AECOPD患者的铜绿假单胞菌感染

Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation: a prospective study C. Garcia-Vidal*, P. Almagro*, V. Romanı´*, M. Rodrı´guez-Carballeira*, E. Cuchi#, L. Canales", D. Blasco+, J.L. Heredia1 and J. Garau* ABSTRACT: Risk factors for Pseudomonas aeruginosa (PA) isolation in patients hospitalised for chronic obstructive pulmonary disease (COPD) exacerbation remain controversial. The aim of our study was to determine the incidence and risk factors for PA isolation in sputum at hospital admission in a prospective cohort of patients with acute exacerbation of COPD. We prospectively studied all patients with COPD exacerbation admitted to our hospital between June 2003 and September 2004. Suspected predictors of PA isolation were studied. Spirometry tests and 6-min walking tests were performed 1 month after the patients were discharged. High- resolution computed tomography (HRCT) was performed in a randomised manner in one out of every two patients to quantify the presence and extent of bronchiectasis. Patients were followed up during the following year for hospital re-admissions. A total of 188 patients were included, of whom 31 (16.5%) had PA in sputum at initial admission. The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index (OR 2.18, CI 95% 1.26–3.78; p50.005), admissions in the previous year (OR 1.65, CI 95% 1.13–2.43; p50.005), systemic steroid treatment (OR 14.7, CI 95% 2.28–94.8; p50.01), and previous isolation of PA (OR 23.1, CI 95% 5.7–94.3; p,0.001) were associated with PA isolation. No relationship was seen between bronchiectasis in HRCT and antibiotic use in the previous 3 months. PA in sputum at hospital admission is more frequent in patients with poorer scoring on the BODE index, previous hospital admissions, oral corticosteroids and prior isolation of PA. KEYWORDS: BODE index, bronchiectasis, chronic obstructive pulmonary disease, hospitalisation, Pseudomonas aeruginosa infection T he role of bacterial infection in chronic obstructive pulmonary disease (COPD) exacerbation remains controversial [1, 2]. Recent studies have correlated COPD exacerba- tion with the overgrowth of the bacterial load or with the acquisition of a new strain of pathogenic bacteria [3–5]. In ambulatory patients, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are the three major pathogens isolated in COPD exacerbations, while Pseudomonas aeruginosa (PA) is uncommon and is usually associated with the greatest degree of functional impairment [6–10]. Hospitalised patients for acute exacerbation of COPD (AECOPD) usually have more advanced disease [11], and the infecting pathogens could be different. Recent European guidelines highlight the need for specific studies on risk factors for PA in COPD exacerbated patients [12]. This is an important issue because empirical antibiotic regi- mens designed to cover this pathogen are different from those aimed to cover for the usual microorganisms. Nevertheless, contradictory results regarding the role of PA in sputum at admission in COPD hospitalised patients have been reported [13–15]. Our hypothesis was that there would be specific risk factors that would predict a change in flora and an increased risk for the presence of PA in sputum in this population. On this basis, the aim of the study was to determine the incidence and risk factors for PA isolation in sputum at hospital admission in a prospective cohort of patients with AECOPD. AFFILIATIONS *Services of Internal Medicine, #Microbiology, "Radiology, 1Pneumology, Hospital Mutua de Terrassa, University of Barcelona, and +Hospital Clinic, Dept of Clinical Microbiology, Hospital Mutua de Terrassa, University of Barcelona, Barcelona, Spain. CORRESPONDENCE C. Garcia-Vidal Service of Internal Medicine Hospital Mutua de Terrassa Plaza Dr. Robert 5 08221 Terrassa Barcelona Spain E-mail: carolgv75@hotmail.com Received: Jan 08 2009 Accepted after revision: March 29 2009 First published online: April 22 2009 European Respiratory Journal Print ISSN 0903-1936 Online ISSN 1399-3003This article has supplementary material accessible from www.erj.ersjournals.com 1072 VOLUME 34 NUMBER 5 EUROPEAN RESPIRATORY JOURNAL Eur Respir J 2009; 34: 1072–1078 DOI: 10.1183/09031936.00003309 Copyright�ERS Journals Ltd 2009 METHODS Subjects We prospectively studied all consecutive patients admitted to our institution (Hospital Mutua de Terrassa, Barcelona, Spain) for AECOPD between June 2003 and September 2004. All episodes of hospital re-admissions of the cohort during the following year, until September 2005, were also prospectively followed up. The study was carried out in a 500-bed university hospital. Inclusion criteria were: hospitalisation for AECOPD, basal forced spirometry showing a forced expiratory volume in 1 s (FEV1) f70% of their reference value, and b2-agonist reversibility of predicted FEV1 of ,15% and/or 200 mL, with FEV1/forced vital capacity (FVC) ,70%. Exclusion criteria included a history of asthma or bronchiectasis as a predomi- nant illness, pneumonia or pulmonary oedema at admission, hospitalisation for causes other than AECOPD, or patient refusal to participate in the study. COPD exacerbation was defined following the criteria of ANTHONISEN et al. [16]. Admission criteria were at the discretion of the emergency room physician. For the purposes of this study, patients were divided into two groups: those in whom PA was isolated in sputum at hospital admission (PA group) and those in whom PA was not isolated in sputum at hospitalisation (non-PA group). Written informed consent was obtained from each subject and the study was approved by the ethics committee at the Hospital Mutua de Terrassa. Clinical evaluation At the initial visit, patients provided a complete clinical history and underwent a physical examination. Information collected included demographic characteristics, body mass index, comorbidity (as measured by the Charlson index), previous functional dependence (Katz score) and dyspnoea measured by the modified Medical Research Council (mMRC). Information on smoking history, number of hospitalisations for COPD within the last year, time to last hospital discharge, use of antibiotics within the last 3 months and prior admission, use of systemic or inhaled corticosteroids, and chronic home use of oxygen therapy prior to admission were also collected. Chronic systemic corticosteroid use was considered when doses equivalent to prednisone o5 mg?day-1 had been given for at least the previous 3 months. Microbiological studies Spontaneous or induced sputum samples were collected at admission and at each re-admission, before antibiotic admin- istration (section 1 of supplementary data). Bacterial agents were classified into potential pathogenic microorganisms (PPMs) and non-PPMs, as previously described [3]. Only PPMs were evaluated. In some patients with at least two isolates of PA in sputum at different admissions, strains were typed by pulsed-field gel electrophoresis. The presence of a mucoid phenotype on PA isolation agar plates was recorded. High-resolution computed tomography evaluation The presence of bronchiectasis was assessed at the first hospital admission. To limit radiation and costs, patients were randomised for a high-resolution computed tomography (HRCT) of the chest, in a 2:1 ratio. The diagnosis of bronchiectasis was based on standard criteria. HRCT scans were interpreted by two experienced radiologists blinded to the patients’ clinical grouping and microbiological status. Posterior consensus was reached in case of disagreement. The bronchiectasis score is detailed in section 2 of the supplementary data. Follow-up A follow-up visit took place ,1 month after discharge. At this visit, forced spirometry and bronchodilatador testing were performed according to standard techniques [17]. The 6-min walking test was performed following the American Thoracic Society recommendations [18]. The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index was also calculated as the sum score proposed by CELLI et al. [19]. In case of hospital re-admission within the first month after discharge, the patient was followed up for 1 month after reaching clinical stability. All patients were followed up for hospital re-admission during the year after discharge. Statistical analysis Sample size calculation was based on FEV1 values; post- bronchodilator FEV1 40% of predicted for PA patients, and 50% for non-PA patients, with an a- and b-error of 0.05 and 0.1, respectively. A 10% patient loss was assumed. Accordingly, the calculated size was 234 patients. To assess factors associated with PA isolation, we compared the PA and non- PA groups. To detect significant differences between groups we used the Chi-squared test with continuity correction for categorical variables. Quantitative variables were analysed using an unpaired t-test or their corresponding nonparame- trical tests when the distribution of data so required. The relationship between bronchiectasis score and FEV1 was calculated with the Pearson correlation coefficient. For multi- variate analysis a logistic regression model was constructed with PA isolation as a dependent variable. In this model independent variables included the most clinically relevant variables that were found to be significant in bivariate analysis. Data analysis was performed using the SPSS for Windows software package (version 11; SPSS Inc., Chicago, IL, USA). In all analyses, we considered p-values f0.05 to be statistically significant. All reported p-values are two-tailed. RESULTS Patient characteristics Over the study period, a total of 254 patients with a suspected diagnosis of AECOPD were admitted to hospital. Of these, 66 patients were excluded for the following reasons: impossibility to perform spirometry or lack of spirometric criteria (26 (10.2%) patients); pneumonia (25 (9.8%) patients); bronchiec- tasis as a main manifestation of disease (six (2.3%) patients); idiopathic fibrosis (four (1.6%) patients); and others (five (2.0%) patients). The studied population were predominantly male (95%), with a mean¡SD age of 72.1¡10.0 yrs and length of stay of 11¡8.7 days. Sociodemographic and functional characteristics are shown in table 1. Of the 188 patients included, 157 (83.5%) were in the non-PA group and 31 (16.5%) were in the PA-group. When comparing groups, no significant differences in age or sex were observed. PA isolation in sputum was more frequent in patients with the worst values of Katz score (4.7 versus 5.6; p50.03) and the mMRC (3.4 versus 2.7; p50.001). The PA group had a stronger C. GARCIA-VIDAL ET AL. COPD AND SMOKING-REALTED DISORDERS c EUROPEAN RESPIRATORY JOURNAL VOLUME 34 NUMBER 5 1073 history of smoking than patients in the non-PA group (mean pack-years of smoking 73.7 versus 56.8; p50.02). Previous hospital admissions in the last month (32.3% versus 14.0%; p50.001) and number of previous episodes of admission within the last year (3.1 versus 0.9; p50.002) were more frequent in the PA group. Acute and chronic steroid therapy were more frequent in patients in the PA group (22.6% versus 6.6% (p50.012) and 12.9% versus 2.5% (p,0.01), respectively). No relationship was found between PA isolation and the use of inhaled steroids or antimicrobial use in the last 3 months. Respiratory parameters significantly associated with the presence of PA in sputum at admission were: severity of disease as measured by post-bronchodilator FEV1 (mean of FEV1 38.7% versus 45.9%; p50.012), the poorest values for the 6-min walking test (217.5 m versus 343.7 m; p,0.001) and chronic home oxygen therapy (32.3 versus 15.6; p50.041). The BODE index was also significantly associated with PA isolation (7.3 versus 5.4; p50.0005). As a summary, data of significant variables in bivariate analysis are shown in table 2. A HRCT scan of the chest was performed in 88 randomised patients. Patients with HRCT were similar with respect to age, previous admissions, corticosteroid use, FEV1, FVC and other measured physiological parameters, compared to those who did not undergo HRCT scanning. 46 (52%) patients had significant detectable bronchiectasis on HRCT (two or more dilated bronchi; global score in percentage o5.6%). Of those in whom bronchiectasis was detected, the median (range) score was 25 (5–56)% (fig. 1). No statistical relationship was seen between the total bronchiectasis score and FEV1 measurement (r250.059; p50.058), 6-min walking test (r250.002; p50.784) or BODE index (r250.009; p50.94). Similarly, no relationship was found between the score of bronchiectasis and positive bacterial culture (p50.76) or PA isolation in sputum at admission (95% CI 0.99–1.05; p50.09). Microbiological findings Of the 188 patients included, 119 (63.3%) had good quality sputum in the first hospital admission. Non-PPMs were isolated in 55% of these patients while PPMs were found in 45% of cases. A single bacterial species was isolated in 50 patients, two species in three patients, and three species in one patient. PA was the most frequently isolated species in patients with valid sputum (31 (26%) out of 119 cases) followed by S. pneumoniae and H. influenzae (11 (9.2%) cases each). The presence of other microorganisms was infrequent. During the initial admission and the subsequent year of prospective follow-up, a total of 469 episodes of hospitalisation due to COPD exacerbation were collected (134 in PA group and 335 in non-PA group), and valid sputum was collected in 220 (47%) episodes. Patients with positive bacterial cultures of sputum (any microorganism) had a lower FEV1 than patients with negative sputum cultures at admission (p50.003). As shown in figure 2, the global incidence of PA isolation in the index of hospitalisation and re-admissions during the subsequent year was 23.18% of all episodes. H. influenzae (11%) and S. pneumoniae (10%) remained common aetiologies for COPD exacerbation in patients requiring hospitalisation. Patients in the PA-group were re-admitted more frequently than patients in the non-PA group (p50.001), and were more likely to present valid sputum during these re-admissions than patients in the non-PA group (p,0.001). The relationship between different microorganisms and FEV1 is shown in figure 3. Among the 31 patients with PA at the first admission, PA was isolated in 12 patients only once, twice in 11 patients, and in eight patients at least three times, in sputum cultures performed during subsequent admissions. Previous isolation of PA was associated with a higher probability of a new PA isolation (p,0.001). Molecular typing of 41 PA strains from 10 patients obtained in different exacerbations showed that the current strain was identical to the original strain in seven (70%) patients and in 37 (90%) of the samples. Of note, all persisting PA strains were non-mucoid (six patients) with a single instance of persisting mucoid strain (one patient) (see supplementary data). Table 3 shows the antibiotic suscept- ibility pattern of PA isolates. Of the 31 patients in the PA group, only four patients received empirical antibiotic treat- ment with pseudomonal coverage (quinolones: n53, ceftazi- dime: n51). 12 patients received antipseudomonal treatment when the microbiological results were known. Factors associated with PA isolation in multivariate analysis Table 4 summarises the results of multivariate analysis of factors potentially associated with PA isolation. Significant variables associated independently with PA isolation were BODE index (OR 2.18, 95% CI 1.26–3.78; p50.005), number of TABLE 1 Characteristics of patients hospitalised with acute chronic obstructive pulmonary disease exacerbation during the period of study Subjects n 188 Age yrs 72.11¡10.0 Male sex 178 (94.7) PBD FEV1 L 1.04¡0.37 PBD FEV1 % pred 44¡14.52 Severity according to GOLD stage Stage II, moderate 65 (34.6) Stage III, severe 95 (50.5) Stage IV, very severe 28 (14.9) Walking test m 330¡105 Charlson index 2.17¡1.3 Katz score 5.46¡1.3 Dyspnoea mMRC 2.78¡1.2 Smoking pack-yrs 59.84¡35.4 Patients with a hospital admission in the previous month 32 (17) Episodes of admission in previous year 1.27¡2.0 Days hospitalised in previous year 12.84¡25.9 Antimicrobials in last 3 months 62 (33) Body mass index 27.8¡5.2 Inhaled steroids 140 (76.5) Systemic steroids 17 (9.3) Data are presented mean¡SD or n (%), unless otherwise specified. PBD: post- bronchodilator; FEV1: forced expiratory volume in 1 s; % pred: % predicted; GOLD: Global Initiative for Chronic Obstructive Pulmonary Disease; mMRC: modified Medical Research Council. COPD AND SMOKING-REALTED DISORDERS C. GARCIA-VIDAL ET AL. 1074 VOLUME 34 NUMBER 5 EUROPEAN RESPIRATORY JOURNAL hospital admissions in the previous year (OR 1.65, 95% CI 1.13–2.43; p50.005), systemic steroid treatment (OR 14.7, 95% CI 2.28–94.8; p50.01), and previous isolation of PA (OR 23.1, 95% CI 5.7–94.3; p,0.001). DISCUSSION In this prospective study we offer a comprehensive evaluation of the incidence and risk factors for PA isolation in a large prospective cohort of patients hospitalised for AECOPD. To our knowledge, this study is the first to assess specifically, in a prospective cohort, the multidimensional risk factors of PA isolation in sputum in patients hospitalised for AECOPD. The most important finding of our study is the strong relationship between PA isolation at hospital admission and several markers of respiratory functional impairment. Additionally, our study shows that the incidence of PA in sputum in this population is high (23% of total episodes). Specifically, this TABLE 2 Characteristics of 188 patients hospitalised with acute chronic obstructive pulmoanry disease# PA group" Non-PA group+ p-value OR (95% CI) Katz index 4.74¡1.9 5.61¡1.1 0.03 0.67 (0.51–0.90) Dyspnoea mMRC 3.43¡0.8 2.66¡1.2 0.001 2.07 (1.22–3.50) Smoking pack-yrs 73.7¡39.7 56.76¡33.8 0.02 1.01 (1.003–1.02) Hospital admission in last month 10 (32) 22 (14) 0.001 2.95 (1.16–7.48) Admissions in previous year 3.06¡3.5 0.91¡1.3 0.002 1.47 (1.19–1.81) Days hospitalised in previous year 38.3¡51.7 8¡12.7 0.004 1.04 (1.02–1.06) Antibiotic treatment in previous 3 months 11 (35.5) 51 (32.5) 0.828 1.14 (0.51–2.57) Systemic corticosteroids 7 (22.6) 10 (6.6) 0.01 3.57 (1.17–10.88) Chronic systemic corticosteroids 4 (12.9) 4 (2.5) 0.01 5.66 (1.3–24) PBD FEV1 % 38.7¡12.2 45.9¡14.7 0.01 0.96 (0.93–0.99) Walking test m 217.5¡103 343.7¡98.5 ,0.001 0.99 (0.98–0.99) BODE index 7.32¡1.72 5.42¡2.53 ,0.001 1.45 (1.17–1.78) Number of Anthonisen criteria 0.735 1 6 (19) 40 (26) 2 8 (26) 41 (26) 3 17 (55) 76 (48) Previous isolation PA 19 (61.3) 12 (7.6) ,0.001 122 (25.5–590) Home oxygen therapy 10 (32.3) 24 (15.3) 0.04 0.48 (0.19–1.1) Data are presented as mean¡ SD or n (%), unless otherwise stated. PA: Pseudomonas aeruginosa; mMRC: modified Medical Research Council; PBD: post- bronchodilator; FEV1: forced expiratory volume in 1 s; BODE: body mass index, airflow obstruction, dyspnoea, exercise capacity. #: PA group compared with 157 patients in the non-PA group; ": n531; +: n5157. 50 40 30 20 10 0 P at ie nt s % Bronchiectasis score % 0–5.6 11.1–22 28–44 >44 FIGURE 1. Total bronchiectasis score in 88 patients. In total, 46 (52%) patients had significant detectable bronchiectasis (two or more dilated bronchi; global score in percentage o5.6%) on high-resolution computed tomography. The overall bronchiectasis score was expressed as a percentage: (Brochiectasis score / bronchiectasis maximum score) 6100. Patients with a score of 0 or 5.6 (less than two affected segments) were considered normal. 60 50 40 30 20 10 0 P at ie nt s % Bacterial isolates Non-PPM PA SP HI ETB MC FIGURE 2. Bacterial isolates of patients with valid sputum. &: i