Comment
result in under-estimation of the true treatment effect for the exacerbation endpoint. This is especially the case if the use of oral antibiotics is unbalanced between treatment groups. Unbalanced use of antibiotics could also affect other outcome measures such as pulmonary function. If more participants in a placebo group are treated with antibiotics and antibiotic treatment improves or maintains lung function in these otherwise unwell individuals, a positive effect of treatment on lung function could be masked. Acute antibiotic events not meeting the definition of pulmonary exacerbation might therefore indicate important events that are ignored in primary assessments of the efficacy of a new treatment. One approach is to ensure detailed sensitivity analyses after a trial has been completed to assess the effect of this background antibiotic use on the key clinical efficacy outcomes. Another approach is to proactively reassess and improve endpoint definitions for future trials. For instance, the use of a strict definition of pulmonary exacerbations in cystic fibrosis trials could be challenged, and work could be done towards the definition of a clinically meaningful endpoint for treatment failure that can broaden the sign and symptom criteria of existing definitions of pulmonary exacerbation, enabling the incorporation of more mild but clinically significant events requiring antibiotic intervention. Fortunately, the availability of patient-reported outcome instruments such as the cystic fibrosis respiratory symptom diary and the cystic fibrosis quality of life revised questionnaire allows us to gain an understanding of which indications for antibiotic usage are meaningful to the individual and not just the physician.10 Use of such instruments might enable a broader assessment of the signs and symptoms indicative of an exacerbation of this disease. In the meantime, people interpreting data from clinical trials in cystic fibrosis should be aware of the potential effect of the
extensive background antibiotic use on the key clinical outcome measures, and in particular the potential for it to mask not only the benefit but the harm of a new treatment. With the pipeline of new treatments requiring assessment rapidly expanding and being more frequently directed towards the paediatric patient population with more mild disease, existing outcome measures in cystic fibrosis should be continually assessed and optimised to enable the undertaking of efficiently designed clinical trials. *Nicole Mayer-Hamblett, Felix Ratjen Department of Pediatrics, University of Washington, and Seattle Children’s Hospital, Seattle, WA, USA (NM-H), Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada (FR) [email protected] We declare that we have no conflicts of interest. 1 2
3 4
5
6
7
8
9
10
Hoffman LR, Ramsey BW. Cystic fibrosis therapeutics: the road ahead. Chest 2013; 143: 207–13. Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med 2010; 182: 298–306. Goss CH, Burns JL. Exacerbations in cystic fibrosis—1: epidemiology and pathogenesis. Thorax 2007; 62: 360–67. Bilton D, Canny G, Conway S, et al. Pulmonary exacerbation: towards a definition for use in clinical trials: Report from the EuroCareCF Working Group on outcome parameters in clinical trials. J Cyst Fibros 2011; 10 (suppl 2): S79–81. Saiman L, Anstead M, Mayer-Hamblett N, et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2010; 303: 1707–15. Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006; 354: 229–40. McCoy KS, Quittner AL, Oermann CM, et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med 2008; 178: 921–28. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med 2011; 165: 847–56. Rosenfeld M, Ratjen F, Brumback L, et al. Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA 2012; 307: 2269–77. Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc 2007; 4: 378–86.
A new Clinical Trials Directive to boost academic trials? Since the European Parliament issued the Clinical Trials Directive in 2001, the number of investigatorinitiated clinical trials has decreased substantially.1 Administrative requirements have become so complex that most academic investigators do not have the necessary resources. A revision of the clinical www.thelancet.com/respiratory Vol 1 April 2013
trial regulation is currently being discussed in the European Parliament; the intention is to convert the directive to a regulation that is binding in all member states. Additionally, the provisional document2 introduces the new category of low intervention clinical trials. Academic researchers applaud this
Published Online March 21, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70041-9 Since this Comment was published Online First it has been updated to include the conflicts of interest statement
99
Still Pictures/Paul Giamou/Aurora/SpecialistStock
Comment
For the trial network see http:// www.ecfs.eu/CTN
100
initiative, but will the new directive really boost investigator-initiated trials? An illustration of this point is seen in trials for patients with cystic fibrosis. Cystic fibrosis is a rare, autosomally inherited recessive disorder. In Europe about 40 000 children and adults have this lifeshortening, multisystem disease. Despite life-long, time-consuming, and costly treatment, most patients ultimately die of lung disease. Airway obstruction by viscid secretions, infection by specific bacteria, and excessive inflammation all add to progressive lung damage. Several approved and partially effective treatments are available for all these components—for example, mucolytics such as dornase alfa, hypertonic saline, and mannitol, and inhaled antibiotics such as tobramycin, aztreonam, and colistin.3 Because some efficacy is proven for every drug, physicians usually prescribe several in combination. This prescription leads to a very high treatment burden for patients, decreases quality of life, and is a risk factor for poor adherence;4 however, the improvement in lung function from these combined treatments does not equal the sum of the lung function improvement observed in the clinical trial of each drug when tested separately. What we therefore urgently need in patients with cystic fibrosis is comparative effectiveness trials5 to ascertain the optimum drug combination for any given situation. Comparative effectiveness research consists of low intervention clinical trials because the drugs are approved, the sideeffect profile is known, and risks to the patient are not increased, but much about best drug use is still to be learned. These trials can only be undertaken by academics; pharmaceutical companies will not provide the necessary investment. Another group in which we need low intervention clinical trials is in young children. Screening at birth for cystic fibrosis is now undertaken in many EU countries. Unfortunately, very little evidence exists outlining what the best treatment for infants is.6 Since many drugs have not been studied in this age group, off-label drug use is common practice. European cystic fibrosis experts therefore agree that every infant identified by newborn screening should have the opportunity to be included in a randomised controlled trial.6 In cystic fibrosis, like in many chronic disorders, much in terms of eventual outcome is already gained or lost in early childhood.
By use of low intervention clinical trials, evidencebased treatments can be generated to rationalise and personalise drug use, and to reduce the cost of treatment. The optimum drug combination can be determined for the individual patient, thereby lowering the treatment burden and reducing side effects. The academic world is ready to undertake such comparative trials to generate high quality data in patients with cystic fibrosis. Like in other disease organisations, we have formed a cystic fibrosis-specific clinical trial network.7 30 cystic fibrosis centres in 11 countries that serve 13 000 patients have organised themselves to undertake high quality clinical research. We have prioritised research topics, standardised how to measure outcome parameters, and have everything in place to collect high quality data. Unfortunately, the current proposal for the Clinical Trials Directive will not improve the feasibility of investigator-initiated trials since it does not relax the criteria surrounding complex, investigational product labelling, safety reporting, drug cost, or insurance. Physicians can freely prescribe approved drugs, even off-label, but since investigators have randomly assigned the patients, the intervention is considered a clinical trial. Low intervention academic trials will only be feasible if we can use most of our scarce resources for the collection of high quality data. Complex labelling of investigational products is not necessary since the drugs are already approved. The drug does not need to be provided for free; since it is part of the current routine treatment, drug costs should be covered by the usual healthcare insurance. A complex safety report is not necessary, even if the drug is prescribed off-label, because the drug is already on the market. If necessary, the national indemnity plan should cover any risk associated with the trial. Additionally, it seems logical that new EU initiatives, such as incentives to aid comparative effectiveness trials, would be accompanied by the necessary allocation of finances. We hope that regulators will consider and deliberate upon these constructive comments and amend the directive accordingly so that high quality investigatorled studies will again increase in number. Not only does the world of cystic fibrosis need them—at the recent EU Parliament meeting these same requests were voiced and echoed by cancer researchers.8 www.thelancet.com/respiratory Vol 1 April 2013
Comment
*Kris De Boeck, Harm Tiddens, Stuart Elborn, Isabelle Fajac, on behalf of the European Cystic Fibrosis Society (ECFS) and the ECFS Clinical Trial Network. Paediatric Pulmonology, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium (KDB); Department of Paediatric Pulmonology and Allergology, Erasmus MS-Sophia, Rotterdam, The Netherlands (HT); Adult CF Centre, Belfast City Hospital, Belfast, UK (SE); and Physiology Department,Cochin Hospital, Paris, France (IF) [email protected]
3
4
5 6
7
We declare that we have no conflicts of interest. 1
2
Welzing L, Harnischmacher U, Weyersberg A, Roth B. Consequences of Directive 2001/20/EC for investigator-initiated trials in the paediatric population—a field report. Eur J Pediatr 2007; 166: 1169–76. European Commission. Proposal for a regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive. Brussels: European Commission, 2012. http://ec.europa.eu/health/files/clinicaltrials/2012_07/proposal/2012_07_ proposal_en.pdf (accessed March 18, 2013).
8
Döring G, Flume P, Heijerman H, et al. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros 2012; 11: 461–79. Sawicki GS, Ren CL, Konstan MW, et al. Treatment complexity in cystic fibrosis: trends over time and associations with site-specific outcomes. J Cyst Fibros 2013; Published online Jan 23. DOI: 10.1016/j.jcf.2012.12.009. Sawicki GS, Tiddens H. Managing treatment complexity in cystic fibrosis: challenges and opportunities. Pediatr Pulmonol 2012; 47: 523–33. Sermet-Gaudelus I, Mayell SJ, Southern KW, et al. Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening. J Cyst Fibros 2010; 9: 323–29. De Boeck K, Bulteel V, Tiddens H, et al; ECFS-CTN network partners. Guideline on the design and conduct of cystic fibrosis clinical trials: the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). J Cyst Fibros 2011; suppl 2: S67–74. The European Society for Paediatric Oncology (SIOP Europe). Marking International Childhood Cancer Day at the European Parliament. Brussels: SIOP Europe, 2012. http://www.siope.eu/SIOPE-EU/English/Home-Page/ Conferences-Events/Past-Events/International-Childhood-CancerDay-2012/page.aspx/260 (accessed March 18, 2013).
If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
Corrections Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med 2013; 1: 158–63—In this Review, published online Jan 30, in the fourth paragraph in the section on treatments to correct the basic CFTR defect, the sentences starting “Patients given ivacaftor orally, twice a day…” and “Treated participants also had…” should cite reference 9 and not reference 4. This correction has been made to the online version as of April 5, 2013, and the printed Review is correct. Vogelmeier CF, Bateman ED, Pallante J, et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol—fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med 2013; 1: 51–60—In this Article (published online Dec 6), an incorrect value was included in table 5. In the QVA149 group, peripheral artery aneurysm should have been 0 and not 1 (0·4). This correction has been made to the online version as of April 5, 2013.
www.thelancet.com/respiratory Vol 1 April 2013
101
result in under-estimation of the true treatment effect for the exacerbation endpoint. This is especially the case if the use of oral antibiotics is unbalanced between treatment groups. Unbalanced use of antibiotics could also affect other outcome measures such as pulmonary function. If more participants in a placebo group are treated with antibiotics and antibiotic treatment improves or maintains lung function in these otherwise unwell individuals, a positive effect of treatment on lung function could be masked. Acute antibiotic events not meeting the definition of pulmonary exacerbation might therefore indicate important events that are ignored in primary assessments of the efficacy of a new treatment. One approach is to ensure detailed sensitivity analyses after a trial has been completed to assess the effect of this background antibiotic use on the key clinical efficacy outcomes. Another approach is to proactively reassess and improve endpoint definitions for future trials. For instance, the use of a strict definition of pulmonary exacerbations in cystic fibrosis trials could be challenged, and work could be done towards the definition of a clinically meaningful endpoint for treatment failure that can broaden the sign and symptom criteria of existing definitions of pulmonary exacerbation, enabling the incorporation of more mild but clinically significant events requiring antibiotic intervention. Fortunately, the availability of patient-reported outcome instruments such as the cystic fibrosis respiratory symptom diary and the cystic fibrosis quality of life revised questionnaire allows us to gain an understanding of which indications for antibiotic usage are meaningful to the individual and not just the physician.10 Use of such instruments might enable a broader assessment of the signs and symptoms indicative of an exacerbation of this disease. In the meantime, people interpreting data from clinical trials in cystic fibrosis should be aware of the potential effect of the
extensive background antibiotic use on the key clinical outcome measures, and in particular the potential for it to mask not only the benefit but the harm of a new treatment. With the pipeline of new treatments requiring assessment rapidly expanding and being more frequently directed towards the paediatric patient population with more mild disease, existing outcome measures in cystic fibrosis should be continually assessed and optimised to enable the undertaking of efficiently designed clinical trials. *Nicole Mayer-Hamblett, Felix Ratjen Department of Pediatrics, University of Washington, and Seattle Children’s Hospital, Seattle, WA, USA (NM-H), Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada (FR) [email protected] We declare that we have no conflicts of interest. 1 2
3 4
5
6
7
8
9
10
Hoffman LR, Ramsey BW. Cystic fibrosis therapeutics: the road ahead. Chest 2013; 143: 207–13. Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med 2010; 182: 298–306. Goss CH, Burns JL. Exacerbations in cystic fibrosis—1: epidemiology and pathogenesis. Thorax 2007; 62: 360–67. Bilton D, Canny G, Conway S, et al. Pulmonary exacerbation: towards a definition for use in clinical trials: Report from the EuroCareCF Working Group on outcome parameters in clinical trials. J Cyst Fibros 2011; 10 (suppl 2): S79–81. Saiman L, Anstead M, Mayer-Hamblett N, et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2010; 303: 1707–15. Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006; 354: 229–40. McCoy KS, Quittner AL, Oermann CM, et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med 2008; 178: 921–28. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med 2011; 165: 847–56. Rosenfeld M, Ratjen F, Brumback L, et al. Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA 2012; 307: 2269–77. Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc 2007; 4: 378–86.
A new Clinical Trials Directive to boost academic trials? Since the European Parliament issued the Clinical Trials Directive in 2001, the number of investigatorinitiated clinical trials has decreased substantially.1 Administrative requirements have become so complex that most academic investigators do not have the necessary resources. A revision of the clinical www.thelancet.com/respiratory Vol 1 April 2013
trial regulation is currently being discussed in the European Parliament; the intention is to convert the directive to a regulation that is binding in all member states. Additionally, the provisional document2 introduces the new category of low intervention clinical trials. Academic researchers applaud this
Published Online March 21, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70041-9 Since this Comment was published Online First it has been updated to include the conflicts of interest statement
99
Still Pictures/Paul Giamou/Aurora/SpecialistStock
Comment
For the trial network see http:// www.ecfs.eu/CTN
100
initiative, but will the new directive really boost investigator-initiated trials? An illustration of this point is seen in trials for patients with cystic fibrosis. Cystic fibrosis is a rare, autosomally inherited recessive disorder. In Europe about 40 000 children and adults have this lifeshortening, multisystem disease. Despite life-long, time-consuming, and costly treatment, most patients ultimately die of lung disease. Airway obstruction by viscid secretions, infection by specific bacteria, and excessive inflammation all add to progressive lung damage. Several approved and partially effective treatments are available for all these components—for example, mucolytics such as dornase alfa, hypertonic saline, and mannitol, and inhaled antibiotics such as tobramycin, aztreonam, and colistin.3 Because some efficacy is proven for every drug, physicians usually prescribe several in combination. This prescription leads to a very high treatment burden for patients, decreases quality of life, and is a risk factor for poor adherence;4 however, the improvement in lung function from these combined treatments does not equal the sum of the lung function improvement observed in the clinical trial of each drug when tested separately. What we therefore urgently need in patients with cystic fibrosis is comparative effectiveness trials5 to ascertain the optimum drug combination for any given situation. Comparative effectiveness research consists of low intervention clinical trials because the drugs are approved, the sideeffect profile is known, and risks to the patient are not increased, but much about best drug use is still to be learned. These trials can only be undertaken by academics; pharmaceutical companies will not provide the necessary investment. Another group in which we need low intervention clinical trials is in young children. Screening at birth for cystic fibrosis is now undertaken in many EU countries. Unfortunately, very little evidence exists outlining what the best treatment for infants is.6 Since many drugs have not been studied in this age group, off-label drug use is common practice. European cystic fibrosis experts therefore agree that every infant identified by newborn screening should have the opportunity to be included in a randomised controlled trial.6 In cystic fibrosis, like in many chronic disorders, much in terms of eventual outcome is already gained or lost in early childhood.
By use of low intervention clinical trials, evidencebased treatments can be generated to rationalise and personalise drug use, and to reduce the cost of treatment. The optimum drug combination can be determined for the individual patient, thereby lowering the treatment burden and reducing side effects. The academic world is ready to undertake such comparative trials to generate high quality data in patients with cystic fibrosis. Like in other disease organisations, we have formed a cystic fibrosis-specific clinical trial network.7 30 cystic fibrosis centres in 11 countries that serve 13 000 patients have organised themselves to undertake high quality clinical research. We have prioritised research topics, standardised how to measure outcome parameters, and have everything in place to collect high quality data. Unfortunately, the current proposal for the Clinical Trials Directive will not improve the feasibility of investigator-initiated trials since it does not relax the criteria surrounding complex, investigational product labelling, safety reporting, drug cost, or insurance. Physicians can freely prescribe approved drugs, even off-label, but since investigators have randomly assigned the patients, the intervention is considered a clinical trial. Low intervention academic trials will only be feasible if we can use most of our scarce resources for the collection of high quality data. Complex labelling of investigational products is not necessary since the drugs are already approved. The drug does not need to be provided for free; since it is part of the current routine treatment, drug costs should be covered by the usual healthcare insurance. A complex safety report is not necessary, even if the drug is prescribed off-label, because the drug is already on the market. If necessary, the national indemnity plan should cover any risk associated with the trial. Additionally, it seems logical that new EU initiatives, such as incentives to aid comparative effectiveness trials, would be accompanied by the necessary allocation of finances. We hope that regulators will consider and deliberate upon these constructive comments and amend the directive accordingly so that high quality investigatorled studies will again increase in number. Not only does the world of cystic fibrosis need them—at the recent EU Parliament meeting these same requests were voiced and echoed by cancer researchers.8 www.thelancet.com/respiratory Vol 1 April 2013
Comment
*Kris De Boeck, Harm Tiddens, Stuart Elborn, Isabelle Fajac, on behalf of the European Cystic Fibrosis Society (ECFS) and the ECFS Clinical Trial Network. Paediatric Pulmonology, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium (KDB); Department of Paediatric Pulmonology and Allergology, Erasmus MS-Sophia, Rotterdam, The Netherlands (HT); Adult CF Centre, Belfast City Hospital, Belfast, UK (SE); and Physiology Department,Cochin Hospital, Paris, France (IF) [email protected]
3
4
5 6
7
We declare that we have no conflicts of interest. 1
2
Welzing L, Harnischmacher U, Weyersberg A, Roth B. Consequences of Directive 2001/20/EC for investigator-initiated trials in the paediatric population—a field report. Eur J Pediatr 2007; 166: 1169–76. European Commission. Proposal for a regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive. Brussels: European Commission, 2012. http://ec.europa.eu/health/files/clinicaltrials/2012_07/proposal/2012_07_ proposal_en.pdf (accessed March 18, 2013).
8
Döring G, Flume P, Heijerman H, et al. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros 2012; 11: 461–79. Sawicki GS, Ren CL, Konstan MW, et al. Treatment complexity in cystic fibrosis: trends over time and associations with site-specific outcomes. J Cyst Fibros 2013; Published online Jan 23. DOI: 10.1016/j.jcf.2012.12.009. Sawicki GS, Tiddens H. Managing treatment complexity in cystic fibrosis: challenges and opportunities. Pediatr Pulmonol 2012; 47: 523–33. Sermet-Gaudelus I, Mayell SJ, Southern KW, et al. Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening. J Cyst Fibros 2010; 9: 323–29. De Boeck K, Bulteel V, Tiddens H, et al; ECFS-CTN network partners. Guideline on the design and conduct of cystic fibrosis clinical trials: the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). J Cyst Fibros 2011; suppl 2: S67–74. The European Society for Paediatric Oncology (SIOP Europe). Marking International Childhood Cancer Day at the European Parliament. Brussels: SIOP Europe, 2012. http://www.siope.eu/SIOPE-EU/English/Home-Page/ Conferences-Events/Past-Events/International-Childhood-CancerDay-2012/page.aspx/260 (accessed March 18, 2013).
If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
Corrections Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med 2013; 1: 158–63—In this Review, published online Jan 30, in the fourth paragraph in the section on treatments to correct the basic CFTR defect, the sentences starting “Patients given ivacaftor orally, twice a day…” and “Treated participants also had…” should cite reference 9 and not reference 4. This correction has been made to the online version as of April 5, 2013, and the printed Review is correct. Vogelmeier CF, Bateman ED, Pallante J, et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol—fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med 2013; 1: 51–60—In this Article (published online Dec 6), an incorrect value was included in table 5. In the QVA149 group, peripheral artery aneurysm should have been 0 and not 1 (0·4). This correction has been made to the online version as of April 5, 2013.
www.thelancet.com/respiratory Vol 1 April 2013
101
