A novel insight into adaptive immunity in chronic obstructive pulmonary disease: B cell activating factor belonging to the tumor necrosis factor family. F. Polverino, S. Baraldo, E. Bazzan, S. Agostino, G, Turato, F. Lunardi, E. Balestro, M. Damin, A. Papi, P. Maestrelli, F. Calabrese, M. Saetta. Am J Respir Crit Care Med. 2010 Oct 15;182(8):1011–9.
RATIONALE: Chronic obstructive pulmonary disease (COPD) is a disorder characterized by an abnormal inflammatory response that persists even after smoking cessation, yet the underlying mechanisms are not fully understood.
OBJECTIVES: To investigate the expression of B-cell activating factor of tumor necrosis factor family (BAFF), a crucial mediator in the crosstalk between innate and adaptive immune responses, in patients with COPD and to explore its correlation with disease severity.
METHODS: Using immunohistochemistry, expression of BAFF was examined in lung specimens from 21 smokers with COPD (FEV(1) = 57 ± 5% predicted), 14 control smokers (FEV(1) = 99 ± 2% predicted) and 8 nonsmokers (FEV(1) = 104 ± 4% predicted). BAFF was quantified in alveolar macrophages and alveolar walls, in bronchiolar and parenchymal lymphoid follicles, and in peripheral airways and pulmonary arterioles.
MEASUREMENTS AND MAIN RESULTS: In alveolar macrophages and parenchymal lymphoid follicles, BAFF expression was increased in smokers with COPD compared with control smokers and nonsmokers (P < 0.05 for all comparisons). In both compartments, BAFF was also up-regulated in control smokers as compared with nonsmokers (P = 0.03 and P = 0.01). Moreover, BAFF was overexpressed in bronchiolar lymphoid follicles, alveolar walls, peripheral airways, and pulmonary arterioles from smokers with COPD compared with nonsmokers (P < 0.05 for all). Among patients with COPD, BAFF(+) macrophages were inversely related to FEV(1) (P = 0.03, Spearman's rho [r(S)] = −0.48), FEV(1)/FVC (P = 0.02, r(S) = −0.50), and Pa(O(2)) values (P = 0.01, r(S) = −0.55).
CONCLUSIONS: This study demonstrated overexpression of BAFF in peripheral lung of patients with COPD, mainly in alveolar macrophages and lymphoid follicles. Moreover, BAFF expression was correlated to the degree of lung function impairment and hypoxia, suggesting that it may have a possible impact on disease severity.
Comments: While we understand that COPD is an inflammatory disease we don't by any means understand the complexity of the inflammatory response or the pathogenesis of persistent inflammation even after a person discontinues smoking. Tissue for this study was from lung volume reduction specimens for those with COPD and from specimens obtained for removal of nodules or suspected carcinomas for the non COPD subjects. Subjects could not have evidence of an exacerbation for more than a month prior to tissue procurement. This study helps us understand that indeed there is likely some form of autoimmunity switched on by the injury that cigarette smoke causes in those individuals genetically susceptible and that it will lead to variable inflammatory responses likely related to several different factors. Certainly a better understanding of the process may lead to novel and more specific therapeutic targets for treating patients with COPD.
Characterizing and Quantifying the Symptomatic Features of COPD Exacerbations. P. W. Jones, W.H. Chen, T.K. Wilcox, S. Sethi, N.K. Leidy; the EXACT-PRO Study Group. Chest 2010 Nov 11. [Epub ahead of print].
BACKGROUND: There is a need for a standardized, valid, and reliable instrument for quantifying exacerbations of chronic obstructive pulmonary disease (COPD).
OBJECTIVE: To identify symptom items that characterize COPD exacerbations to form a new patient diary for evaluating exacerbation frequency, severity, and duration.
METHODS: 23 symptom items identified from patient interviews were administered to 410 COPD patients with mean age 65 ±10 (SD) years, stable FEV(1) 51 ± 20% predicted; mean of 1.8 ± 1.8 exacerbations in the preceding 12 months. 222 had a physician-diagnosed exacerbation; 188 were stable. Item-level analyses (floor and ceiling effects, criterion keying, item-total correlation) were used in the first stage of item reduction. Further reduction was conducted using Rasch model and descriptive item analyses. Exploratory factor analysis (EFA) was performed on the items that survived the exclusion process.
RESULTS: No item behaved differently between stable and exacerbation. One item was removed after item-level analysis, 8 were removed following Rasch analysis. Together, the surviving 14 items met the criteria for a unidimensional measure of exacerbation severity. Internal consistency (Person Separation Index) was excellent at 0.92. Post-hoc EFA revealed one dominant factor, with three domains (breathlessness, cough and sputum, chest symptoms) that accounted for 68% of the variance.
CONCLUSIONS: An exacerbation appears to be a quantitative rather than qualitative change from the stable state. This analysis identified a range of symptoms that form a unidimensional construct of overall exacerbation severity. The 14-items identified form the EXACT, a daily diary for detecting and quantifying exacerbation severity in COPD.
Comments: Exacerbations remain one of if not the major source of health care costs for patients with COPD and as yet an instrument has not been established that allows one to quantify the severity of a COPD exacerbation either for decisions of empiric initial therapy, predicting prognosis, or assessing impact of therapeutic or other interventions. This questionnaire has 14 items which may still be too long for use in regular clinical practice, however, if possible, further validation and refinement to a smaller set of questions (5–7) may result in its adoption beyond clinical research.
Susceptibility to exacerbation in chronic obstructive pulmonary disease. J.R. Hurst, J. Vestbo, A. Anzueto, N. Locantore, H. Mullerova, R. Tal-Singer, B. Miller, D.A. Lomas, A. Agusti, W. Macnee, P. Calverley, S. Rennard, E.F. Wouters, J.A. Wedzicha; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. N Engl J Med. 2010 Sep 16;363(12):1128–38.
BACKGROUND: Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity.
METHODS: We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years.
RESULTS: Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count.
CONCLUSIONS: Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
Comments: This article helps us to understand that there is clearly a frequent exacerbation sub-phenotype that cannot be identified on basis of COPD stage (i.e. lung function) alone. There has been increasing evidence supporting that reflux disease or heartburn may be associated with this exacerbation phenotype. There is also reported a high incidence of aspiration in patients with COPD likely related to age and other co-morbid conditions. Whether reflux is a cause for frequent exacerbations or whether frequent exacerbations and attendant medication use and comorbidities promote reflux is a question that requires further study. This study suggests that perhaps documentation of dates should be a standard component of our medical records as a way of sub phenotyping our COPD patients. This may allow more rationale use of current and future medications.
Chronic macrolide therapy in inflammatory airways diseases. A.L. Friedlander, R.K. Albert. Chest 2010 Nov;138(5)1202–12.
Long-term therapy with the macrolide antibiotic erythromycin was shown to alter the clinical course of diffuse panbronchiolitis in the late 1980s. Since that time, macrolides have been found to have a large number of antiinflammatory properties in addition to being antimicrobials. These observations provided the rationale for many studies performed over the last decade to assess the usefulness of macrolides in other inflammatory airways diseases, such as cystic fibrosis, asthma, COPD, and bronchiolitis obliterans syndrome. This review summarizes the immunomodulatory properties of macrolides and the results of these recent studies demonstrating their potential for being disease-modifying agents.
Comments: This is an excellent review for the clinician of the science behind the anti-inflammatory properties of macrolides and the rationale for their use in patients with a host of chronic obstructive lung diseases including COPD. The article also provides a summary of the trials that have been published to date and the current large scale NIH funded trial on use of azithromycin in COPD patients that have been recently completed but results not presented to date.