Chronic obstructive pulmonary disease and lung cancer: new molecular insights. I.M. Adcock, G. Caramori, P.J. Barnes. Respiration. 2011;81(4):265–84. Epub 2011 Mar 24.
Both chronic obstructive pulmonary disease (COPD) and lung cancer are major causes of death worldwide. In most cases this reflects cigarette smoke exposure which is able to induce an inflammatory response in the airways of smokers. Indeed, COPD is characterized by lower airway inflammation, and importantly, the presence of COPD is by far the greatest risk factor for lung cancer amongst smokers. Cigarette smoke induces the release of many inflammatory mediators and growth factors including TGF-β, EGFR, IL-1, IL-8 and G-CSF through oxidative stress pathways and this inflammation may persist for decades after smoking cessation. Mucus production is also increased by these inflammatory mediators, further linking airway inflammation to an important mechanism of lung cancer. A greater understanding of the molecular and cellular pathobiology that distinguishes smokers with lung cancer from smokers with and without COPD is needed to unravel the complex molecular interactions between COPD and lung cancer. By understanding the common signalling pathways involved in COPD and lung cancer the hope is that treatments will be developed that not only treat the underlying disease process in COPD, but also reduce the currently high risk of developing lung cancer in these patients.
Comments: This is a thought provoking and informative review of the relationships between smoking, COPD and lung cancer. It is clear that those who have the genetic predisposition to develop a tissue injury (inflammatory/oxidative stress) response to cigarette smoke are some of the same individuals that have a higher likelihood of developing lung cancer due to cigarette smoking. The authors provide a cogent argument for why it should be possible to reduce the risk of lung cancer in such patients if we are able to suppress certain key elements of the tissue injury response that occurs in susceptible smokers and ex-smokers that develop COPD.
Reported Pneumonia in Patients With COPD: Findings From the INSPIRE Study. P.M.A. Calverley, R.A. Stockley, T.A. Seemungal, G. Hagan, L.R. Willits, J.H. Riley, J.A. Wedzicha, on behalf of the Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) Investigators. Chest. 2011 Mar;139(3):505–512.
BACKGROUND: Pneumonia is an important complication of COPD and is reported more often in patients receiving inhaled corticosteroids (ICSs). Little is known about the clinical course and factors predisposing to pneumonia in patients with COPD. We investigated patient characteristics and symptoms occurring before pneumonia reports in the Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) study.
METHODS: This was a 2-year, double-blind, double-dummy parallel study of 1,323 patients randomized to salmeterol/fluticasone propionate 50/500 μg bid (SFC) or tiotropium 18 μg once daily (Tio). Baseline demographics, including serum C-reactive protein (CRP) levels, were measured, and daily record cards (DRCs) were completed.
RESULTS: We identified 87 pneumonia reports from adverse event records (SFC = 62; Tio = 25) in 74 patients (SFC = 50; Tio = 24), compared with 2,255 exacerbations (SFC = 1,185; Tio = 1,070). Pneumonia was more common in patients with severe dyspnea and in those with a baseline CRP level > 10 mg/L. Numbers of de novo pneumonias (events that were not preceded by symptoms of an exacerbation) were similar between treatment groups, but pneumonia was more likely after either a treated or untreated unresolved exacerbation in patients receiving ICSs (SFC = 32; Tio = 7). Similar results were seen when analysis was confined to radiologically confirmed events.
CONCLUSIONS: Pneumonia is much less frequent than exacerbation in COPD. The excess of events with ICS treatment appears to be associated with protracted symptomatic exacerbations. Earlier identification and treatment of these events to prevent pneumonia merits further investigation.
Comments: The core finding of this study is that subjects on inhaled steroids with treated or untreated unresolved exacerbations of COPD are those found to be at increased risk of pneumonia. This still leaves the question of whether subjects on ICS are less likely to have purely inflammatory exacerbations and thus increase the likelihood (select) for having infectious related exacerbations that eventually may overwhelm the immunosuppressive effects of the ICS and manifest as pneumonia. This could help to explain the higher dropout rate of those on tiotropium (who may have left because of a severe exacerbation and be put on antibiotics once they left the trial) and also could help to explain why less potent steroids may seem to be less commonly associated with pneumonia. I agree with the authors that the reductions in exacerbations overall outweigh the number of pneumonia events and that the most prudent course from a clinician perspective may be to focus on how to identify such events earlier or have a higher index of suspicion of infection related exacerbations for patients on ICS.
Impact of Inhaled corticosteroid use on outcome in COPD patients admitted with pneumonia. A. Singanayagam, J.D. Chalmers, A.R. Akram, A.T. Hill. Eur Respir J. 2011 Mar 23.
The aim of this study was to investigate if inhaled corticosteroid(ICS) use impacts on outcome in patients with chronic obstructive pulmonary disease(COPD) admitted with community-acquired pneumonia(CAP). A prospective observational study of patients with spirometry-confirmed COPD presenting with a primary diagnosis of CAP in Lothian, UK. Outcome measures were compared between ICS users and non-users. Of 490 patients included in the study, 76.7% were classified as ICS users. ICS users had higher GOLD stage compared with non-users (mean(SD) 3.2(0.8) vs 2.6(0.9); p < 0.0001). There were no significant differences in pneumonia severity (mean(SD) pneumonia severity index(PSI) 4.2(0.8) vs 4.3(0.8), p = 0.3; mean(SD) CURB65 score 2.1(1.3) vs 2.3(1.3), p = 0.07) or markers of systemic inflammation (median CRP 148(58–268) vs 183(85–302) mg·L(−1); p = 0.08) between ICS users and non-users. On multivariable analysis, after adjustment for COPD severity and PSI, ICS use was not independently associated with 30-day mortality (OR 1.71 [95% CI 0.75–3.90], p = 0.2), 6-month mortality (OR 1.62 [95% CI 0.82–3.16], p = 0.2), requirement for mechanical ventilation and/or inotropic support (OR 0.73 [95% CI 0.33–1.62], p = 0.4) or development of complicated pneumonia (OR 0.71 [95% CI 0.25–1.99], p = 0.5). Prior ICS use has no impact on outcome in patients with COPD admitted with CAP.
Comments: With the ongoing concern and indeed controversy as to the link between ICS use and the development of pneumonia this study is hopefully reassuring for many and perhaps reflects their clinical experience with regard to ICS use and the risk of pneumonia. Even with the findings of this study it is still critical for us to more clearly delineate the relationship between ICS use and the development of Pneumonia.
Mannose-Binding Lectin Gene Polymorphism Contributes to Recurrence of Infective Exacerbation in Patients With COPD. C.L. Lin, L.K. Sium J.C. Lin, C.Y. Liu, C.F Chian, C.N. Lee, F.Y Chang. Chest. 2011 Jan;139(1):43–51.
BACKGROUND: Mannose-binding lectin (MBL) deficiency is associated with susceptibility to respiratory infections. We investigated the impact of MBL2 gene polymorphisms and MBL deficiency on the recurrence of infective exacerbation in patients with COPD.
METHODS: A prospective study was conducted among 215 patients with COPD and 137 healthy subjects. MBL deficiency was determined by the MBL2 gene polymorphisms and serum levels of MBL.
RESULTS: The average frequency of infective exacerbations over 3 years in the 215 patients with COPD was 2.5 ± 1.3 episodes. The COPD group with three or more episodes of infective exacerbation (recurrent exacerbators) included 96 patients, and the remaining 119 patients had two or fewer episodes (less-frequent exacerbators). Among the 96 recurrent exacerbators, 12 (12.50%) had the MBL deficiency genotype compared with 5 (4.20%) among the less-frequent exacerbators (OR, 3.25; 95% CI, 1.01–11.07; P = .0253). In recurrent exacerbators, the frequency of infective exacerbation was significantly higher in patients with MBL-deficient genotypes than in those with non-MBL-deficient genotypes (4.75 ± 1.22 vs 3.52 ± 0.78, respectively; P < .0001). In addition, mortality was significantly increased in recurrent exacerbators with MBL-deficient genotypes compared with those with non-MBL-deficient genotypes (66.7% vs 31.0%, respectively; P = .0153).
CONCLUSIONS: MBL deficiency due to MBL2 polymorphisms increases the risk of recurrent infective exacerbation and worsens its outcome in patients with COPD.
Comments: The work by this group and others certainly gives credence to the notion that there are frequent exacerbator subgroups or phenotypes with some related to genetic predisposition (likely a complex heterogeneous group) and others likely related to clinical characteristics such as airway structural damage and remodeling, bacterial colonization and/or co-morbidities such as cardiovascular disease, or GERD and aspiration. Further work to define these phenotypes is critical to individualize care and reduce exacerbation frequency and its attendant complications.