National Emphysema Treatment Trial State of the Art: Genetics of Emphysema; C. P. Hersh, D. L. DeMeo, E. K. Silverman (Proc Am Thorac Soc 2008 May 1;5(4):486–493).
Although a hereditary contribution to emphysema has been long suspected, severe α1-antitrypsin deficiency remains the only conclusively proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Recently, genome-wide linkage analysis has led to the identification of two promising candidate genes for COPD: TGFB1 and SERPINE2. Like multiple other COPD candidate gene associations, even these positionally identified genes have not been universally replicated across all studies. Differences in phenotype definition may contribute to nonreplication in genetic studies of heterogeneous disorders such as COPD. The use of precisely measured phenotypes, including emphysema quantification on high-resolution chest computed tomography scans, has aided in the discovery of additional genes for clinically relevant COPD-related traits. The use of computed tomography scans to assess emphysema and airway disease as well as newer genetic technologies, including gene expression microarrays and genome-wide association studies, has great potential to detect novel genes affecting COPD susceptibility, severity, and response to treatment.
Comments: The genetics of COPD are clearly highly complex and involve significant gene-environment interaction. The authors provide a succinct yet excellent overview of the current knowledge and understanding of the genetics of COPD. They discuss alpha 1 antitrypsin as the prototype for the study of COPD genetics but then describe other candidate genes according to the current methods available for the study of COPD genetics. They also point out the challenges, limitations and complexity of studying the genetics of COPD and finally outline the ways in which understanding the genetics may allow early detection and, predict response to current and novel therapies including lung volume reduction surgery. The authors also outline the dearth of data and the need for further studies in particular groups such as African Americans and Hispanics.
The Effects of Fluticasone with or without Salmeterol on Systemic Biomarkers of Inflammation in Chronic Obstructive Pulmonary Disease; D. D. Sin, S. F. P. Man, D. D. Marciniuk, G. Ford, M. FitzGerald, E. Wong, E. York, R. R. Mainra, W. Ramesh, L. S. Melenka, E. Wilde, R. L. Cowie, D. Williams, W. Q. Gan, R. Rousseau for the ABC (Advair, Biomarkers in COPD) Investigators (Am J Respir Crit Care Med 2008 Jun 1;177(11):1207–1214).
Rationale. Small studies have suggested that inhaled corticosteroids can suppress systemic inflammation in chronic obstructive pulmonary disease (COPD).
Objectives. To determine the effect of inhaled corticosteroids with or without long-acting β 2-adrenergic agonist on systemic biomarkers of inflammation.
Methods. We conducted a double-blind randomized placebo-controlled trial across 11 centers (n = 289 patients with FEV1 of 47.8 ± 16.2% of predicted) to compare the effects of inhaled fluticasone alone or in combination with salmeterol against placebo on circulating biomarkers of systemic inflammation over 4 weeks. The primary endpoint was C-reactive protein (CRP) level. Secondary molecules of interest were IL-6 and surfactant protein D (SP-D).
Measurements and Main Results. Neither fluticasone nor the combination of fluticasone/salmeterol had a significant effect on CRP or IL-6 levels. There was, however, a significant reduction in SP-D levels with fluticasone and fluticasone/salmeterol compared with placebo (P = 0.002). Health status also improved significantly in both the fluticasone and fluticasone/salmeterol groups compared with placebo, driven mostly by improvements in the symptom scores. Changes in the circulating SP-D levels were related to changes in health status scores. FEV1 improved significantly only in the fluticasone/salmeterol group compared with placebo.
Conclusions. ICS in conjunction with long-acting β2-adrenergic agonist do not reduce CRP or IL-6 levels in serum of patients with COPD over 4 weeks. They do, however, significantly reduce serum SP-D levels. These data suggest that these drugs reduce lung-specific but not generalized biomarkers of systemic inflammation in COPD.
Comments: With increasing interest in characterizing the systemic inflammatory component of COPD this multi center trial sponsored by Glaxo Canada has ambitiously set out to examine the effects of inhaled fluticasone alone or in combination with salmeterol against placebo. Sin and colleagues have been at the forefront of studying the systemic inflammatory response and had earlier reported correlations between COPD severity and IL-6 and CRP levels. Iit is interesting that they now report no effects of Fluticasone or Fluticasone/Salmeterol on CRP or IL-6 levels. The study reports of an association with surfactant protein D as a more specific marker for COPD. There are several reasons this study may not have identified a significant reduction of CRP and IL-6 compared to previous studies. Ppatients had lower lung function and there were more current smokers in the current group plus patients in the current study were likely to have been on inhaled corticosteroids before starting the study. Hence it would seem that we should not discount the potential effects of steroids on these other markers of systemic inflammation until further studies are done on milder patients with better preserved lung function. This may be important from a prevention point of view and may identify a potential benefit of using inhaled corticosteroids earlier in the course of COPD to have a more profound impact on systemic consequences such as cardiovascular disease.
Use of B-type Natriuretic Peptide in the Risk Stratifiaction of Acute Exacerbations of Chronic Obstructive Pulmonary Disease; D. Stolz, T. Breidthardt, M. Christ-Crain, R. Bingisser, D. Miedinger, J. Leuppi, M. Tamm, C. Mueller (Chest 2008 May;133(5):1088–1094).
Background. In patients with chronic obstructive pulmonary disease (COPD) prognosis might be determined at least in part by the extent of cardiac stress induced by hypoxia and pulmonary arterial hypertension.
Methods. B-type natriuretic peptide (BNP), a quantitative marker of cardiac stress, was determined in 208 consecutive patients presenting to the emergency department with an acute exacerbation of COPD (AECOPD). The accuracy of BNP to predict death at 2-years follow up was evaluated as the primary endpoint. The need for intensive care and in-hospital mortality were determined as secondary endpoints.
Results. BNP levels were significantly elevated during the acute exacerbation compared to recovery (65 pg/ml [34–189] vs. 45pg/ml [25–85], p < 0.001), particularly in those patients requiring ICU treatment (105 pg/ml [66–553] vs. 60 pg/ml [31-169], p = 0.007]. In multivariate Cox regression analysis BNP accurately predicted the need for ICU care (HR 1.13; 95%CI 1.03–1.24 for an increase in BNP of 100 pg/ml; p = 0.008). In a receiver operating characteristic (ROC) analysis to evaluate the potential of BNP levels to predict short- and long-term mortality the area under the curves was 0.55 (SD 0.71, 95%CI 0.41–0.68) and 0.56 (SD 0.53; 95%CI 0.45–0.66) respectively.
Conclusions. In patients with AECOPD, BNP levels independently predict the need for intensive care. However, BNP levels failed to adequately predict short-and longterm mortality in AECOPD patients.
Comments: Exacerbations continue to represent the major source of costs involved in care of COPD patients. Finding biological markers or indices that may be used to anticipate exacerbations or perhaps appropriate levels of care could be very useful. The authors hypothesized that hypoxia induced vasoconstriction of small pulmonary arterioles would be associated with increased pulmonary pressures and cardiac stress leading to elevated BNP levels and perhaps correlate with the severity of exacerbation and perhaps short and long term mortality. The primary outcome was whether BNP levels predicted ICU admission. Patients for this study were part of another study examining the utility of using Procalcitonin levels to guide use of antibiotics in COPD. Patients were evaluated by general internists for study recruitment utilizing GOLD criteria. COPD exacerbations were defined and classified according to Anthonison criteria. Outcomes were assessed at 2 years after hospital admission by contacting the patients' family physicians. Echocardiogram results were available from retrospective studies for 157 of the 208 patients and criteria for having evidence of pulmonary hypertension was a pressure above 35 mmHg. Interestingly admission BNP levels were not different between patients with steady state pulmonary hypertension and patients without signs of pulmonary hypertension in their prior echocardiograms. It is not clear that all echocardiograms were obtained during a time when patients were clinically stable from a cardio-pulmonary point of view. Follow up BNP levels were measured 14–18 days after discharge from hospital. Co-morbidities for these patients included cardiomyopathies (44%) (with coronary artery disease (48%) plus hypertensive heart disease in (35%) as the major etiologies for cardiomyopathy) in addition to arterial hypertension (24%) and malignancies 13%). There were 94 (45%) patients that were smokers, however, this did not seem to confer any increase in BNP levels. Hoping to find correlations between a single BNP level at the time of an acute exacerbation (albeit one requiring hospital admission) may be anticipated to not necessarily reflect mortality rates 2 years down the road. There are likely many factors that may affect BNP levels for any given measurement including amongst other things left ventricular systolic and diastolic dysfunction, right ventricular dysfunction, and valvular dysfunction. There are likely more immediate outcomes such as the need for ICU admission, cardiac events, sooner time to next exacerbation or perhaps even predicting benefits of statin therapy on reducing subsequent exacerbations that should be studied to further explore the utility of this biomarker.
Ronald Balkissoon, M.D.