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• W1994153209 abstract "Acute exacerbation of COPD is an illness that is frequently caused by bacterial microorganisms. In addition, pneumonia may cause the exacerbation in an unknown percentage of cases. There is no doubt that COPD is a risk factor for the acquisition of pneumonia, as shown by the increased risk (relative risk, 16) reported by Soriano et al1Soriano JB Visick GT Muellerova H Payvandi N Hansell AL Patterns of comorbidities in newly diagnosed COPD and asthma in primary care.Chest. 2005; 128: 2099-2107Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar some years ago when comparing patients with and without COPD. In fact, in many studies of community-acquired pneumonia (CAP), COPD is the first or second comorbidity found. For many years, this susceptibility to pneumonia has been explained by alterations in mechanical and cellular defenses in patients with COPD, especially in the more severe stages of the disease. However, it was not realized that COPD is frequently treated with drugs that might favor the development of pneumonia. Inhaled steroids were introduced many years ago for the treatment of asthma, and these drugs are frequently administered in patients with COPD, alone or in combination with β-agonists, without being indicated in all stages of the disease.2Rabe KF Hurd S Anzueto A Global Initiative for Chronic Obstructive Lung Disease (GOLD) et al.Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD executive summary.Am J Respir Crit Care Med. 2007; 176: 532-555Crossref PubMed Scopus (4425) Google Scholar The first evidence demonstrating the possible association of inhaled steroids with an increased risk of developing pneumonia was established in the Towards a Revolution in COPD Health (TORCH) study.3Calverly PM Anderson JA Celli B TORCH Investigators et al.Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 775-789Crossref PubMed Scopus (2835) Google Scholar In this study, patients with COPD who received inhaled propionate of fluticasone alone or in combination with salmeterol had a twofold higher rate of pneumonia compared with patients in the placebo arm. Obviously, this complication was not very seriously taken into account since most of the cases of pneumonia were diagnosed without radiographic confirmation. Later, using a nested case-control design, Ernst and colleagues4Ernst P Gonzalez AV Brassard P Suissa S Inhaled cortico steroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia.Am J Respir Crit Care Med. 2007; 176: 162-166Crossref PubMed Scopus (353) Google Scholar showed that the risk for CAP requiring hospitalization was increased in patients with COPD who were taking inhaled steroids and that this risk depended on the dosage and duration of treatment. The risk for severe pneumonia leading to death within 30 days of hospitalization was also increased. In an accompanying editorial, a prospective evaluation based on a radiographic definition of pneumonia was recommended.5Woodhead M Inhaled corticosteroids cause pneumonia … or do they?.Am J Respir Crit Care Med. 2007; 176: 111-112Crossref PubMed Scopus (16) Google Scholar The subsequent Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) study comparing salmeterol plus fluticasone propionate 50/500 μg bid (SFC) with tiotropium bromide 18 μg once a day (Tio) found that despite the rates of exacerbations being similar in both groups, mortality was lower in the SFC arm. However, the rate of CAP in the arm receiving inhaled steroids was double (8%) that of the ipratropium arm (4%).6Wedzicha JA Calverley PM Seemungal TA Hagan G Ansari Z Stockley RA INSPIRE Investigators The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.Am J Respir Crit Care Med. 2008; 177: 19-26Crossref PubMed Scopus (738) Google Scholar Again, some of the cases of pneumonia were not radiographically confirmed. In the present issue of CHEST (see page 505), Calverley and colleagues7Calverley PMA Stockley RA Seemungal TA on behalf of the INSPIRE Investigators et al.Reported pneumonia in patients with COPD: findings from the INSPIRE study.Chest. 2011; 139: 505-512Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar report the findings of a post hoc analysis of pneumonia cases from the INSPIRE study. These authors reviewed the records of the patients in whom pneumonia was reported as a side effect, using a rule-based approach to define three situations: (1) pneumonia following an untreated resolved exacerbation or an acute exacerbation that resolved with health-care use (treatment with oral corticosteroids and/or antibiotics or by hospitalization), (2) pneumonia following an exacerbation treated via health-care use or an untreated unresolved exacerbation, and (3) de novo pneumonia. A total of 87 cases of pneumonia were reported, with 71 being classified as severe events. Radiographic examinations were performed in 64 patients, and 50 showed the presence of pulmonary infiltrates. The estimated on-treatment probability of having pneumonia within 2 years was 9.4% in the SFC arm and 4.9% in the Tio arm. The hazard ratio for time to the first onset of pneumonia was 1.94 for SFC vs Tio. Almirall and colleagues8Almirall J Bolíbar I Serra-Prat M the Community-Acquired Pneumonia in Catalan Countries (PACAP) Inhaled drugs as risk factors for community-acquired pneumonia.Eur Respir J. 2010; 36: 1080-1087Crossref PubMed Scopus (31) Google Scholar investigated the risk of acquiring pneumonia during a 1-year period in a case-control study. In patients with COPD, the use of inhaled steroids had a relative risk of 3.26, while inhaled β2-agonists did not show a significant effect. From these studies,3Calverly PM Anderson JA Celli B TORCH Investigators et al.Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 775-789Crossref PubMed Scopus (2835) Google Scholar, 4Ernst P Gonzalez AV Brassard P Suissa S Inhaled cortico steroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia.Am J Respir Crit Care Med. 2007; 176: 162-166Crossref PubMed Scopus (353) Google Scholar, 7Calverley PMA Stockley RA Seemungal TA on behalf of the INSPIRE Investigators et al.Reported pneumonia in patients with COPD: findings from the INSPIRE study.Chest. 2011; 139: 505-512Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 8Almirall J Bolíbar I Serra-Prat M the Community-Acquired Pneumonia in Catalan Countries (PACAP) Inhaled drugs as risk factors for community-acquired pneumonia.Eur Respir J. 2010; 36: 1080-1087Crossref PubMed Scopus (31) Google Scholar we can conclude that the prolonged use of inhaled steroids increases the risk of acquiring CAP. Although we have to admit that the definition of pneumonia was not predetermined in two trials3Calverly PM Anderson JA Celli B TORCH Investigators et al.Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 775-789Crossref PubMed Scopus (2835) Google Scholar, 8Almirall J Bolíbar I Serra-Prat M the Community-Acquired Pneumonia in Catalan Countries (PACAP) Inhaled drugs as risk factors for community-acquired pneumonia.Eur Respir J. 2010; 36: 1080-1087Crossref PubMed Scopus (31) Google Scholar and that a proportion of cases of pneumonia were diagnosed without radiographic confirmation, the overall trend seems clear. The pathophysiologic basis behind this finding could involve a decrease in the cellular alveolar defenses, which can occur in patients treated with inhaled steroids over a long period of time. Some have speculated that the type of inhaled steroid and the form of administration could influence the risk of developing CAP. It has been suggested that fluticasone carries a higher risk since it has a higher antiinflammatory effect and a more effective alveoli deposition compared with budesonide. In a meta-analysis of seven randomized trials comparing inhaled budesonide with controls, Sin and colleagues9Sin DD Tashkin D Zhang X et al.Budesonide and the risk of pneumonia: a meta-analysis of individual patient data.Lancet. 2009; 374: 712-719Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar did not find an increased risk of pneumonia. Several limitations of this meta-analysis were subsequently corrected in an update of 24 randomized clinical trials.10Singh S Loke YK Risk of pneumonia associated with long-term use of inhaled corticosteroids in chronic obstructive pulmonary disease: a critical review and update.Curr Opin Pulm Med. 2010; 16: 118-122Crossref PubMed Scopus (95) Google Scholar In this updated meta-analysis, the relative risk of pneumonia with inhaled corticosteroids was 1.57. Inhaled fluticasone and mometasone remained significantly associated with an increase in the risk of pneumonia. Evidence as to whether budesonide is different from other inhaled corticosteroids remains inconclusive. The present study by Calverley et al7Calverley PMA Stockley RA Seemungal TA on behalf of the INSPIRE Investigators et al.Reported pneumonia in patients with COPD: findings from the INSPIRE study.Chest. 2011; 139: 505-512Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar adds important information to the issue of inhaled steroids and their impact on pneumonia. It shows that the clinical path prior to the development of pneumonia can be different. In this context, the finding that inhaled steroids are particularly involved in patients with a history of a protracted period of symptoms prior to the development of pneumonia is highly challenging. Currently, careful clinical observation of such patients seems prudent. Further studies are urgently needed to clarify the exact mechanisms behind this sequence. Some studies have suggested that COPD may be a protective factor for better outcomes (protecting against treatment failure, pulmonary complications, systemic complications, and mortality) in patients with CAP.11Menéndez R Torres A Zalacaín R Neumofail Group et al.Risk factors of treatment failure in community acquired pneumonia: implications for disease outcome.Thorax. 2004; 59: 960-965Crossref PubMed Scopus (236) Google Scholar There is no clear explanation for this finding, but in a recent cellular study by our group,12Gutierrez P Closa D Piñer R Bulbena O Menéndez R Torres A Macrophage activation in exacerbated COPD with and without community-acquired pneumonia.Eur Respir J. 2010; 36: 285-291Crossref PubMed Scopus (40) Google Scholar we observed the activation of different phenotype macrophages when comparing CAP with and without COPD that may be indicative of different inflammatory responses. This study has shown that the microenvironment in the lung modulates the classic M1 activation associated with the antimicrobial activity of alveolar macrophages, with significant increases in the expression of tumor necrosis factor-α and IL-6. Bacterial products may be involved in this effect, together with different cytokines or lipid mediators, such as lipopolysaccharide, that also promote and maintain the M1 response, resulting in positive proinflammatory feedback. By contrast, this type of activation was not observed in patients with COPD exacerbation or those with CAP and COPD. This different type of activation induces different inflammatory responses and may be involved in the better outcomes for patients with CAP that were observed in some studies when COPD and CAP presented simultaneously. The role that inhaled steroids might play in all of this is unknown. In summary, there is evidence showing an increased risk of acquiring CAP with the use of inhaled steroids in patients with COPD. The dosages and period of administration dependance requires futher investigations.13Mapel D Schum M Yood M et al.Pneumonia among COPD patients using inhaled corticosteroids and long-acting bronchodilators.Prim Care Respir J. 2010; 19: 109-117Crossref PubMed Scopus (27) Google Scholar, 14Ferguson GT Anzueto A Fei R et al.Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations.Respir Med. 2008; 102: 1099-1108Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar The role of the type of inhaled steroids is still a matter of debate. Patients on inhaled steroids with treated or untreated unresolved exacerbations of COPD are those found to be at increased risk of pneumonia." @default.
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• W1994153209 title "The Strange Case of Community-Acquired Pneumonia in COPD" @default.
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