Abstract
We carried out a comprehensive microbiological study of the upper and lower airways in patients with severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation in order to describe microbial patterns and analyze their clinical significance. Quantitative cultures of tracheobronchial aspirates (TBAs), bronchoscopically retrieved protected specimen brush (PSB) and bronchoalveolar lavage fluid (BALF) at admission to the ICU and after 72 h, as well as serology for bacteria and respiratory viruses were performed. Fifty patients (mean age 68 ± 8, 46 males) were studied prospectively. Potentially pathogenic microorganisms (PPMs) and/or a positive serology were present in 36 of 50 (72%) patients, including 12 (33%) polymicrobial cases. Only six (12%) had no pathogen in any sample in the absence of antimicrobial pretreatment. Microbial patterns corresponded to community-acquired pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) in 19 of 34 (56%) and to gram-negative enteric bacilli (GNEB), Pseudomonas, and Stenotrophomonas spp. in 15 of 34 (44%) of isolates. Chlamydia pneumoniae and respiratory viruses were found in 18% and 16% of investigations, respectively. Repeated investigation after 72 h in 19 patients with PPMs in the initial investigation revealed eradication of virtually all isolates of community-acquired pathogens and GNEB but persistence of three of five Pseudomonas spp. and both Stenotrophomonas spp. as well as the emergence of new GNEB, Pseudomonas and Stenotrophomonas spp. Clinical parameters neither predicted the presence of PPMs nor of GNEB and Pseudomonas/Stenotrophomonas spp. Nevertheless, severe pneumonia attributable to initially isolated pathogens occurred in two patients with severe COPD exacerbation. We conclude that pathogens were more frequently present than previously reported. The rate of GNEB and Pseudomonas/Stenotrophomonas spp. isolates was high. The presence of pathogens was clinically unpredictable. Thus, in this population of patients with severe exacerbations of COPD, it may be advisable to obtain respiratory samples and to treat according to diagnostic results. Further studies are warranted to clarify this issue.
The natural history of chronic obstructive pulmonary disease (COPD) is characterized by frequent exacerbations with an increase of cough, purulent sputum production, and dyspnea. In some patients, mostly those with severe airflow obstruction, severe respiratory failure occurs and may require mechanical ventilation. Bacterial infections have generally been considered as the leading cause of exacerbations in COPD (1, 2).
Notwithstanding, the role of bacterial infections in acute exacerbations is a matter of debate. Because lower respiratory tract bacterial colonization is frequently present in COPD patients (3, 4), the principal problem is to differentiate between bronchial colonization and infection. Most earlier studies have relied on sputum as a diagnostic technique (5-7). However, the performance of the sputum technique is poor, especially with regard to the differentiation of colonization and infection (8). Moreover, although Mycoplasma pneumoniae and Chlamydia pneumoniae as well as respiratory viruses with or without bacterial copathogens have been recognized in exacerbation episodes (9-15), their significance remains unsettled.
Fagon and coworkers were the first to use flexible bronchoscopy and the protected specimen brush (PSB) with quantitative cultures to characterize distal airway microflora in patients suffering from severe exacerbations requiring mechanical ventilation (16). Only recently, Monsó and coworkers reported the results of bacteriologic examination by the same technique in outpatients with stable disease and with moderately severe exacerbations (17). Both studies confirmed evidence for bacterial bronchial pathogens in about 50% of cases. On the other hand, these findings implied the absence of pathogens in the other 50%, and a comparison of both groups in the study of Fagon and coworkers did not reveal differences with regard to the outcome.
However, both did not assess the validity of the findings of the PSB technique compared with the results of other techniques such as bronchoalveolar lavage (BAL). In addition, they did not perform serological studies of bacteria and respiratory viruses. Neither did they provide sequential sampling of lower respiratory secretions in order to assess the effects of antimicrobial therapy.
In order to determine the precise microbial pattern of the upper and lower respiratory tract during severe exacerbations requiring mechanical ventilation, we carried out a study comparing the findings of PSB with those of pharyngeal swabs, tracheobronchial aspirates (TBAs), and bronchoalveolar lavage fluid (BALF). We included serological studies looking for evidence of infections with bacteria and respiratory viruses. We also studied the changes in bronchial microbial patterns after the introduction of antimicrobial treatment. Finally, we tried to find out the relationship between clinical and microbiological findings. These findings should provide further insights into the role of bronchial pathogens during severe exacerbations.
Overall 50 patients admitted to our intensive care unit (ICU) with COPD, a severe exacerbation and acute respiratory failure requiring mechanical ventilation were prospectively studied during an 18-mo period. All patients fulfilled the diagnostic criteria of COPD (18). They presented with clinical symptoms of marked increase in dyspnea, cough and/or purulent expectoration and had failed to respond to an ambulatory treatment. All patients had hypercapnic ventilatory failure at admission to the ICU and all required mechanical ventilation within the first 24 h after admission. Exclusion criteria were: hospitalization during the last 3 mo, prior antimicrobial treatment within the last 4 wk other than for acute illness during the last 24 h, evidence of bronchiectasis according to clinical criteria and chest radiograph, evidence of infiltrates on chest radiograph as well as severe immunosuppression, malignancies, and coagulopathies.
The following variables at admission were recorded: age, gender, smoking habits and alcohol status, comorbidity, previous glucocorticoid therapy, number of hospitalizations during the last 12 mo, ventilatory capacity (recorded in a stable state within 3 mo prior to hospital discharge), antimicrobial pretreatment during the last 24 h, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, arterial blood gases, and the oxygenation index (PaO2 /Fi O2 ).
The study protocol was approved by the local ethical committee. Informed consent was obtained from the next of kin.
All patients were subject to microbiological evaluation by a variety of samples of both the upper and lower respiratory tract obtained within the first 24 h of mechanical ventilation. The sequence of sampling was always the same, including a pharyngeal swab (PS; Eurotubo; Industrias Aulabor, S.A., Barcelona, Spain), a tracheobronchial aspirate using a sputum suction strap (TBAS; Proclinics, Barcelona, Spain), as well as a PSB (Microbiology brush; Mill-Rose Inc., Mentor, OH) and a BAL via fiberbronchoscopy (Pentax FB18; Asahi Optical Ltd., Japan). Prior to fiberbronchoscopy, patients were sedated with 50 mg propofol or 15 mg of midazolam intravenously. Ventilator settings were adapted appropriately in order to ensure proper ventilation and oxygenation. After an inspection of the bronchial tree, carefully avoiding any suction via the inner channel of the bronchoscope, a PSB was obtained as described by Wimberley and coworkers (19) in a segmental orifice of the right lower lobe. BAL was performed at the same site with 5 × 30 ml of nonbacteriostatic saline. The first reaspirated portion was discarded. The same sampling of respiratory secretions (except for phayrngeal swabs) in the same sequence was repeated after 72 h.
In addition, serum samples obtained at admission and after 4 wk were investigated for serological evidence of infections with Chlamydia spp., Mycoplasma pneumoniae, Legionella pneumophila, and Coxiella burnetii as well as respiratory viruses (influenzavirus A and B, parainfluenzaviruses, respiratory syncytial virus, adenovirus, and herpes simplex virus).
All patients were reassessed clinically after 4 wk of hospital discharge.
All respiratory samples (pharyngeal swab, TBAS, PSB, and BALF) were stained with Gram and homogenized, and undiluted as well as serially diluted secretions (10−1, 10−2, 10−3) were plated on blood, chocolate, Wilkens-Chalgren, and Sabouraud agar. Cultures were evaluated for growth after 24 and 48 h. Negative bacterial cultures were discarded after 5 d, and negative fungal cultures after 4 wk. Identification of microorganisms was performed according to standard methods (20). Susceptibility testing was performed using the agar diffusion method. Results of quantitative cultures were expressed as colony-forming units per milliliter (cfu/ml).
Bacterial agents were classified into potentially pathogenic microorganisms (PPMs) or nonpotential pathogenic microorganisms (non-PPMs) as described elsewhere (4). In order to minimize the risk of dealing with contaminants, an arbitrary cutoff point was chosen. PPMs were only regarded as significant in case of reaching ⩾ 105 in TBAS, ⩾ 102 cfu/ml in PSB, and ⩾ 103 cfu/ml in BALF. Pharyngeal swabs were also cultured quantitatively in order to avoid loss of information in case of bacterial overgrowth.
Serological titers of Mycoplasma pneumoniae and respiratory viruses were considered as diagnostic in case of seroconversion, i.e., at least a four-fold rise in titer. A seroconversion reaching a titer of ⩾ 1:128 was considered diagnostic for Legionella pneumophila, seroconversion reaching a titer of ⩾ 1:512 or an IgM titer ⩾ 1:32 for Chlamydia pneumoniae and seroconversion or an IgM titer of ⩾ 1:80 for Coxiella burnetii.
All patients initially received empirical antimicrobial treatment, and the regimen was adjusted according to microbiological results after 48 h. Antimicrobial treatment was not stopped in case of negative microbiological findings.
Continuous variables were compared using the nonparametric Mann-Whitney U test, categorial variables using the chi-square test or Fisher exact test, where appropriate. In order to compare the yield of PSB, BALF, and TBAS as well as of these with PS for bacterial pathogens, and to correct for agreements accounted for by chance, the kappa coefficient was determined. All reported p values are two-tailed. The level of significance was set at 5%.
The 50 study subjects (46 males, 4 females) had a mean age of 69 ± 8 yr. Twenty-one were current smokers, 29 ex-smokers since at least 1 yr. Of 43 spirometries available, mean FEV1% predicted was 32 ± 14, mean FEV1/FVC ratio 44 ± 18% predicted. Six patients had mild (FEV1 > 50% predicted), 10 moderate (FEV1 49–35% predicted), and 27 severe (FEV1 < 35% predicted) airflow limitation as defined by the American Thoracic Society (18). Comorbid conditions were present in 38 (76%) cases. Forty-one patients (82%) had been hospitalized at least once during the last year. The most relevant patient characteristics are summarized in Table 1.
| Age, yr (mean ± SD) | 68 ± 8 | |
| Gender (male/female) | 46/4 | |
| Smokers/Ex-smokers, n | 21/29 | |
| Prior hospitalizations within the last year, n (%) | ||
| Overall | 41 (82) | |
| 1 | 10 | |
| > 1 | 31 | |
| Comorbidity present, n (%) | 38 (76) | |
| Cardiac | 24 | |
| Diabetes mellitus | 10 | |
| Miscellaneous | 11 | |
| FEV1 % predicted, mean ± SD | 32 ± 14 | |
| FEV1/FVC % predicted, mean ± SD | 44 ± 18 | |
| PaO2 /Fi O2 , mean ± SD | 219 ± 91 | |
| APACHE II, mean ± SD | 18 ± 7 | |
| Antimicrobial treatment within the last 24 h, n (%) | 21 (42) | |
| Previous glucocorticoid therapy, n (%) | 10 (20) | |
| Days of mechanical ventilation, mean ± SD | 8 ± 7 | |
| Days of treatment in ICU, mean ± SD | 10 ± 7 | |
| Days of in-hospital treatment, mean ± SD | 20 ± 9 | |
| Mortality, n (%) | 3 (6) |
All patients were investigated by PSB and all but one by TBAS. BAL was performed in 41 patients. In the remaining cases, BAL was not performed because of unstable clinical conditions. Pharyngeal swabs were obtained in 29 cases. Not all patients could be reinvestigated because some were already extubated or facing the weaning phase. Thus, fiberbronchoscopy with PSB was performed twice in 33 cases, with BAL in 14, and TBAS in 29 patients. Adequate pairs of serologies were available in 38 cases.
Twenty-one patients had received antimicrobial treatment during the last 24 h prior to the admission to the ICU. In five of these 21 patients, antimicrobial therapy was changed after admission to the ICU. In the ICU, 27 patients were empirically treated with amoxicillin–clavulanic acid 1 g every 8 h, 20 with ceftriaxone 2 g every 24 h, two with a combination of ceftriaxone 2 g every 24 h and erythromycin 1 g every 8 h, and one with cefonicid 1 g every 24 h. Microbial investigations directed a modification of antimicrobial therapy in 11 patients.
Cultures of PSB at ⩾ 102 cfu/ml yielded 26 PPMs in 23 of 50 (46%) patients, and 11 non-PPMs were found in 8 of 50 (16%) patients (plus one case with Candida spp.). Cultures of BALF at ⩾ 103 cfu/ml yielded 22 PPMs in 18 of 41 (44%) and 10 non-PPMs in 8 of 41 (20%) patients (plus two cases with Candida spp.), and those of TBAS at ⩾ 105 cfu/ml yielded 22 PPMs in 20 of 49 (41%) and 10 non-PPMs in 8 of 49 (16%) patients (plus two cases with Candida spp.). The total number of pathogens was 34 (Table 2).
| Total | PSB (n = 50) | BALF (n = 41) | TBAS (n = 49) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| < co | ⩾ co | < 102 | ⩾ 102 | < 103 | ⩾ 103 | < 105 | ⩾ 105 | |||||||||
| PPMs | ||||||||||||||||
| Streptococcus pneumoniae | 1 | 4 | 0 | 4 | 1 | 4 | 0 | 4 | ||||||||
| Haemophilus influenzae | 1 | 11 | 1 | 10 | 1 | 5 | 2 | 9 | ||||||||
| Moraxella catarrhalis | 1 | 4 | 0 | 4 | 2 | 3 | 0 | 4 | ||||||||
| Escherichia coli | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | ||||||||
| Proteus mirabilis | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | ||||||||
| Serratia marcescens | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | ||||||||
| Enterobacter cloacae | 0 | 2 | 1 | 1 | 0 | 2 | 0 | 1 | ||||||||
| Pseudomonas spp. | 0 | 9 | 0 | 5 | 0 | 4 | 2 | 3 | ||||||||
| Stenotrophomonas maltophilia | 0 | 2 | 0 | 2 | 0 | 2 | 0 | 1 | ||||||||
| Total PPMs | 4 | 34 | 2 | 26 | 4 | 22 | 6 | 22 | ||||||||
| Non-PPMs | ||||||||||||||||
| Streptococcus vividans | 6 | 13 | 2 | 8 | 3 | 6 | 6 | 6 | ||||||||
| Streptococcus mitis | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | ||||||||
| Streptococcus group F | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | ||||||||
| Staphylococcus epidermidis | 4 | 8 | 1 | 2 | 1 | 2 | 6 | 1 | ||||||||
| Neisseria spp. | 3 | 1 | 1 | 0 | 0 | 0 | 2 | 1 | ||||||||
| Corynebacterium spp. | 0 | 2 | 1 | 0 | 0 | 1 | 0 | 2 | ||||||||
| Candida spp. | 1 | 4 | 1 | 1 | 1 | 2 | 2 | 2 | ||||||||
| Total Non-PPMs | 14 | 30 | 6 | 12 | 5 | 12 | 16 | 12 | ||||||||
PPMs accounted for community-acquired pathogens in 19 of 34 (56%) and for gram-negative enteric bacilli (GNEB) and Pseudomonas/Stenotrophomonas spp. in 15 of 34 (44%) of isolates. More than one pathogen was present in six (12%) of patients. In detail, Haemophilus influenzae was found in 11 (33%), Pseudomonas spp. in 9 (27%), Streptococcus pneumoniae, Moraxella catarrhalis, and Gram-negative enteric aerobic bacilli (GNEB; Enterobacter spp. [two], Proteus mirabilis, Serratia marcescens) in 4 (12%), and Stenotrophomonas maltophilia in 2 (9%) cases. Streptococcus viridans (13 of 30, 43%) was the most frequent non-PPM (Table 2).
For PPMs recovered above the predefined cutoffs, the concordance rates of PSB, BALF, and TBAS were moderate (PSB and BALF k = 0.6, p = 0.0003, PSB and TBAS k = 0.59, p = 0.0001, BALF and TBAS k = 0.17, p = 0.3).
Serological samples were positive according to the criteria defined above in 15 of 38 (40%) cases, with Chlamydia pneumoniae (7, 18%), Influenza virus (5, 13%), Coxiella burnetii, Chlamydia psittaci, and respiratory syncytial virus in one case each (3%). Patients with serological evidence of C. pneumoniae and influenza virus had concomitant PPMs in two and three cases, respectively.
Considering the results of PSB, BALF, TBAS, and serology together, overall 36 of 50 (72%) patients had PPMs in at least one sample in significant amounts and/or a positive serologic result. Twenty-three of 36 patients had at least two samples positive, the remaining 13 only one (two patients exclusively PSB, one BALF, two TBAS, eight serology).
GNEB and Pseudomonas/Stenotrophomonas spp. were present in 14 of 50 (28%) of the whole population and in 14 of 36 (39%) patients with evidence for pathogens. Although there was a trend for GNEB and Pseudomonas/Stenotrophomonas spp. to occur more frequently in the elderly and in the most frequently hospitalized group, the differences did not reach statistical significance (Table 3).
| GNEB and/orPseudomonas/Stenotrophomonasspp. Not Present (n = 36) | GNEB and/orPseudomonas/Stenotrophomonas spp. Present (n = 14) | |||
|---|---|---|---|---|
| Age | ||||
| < 65 yr | 10 (28%) | 3 (21%) | ||
| ⩾ 65 yr | 26 (72%) | 11 (79%) | ||
| Smoking status | ||||
| Ex-smoker | 19 (53%) | 9 (64%) | ||
| Current smoker | 17 (47%) | 5 (36%) | ||
| Alcohol status | ||||
| < 80 g/d | 26 (72%) | 12 (92%) | ||
| ⩾ 80 g/d | 10 (28%) | 2 (8%) | ||
| Current glucocorticoid therapy | ||||
| No | 29 (81%) | 11 (79%) | ||
| Yes | 7 (19%) | 3 (21%) | ||
| FEV1 % predicted | ||||
| ⩾ 50 | 4 (14%) | 2 (15%) | ||
| 49–35 | 7 (23%) | 3 (23%) | ||
| < 35 | 19 (63%) | 8 (62%) | ||
| Prior hospitalizations within the last year | ||||
| None | 6 (17%) | 3 (22%) | ||
| One | 9 (25%) | 1 (7%) | ||
| > 1 | 21 (58%) | 10 (71%) | ||
On the other hand, two had one PPM below the cutoff, eight had exclusively non-PPMs (four in amounts above the cutoff), and four patients had sterile samples as well as negative serologies.
The number of bacterial pathogens recovered in any sample of the lower respiratory tract was lower but not significantly affected by a previous antimicrobial therapy (22 of 29 [76%] positive results in patients without antimicrobial pretreatment versus 14 of 21 [67%] positive in pretreated patients, p = NS). Six patients(12%) completely evaluated by PSB, BALF, TBAS, and with paired serology had no PPM in any sample above the cutoff in the absence of antimicrobial pretreatment and negative serologies.
Repeated sampling after 72 h of treatment in 33 cases yielded persistent PPMs in 5 of 19 (26%) cases with PPMs in the initial investigation (Table 4). Eight of nine isolates of Haemophilus influenzae, and all of Streptococcus pneumoniae and Moraxella catarrhalis, as well as GNEB were eradicated. However, three of five isolates of Pseudomonas spp. and both of Stenotrophomonas maltophilia persisted. Except one H. influenzae, all persistent pathogens were not adequately covered with the initial empirical antimicrobial regimen. On the other hand, overall four new GNEB and three new isolates of Pseudomonas aeruginosa were detected in four patients (21%). These cases were treated within the first 72 h with six antibiotics, including amoxycillin–clavulanic acid in three, ceftriaxone in two, and cefotaxime in one. In 14 patients without previous PPMs, five (36%) had new PPMs (Staphylococcus aureus, GNEB [three], and S. maltophilia). These had received five antibiotics, including amoxycillin–clavulanic acid in three and ceftriaxone in two (Table 4).
| PPM | n | Eradicated/Persistent | Patients with New PPMs | |||
| Streptococcus pneumoniae | 1 | 1 eradicated | — | |||
| Haemophilus influenzae | 9 | 8 eradicated/1 persistent | 1. GNEB* | |||
| 2. GNEB† + P. aeruginosa | ||||||
| 3. GNEB ‡ + P. aeruginosa | ||||||
| Moraxella catarrhalis | 4 | 4 eradicated | — | |||
| GNEB | 5 | 5 eradicated | — | |||
| Escherichia coli | 1 | |||||
| Proteus mirabilis | 1 | |||||
| Serratia marcescens | 1 | |||||
| Enterobacter cloacae | 2 | |||||
| Pseudomonas aeruginosa | 3 | 1 eradicated/2 persistent | — | |||
| Pseudomonas fluorescens | 2 | 1 eradicated/1 persistent | — | |||
| Stenotrophomonas maltophilia | 2 | 2 persistent | 4. GNEB‡ + P. aeruginosa | |||
| Patients without PPMs in the Initial Investigation | n | Patients with New PPMs | ||||
| — | 14 | — | 1. S. maltophilia | |||
| 2. S. aureus | ||||||
| 3. GNEB* | ||||||
| 4. GNEB* | ||||||
| 5. GNEB§ |
Finally, 62 microorganisms were isolated from 28 of 29 culture positive pharyngeal swabs (PS). Most corresponded to non-PPMs (Streptococcus viridans [22 microoganisms], Streptococcus epidermidis [8], Candida spp. [7], Neisseria spp. [6], Corynebacterium spp. [5], Enterococcus spp. [3]). GNEB, Pseudomonas/Stenotrophomonas spp., as well as S. pneumoniae, H. influenzae, and M. catarrhalis were only infrequently found (n = 11). Concordance rates of PPMs above the predefined cutoff corresponded to random (PSB and PS k = 0.07, p = 0.47; BALF and PS k = −0.08, p = 0.38; TBAS and PS k = 0.08, p = 0.39).
Twelve patients (24%) had complications during ICU stay, including pneumothorax in four, pneumonia in three (due to Pseudomonas aeruginosa [case 1] already present initally, acquired S. maltophilia [case 2], and S. maltophilia already present initially and acquired P. aeruginosa [case 3]), septic shock in two, tracheobronchitis due to methicillin-resistant Staphylococcus aureus (MRSA), as well as upper gastrointestinal bleeding and sepsis in one case each. Five patients needed tracheostomy. Overall, the outcome was favorable, with a mortality rate of only 3 of 50 (6%). Two patients died because of pneumonia (case 2 and 3). A third patient died because of septic shock.
The severity of airflow obstruction, acute clinical illness, and the morbidity were not significantly different in patients with PPMs or GNEB and Pseudomonas/Stenotrophomonas spp. as compared with those patients without (Tables 5 and 6).
| Cases With PPMs in Any Sample of the Lower Respiratory Tract and/or Positive Serology (n = 36 ) | Cases Without Significant Pathogen (n = 14) | |||
|---|---|---|---|---|
| FEV1 % predicted | 33 ± 14.9 | 30.9 ± 10 | ||
| APACHE II at admission | 17.5 ± 6.9 | 21.1 ± 5.1 | ||
| PaO2 /Fi O2 | 224 ± 98.6 | 206.4 ± 66.2 | ||
| Mechanical ventilation, d | 7.4 ± 6.7 | 9.6 ± 6.5 | ||
| ICU stay, d | 9.2 ± 6.7 | 10.9 ± 6.5 | ||
| Hospitalization, d | 19.8 ± 10.4 | 19.7 ± 7.7 |
| Cases Without Pathogens (GNEB, Pseudomonas/Stenotrophomonas spp.) in Any Sample of the Lower Respiratory Tract (n = 36) | Cases With Pathogens (GNEB, Pseudomonas/Stenotrophomonas spp.) in Any Sample of the Lower Respiratory Tract (n = 14) | |||
|---|---|---|---|---|
| FEV1 % predicted | 32.6 ± 13.5 | 32.3 ± 15.1 | ||
| APACHE II at admission | 18.0 ± 6.3 | 19.5 ± 7.2 | ||
| PaO2 /Fi O2 | 219 ± 89 | 222 ± 100 | ||
| Mechanical ventilation, d | 7.9 ± 6.4 | 7.1 ± 6.9 | ||
| ICU stay, d | 9.6 ± 6.6 | 8.9 ± 6.5 | ||
| Hospitalization, d | 19.4 ± 9.6 | 18.1 ± 8.6 |
Short-term survival after 4 wk of hospital discharge still was favorable. Three patients died shortly after hospital discharge, and five could not be present at the control visit because they were bedridden. The remaining 39 patients were alive and in an at least reasonable clinical condition.
The main findings of this study are as follows: (1) The majority of patients, 36 of 50 (72%) with severe exacerbations requiring ventilatory support had PPMs as determined by extensive noninvasive and invasive sampling and/or positive serology; (2) GNEB and Pseudomonas/Stenotrophomonas spp. were present in 14 of 50 (28%) of the whole population, in 14 of 36 (39%) patients with evidence for pathogens and accounted for 15 of 34 (44%) of PPMs; (3) Fifteen of 38 (40%) patients had positive serologies and 13 had serological evidence of acute infection with Chlamydia pneumoniae or respiratory viruses; (4) In 19 patients with PPMs at the initial evaluation reevaluated after 72 h of antimicrobial treatment, virtually all community pathogens and GNEB were eradicated, whereas three of five isolates of Pseudomonas spp. and both Stenotrophomonas spp. persisted in the presence of inadequate initial antimicrobial therapy. Moreover, new GNEB, Pseudomonas and Stenotrophomonas spp. emerged in 4 of 19 (21%) patients with and 5 of 14 (36%) without initial PPMs; (5) Clinical parameters to predict the presence or absence of PPMs or GNEB and Pseudomonas/ Stenotrophomonas spp., respectively, were not found; (6) Severe pneumonia attributable to initially isolated pathogens occurred in two cases.
The study of the role of bronchial infection in acute exacerbations of COPD has yielded conflicting results. Most studies were conducted in populations with mild-to-moderate exacerbations treatable on an outpatient basis, and the majority were designed as trials evaluating the effect of antimicrobial treatment which may be regarded as an indirect means to evaluate the role of bacterial infection in acute exacerbations (21-23). Early studies evaluating the microbial flora of patients with chronic bronchitis relied on sputum cultures (5-7, 21). However, sputum is especially vulnerable to sampling errors and oropharyngeal contamination, and, therefore, nowadays considered to represent an inadequate tool for the evaluation of the role of bacterial infection in acute exacerbations.
Important insights into the distal bacterial flora have been provided by studies using the PSB with quantitative cultures. Monsó and coworkers, investigating outpatients both in a stable state and during mild-to-moderate acute exacerbations, could show that 25% of patients were colonized with bacterial pathogens, as compared with around 50% during acute exacerbations (17). Up to now, only one study investigated acute exacerbations requiring mechanical ventilation using the PSB technique (16). Fagon and coworkers found positive bacterial results in 50% of cases. The mortality rate and the duration of both mechanical ventilation and hospitalization were not different in patients with or without positive microbiological results. Thus, these studies suggested that bronchial infection by bacterial pathogens may have a role in up to 50% of cases of acute exacerbations.
The present study adds important aspects to this topic. First, whereas PSB had PPMs in 46% of investigations, a rate similar to that reported by Fagon and coworkers, the rate with evidence for pathogens increased up to 72% by a comprehensive microbiological evaluation including TBAS, BAL, and serology. Second, among these techniques used additionally to PSB, serology had the highest independent impact on this increased yield. And third, the rate of GNEB and Pseudomonas/Stenotrophomonas spp. was unexpectedly high.
Infections due to GNEB and Pseudomonas and Stenotrophomonas spp. are of special concern in the treatment of acute severe exacerbations as these would require specific and prolonged antimicrobial treatment. In the studies using bronchoscopy and the PSB, these pathogens were only infrequently found in outpatients, with a rate of 5% (24) and 7% (17), and more frequently (16%) in mechanically ventilated patients (16). Considering all lower respiratory tract samples, we found a higher overall rate of 28%. These pathogens were present in 39% of patients with PPMs, and even accounted for 44% of all PPMs identified.
An essential consideration when assessing the frequency of infections with these pathogens is the presence of bronchiectasis, as this would clearly increase the expected rate. Clinical and radiographic criteria did not support the presence of bronchiectasis in our study population. Although subtle and localized bronchiectasis may have been missed by these criteria, the incidence of these minor alterations is expected to be high in severe COPD, and it would be inadequate from a clinical point of view to exclude this subgroup.
Most importantly, the presence of GNEB and Pseudomonas/Stenotrophomonas spp. could not be predicted by age, smoker and alcohol status, current glucocorticoid therapy, FEV1% predicted, or number of previous hospitalizations. Although there was a tendency of GNEB and Pseudomonas/Stenotrophomonas spp. to occur more frequently in elderly patients and in those being most frequently hospitalized, these differences did not reach statistical significance. Those patients most frequently hospitalized probably represent also those who may have received the highest number of antimicrobial regimen. However, these data could not be reliably assessed in our population. Although most previous hospitalizations were due to exacerbations of COPD, it was also not possible to assess exactly the number of exacerbations in the preceding year. It should be taken into account that the number of patients studied may have been too low to exclude a type 2 error. Finally, since our study focused on the homogeneous population of severe exacerbations requiring mechanical ventilation, the lack of relation of patient factors with bronchial bacteriology may not be representative of the COPD population or of COPD exacerbations in general. In any case, the presence of GNEB and Pseudomonas/Stenotrophomonas spp. must be taken into account in all patients presenting with acute exacerbations and respiratory failure.
Chlamydia pneumoniae has only recently been addressed as a possible cause of acute exacerbations. Beaty and coworkers found a low incidence of acute Chlamydia pneumoniae infection in acute exacerbations of 5%, possibly due to a low incidence in the community during the study period (14). Blasi and coworkers, in the largest series published so far, and including only mild-to-moderate exacerbations, found a comparable incidence of 4% (15). Our study is the first including patients with severe exacerbations and respiratory failure, and we found a high incidence of acute seropositivity for C. pneumoniae of 18%. Of these, 29% were mixed infections revealing a bacterial copathogen. These findings may indicate a significant role for C. pneumoniae in acute exacerbations. On the other hand, we did not find a single case of infection due to Mycoplasma pneumoniae.
Respiratory viruses were also found in 16% of investigated cases, mostly due to influenza virus but also including one case with respiratory syncytial virus. This rate is at the lower extreme of the results of several studies including all degrees of severity and reporting a rate of 18 to 52% (5-7, 10, 12, 13). Influenza virus infection was associated with bacterial copathogens in three of five cases (60%).
The high rate of mixed infections indicates that these agents may predispose to bacterial superinfection rather than act as independent pathogens by impairment of local host defenses. Two studies, however, could not establish an increased recovery of bacteria in cases of virus-related exacerbations (5, 11). In any case, our findings support the notion that pure viral infections may be responsible for acute exacerbations and occasionally even result in severe respiratory failure.
The repeated microbiological evaluation after 72 h demonstrated three patterns of treatment response: the eradication of virtually all community-acquired pathogens and GNEBs; the persistence of most Pseudomonas and all Stenotrophomonas spp.; and the emergence of new GNEB and Pseudomonas as well as Stenotrophomonas spp. Obviously, the first group of pathogens is rapidly eradicated when susceptible to the chosen antimicrobial agent. The second group requires specifically directed and prolonged antimicrobial treatment and even then may not be fully eradicated in the majority of cases. All patients with Pseudomonas/Stenotrophomonas spp. had an initial empirical antimicrobial treatment that did not cover these pathogens. Even those two cases with negative findings in the repeated evaluation may therefore be attributed to sampling errors rather than eradication. Finally, the emergence of GNEB and Pseudomonas and Stenotrophomonas spp. as colonizers of the bronchial tree is a well described event, especially in prior antimicrobial treatment (25).
Antimicrobial pretreatment did not significantly affect the number of bacterial pathogens in any sample of the lower respiratory tract. Nevertheless, because antimicrobial therapy present in 21 patients was changed on five occasions prior to the sampling procedures we cannot exclude that some pathogens were missed, especially community-acquired ones. It is noteworthy that there remained a significant number of cases (12% in this series) without evidence for any pathogens even in the absence of antimicrobial pretreatment. Moreover, neither the presence of PPMs nor that of GNEB and Pseudomonas/Stenotrophomonas spp. did influence the severity of acute clinical illness, nor did it affect the length of mechanical ventilation, ICU or hospital stay. This observation is in accordance with the findings of others (16). These findings may support the view that bronchial infections at least may not represent the sole cause of acute and severe exacerbations.
The outcome of the patients was generally favorable. However, overall three patients developed nosocomial pneumonia, two of them due to P. aeruginosa and S. maltophilia each present in the initial culture and persisting for 72 h, and one due to S. maltophilia acquired after 72 h.
Because it is impossible to distinguish bronchial colonization from infection on clinical or microbiological grounds, and to predict the presence of GNEB and Pseudomonas/Stenotrophomonas spp. which in turn may predispose to severe pneumonia, our current approach would be to recommend to treat with antimicrobial therapy all patients with severe exacerbations. Furthermore, in order to ensure an appropriate antimicrobial treatment, our data suggest that it is important to obtain bronchial secretions for microbiological examination of patients with severe exacerbations of COPD.
In conclusion, the rate of patients with severe exacerbations requiring mechanical ventilation yielding PPMs is higher than previously reported. The rate of GNEB and Pseudomonas/Stenotrophomonas spp. is high, and the persistence of the latter may predispose to pneumonia. Chlamydia pneumoniae as well as respiratory viruses are involved in a considerable amount of cases. Currently, there are no markers of acute illness and clinical course that allow one to differentiate the presence or absence of PPM in these patients. Thus, specific antimicrobial treatment may be advisable at least in all acute severe exacerbations requiring mechanical ventilation.
Supported by Institut D'investigacions Biomediques August Pi i Sumyer, SEPAR, SGR 1997-00086 and Glaxo Wellcome.
| 1. | Burrows B., Earle R. H.Course and prognosis of chronic obstructive lung disease: a prospective study of 200 patients. N. Engl. J. Med.2801969397404 |
| 2. | Tager I., Speizer F. E.Role of infection in chronic bronchitis. N. Engl. J. Med.12921975563571 |
| 3. | Haas H., Morris J. F., Samson S., Kilbourn J. P., Kim P. J.Bacterial flora of the respiratory tract in chronic bronchitis: comparison of transtracheal, fiberbronchoscopic and oropharyngeal sampling methods. Am. Rev. Respir. Dis.11619774147 |
| 4. | Cabello H., Torres A., Celis R., El-Ebiary M., Puig de la Bellacasa J., Xaubet A., Gonzalez J., Agusti C., Soler N.Distal airway bacterial colonisation in healthy subjects and chronic lung diseases: a bronchoscopic study. Eur. Respir. J.10199711371144 |
| 5. | Gump D. W., Phillips C. A., Forsyth B. R., McIntosh K., Lamborn K. R., Stouch W. H.Role of infection in chronic bronchitis. Am. Rev. Respir. Dis.1131976465474 |
| 6. | Lambert H. P., Stern H.Infective factors in exacerbations of bronchitis and asthma. B.M.J.301972323327 |
| 7. | McHardy V. U., Inglis J. M., Calder M. A.A study of infective and other factors in exacerbations of chronic bronchitis. Br. J. Dis. Chest741980228238 |
| 8. | Lentino J. R., Lucks D. A.Nonvalue of sputum culture in the management of lower respiratory tract infections. J. Clin. Microbiol.251987758762 |
| 9. | McNamara M. J., Phillips I. A., Williams O. B.Viral and Mycoplasma pneumoniae infections in exacerbations of chronic lung disease. Am. Rev. Respir. Dis.10019691924 |
| 10. | Lamy M. E., Pouthier-Simon F., Debacker-Williame E.Respiratory viral infections in hospital patients with chronic bronchitis. Chest631973336341 |
| 11. | Smith C. B., Golden C. A., Klauber M. R., Kanner R., Renzetti A.Interactions between viruses and bacteria in patients with chronic bronchitis. J. Infect. Dis.1341976552561 |
| 12. | Buscho L. D., Saxtan D., Shultz P. S.Respiratory viral infections in hospital patients with chronic bronchitis. Chest631978336341 |
| 13. | Smith C. B., Golden C. A., Kanner R. E., Renzetti A. D.Association of viral and Mycoplasma pneumoniae infections with acute respiratory illness in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis.1211980225232 |
| 14. | Beaty C. D., Grayston J. T., Wang S. P., Kuo C. C., Reto C. S., Martin T. R.Chlamydia pneumoniae, strain TWAR, infection in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis.144199114081410 |
| 15. | Blasi F., Legnani D., Lombardo W. M., Negretto G. G., Magliano E., Pozzoli R., Chiodo F., Fasoli A., Allergra L.Chlamydia pneumoniae infection in acute exacerbations of chronic obstructive pulmonary disease (COPD). Eur. Respir. J.619931922 |
| 16. | Fagon J. Y., Chastre J., Trouillet J. L., Domart Y., Dombret M. C., Bornet M., Gibert C.Characterization of distal microflora during acute exacerbations of chronic bronchitis. Am. Rev. Respir. Dis.142199010041008 |
| 17. | Monsó E., Ruiz J., Rosell A., Manterola J., Fiz J., Morera J., Ausina V.Bacterial infection in chronic obstructive pulmonary disease: a study of stable and exacerbated outpatients using the protected specimen brush. Am. J. Respir. Crit. Care Med.152199513161320 |
| 18. | American Thoracic SocietyStandards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med.152(Suppl.)1995S78S83 |
| 19. | Wimberley N., Faling L. J., Bartlett J. G.A fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial culture. Am. Rev. Respir. Dis.1191979337343 |
| 20. | Balows, A., and W. J. Harsier, Jr. 1991. Manual of Clinical Microbiology, 5th ed., Section III. American Society of Microbiology, Washington, DC. 209–553. |
| 21. | Nicotra M. B., Rivera M., Awe R. J.Antibiotic therapy of acute exacerbations of chronic bronchitis: a controlled study using tetracycline. Ann. Intern. Med.9719821821 |
| 22. | Anthonisen N., Manfreda J., Warren C. P. W., Hershfield E. S., Harding G. K. M., Nelson N. A.Antibiotic therapy in excerbations of chronic obstructive pulmonary disease. Ann. Intern. Med.1061987196204 |
| 23. | Fagon J. Y., Chastre J.Severe exacerbations of COPD patients: the role of pulmonary infections. Semin. Respir. Infect.111996109118 |
| 24. | Martinez J. A., Rodriguez E., Bastida T., Buges J., Torres M.Quantitative study of the bronchial bacterial flora in acute exacerbations of chronic bronchitis. Chest1051994976 |
| 25. | Johanson W. G., Pierce A. K., Sanford J. P., Thomas G. D.Nosocomial respiratory infections with gram-negative bacilli: the significance of colonization of the respiratory tract. Ann. Intern. Med.771972701706 |
Néstor Soler was a 1996 research fellow from the Hospital Clinic Barcelona. Dr. Santiago Ewig was a 1997 research fellow from the Medizinische Universitätsklinik and Poliklinik Bonn, Bonn, Germany.
