Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. C. Llor, A. Moragas, S. Hernandez, C. Bayona, M. Miravitlles. Am J Respir Crit Care Med. 2012 Oct 15;186(8):716-23. doi: 10.1164/rccm.201206-0996OC. Epub 2012 Aug 23.
RATIONALE: Antimicrobial therapy remains a controversial issue in non-severe exacerbations of chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of antibiotic therapy in moderate exacerbations of mild-to-moderate COPD.
METHODS: This study involved a multicenter, parallel, double-blind, placebo-controlled, randomized clinical trial. Patients aged 40 years or older, smokers, or ex-smokers of 10 pack-years or more with spirometrically confirmed mild-to-moderate COPD (FEV(1) > 50% predicted and FEV(1)/FVC ratio < 0.7) and diagnosed with an exacerbation were enrolled in the study. The patients were randomized to receive amoxicillin/clavulanate 500/125 mg three times a day or placebo three times a day for 8 days
MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was clinical cure at end of therapy visit (EOT) at Days 9 to 11. A total of 310 subjects fulfilled all the criteria for efficacy analysis. A total of 117 patients with amoxicillin/clavulanate (74.1%) and 91 with placebo (59.9%) were considered cured at EOT (difference, 14.2%; 95% confidence interval, 3.7-24.3). The median time to the next exacerbation was significantly longer in patients receiving antibiotic compared with placebo (233 d [interquartile range, 110-365] compared with 160 d [interquartile range, 66-365]; P < 0.05). The best C-reactive protein serum cut-off for predicting clinical failure with placebo was 40 mg/L, with an area under the curve of 0.732 (95% confidence interval, 0.614-0.851).
CONCLUSIONS: Treatment of ambulatory exacerbations of mild-to-moderate COPD with amoxicillin/clavulanate is more effective and significantly prolongs the time to the next exacerbation compared with placebo. Clinical trial registered with www.clinical.gov (NCT00495586).
Comments: This study addresses the question of whether it is efficacious to empirically prescribe Amoxicillin/ Clavulinate for non-severe exacerbations of COPD. Previous exacerbation studies have suggested 30-50 percent of exacerbations may be non-infectious. Non-severe exacerbations were defined as the presence of at least one of: increased dyspnea, increased sputum volume or increased sputum purulence. Oral steroids up to 60 mg per day for 10 days were allowed but not required (16.5% AMX group and 17.8% in PBO group) and no clear criteria were given to differentiate non-severe from severe exacerbation. Chest x-rays were not required to rule out pneumonia and only 64 patients had chest X-rays and 3 cases of pneumonia were excluded. No clear criteria were stipulated for cure. Interestingly there was a statistically higher number of subjects in placebo group that had sputum purulence (65.1%) versus the AMX group (53.8%) (p< 0.05). Baseline ICS/LABA use was 19.6% in the AMX group and 12.5% in the PBO group although this was not statistically significant. The authors recruited less than half of the projected number of patients needed according to their sample size estimate and perhaps full recruitment would have evened out some of the discrepancies between the two groups. While the final results for primary outcome (cure at end of therapy) and secondary outcome, days to next exacerbation were statistically significant, the differences in the groups and lack of clear criteria for various parameters as outlined above still leaves this question not definitively answered by this study.
Comparison of the anti-inflammatory effects of Cilomilast, Budesonide and a p38 Mitogen activated protein kinase inhibitor in COPD lung tissue macrophages. M.J. Ratcliffe, I.G. Dougall. BMC Pharmacol Toxicol. 2012 Nov 13;13(1):15.
Chronic Obstructive Pulmonary Disease (COPD) is a disease characterized by a largely irreversible airflow obstruction and a persistent, excessive inflammatory response. Alveolar macrophages (AMs) are increased in the lungs of COPD patients, and act as orchestrators of the inflammatory response, releasing a range of mediators to coordinate recruitment and activation of leukocytes. Attempts to treat the inflammatory component of COPD with anti-inflammatory drugs such as steroids, has met with limited success. In this study, we compared the ability of the phosphodiesterase IV (PDEIV) inhibitor Cilomilast, the steroid Budesonide, and the p38 mitogen activated protein kinase inhibitor BIRB-796 to inhibit tumour necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) releases from AMs isolated from COPD lung transplant tissue. All studies were carried out with appropriate ethical approval and written, informed consent was obtained from each subject. Cilomilast had little effect on cytokine release from AMs. There was considerable variability in the responsiveness of AMs to Budesonide, with a subset of AMs responding poorly to Budesonide. BIRB-796 inhibited TNFalpha release from all AM donors, including those that responded poorly to steroids. Treatment with BIRB-796 and Budesonide together gave an additive decreased in TNFa release. These results suggest that a p38 inhibitor may provide advantages over existing anti-inflammatory treatments for COPD, either as an add-on to existing therapy, or to treat patients who respond poorly to steroids.
Comment: While the use of inhaled corticosteroids (ICS) as maintenance therapy for at least a subset of patients with COPD has gained acceptance and incorporation into Guidelines it is recognized that the inflammation of COPD is typically less than optimally responsive to steroids. The phosphodiesterase 4 inhibitors have benefited some patients with COPD but have not replaced the role of ICS for the majority of COPD patients. There remains an ongoing quest to find anti-inflammatory agents that target the inflammation found in COPD and the findings from this study suggest that treatment with a p38 Mitogen activated protein kinase (MAP) inhibitor may indeed be better suited to reduce the inflammatory response in COPD.
Statins, systemic inflammation and risk of death in COPD: The Rotterdam study. L. Lahousse, D.W. Loth, G.F. Joos, A. Hofman, H.G. Leufkens, G.G. Brusselle, B.H. Stricker. Pulm Pharmacol Ther. 2012 Nov 7.
BACKGROUND: Studies suggest that statins decrease mortality in COPD patients but it is unknown which patients might benefit most. OBJECTIVES: We investigated whether statins were associated with reduced mortality in COPD patients and whether effects differed according to baseline high-sensitivity C-reactive protein (hsCRP) concentration, a marker of systemic inflammation.
METHODS: This nested case-control study was part of the Rotterdam Study, a prospective population-based cohort study among 7983 subjects ≥ 55 years. Using automated pharmacy records, we evaluated statin use of 363 cases (COPD patients who died during follow-up of 17 years) with 2345 age and sex matched controls (COPD patients who survived the follow-up period of the index case).
RESULTS: Compared to never use, long-term statin use (>2 years) was associated with a 39% decreased risk of death in COPD patients. Stratified according to the level of systemic inflammation, long-term statin use was associated with a 78% reduced mortality if hsCRP level > 3 mg/L, versus a non significant 21% reduced mortality if hsCRP level ≤ 3 mg/L.
CONCLUSIONS: Statin use is associated with a beneficial effect on all-cause mortality in COPD, depending on the baseline level of systemic inflammation.
Comment: It has been reported that there is evidence of persistent systemic inflammation including increased levels of IL-6 and high sensitivity C reactive protein (hsCRP) in COPD patients. Previous reports have demonstrated a correlation between severity of disease and levels of these biomarkers. Statins have lipid lowering effects but also have pleiotropic anti-inflammatory and immune-modulating properties and are able to reduce levels of inflammatory markers such as CRP possibly through mechanisms that involve guanosine triphosphate. Several studies have now demonstrated that subjects that smoke and have COPD are at substantially increased risk of having cardiovascular disease than smokers who do not have COPD. There have been previous systematic reviews and one prospective study that have suggested statins may reduce mortality in COPD. The Rotterdam study is a large prospective population based cohort study of a well defined cohort in a suburb of Rotterdam with long term follow up from 1991- 2008. The population is highly homogenous with over 99.8% of Caucasian decent. Physician diagnosed asthma patients were excluded. Statins included in study were simvastatin pravastatin fluvastatin, atorvastatin, cerivastatin and rosuvastatin. Cases were more frequently current smokers and had a higher prevalence of cardiovascular disease at baseline. In this cohort most cases died due to cardiovascular causes 38.3% followed by pulmonary complications of COPD 19.6%, bronchial carcinoma 10.5%. Cases had slightly higher pack year history 30 (14-50) vs 28 (13-47) diabetes 12% vs 7% and cardiovascular co- variables 45% vs 31%. They also had a much higher rate of use of oral corticosteroids 38% versus 13%. Statin use for more than 2 years was present in only 11% of cases and 12% of controls and for 1 month - 2 years in only 5% and 8% respectively. This study is limited in interpretation as it is an observational study, small number of participants on prolonged statin therapy and a rather homogenous (albeit well characterized) cohort in a nested case control designed study. The findings of this study may simply reflect the reduction in cardiovascular mortality in subjects predisposed to cardiovascular disease from tobacco smoking rather than any effects on the pulmonary disease component of COPD. Currently there is a large prospective randomized control trial funded by the NIH that will address this question more definitively.
Early-Onset Chronic Obstructive Pulmonary Disease Is Associated with Female Sex, Maternal Factors, and African American Race in the COPDGene Study. Marilyn G. Foreman,1 Lening Zhang,2 James Murphy,2 Nadia N. Hansel,3 Barry Make,2 John E. Hokanson,4 George Washko,5 Elizabeth A. Regan,2 James D. Crapo,2 Edwin K. Silverman,5,6 Dawn L. DeMeo,5,6 and the COPDGene Investigators. Am J Respir Crit Care Med. 2011 August 15; 184(4): 414–420.
RATIONALE: The characterization of young adults who develop late-onset diseases may augment the detection of novel genes and promote new pathogenic insights.
METHODS: We analyzed data from 2,500 individuals of African and European ancestry in the COPDGene Study. Subjects with severe, early-onset chronic obstructive pulmonary disease (COPD) (n = 70, age < 55 yr, FEV1 < 50% predicted) were compared with older subjects with COPD (n = 306, age > 64 yr, FEV1 < 50% predicted).
MEASUREMENTS AND MAIN RESULTS: Subjects with severe, early-onset COPD were predominantly females (66%), P = 0.0004. Proportionally, early-onset COPD was seen in 42% (25 of 59) of African Americans versus 14% (45 of 317) of non-Hispanic whites, P < 0.0001. Other risk factors included current smoking (56 vs. 17%, P < 0.0001) and self-report of asthma (39 vs. 25%, P = 0.008). Maternal smoking (70 vs. 44%, P = 0.0001) and maternal COPD (23 vs. 12%, P = 0.03) were reported more commonly in subjects with early-onset COPD. Multivariable regression analysis found association with African American race, odds ratio (OR), 7.5 (95% confidence interval [CI], 2.3–24; P = 0.0007); maternal COPD, OR, 4.7 (95% CI, 1.3–17; P = 0.02); female sex, OR, 3.1 (95% CI, 1.1–8.7; P = 0.03); and each pack-year of smoking, OR, 0.98 (95% CI, 0.96–1.0; P = 0.03).
CONCLUSIONS: These observations support the hypothesis that severe, early-onset COPD is prevalent in females and is influenced by maternal factors. Future genetic studies should evaluate (1) gene-by-sex interactions to address sex-specific genetic contributions and (2) gene-by-race interactions.
Comments: The archetypical image of the smoker has been the “Marlboro man” and similarly the common depiction of a COPD patient has often been male yet at the current time more woman die from COPD than men. We know that airway hyperresponsiveness increases the risk of developing COPD and that women have higher prevalence of airway hyperresponsiveness. The Lung Health study demonstrated that 60% of woman and 40% of men with a diagnosis of COPD had a Methacholine PC20 FEV-1 of less than 10 mg/ml. Hence whether we call it asthma or simply airway hyperresponsiveness it would be very interesting to look at what is the difference in rates of airway hyperresponsiveness in these early onset subjects versus the later onset group. It is also intriguing that there is an increased prevalence of early onset of COPD in African Americans. While clearly there are environmental and socioeconomic factors that may contribute to these findings, the data is compelling that suggests indeed there may be genetic factors that predispose to more severe and early disease in this group. Findings from this study may not only have implications for better understanding the impact of COPD in African Americans but may also provide some insights into the complex phenomenon of so called “‘urban asthma”.