Serum PARC/CCL-18 Concentrations and Health Outcomes in Chronic Obstructive Pulmonary Disease. D.D. Sin, B. Miller, A. Duvoix, S.F. Man, X. Zhang, E.K. Silverman, J.E. Connett, N.A. Anthonisen, R.A. Wise, D. Tashkin, B.R. Celli, L. Edwards, N. Locantore, W. Macnee, R. Tal-Singer, D.A. Lomas, on behalf of the ECLIPSE Investigators. Am J Respir Crit Care Med. 2011 Jan 14. [Epub ahead of print]
RATIONALE: There are no accepted blood based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum.
OBJECTIVES: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical endpoints of hospitalization and mortality.
MEASUREMENTS: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and LHS (Lung Health Study) studies and a prednisolone intervention study.
RESULTS: Serum PARC/CCL-18 levels were higher in COPD than in smokers or lifetime non-smokers without COPD (105 ng/mL vs 81 ng/mL vs 80 ng/mL; p < .0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort.
CONCLUSIONS: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD. www.clinicaltrials.gov NCT00292552.
Comments: To move forward in developing new drugs for COPD it is important that we have a better understanding of the pathogenesis of COPD and have useful biomarkers to differentiate sub-phenotypes, response to therapy and perhaps prognosis. PARC/CCL-18 may have advantages over other biomarkers such as CRP as it is secreted predominantly (but not exclusively) in the lung by monocytes/macrophages and dendritic cells. The fact that the assessment of this biomarker in the blood had better correlations with cardiovascular mortality than with such things as FEV-1 or GOLD stage could reflect that PARC tracks extra-pulmonary manifestations of COPD better than the process in the lungs. It is likely that a number of new biomarkers will be needed to adequately follow the pulmonary and extrapulmonary effects of COPD.
Statin Reverses Smoke-induced Pulmonary Hypertension and Prevents Emphysema but Not Airway Remodeling. J. L. Wright, S. Zhou, O. Preobrazhenska, C. Marshall, D.D. Sin, I. Laher, S. Golbidi, A.M. Churg. Am J Respir Crit Care Med 2011 Jan 1;183(1):50-8.
RATIONALE: The potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect.
OBJECTIVES: To determine whether an intervention of simvastatin could alter cigarette smoke-induced pulmonary hypertension.
METHODS: We exposed guinea pigs to cigarette smoke for 6 months. In half the animals, simvastatin therapy was initiated after 3 months of smoke exposure. Pulmonary arterial systolic pressures were monitored weekly with a radiotelemetric catheter; additional physiologic and morphologic measurements were made at sacrifice after 6 months. Precision-cut lung explants were assessed for evidence of endothelial dysfunction, and in situ vascular nitric oxide generation was measured with 4,5-diaminofluorescein diacetate.
MEASUREMENTS AND MAIN RESULTS: Cigarette smoke increased the pulmonary arterial systolic pressure after approximately 4 weeks. Simvastatin returned the pressure to control levels within 4 weeks of starting treatment, and ameliorated smoke-induced small arterial remodeling as well as emphysema measured both physiologically and morphometrically at 6 months, but did not prevent smoke-induced small airway remodeling either physiologically or morphologically. In precision-cut lung slices simvastatin reversed small arterial endothelial dysfunction, and partially reversed smoke-induced loss of vascular nitric oxide generation.
CONCLUSIONS: Simvastatin, as an intervention therapy, reverses the pulmonary vascular effects of cigarette smoke, including pulmonary hypertension, and prevents smoke-induced emphysema, but does not prevent small airway remodeling. This is the first demonstration that an intervention can reverse a COPD-associated cigarette smoke-induced anatomic abnormality. The study also shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD.
Comments: There are now several articles in the literature that suggest that statins may reduce exacerbation and mortality while improving pulmonary function, exercise tolerance, pulmonary hypertension and markers of inflammation in patients with COPD yet the results remain controversial and the underlying mechanism is not understood. Previous animal studies have shown the ability of statins to inhibit pulmonary hypertension and emphysema in rat lungs and have suggested reductions in airway remodeling. While the numbers of animals in each study group are small (4), this study also suggests that the underlying mechanisms of pulmonary hypertension in patients with COPD likely have less to do with reflex vasoconstriction due to chronic hypoxemia and loss of vascular bed in emphysematous lung and more to do with increased generation of active vasoconstrictors and vaso-proliferative mediators such as vascular endothelial growth factor (VEGF) and endothelin-1. Translating this line of investigation to humans will be critical to establishing whether or not it is only specific subsets of COPD patients with emphysema and/or pulmonary hypertension that are the ones that should be given statins for a COPD indication regardless of their lipid status. Part of the controversy and mixed results of previous studies may be related to differences in subject selection characteristics.
Eur Respir J. 2010 Oct;36(4):751–7. Epub 2010 Apr 22.
Inhaled corticosteroid use is associated with lower mortality for subjects with COPD and hospitalised with pneumonia. R. Malo de Molina, E.M. Mortensen, M.I. Restrepo, L.A. Copeland, M.J. Pugh, A. Anzueto. Eur Respir J. 2010 Oct;36(4):751–7.
Recent studies suggest that use of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) may be associated with a higher incidence of pneumonia. However, it is unclear whether COPD subjects on ICS who develop pneumonia have worse outcomes. Therefore, our aim was to examine the association of prior outpatient ICS therapy with mortality in hospitalised COPD subjects with pneumonia. We included subjects ≥64 yrs of age, hospitalised with pneumonia in US Veterans Affairs hospitals, and assessed the association of ICS exposure with mortality for hospitalised COPD subjects with pneumonia in a covariate-adjusted regression model. We identified 6,353 subjects with a diagnosis of pneumonia and prior COPD, of whom 38% were on ICS. Mortality was 9% at 30 days and 16% at 90 days. In regression analyses, outpatient ICS therapy was associated with lower mortality at both 30 days (OR 0.76, 95% CI 0.70–0.83), and 90 days (OR 0.80, 95% CI 0.75–0.86). Outpatient therapy with ICS was associated with a significantly lower 30- and 90-day mortality in hospitalised COPD patients with pneumonia.
Comments: Whether inhaled corticosteroids (ICS) actually lead to a higher incidence of pneumonia in subjects with COPD remains controversial. The observations may be a function of the detection of “pneumonia” in the ICS group in the context of a randomized control trial where those not on anti-inflammatory medications exacerbate due to purely inflammatory (non-infectious) etiologies while those on ICS are therefore more likely to have an infection related exacerbation that may be labeled as “pneumonia” (often without radiographic confirmation). It is possible that the immunosuppression caused by ICS could render subjects more susceptible to more severe infective exacerbations or pneumonia but this study would suggest that is not the whole story. While the study is retrospective in nature, the findings are fairly compelling that ICS use reduced the 30 and 90 day mortality of patients admitted with a diagnosis of pneumonia. Note that the ICS cohort included those who were on ICS alone or as combination therapy. There were no differences with regard to oral corticosteroid use between the ICS group and the non ICS use group. Since we do not know the overall use of ICS in the broader cohort of Veteran patients with COPD we cannot calculate if there was a higher incidence of pneumonia in ICS users versus non ICS users. Nonetheless, it is worth noting that only 38% of the pneumonia cases detected were in ICS users.
Procalcitonin vs C-reactive protein as predictive markers of response to antibiotic therapy in acute exacerbations of COPD. J.M. Daniels, M. Schoorl, D. Snijders, D.L. Knol, R. Lutter, H.M. Jansen, W.G. Boersma. Chest. 2010 Nov;138(5):1108–15.
BACKGROUND: Rational prescription of antibiotics in acute exacerbations of COPD (AECOPD) requires predictive markers. We aimed to analyze whether markers of systemic inflammation can predict response to antibiotics in AECOPD.
METHODS: We used data from 243 exacerbations out of 205 patients from a placebo-controlled trial on doxycycline in addition to systemic corticosteroids for AECOPD. Clinical and microbiologic response, serum C-reactive protein (CRP) level (cutoffs 5 and 50 mg/L), and serum procalcitonin level (PCT) (cutoffs 0.1 and 0.25 μg) were assessed.
RESULTS: Potential bacterial pathogens were identified in the majority of exacerbations (58%). We found a modest positive correlation between PCT and CRP (r = 0.46, P < .001). The majority of patients (75%) had low PCT levels, with mostly elevated CRP levels. Although CRP levels were higher in the presence of bacteria (median, 33.0 mg/L [interquartile range, 9.75–88.25] vs 17 mg/L [interquartile range, 5.0–61.0] [P = .004]), PCT levels were similar. PCT and CRP performed similarly as markers of clinical success, and we found a clinical success rate of 90% in patients with CRP ≤ 5 mg/L. A significant effect of doxycycline was observed in patients with a PCT level < .1μg/L (treatment effect, 18.4%; P = .003). A gradually increasing treatment effect of antibiotics (6%, 10%, and 18%), although not significant, was found for patients with CRP values of ≤5, 6–50, and >50 mg/L, respectively.
CONCLUSIONS: Contrary to the current literature, this study suggests that patients with low PCT values do benefit from antibiotics. CRP might be a more valuable marker in these patients.
Comment: The utility of Procalcitonin in guiding antibiotic therapy has been controversial and this study just further adds to the controversy. Clearly there are many patients with low Procalcitonin levels that may have pathogens and respond to antibiotic therapy. Further while the cutoff of CRP > than 50 mg/L was a good predictor of a good antibiotic response, the large inter-quartile range suggests that there are many patients that could benefit with CRP levels that are lower. In this study they excluded patients with fever to hopefully reduce the number of patients in the study that had pneumonia. Despite this they still found potential pathogens in 58% of patients. Hence, while the use of biomarkers to help guide antibiotic therapy is a great concept, this study suggests that we still do not have markers that have great clinical utility.