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of whether they are causative or part of a pathway, which is more plausible for C-reactive protein. Existing databases, such as the Copenhagen Heart Study and the Copenhagen General Population Study, that include thousands of patients with COPD can provide even more powerful information about prediction, especially if they consider multimorbidity and disease-overarching predictors.4,5 Ideally, as indicated by Puhan and colleagues, identification of baseline risks through prognostic studies might help to target therapy and can make important and long-needed contributions to, for instance, guideline development.6 However, every decision has benefits and downsides, and it is futile to provide prognostic data if it does not lead to altered management and net benefit for the patient. For the patient, making a prognosis can be equated to making a disease-specific diagnosis about baseline risk. For example, determining an ADO score of 5 in a 48-year-old patient with longer-standing COPD leads to the diagnosis of COPD with a 31% risk of death in the next 3 years. Thus what we call prognosis becomes a diagnosis for which prognostic data provides information about baseline risk. This baseline risk determines how the relative treatment effects translate into absolute effects. For a 48-year-old patient in hospital for an exacerbation with an ADO score of 0, the risk is ten-fold lower (COPD with a 3% risk of death) and absolute risk reductions will differ appreciably. In this prognostic–diagnostic– treatment triad, downstream events become important (desirable and undesirable consequences from acting on the information).7 The framework of using prognostic information appropriately includes several steps. First, use prognostic information for baseline risk and to diagnose disease severity (such as the baseline mortality risks of 30% and 3%, ideally supported by estimates of baseline risk for other outcomes that are important to patients such
as exacerbations, quality of life, and adverse effects). Second, consider the classification and frequency of true and false positive and negative predictions in treatment decisions. Third, make judgments about expected absolute benefits and downsides for this classification on the basis of relative effects for each of the important outcomes, with use of relative risk reductions from high-quality systematic reviews. Fourth, balance the expected benefits against downsides. Fifth, the patient and clinician make treatment decision together. When there is multimorbidity, patients might have to make decisions about which therapy for their multiple conditions comes with the largest net benefit, possibly with the help of decision aids. Holger Schünemann Department of Clinical Epidemiology and Biostatistics, Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre L8N 3Z5, Hamilton, ON, Canada schuneh@mcmaster.ca I have worked closely for several years with Milo Puhan, supervised his PhD thesis, and still collaborate with him. 1
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WHO. 2008–2013 action plan for the global strategy for the prevention and control of non communicable diseases: prevent and control cardiovascular diseases, cancers, chronic respiratory diseases, diabetes. 2008. http://www.who.int/nmh/publications/ncd_action_plan_en.pdf (accessed Aug 18, 2009). Puhan MA, Garcia-Aymerich J, Frey M, et al. Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index. Lancet 2009; 374: 704–11. Nannini LJ, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler versus inhaled steroids for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007; 4: CD006826. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175: 250–55. Dahl M, Bowler RP, Juul K, Crapo JD, Levy S, Nordestgaard BG. Superoxide dismutase 3 polymorphism associated with reduced lung function in two large populations. Am J Respir Crit Care Med 2008; 178: 906–12. Schunemann HJ, Woodhead M, Anzueto A, et al. A vision statement on guideline development for respiratory disease: the example of COPD. Lancet 2009; 373: 774–79. Schunemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ 2008; 336: 1106–10.
Inhaled corticosteroids in COPD and the risk of pneumonia See Articles page 712
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Community-acquired pneumonia is one of the major infectious diseases with an incidence of 5–10 per 1000 adults per year.1 Chronic obstructive pulmonary disease (COPD) is one of the most important risk factors for a complicated course of pneumonia. Mortality is inversely correlated to the forced expiratory volume in 1 s.2
In the TORCH study, for the first time, results showed that the inhaled corticosteroid, fluticasone, increased the risk of community-acquired pneumonia during a 3-year observational period.3 This observation was subsequently confirmed in other randomised trials.4,5 Additionally, a large Canadian observational study, www.thelancet.com Vol 374 August 29, 2009
including nearly 100 000 cases and controls, showed a dose-dependent risk for pneumonia in COPD patients using inhaled corticosteroid.6 In recent months, two meta-analyses have been published7,8 that included all published randomised trials with inhaled corticosteroids. Both analyses confirmed the overall increased risk for communityacquired pneumonia when patients with COPD had received long-term therapy with inhaled corticosteroids. However, there was significant heterogeneity between the included studies, and the authors of the metaanalyses refrained from rendering a final judgment. The pathophysiological mechanisms, which could contribute to an increased risk for pneumonia during treatment with inhaled corticosteroids, are not understood. The influences of these drugs on the cellular immune system, such as the phagocytosis of alveolar macrophages, might have a role, or indeed alterations in humoral immunity (eg, via a reduction of secretory IgA) might be important. In addition, differences exist in the method of action and metabolism of different inhaled corticosteroids, which might result in different effects on local immunity. This variability might become especially important in patients with chronic airway colonisation by pathogenic bacteria, which has been identified as a relevant risk factor for exacerbation of COPD,9 and probably also for the development of communityacquired pneumonia.10 The meta-analysis by Don Sin and colleagues11 in The Lancet today overcomes some of the limitations from the two previous meta-analyses. Because the authors had access to patient-level data, they were able to control for potential confounders, such as age, symptoms, and lung function. Additionally, they used a random-effects model for their analysis, which explicitly allows heterogeneity between source studies. In their analysis, they did not find an increased rate of community-acquired pneumonia when budesonide was used as long-term therapy in patients with COPD. However, important limitations in the methods of all previous studies on inhaled corticosteroids and community-acquired pneumonia were also found in today’s meta-analysis. All source studies included had a maximum observation period of 1 year. Longer observation times would be desirable, because there are seasonal variations in the incidences of communityacquired pneumonia.12 Interestingly, none of the studies www.thelancet.com Vol 374 August 29, 2009
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required a chest radiograph to make the diagnosis of community-acquired pneumonia. The sensitivity and specificity of clinical variables are low, and therefore establishing the diagnoses of community-acquired pneumonia on the basis of only clinical observations has proven unreliable.13 In particular, the differentiation between community-acquired pneumonia and acute exacerbation of COPD is difficult. This problem also exists in patients who had been hospitalised, on which the authors of today’s meta-analysis have been focusing. Hospitalisation of these patients increases the likelihood of an authentic diagnosis of community-acquired pneumonia, but some uncertainty remains. Some studies have revealed an increased risk of pneumonia in patients taking inhaled corticosteroids, but this increase did not affect mortality in these patients. This result seems astonishing, in view of the fact that community-acquired pneumonia is associated with a mean mortality of 8%, and an in-hospital mortality of 14%.14 These findings therefore suggest that inhaled corticosteroids might cause community-acquired pneumonia more often but that the episode is of reduced severity. On the other hand, some observational studies suggest that the course of community-acquired pneumonia is positively influenced by the administration of corticosteroids.15 Early inhibition of pro-inflammatory cytokines by inhaled corticosteroids might have a crucial role. Until today’s report, there was no proof from randomised trials for this theory. 669
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At the moment there is no reason to deviate from the current guideline recommendations for the use of inhaled corticosteroids in COPD. In the assessment of the safety of any drug, the benefit–risk ratio is an important criterion. In assessment of the role of inhaled corticosteroids, the rate of community-acquired pneumonia might affect the clinical use of such drugs if there is any suspicion of additional morbidity or mortality. But this signal was not found in any of the studies discussed here. More importantly, the rates of exacerbations, which have a major effect on prognosis in patients with COPD, could be largely reduced.16 Nevertheless, there is something to learn for future studies. In COPD studies, a definition of communityacquired pneumonia that meets the international guidelines should become standard, and all cases with suspicion of pneumonia should have a chest radiograph. Additionally, pulmonary function should be tested as part of pneumonia studies to facilitate assessment of the severity of COPD as well as correlating the disease’s severity with the clinical course of pneumonia. Improving the quality of clinical data is the only way to adequately answer the question of a possible increased risk of pneumonia with use of inhaled corticosteroids.
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Tobias Welte Department of Respiratory Medicine, Medizinische Hochschule, 30659 Hannover, Germany welte.tobias@mh-hannover.de
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Welte T, Köhnlein T. Global and local epidemiology of community-acquired pneumonia: the experience of the CAPNETZ Network. Semin Respir Crit Care Med 2009; 30: 127–35. Restrepo MI, Mortensen EM, Pugh JA, Anzueto A. COPD is associated with increased mortality in patients with community-acquired pneumonia. Eur Respir J 2006; 28: 346–51. Calverley PM, Anderson JA, Celli B, et al, for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775–89. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, for the INSPIRE Investigators. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008; 177: 19–26. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175: 144–49. Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med 2007; 176: 162–66. Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med 2009; 169: 219–29. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 2008; 300: 2407–16. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007; 370: 786–96. von Baum H, Welte T, Marre R, Suttorp N, Ewig S, for THE CAPNETZ STUDY GROUP. Community-acquired pneumonia through enterobacteriaceae and Pseudomonas aeruginosa: diagnosis, incidence and predictors. Eur Respir J 2009; published online Aug 13. DOI:10.1183/09031936.00091809. Sin DD, Tashkin D, Zhang X, et al. Budesonide and the risk of pneumonia: a meta-analysis of individual patient data. Lancet 2009; 374: 712–19. von Baum H, Welte T, Marre R, Suttorp N, Lück C, Ewig S. Mycoplasma pneumoniae pneumonia revisited within the German Competence Network for Community-acquired pneumonia (CAPNETZ). BMC Infect Dis 2009; 9: 62. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997; 278: 1440–45. Welte T, Suttorp N, Marre R. CAPNETZ-community-acquired pneumonia competence network. Infection 2004; 32: 234–38. Garcia-Vidal C, Calbo E, Pascual V, Ferrer C, Quintana S, Garau J. Effects of systemic steroids in patients with severe community-acquired pneumonia. Eur Respir J 2007; 30: 951–56. Welte T. Optimising treatment for COPD—new strategies for combination therapy. Int J Clin Pract 2009; 63: 1136–49.
I declare that I have no conflicts of interest.
Time to define the disorders of the syndrome of COPD Whether an adult presenting with symptoms and signs of airflow obstruction has chronic obstructive pulmonary disease (COPD) or asthma is important, not least because the decision predetermines management. To assist the physician guidelines have proposed diagnostic criteria to distinguish between the two disorders. For COPD there is a requirement for a postbronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio of below 0·7 to identify patients with poorly reversible airflow obstruction,1 whereas in asthma the diagnosis is based on reversible airflow obstruction that varies 670
spontaneously or after treatment.2 However, many patients with stable COPD have bronchodilator reversibility that would meet the diagnostic criteria for asthma.3 Conversely, a subgroup of patients with longstanding asthma have a poorly reversible component to their airflow obstruction, and thereby meet the diagnostic criteria for COPD.4 Furthermore, the classification of patients as having COPD or asthma could vary from day to day, with established diagnostic criteria.5 The paradox is even greater when recommended treatments are considered, in which inhaled shortacting and longacting β agonists and anticholinergic drugs are www.thelancet.com Vol 374 August 29, 2009