nonsmokers and former smokers; 1 = smokers), and FEV1 (0 = > 50%; 1 = < 50%). Variables with p < 0.10 were accepted for the model, and cutoff points of the numerical variables were chosen with the medians of each taken into account.
Statistical analysis was performed by using analysis software for Windows (version 6.12; SAS Institute; Cary, SC). A p < 0.05 was deemed significant.
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Results |
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Patient characteristics are shown in Table 1 .
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Eleven patients were active smokers; in 6 of these patients, H influenzae was isolated in sputum samples, representing 30% of patients with this germ (6/20). The remaining five smokers were distributed as follows: 1 with S pneumoniae in sputum (1/9; 11%); 1 with M catarrhalis in sputum (1/8; 12.5%); 2 with P aeruginosa in sputum (2/14; 14%); and 1 with non-PPMs in sputum (1/33; 3%).
The results of the pulmonary function tests of patients with different germs isolated in sputum are depicted in Table 2 . The lower values of FEV1 and FEV1 as percent predicted corresponded to those patients in which P aeruginosa was isolated. No patient with an isolation of P aeruginosa showed FEV1 > 1,700 mL. Although a large overlap in FEV1 values existed among the different groups, the most preserved pulmonary function was observed in patients carrying non-PPMs and S pneumoniae. Mean values of FEV1, as well as SDs and ranges for all groups of patients, are shown in Figure 1 .
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Discussion |
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Similar results were reported by Eller et al20 in a group of exacerbated COPD patients, where a correlation was also found between the deterioration of lung function and the bacteria isolated in sputum. Of special interest is their observation that the Gram-negative bacteria and the Pseudomonas spp were the predominant bacteria in patients with the most severely impaired FEV1.
Serious doubts have been raised as to the use of sputum as a sample for microbiological study, and the possibility of contamination by saprophytic oropharyngeal flora is well known. In an attempt to circumvent this problem, several authors proposed using sputum validity criteria for microbiological analysis.15 16 This study employed very restrictive criteria along with quantitative analysis, and only bacteria that grew in concentrations of > 106 cfu (105 cfu for pneumococcus) were considered as possible etiologic agents of exacerbations. With the implementation of these criteria, multiple studies have continued to use sputum as an easy-to-obtain and noninvasive form of sample, and if one is aware of and accepts its limitations, it can be useful in analyzing bronchial infection.15 16 20 21 22
Another datum that supports the validity of our results is the similarity of our results to those obtained in other works in our area using more specific techniques such as the protected specimen brush. Thus, Monsó et al7 found H influenzae to be the most frequently isolated PPM in patients with exacerbated COPD. Zalacaín et al,8 who studied a group of severe COPD patients with FEV1 < 50% and used the same type of sample, also found that H influenzae was the most common bacteria isolated. In a recent study, Soler et al23 observed an unexpectedly high rate of Gram-negative bacteria and Pseudomonas/Stenotrophomonas spp isolations in respiratory samples of patients with severe exacerbations of COPD requiring mechanical ventilation; these pathogens accounted for 44% of all PPMs identified, whereas H influenzae was found in 33% of PPMs isolated, and S pneumoniae constituted only 11% of PPMs isolated. Considering that most of their patients (44/50; 88%) had an FEV1 < 50%, their results are similar to ours because in our patients with FEV1 < 50%, we also observed that S pneumoniae was isolated with less frequency than were H influenzae and P aeruginosa.
The isolation of P aeruginosa in the sputum of patients with exacerbated severe COPD also deserves mention. In 1990, Fagon et al,6 using endoscopic techniques, found that 18% of exacerbated COPD patients who required mechanical ventilation presented high concentrations of Gram-negative bacteria, particularly P aeruginosa, in bronchial secretions. However, Cabello et al18 found a very high rate (83%) of bronchial colonization in COPD patients, but they found no cases of colonization by P aeruginosa, although none of their patients presented with FEV1 < 45%. In our series, Pseudomonas was not isolated in any patient with FEV1 > 1,700 mL. Thus, this germ would appear to be responsible for acute episodes only in patients with severe pulmonary function impairment because only 1 of the 14 isolations of Pseudomonas in our patients occurred in a patient with FEV1 > 50%. This finding had already been reported in patients with bronchiectasis, in whom isolation of P aeruginosa in sputum occurred in patients with poorer pulmonary function.24 This observation supports the hypothesis that the adherence of P aeruginosa to the respiratory epithelium requires the existence of a prior lesion of the bronchial wall,25 such as the one that presumably exists in COPD patients with severe airflow obstruction. These lesions can mimic those of subtle or initial bronchiectasis, and we agree with Soler et al23 that the incidence of these minor alterations is expected to be high in patients with severe COPD and that it would be inadequate from a clinical point of view to exclude this subgroup from studies dealing with the etiology of exacerbations. Moreover, the real incidence of such lesions is unknown because high-resolution CT is not routinely performed in COPD patients. However, evidence of proven bronchiectasis was an exclusion criterion that was used in the present study to exclude patients with evident bronchiectasis who were mistakenly classified as having COPD. Although the possibility that a few of our patients had subtle and localized bronchiectasis cannot be ruled out, neither clinical nor radiographic criteria supported the presence of bronchiectasis in our study population.
Another possible explanation for the increasing rates with which the isolation of P aeruginosa occurs in severe COPD patients stems from the selection of germs caused by the ecologic pressure exerted by the use of previous antibiotics. Patients with greater airflow impairment tend to have a disease with longer duration, and they have a greater probability of having suffered previous exacerbations that required antibiotic treatment. The use of previous courses of antibiotics has been identified as a risk factor with regard to the presence of ß-lactamase-producing bacteria in the sputum of patients with exacerbations of COPD.22 Also, the tendency of Gram-negative bacteria and Pseudomonas to occur more often in the elderly and in the most frequently hospitalized group has been reported23 because these populations are more likely to have received numerous previous courses of antibiotics.
Unlike the study by Eller et al,20 we found no evidence that Staphylococcus aureus is a cause of the exacerbations in our population. This difference could be explained by the changes in flora occurring over time, or it could be due to a different geographic distribution of microorganisms (the latter study was retrospective, conducted between 1990 and 1995 in Germany). Our results concur with others recently reported in our area in that either no isolation of S aureus was noted among 60 exacerbated COPD patients,23 or only 1 out of 27 cases was noted.18
The discovery that the possibility of isolating S pneumoniae increases significantly when the exacerbation comes > 2 months after the previous episode is difficult to understand. It could be explained by the diminished capacity of pneumococcus to persist in the respiratory epithelium after a course of antibiotics, causing the pneumococcus to require more time than other bacteria to reproduce. However, current knowledge does not support this theory because the capacity of S pneumoniae to persist in the respiratory tract of COPD patients for many months despite the existence of specific antibodies has been well documented.26 A more feasible explanation derives from the evidence that S pneumoniae is an invasive bacterium, even in healthy epithelium, meaning that it may infect a bronchial mucosa that is intact.26 For this reason, it may be easy for S pneumoniae to colonize and infect mild COPD patients with healthier epithelium or patients whose epithelium had time to recover because the exacerbations occurred a long time ago. This observation should be pursued with future research involving a greater number of patients.
We have observed that active smoking is associated independently and very significantly with the isolation of H influenzae in the sputum of exacerbated COPD patients. If we accept that airways colonization is a preliminary and indispensable step for the development of infection, our results concur with those of Monsó et al27 who, while using the protected specimen brush, observed that the main predictor of airways colonization in stable chronic bronchitis (which is basically due to H influenzae) was active smoking. When considering the effects of active smoking on the probability of their isolation, it should be taken into account that the number of patients with some of the other bacteria may have been too low to exclude a type 2 error.
In the sensitivity analysis of germs to different antimicrobial agents, one well-known fact drew our attention: amoxicillin, erythromycin, and co-trimoxazole have ceased to have a satisfactory efficacy profile for the treatment of the more common respiratory pathogens. The amoxicillin-clavulanic acid combination presented a very suitable spectrum for all germs except Pseudomonas because only 2 of the 14 strains were sensitive to this drug. This fact renders it rather inadvisable as a first choice treatment for more severe patients. The same occurs with cefixime, which exhibits acceptable activity in the spectrum of germs found in mild patients but is not active against Pseudomonas. Finally, cefuroxime and ciprofloxacin presented the broadest spectrum with acceptable activity against Pseudomonas, and even the majority of the S pneumoniae strains were sensitive to ciprofloxacin. Overall, 90% and 88% of the isolated strains were sensitive to cefuroxime and ciprofloxacin, respectively. Because the differences between these antibiotics and those mentioned above are due, above all, to their differential action on Pseudomonas, the findings of our study suggest that the degree of functional respiratory impairment could be used in the selection of empiric antibiotic treatment for the acute exacerbations of COPD.
In conclusion, microorganisms causing the acute exacerbations of COPD are distributed unevenly among patients with different degrees of severity, with patients more severely affected showing a greater incidence of Pseudomonas and H influenzae. Besides FEV1, other easy-to-obtain clinical data, such as active smoking and the time since the last exacerbation, may help in choosing the appropriate empiric treatment for exacerbations. Different studies have demonstrated failure rates ranging from 13 to 26% in the ambulatory treatment of exacerbations of chronic bronchitis and COPD,12 13 28 with failure rates even more frequent in severe patients.29 The influence that new empiric treatments, which are used according to the degree of functional impairment, may have on improving the condition of the patient is a subject worthy of further investigation.
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Appendix |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendixReferences |
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Participating Investigators
E. Fernández-Laso, MD, Hospital Magdalena,
Castellón, Spain; J.A. Maldonado, MD, R. Ayerbe
García, MD, and M. Gómez Entrena, MD, Hospital
Juan Ramón Jiménez, Huelva, Spain; J.A. Martos, MD,
Hospital San Rafael, Barcelona, Spain; E. Balcells, MD, and G. Levy,
MD, Hospital Vall d'Hebron, Barcelona, Spain; E. Marquilles, MD, and
E. Martín, MD, Hospital Manresa, Manresa, Barcelona, Spain; J.
Serra-Batlle, MD, and J. Casadevall, MD, Hospital de Vic, Vic,
Barcelona, Spain; J. Dominguez del Valle, MD, Hospital de
Navarra, Pamplona, Spain; A. Marín, MD, and M. Gallego, MD,
Hospital Parc Taulí, Sabadell, Barcelona, Spain.
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Acknowledgements |
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Footnotes |
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Study supported by QF Bayer, Spain.
Abbreviations: PPM = potentially pathogenic microorganism
Received for publication July 29, 1998. Accepted for publication February 2, 1999.
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References |
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S. Sethi, T. F. Murphy |
2 test; p < 0.05.