RISK FACTORS AND PROGNOSIS OF COMMUNITY- ACQUIRED PNEUMONIA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

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1 RISK FACTORS AND PROGNOSIS OF COMMUNITY- ACQUIRED PNEUMONIA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IMPACT OF THE INFLAMMATORY RESPONSE Principal investigators: Dr Antoni Torres Martí Hospital Clínic i Provincial de Barcelona IDIBAPS Dr Rosario Menéndez Villanueva Hospital Universitario La Fe, Valencia Duration: 3 years

2 1. Summary The project was run in 2 tertiary-level university hospitals (Hospital Clínico in Barcelona and Hospital La Fe in Valencia); it consisted of two parts: - Case-control study to investigate the risk factors for Community- Acquired Pneumonia (CAP) in Chronic Obstructive Pulmonary disease (COPD) in hospitalised patients and compare them with COPD patients hospitalised for respiratory infection. To do so compared these factors were compared: host and clinical presentation, microbial aetiology, blood inflammation parameters (cytokines, procalcitonin and C reactive protein) and genetic polymorphisms of the TNF and the B protein of the surfactant (Lt alpha 250, TNF alpha 308, SPB 2680C) between the two groups of COPD patients matched by age and admission date. - Study of follow-up cohorts of patients with CAP and COPD versus two control groups: exacerbated COPD and CAP without COPD; as well as the clinical variables and the microbial aetiology, we measured the inflammation parameters on days 1, 3 and 30 from admission. The genetic polymorphisms were measured on day 1. The three cohorts of patients were monitored for a year to find the mortality after one year of hospitalisation. All included patients were monitored from their admission for CAP (with or without COPD) or exacerbation of their COPD, using pharyngeal smears, the usual microbiological tests (sputum (culture and antibiogram, Gram and colonies count), Legionella Ag and pneumococcus in urine, haemocultures, serology of virus and atypical) and blood sampling (days 1, 3 and 30) for inflammation and 2

3 genetic parameters. Therapeutic response and clinical stability were evaluated, in cases of CAP and COPD exacerbated being defined as those that presented a failure of antibiotic treatment. During the rest of the admission period assessment was made of the complications and days of hospital stay, and all the variables already defined in the study were gathered. In the case of COPD patients respiratory function tests were carried out a month after hospital admission (in the cases without tests in the 6 months prior to admission) and at one year, as well as control of later worsening. At the same time a substudy was performed to assess the effect of the sputum of patients with COPD and/or CAP on phenotype changes in a cell line of macrophages in vitro. Four groups were compared: 16 sputums of patients with COPD without pneumonia, 15 of patients with CAP without COPD, 11 of patients with CAP and COPD and finally 7 induced sputums of healthy controls. 2. Results Below are the most important results of the 3 populations studied. Descriptive results of the 3 groups studied: exacerbated COPD, CAP and CAP + COPD In the case-control study to find the CAP risk factors in patients with COPD and compare them with exacerbated COPD we found that: 1. The patients with exacerbated COPD have a more serious obstruction than patients with CAP + COPD. Likewise, the degree of prior dyspnoea is also higher in the COPD versus the patients with CAP+COPD. 3

4 2. The COPD patients with a greater number of hours of requirement for previous oxygen therapy have exacerbation more often than pneumonia. 3. The patients with COPD who develop pneumonia instead of severe exacerbation have a significantly higher use of long-acting bronchodilators and lower of short-acting, with no significant differences in relation to the treatment with inhaled corticoids. 4. The need for NIMV during admission was significantly higher in exacerbated COPD than in pneumonia. TABLE 1. Demographic data, toxic habits and initial severity of the three groups studied. CAP CAP + COPD COPD N (%) Age, mean ± SD 64.7± ± ± Sex, M/F (%) (58/42) (98/2) (94/6) Smoker (%) No 50% 7 0 Yes + ex-smoker 50% P * Alcoholism (%) No Yes + ex-alcoholism Fine s score (%) I-III

5 IV-V TABLE 2. Results of functional stage according to criteria of GOLD, SEPAR and dyspnoea in COPD patients stratified with or without CAP. Functional stage GOLD (%) CAP+COPD COPD P* I IIA IIB III 3 14 Functional stage SEPAR (%) Slight Moderate Severe Basal dyspnoea degree (%) 12 5 I II III 7 8 IV Oxygen therapy (%) <18h/day h/day

6 Global results of therapeutic failure, hospital readmission and mortality in the CAP cohort with or without COPD. In the cohorts monitoring study the most important findings were: 1. The mortality in the group with CAP without COPD was significantly higher than the CAP+COPD and exacerbated COPD. a. In the pneumonias the mortality was significantly higher in the patients with greater initial systemic inflammation and on day 3: cytokines IL 6 and IL 8 and PCR. b. In the patients with COPD the initial severity of the pneumonia, measured by Fine s score (PSI), was greater than in patients without COPD although the mortality and failure were less. 2. The systemic inflammation levels were significantly higher on day 1, with a mean decrease of 50% on day 3 and another decrease on day 30. a. The systemic inflammation caused by the pneumonia is at least 5 times higher than that produced by the exacerbation of COPD. b. The systemic inflammation in the pneumonia of the patient with COPD was slightly lower than pneumonia in other comorbidities. 6

7 CAP CAP+COPD CAP failure Intrahospital mortality 30-day mortality Readmission at 30 days Fig 1. Differences in the percentage of failure and mortality of the patients with CAP+COPD (higher in the group with CAP without COPD) and higher percentage of readmissions in the group with associated COPD. 3. Results of cytokines in the 3 populations. TABLE 3. Results in the pneumonias group (with and without COPD) of markers and cytokines according to therapeutic failure or otherwise. Results expressed in medians (P25-P75) 7

8 FAILURE NO SI P* PCR day 1 (mg/l) day ( ) 48.1 ( ) ( ) ( ) PCT 0.35(0.09- day ) 0.39( ) (ng/ml) 0.11( ( ) 0.01 day ) IL 6 day 1 83(29-219) 228( ) (pg/ml) 21(9-44) 103(48-253) day 3 IL 10 day 3(0-11) 3(0-13) 0.6 1(pg/ml) 10(4-19) 15(6-20.5) 0.2 day 3 Mann-Whitney U test 4. Results of the cell line substudy The points below show the most important results of this substudy linked to the project: 8

9 1. The macrophages incubated with sputum obtained from patients with CAP showed a higher expression of the inflammatory cytokines TNF and IL In the macrophages incubated with sputum from patients with COPD induction of the mannose receptor, arginase and IL-6 was observed, but not of TNF. 3. In patients with COPD and CAP a moderate but not significant increase was detected in the mannose receptor and arginase and TNF, but only the induction of IL-6 was sustained. Conclusions: a. The sputum of patients with COPD and CAP induces a macrophage activation different from that induced by the sputum of patients with isolated CAP or COPD. b. This difference in activation cold result in a different inflammatory response, which could impact on the prognosis observed in COPD patients who develop CAP. 3. Relevance and possible clinical implications of the final results obtained Differences were found in the medication used in patients with COPD who develop pneumonia or severe exacerbation, which makes it possible to characterise this oblation better and to determine the course of this disease. This information could be of use in preventive strategies. 9

10 This study provided new information on the systemic inflammatory response in COPD with pneumonia or with exacerbation, which could contribute to better handling of this disease. The profile of inflammatory response has prognostic implications, which could help in designing different treatment strategies according to the profile of this response. Complementarily, the analysis of the inflammatory response and of the different phenotype activation of the pulmonary macrophage in COPD, with or without CAP may make possible deeper knowledge on a closer therapeutic approach from a different direction. 4. Publications A study has been published with the CAP part of the data base without including the exacerbated COPD, as below. Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia. Thorax 2009 (in press). Rosario Menéndez 1,7 MD, PhD, Raquel Martínez 1,7-9 MD, Soledad Reyes 1 MD, Jose Mensa MD 2,7, Xavier Filella 3 MD, Mª Angeles Marcos 4 MD, Angela Martínez 1 RN, Cristina Esquinas 5 RN, Paula Ramirez 6 MD, Antoni Torres 5,7 MD, PhD. Biological markers and clinical stability in community-acquired pneumonia. Do they add information? Clinical Infectious Diseases 2009 (in review) R Menéndez, R Martinez, S Reyes, J Mensa, E Polverino, X Filella, C Esquinas, A Martinez, P Ramirez, A Torres. 10

11 Another original has been written for submission to the journal: American Journal of Respiratory and Critical Care Medicine. Differential macrophage activation phenotype in COPD patients with community-acquired pneumonia. Gutierrez PT, Closa D, R Piñer, O Bulbena, R Menéndez, Torres A. 11