Comparison of spirometry criteria for the diagnosis of COPD: results from the BOLD Study. W.M. Vollmer, T. Gíslason, P. Burney, P.L. Enright, A. Gulsvik, A. Kocabas, A.S. Buist, The BOLD Collaborative Research Group F. (Eur Respir J; 2009 May 21. Epub ahead of print).
Published guidelines recommend spirometry to accurately diagnose COPD. However, even spirometry-based COPD prevalence estimates can vary widely. We compared properties of several spirometry-based COPD definitions using data from the international Burden of Obstructive Lung Disease (BOLD) study. 14 sites recruited population-based samples of adults aged 40 and older. Procedures included standardized questionnaires and post-bronchodilator spirometry. 10,001 individuals provided usable data. Use of the lower limit of normal (LLN) FEV1/FVC reduced the age-related increases in COPD prevalence that are seen among healthy never smokers when using the fixed ratio criterion (FEV1/FVC < 0.7) as recommended by the Global Initiative for Obstructive Lung Disease (GOLD). The added requirement of an FEV1 either < 80% predicted, or below the LLN, further reduced age-related increases and also led to the least site-to-site variability in prevalence estimates after adjusting for potential confounders. Use of the FEV1/FEV6 ratio in place of the FEV1/FVC yielded similar prevalence estimates. Use of the FEV1/FVC < LLN criterion instead of the FEV1/FVC < 0.7 should minimize known age biases and better reflect clinically significant irreversible airflow limitation. Our study also supports the use of the FEV1/FEV6 as a practical substitute for the FEV1/FVC.
Comments. This paper points to the limitations of the FEV(1)/FVC ratio cutoff of 70% as criteria for diagnosing COPD. There was a great deal of variability in the male to female ratio and the pack year history of participants across study centers. This study did not make race corrections for any of its spirometric values, but the focus of looking at the ratio probably makes this relatively unimportant for this study. Some centers such as Vancouver, Cape Town and Manila and Guangzhou may have had more diverse populations represented but no ethnic or racial demographic data was reported. There was only one US site. There are clearly limitations of using the current GOLD definition of COPD diagnosed on the basis of the FEV1/FVC ratio of less than 70%, not only because of the issues outlined in this article but also because of subjects who are obese having a preserved ratio when they indeed have evidence of airflow obstruction. With that in mind the findings from this paper will hopefully help lead to revisions of the GOLD criteria to further reflect the limitations of using just the FEV-1/FVC cutoff of 70%. This paper is also useful for providing guidance on how to interpret and use the lower limit of normal of the FEV1 and the FEV1/FEV6 in making the diagnosis.
Marijuana and chronic obstructive lung disease: a population-based study. W.C. Tan, C. Lo, A. Jong, L. Xing, M.J. Fitzgerald, W.M. Vollmer, S.A. Buist, D.D. Sin; Vancouver Burden of Obstructive Lung Disease (BOLD) Research Group. (CMAJ. 2009 Apr 14;180(8):814–20).
Background: Our aim was to determine the combined and independent effects of tobacco and marijuana smoking on respiratory symptoms and chronic obstructive pulmonary disease (COPD) in the general population.
Method: We surveyed a random sample of 878 people, 40 years or older, living in Vancouver, Canada, about their respiratory history and their history of tobacco and marijuana smoking. We performed spirometric testing before and after administration of 200 microg of salbutamol. We examined the association between tobacco and marijuana smoking and COPD.
Results: The prevalence of a history of smoking in this sample was 45.5% (95% confidence interval [CI] 42.2%-48.8%) for marijuana use and 53.1% (95% CI 49.8%-56.4%) for tobacco use. The prevalence of current smoking (in the past 12 months) was 14% for marijuana use and 14% for tobacco use. Compared with nonsmokers, participants who reported smoking only tobacco, but not those who reported smoking only marijuana, experienced more frequent respiratory symptoms (odds ratio [OR] 1.50, 95% CI 1.05–2.14) and were more likely to have COPD (OR 2.74, 95% CI 1.66–4.52). Concurrent use of marijuana and tobacco was associated with increased risk (adjusted for age, asthma and comorbidities) of respiratory symptoms (OR 2.39, 95% CI 1.58–3.62) and COPD (OR 2.90, 95% CI 1.53–5.51) if the lifetime dose of marijuana exceeded 50 marijuana cigarettes. The risks of respiratory symptoms and of COPD were related to a synergistic interaction between marijuana and tobacco.
Interpretation: Smoking both tobacco and marijuana synergistically increased the risk of respiratory symptoms and COPD. Smoking only marijuana was not associated with an increased risk of respiratory symptoms or COPD.
Comments. The final conclusions of this article are misleading and suggest that smoking marijuana alone may not lead to COPD or to respiratory symptoms, yet their post hoc analysis revealed that they were underpowered to detect an effect of marijuana use alone. Further, there is an abundance of data that would equally argue that marijuana is indeed capable of causing symptoms and at least contributing to the development of COPD. Tobacco and marijuana are both plant derived substances that are combusted and inhaled and have largely the same chemical and particulate constituents aside for nicotine (tobacco) and Δ 9-tetrahydrocannabinol (THC) in marijuana. The main difference between tobacco and marijuana risk of causing lung injury is likely exposure or dose rather than any intrinsic chemical combustible product difference between the two substances. It is generally agreed that people are at increased risk of COPD only after a 10 to 20 pack-year history (smoking 20 cigarettes a day 365 days a year for 10 to 20 years), that is the equivalent of 73,000–146,000 cigarettes. In this study heavy marijuana users were those defined as having smoked 3–5 “joints” per day. Using 5 marijuana cigarettes per day would only be 36,500 joints for a 20 year habitual user or 18,250 for a 10 year habitual user. Hence it is highly unlikely, even given variablitiy in the composition, amount per joint, and the way in which the marijuana is smoked that even heavy marijuana users have more than about an equivalent 5 pack year history of marijuana use. In fact the inter-quartile range for lifetime marijuana cigarette use was (5.0–1111), suggesting that actual use was far less than the equivalent of a 5 pack-year tobacco history. Further the authors suggest that there may be a synergistic action between tobacco and marijuana with marijuana priming the airways for injury by tobacco. The definition of true synergy is that the effect is greater than the sum of the effects of each consituent and the authors do not provide data to support this as a true synergistic relationship as opposed to an additive effect. Hence, since dose may be a significiant factor and for obvious ethical and practical reason sa proper human study design will unlikely to be possible to address this issue definitively, Animal models of COPD could be used to examine this question. One could compare effects of comparable exposure to tobacco vs marijuana in an incremental dosing fashion to see if there is any difference in inflammatory and/or histological changes. Perhaps for once we will not have to feel so bad for the laboratory animals. Regardless, until more definitive studies are done to prove otherwise it would seem prudent to err on the side of caution that marijuana smoking is potentially injurious to the lung and is just as likely as tobacco smoke to add to the burden of pro-inflammatory chemical and particulate deposition in the lung.
Effect of N-acetylcysteine on airtrapping in COPD: A randomized placebo controlled trial. D. Stav, M. Raz. (Chest; May 15 2009. Epub ahead of Print).
Background: FEV1 is used for classification of disease severity and is a good predictor of COPD mortality. However, it is a poor predictor of clinical symptoms, exercise tolerance, and response to bronchodilators in COPD. Progressive reduction in inspiratory capacity (IC) during exercise reflects dynamic hyperinflation and is a good predictor of decreased exercise ability as well as increased exertional dyspnea. In animal models of COPD, N-acetylcysteine (NAC), an antioxidant/mucous modifier, has been shown to modify small airways, which mainly causes lung hyperinflation.
Objective: To examine the effect of NAC 1,200 mg/d on lung hyperinflation at rest and after exercise in patients with moderate and severe COPD.
Methods: This was a randomized, double-blind, cross-over study that included 24 eligible patients > 40 years of age with a diagnosis of COPD, and FEV1 < 70% of predicted, FEV1/FVC ratio < 0.70, and functional residual capacity > 120% of predicted normal. Patients were randomized to placebo or NAC twice daily for 6 weeks. This was followed by 2 weeks' washout, and then patients were crossed over to alternate therapy for a further 6 weeks. Evaluation was performed after each 6 weeks of each treatment.
Results: IC and FVC were higher especially after exercise after NAC treatment compared to placebo. In addition, the relationship of residual volume to total lung capacity was reduced in a similar pattern. Furthermore, endurance time was longer after NAC treatment compared to placebo.
Conclusions: NAC treatment of stable, moderate and severe COPD patients has a beneficial effect on physical performance, probably due to a reduction in air trapping.
Comments. There have been several studies that have been essentially negative with regard to the use of NAC however many of us note patients who do indeed report benefit from using it. As with other interventions in COPD we appreciate more and more the limitations of outcomes centered around the FEV1 to assess efficacy. Hence, it is encouraging to see that a signal can be seen by looking at assessments of small airway function with IC and FVC and exercise endurance improvements suggesting less dynamic hyperinflation during exercise.
Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. C. Crim, P.M. Calverley, J.A. Anderson, B. Celli, G.T. Ferguson, C. Jenkins, P.W. Jones, L.R. Willits, J.C. Yates, J. Vestbo. (Eur Respir J. 2009 May 14. Epub ahead of print).
Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post-hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analyzed and identified potential risk factors for adverse event reports of pneumonia in this randomized, double-blind trial comparing twice-daily inhaled salmeterol 50 mcg (SAL), fluticasone propionate 500 mcg (FP), and the combination (SFC) with placebo in 6,184 patients with moderate-severe COPD over 3 years. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment years, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment years, respectively). Risk factors for pneumonia were age > / = 55 years, FEV1 < 50% predicted, COPD exacerbations in the year prior to the study, worse MRC dyspnoea scores and BMI < 25kg.m(−2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, health-care providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.
Comments. This study and others demonstrate that the “Pneumonia signal” with ICS is real. Despite this, hopefully there are not many who would be dissuaded from using combination therapy in at least a subgroup of patients with COPD. The weight of evidence continues to support the use of ICS as part of combination with LABAs for patients with frequent exacerbations or significant symptoms not controlled with bronchodilators alone. The first issue is that many of the so-called pneumonias may not represent true pneumonia's, as few cases were confirmed by chest radiograph or other imaging such as CT. Indeed, there are many patients that are thought to have pneumonia on clinical grounds despite no clear “new infiltrate” on imaging studies so the lack of chest radiograph documentation may not be so critical to understanding this phenomenon. It may be best to think of these infections as severe lower respiratory tract infections (LRTIs) that may be tracheobronchitis/bronchiolitis and/or pneumonia. It should be mentioned that there isn't documentation insofar that these events are more likely to be infectious or bacterial versus other microbial agents so this does remain speculative. Nonetheless the patients that developed “pneumonia” seemed to be older and have more severe COPD. It is important to note that there was a greater withdrawal of subjects in the placebo arm hence, patients not receiving benefit of ICS may drop out sooner due to milder non-infectious exacerbations and only those on ICS and with more severe disease and more prone to exacerbations “survive” in the study (i.e., remain exacerbation free or well enough long enough) to eventually develop a more severe bacterial lower respiratory tract infection with constitutional symptoms. These are more likely to be diagnosed as “pneumonia” with or without benefit of chest X-ray documentation. Regardless of the general consensus that corticosteroids do not have major effects on neutrophil function ICS may initially attenuate other elements of the localized inflammatory response allowing the microbial load to grow without the usual signs and symptoms until they overwhelm the suppressive effects of the ICS. This is supported by other studies that demonstrate at least a trend suggesting that the higher the ICS dose the greater the risk for “pneumonia”. It may also be that certain subjects more prone to aspiration or subjects with pre-existing bronchiectasis are at greatest risk of developing these LRTI events. With these issues in mind, this study and others suggest that subjects who are developing recurrent severe lower respiratory tract infections or so-called “pneumonia's” should be evaluated for pre-existing problems that may make them more prone to lower respiratory tract infections and that they be educated on detecting early signs such as increased sputum purulence, mild fever, fatigue, etc. as suggesting a bacterial infection and seek medical attention early. Fortunately so far there do not seem to be more serious outcomes for the group who do develop these so-called “pneumonias”. Clearly, more studies are required to clarify this very important issue.