COPD INFECTIOUS EXACERBATIONS: RISK FACTORS FOR ISOLATING PSEUDOMONAS AERUGINOSA AND INFLUENCE OF VIRULENCE GENES ON MORTALITY

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Cornelia Gilmore
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1 COPD INFECTIOUS EXACERBATIONS: RISK FACTORS FOR ISOLATING PSEUDOMONAS AERUGINOSA AND INFLUENCE OF VIRULENCE GENES ON MORTALITY Principal investigator: Dr Concepción Montón Soler. Hospital de Sabadell Duration: 2 years

2 1.Summary Infections, both viral and bacterial, are a frequent cause of exacerbation in COPD (chronic obstructive pulmonary disease). But there are still some unanswered questions, such as the real role of viral infections or the specific risk factors for each microorganism in the case of bacterial infections, which are more frequent in severe COPD (FEV1<50%). Objectives 1. To study the prevalence and the risk factors of patients with COPD and FEV1<50% presenting infections by Pseudomonas aeruginosa. 2. To analyse the virulence factors of the different strains of Pseudomonas aeruginosa and their relationship with the seriousness of patients exacerbations. Design A prospective follow-up study including patients with COPD and FEV1<50% who meet the Anthonisen criteria (2 of 3) for exacerbation of their COPD. Patients will be excluded with nosocomial infections, known bronchiectasis, pneumonias or secondary exacerbations of other causes, immunodepression and patients from whom a respiratory sample cannot be obtained. In each exacerbation a quantitative sputum culture, PCR for virus and blood analysis (with determination of C reactive protein) will be performed. If Pseudomonas aeruginosa is isolated 4 strains will be frozen for the study of polyclonality, antibiotypes, Exo-U secretion and quorum sensing factors. All patients will be given a respiratory function study (spirometry and arterial gasometry) and a thoracic CAT in clinical stability phase. During follow-up the number and severity of the exacerbations, the causal agents, the previous use of antibiotics and corticosteroids and their evolution will be recorded. 2

3 2. Results We evaluated 118 patients with severe COPD, 117 men and 1 woman, mean age 69 ± 8 years. Sixty per cent 60% of the patients were classified as COPD GOLD IV and the BODE index was 5.4 ± 1.6. The extent of the bronchiectasis in the thoracic CAT was evaluated according to a preestablished scoring system, with a minimum value of 0 for absence of bronchiectasis and a maximum value of 24 for affectation of all the pulmonary lobes. No bronchiectasis was observed in 44 patients (37.3%), while 55 patients (46.6%) scored between 1-4, and 19 patients (16.1%) presented more extensive bronchiectasis with scores above 5. During the follow-up period, the patients presented a total of 453 exacerbations of their COPD, in 343 of which it was possible to perform a quantitative sputum culture and a determination of C reactive protein. Of the 343 quantitative sputum cultures performed in the exacerbations, we found 95 samples of poor-quality sputum and 248 samples of good-quality sputum (grades IV-V of the of Murray-Washington classification), of which 69 cultures were negative and 179 cultures were positive for potentially pathogenic germs. The most frequently isolated were Haemophilus influenzae, in first place, and Pseudomonas aeruginosa in second place (table 1). Table 1. Potentially pathogenic germs isolated in the exacerbations (n=179) Haemophilus influenzae 66 (36.9%) Pseudomonas aeruginosa 35 (19.6%) Streptococcus pneumoniae 33 (18.4%) Moraxella catarrhalis 27 (15.1%) Other germs 18 (10.1%) During the follow-up Pseudomonas aeruginosa was isolated in 42 patients (35%) on one or more occasion. Comparison of the clinical characteristics (table 2) of patients with some positive sputum culture for P. aeruginosa and patients where it was not 3

4 isolated, no significant differences were found in age, toxic habits (active smoking, accumulated dose of packets/ year, active alcoholism) or in vaccination index (flu and pneumococcus). Nor were differences observed in the variables connected with the severity of the COPD (body mass index (BMI), FEV1, GOLD classification, BODE index, home oxygen therapy). The score for the extent of the bronchiectasis in the thoracic CAT was significantly higher in patients with some isolation of P. aeruginosa. The number of exacerbations in patients with P. aeruginosa was in comparison with the rest of the patients, as were the mean of antibiotic treatments received, the mean number of corticotherapy regimens received and the mean number of days of hospitalisation during the follow-up. Mortality was higher in the group of patients with some isolation of P. aeruginosa (26% vs. 8%, p=0.012). The multivariate analysis of risk factors of P. aeruginosa exacerbation showed that the extent of the bronchiectasis (OR 8.34, CI 95%: ) and the number of antibiotic treatments (OR 1.17, CI 95%: ,.33) were significantly associated with a higher probability of exacerbation by P. aeruginosa. Table 2. Clinical characteristics of patients with and without isolation of P. aeruginosa Patients with P. aeruginosa (n = 42) Patients without P. aeruginosa (n = 76) P Age Tobacco (active 4.8% 14.5% 0.13 smokers) Packets-year Chronic drinking 2.4% 2.6% 1,00 Anti-flu vaccination 92.9% 86.8%

5 Antipneumococcal 54.8% 44.7% 0.34 vaccination BMI FEV1 (L) FEV1 (%) GOLD IV 63.4% 57.3% 0.55 BODE OCD 58% 42% 0.24 Bronchiectasis score 3 ± ± No. exacerbations Antibiotic treatments Corticotherapy regimens Days of hospitalisation For the determination of C reactive protein as a systemic inflammatory response marker, the highest values were found in the exacerbations with isolation of potentially pathogenic microorganisms, and this difference was significant (table 3). However, differences were observed in the systemic inflammatory response depending on the microorganism causing the exacerbation. S. pneumoniae and H. Influenzae were the germs that produced the most marked systemic inflammatory response, whereas P. aeruginosa produced the lowest systemic inflammatory response (table 4). Table 3. Determination of C reactive protein and sputum cultures of in the exacerbations 5

6 Sputum cultures Episodes C reactive protein * ±6.10 Negative ±8.07 Poor quality ±8.02 Positive *P = Table 4. Determination of C reactive protein and causal microorganisms of the exacerbations Microorganisms Protein C reactive * P. aeruginosa 5-34±5-45 M. catarrhalis 6-59±6-97 H. influenzae 10.01±8-51 S. pneumoniae 12,05±8-65 * P= Relevance and possible clinical implications of the final results obtained The most important conclusions of the final results obtained are that the prevalence of exacerbations from P. aeruginosa in severe COPD 6

7 was 35% and that the extent of the bronchiectasis and the number of antibiotic treatment regimens received were significantly associated with the risk of Pseudomonas aeruginosa infection. These conclusions have a clear clinical implication in prescribing antibiotic treatment for the exacerbation of severe COPD: P. aeruginosa must be regarded as a causal relatively frequent causal agent, especially in patients with severe COPD with bronchiectasis confirmed by thoracic CAT who receive frequent regimens of antibiotic treatment. Thus, it is necessary to perform a thoracic CAT in clinical stability phase as part of the usual assessment of patients with severe COPD. Moreover, the determination of the C reactive protein as a systemic inflammatory response marker might be useful for orientation about the possible causal microorganism of the exacerbation. 4. Publications X. Pomares, C. Montón, M. Gallego, D. Mariscal, S. Acebo, E. Castañer, J. Vallés, A. Marín. Utilitat de la Proteïna C Reactiva en el diagnòstic i seguiment de l exacerbació infecciosa de la malaltia pulmonar obstructiva crònica greu. XXV Diada Pneumològica de la SOCAP. Barcelona, April Annals de Medicina 2007; 90 (supl.3): 17. X. Pomares, C. Montón, M. Gallego, D. Mariscal, J. Vallés, E. Castañar, A. García, A. Marín. Utilidad de la Proteína C Reactiva en el diagnóstico y seguimiento de la exacerbación infecciosa de la EPOC severa. XL Congreso Nacional de la SEPAR. Barcelona, June Archivos de Bronconeumología 2007; 43: 62. X. Pomares, C. Montón, M. Gallego, D. Mariscal, E. Castañer J. Vallés, A. Marín. 7

8 C-Reactive Protein usefulness in diagnosis and follow-up of COPD infectious exacerbations. European Respiratory Society 17 th Annual Congress. Stockholm, September European Respiratory Journal 226s: E1380. M. Sancho, D. Mariscal, E. Castañer, C. Montón, X. Pomares, C. Veigas, J. Vallés, M. Gallego. Influència de les bronquiectàsies a les exacerbacions de la MPOC degudes a Pseudomonas Aeruginosa. XXVII Diada Pneumològica de la SOCAP. Barcelona, March Annals de Medicina 2009; (in press). M. Sancho, D. Mariscal, E. Castañer, C. Montón, X. Pomares, D. Suárez, J. Vallés, M. Gallego. Influencia de las bronquiectasias en las exacerbaciones de la EPOC debidas a Pseudomonas Aeruginosa. 42º Congreso Nacional de la SEPAR. Santander, June Archivos de Bronconeumología 2009; (in press). 8

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PLAN OF ACTION FOR. Physician Name Signature License Date PLAN OF ACTION FOR Patient s copy (patient s name) I Feel Well Lignes I feel short directrices of breath: I cough up sputum daily. No Yes, colour: I cough regularly. No Yes I Feel Worse I have changes