- Email: [email protected]
Inhaled epinephrine does not shorten hospital stay for infants with bronchiolitis destined to develop repeated bronchospasm
Comment
antibodies. A phase 3 study might be needed to show a significant cost-benefit ratio, in view of the likelihood of tralokinumab being an add-on drug, and to make this treatment a viable option for patients with asthma, and two randomised trials are underway. Because of the diversity of statistical methods that are being applied to the study of biological control in patients with asthma, and the differing outcome variables used, the comparison of one biological drug to another is at times difficult, if not impossible. As noted in several expert panel position papers, 9,10 it would help both the asthma practitioner and the pharmaceutical industry to have one, well defined set of outcome variables by which to compare newly emerging therapies as well as head-to-head trials. Additionally, the COMET initiative could provide a standardised platform for analysis of asthma studies, and these studies should concentrate on changes in variables that are clinically relevant, and not just statistically significant. Moreover, because many of the upcoming biological therapies are directed at the same target, such a platform would enable direct comparison of these drugs even if they are not included in the same study.
*Phillip E Korenblat, H James Wedner Division of Allergy and Clinical Immunology, Washington University School of Medicine, St Louis, MO 63141, USA [email protected] We declare no conflicts of interest. 1 2
3 4
5
6 7
8 9
10
Kau AL, Korenblat P. Anti-interleukins 4 and 13 for asthma in era of endotypes. Curr Opinion Allergy Clin Immunol 2014; 6: 570–75. Jia G, Erickson RW, Choy DF, et al. Periostin a systemic biomarker of eosinophilic airway inflammation in asthma patients. J Allergy Clin Immunol 2012; 130: 647–54. Ortega HG, Liu MC, Pavord DM, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371: 1198–207. Castro M, Wenzel S, Bleecker E, et al. Benrolizumab, an anti-interlukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014; 11: 879–90. Noonan M, Korenblat P, Mosesova S, et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol 2013; 132: 567–74. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistant asthma with elevated eosinophil levels. N Engl J Med 2013; 368: 2455–66. Brightling C, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in patients with uncontrolled severe asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015; published online July 29. http://dx.doi.org/10.1016/S2213-2600(15)00197-6. Corren J, Lemanski CJ, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: 1088–98. Reddel HK, Taylor DR, Bateman ED. An Official American Thoracic Society/ European Respiratory Society Statement: asthma control and exacerbations. Standardizing endpoints for clinical asthma and clinical practice. Am J Resp Crit Care Med 2009; 180: 59–99. Busse WW, Morgan WJ, Taggart V, Togias A. Asthma outcomes workshop: overview. JACI 2012; 129: s1–s8.
For the COMET initiative see http://www.comet-initiative. org/
Inhaled epinephrine does not shorten hospital stay for infants with bronchiolitis destined to develop repeated bronchospasm Recent studies have added to the evidence for lack of efficacy of bronchodilators for infants admitted to hospital with viral bronchiolitis. Bronchiolitis is a leading cause of hospital admission for infants, and many organisations have reported variation in care and published guidelines to improve management of this common condition.1–3 In a multicentre, randomised trial from Norway, Skjerven and colleagues4 found that administration of inhaled epinephrine on an asneeded basis was no different than normal saline control treatment in improving hospital length of stay or other outcomes. Furthermore, infants receiving a fixed schedule of regular epinephrine treatments had worse outcomes than those receiving it as-needed. In that trial, presence of atopic eczema, a previous episode of wheezing, or family history of atopy did not affect the treatment response to epinephrine. www.thelancet.com/respiratory Vol 3 September 2015
In The Lancet Respiratory Medicine, Skjerven and colleagues5 extend their previous findings by following these same infants to 2 years of age. Similar to findings in other studies, a substantial proportion (143 [48·6%] of 294 patients) of these children who had been admitted to hospital for bronchiolitis continued to have recurrent bronchial obstruction at follow-up. The investigators assessed the hypothesis that infants destined for recurrent bronchial obstruction, atopy, or allergic sensitisation might have responded better to epinephrine at the time of their initial admission to hospital for bronchiolitis. A future tendency towards these conditions is often used by clinicians to justify treatment with bronchodilators for infants with bronchiolitis. Contrary to this hypothesis, infants with subsequent obstruction did not have a differential response to epinephrine at the time of the
Published Online August 26, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00333-1 See Articles page 702
665
Ian Boddy/Science Photo Library
Comment
initial trial procedure, and infants with later atopy or allergic sensitisation who received epinephrine had a longer length of stay in the hospital compared with infants who did not go on to develop atopy or allergic sensitisation. This study informs about the pathophysiology of bronchiolitis rather than suggesting that clinicians alter practice from current recommendations. None of these factors measured at the time of hospital admission predicted any differential response to epinephrine to guide management decisions. These studies support international guidelines that recommend against use of bronchodilators for infants admitted to hospital with bronchiolitis.1,2 Additionally, there are important limitations of this study that could affect the findings. Hospital length of stay has shortcomings as an outcome measure of response to therapy because timing of discharge might involve other factors such as family readiness, staff routines, and time of day. More importantly, this was a study of infants admitted to hospital, not a population-based study, and it is possible that bronchodilators could have a differential response in some subgroups of infants that prevented hospital admission in the first place. However, such speculation runs contrary to the overwhelming body of evidence studying bronchiolitis in many settings and finding negligible effect of bronchodilators.6 Acknowledging these limitations, this study does add some additional information about one of the classic chicken or egg questions of paediatrics.7 We 666
know that hospital admission with bronchiolitis increases the risk of subsequent wheezing for an infant, but is this a result of the bronchial viral infection, or does the virus unmask an existing pre-disposition in the infant towards wheezing?8 This study would add to the literature suggesting that the infants are similar at the time of hospital admission with bronchiolitis, and traits leading to recurrent wheezing and bronchodilator response develop later. Recent investigations have found that preventing bronchiolitis by passive immunisation for respiratory syncytial virus with palivizumab in premature infants without lung disease does reduce the risk of recurrent wheezing, suggesting the virus plays a part in the development of this phenotype.9 However, other studies have found evidence of host factors existing before bronchiolitis that predict both bronchiolitis and recurrent wheezing, including lung function, bronchial hyper-responsiveness, genetic, and immunological predictors.8 Progression from bronchiolitis to recurrent wheezing is probably a multifactorial process that will be further elucidated by future cohort studies. For now, clinicians can continue to focus on supportive care rather than prescription of epinephrine or bronchodilators for infants admitted with bronchiolitis. They can counsel parents that there is an increased risk of recurrent wheezing for these infants, but there does not seem to be a useful relation between how the infants respond at time of hospital admission and the development of these future characteristics. Joseph J Zorc Perelman School of Medicine, University of Pennsylvania and The Children’s Hospital of Philadelphia, Philadelphia, PA, USA [email protected] I declare no competing interests. 1 2
3
4
5
Scottish Intercollegiate Guidelines Network. Bronchiolitis in children. 2006. http://wwwsignacuk/pdf/sign91pdf (accessed Aug 14, 2015). Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical Practice Guideline: The diagnosis, management, and prevention of bronchiolitis. Pediatrics 2014; 134: e1474–e502. Paediatric Society New Zealand. Guidelines. Wheeze and chest infection in children under 1 year. http://wwwpaediatricsorgnz/files/guidelines/ Wheezeendorsedpdf (accessed Aug 14, 2015). Skjerven HO, Hunderi JO, Brugmann-Pieper SK, et al. Racemic adrenaline and inhalation strategies in acute bronchiolitis. N Engl J Med 2013; 368: 2286–93. Skjerven HO, Rolfsjord LB, Berents TL, et al. Allergic diseases and the effect of inhaled epinephrine in children with acute bronchiolitis: follow-up from the randomised, controlled, double-blind, Bronchiolitis ALL trial. Lancet Respir Med 2015; published online Aug 26. http://dx.doi. org/10.1016/S2213-2600(15)00319-7.
www.thelancet.com/respiratory Vol 3 September 2015
Comment
6 7
Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2014; 6: CD001266. Bont LL, Ramilo, O. The relationship between RSV bronchiolitis and recurrent wheeze: the chicken and the egg. Early Hum Dev 2011; 87 (suppl 1): S51–54.
8 9
Gidaris D, Urquhart D, Anthracopoulos MB. ‘They said it was bronchiolitis; is it going to turn into asthma doctor?’. Respirology 2014; 19: 1158–64. Blanken M, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze. N Engl J Med 2013; 369: 782–83.
First comprehensive assessment of the burden of consultations for influenza in the USA
www.thelancet.com/respiratory Vol 3 September 2015
2–17 years consistently having the highest incidence of influenza consultations. Additionally, low levels of influenza consultation were reported in adults older than 65 years. This age pattern is highly consistent with data from other surveillance systems internationally and with community studies of influenza, but contrasts sharply with the distribution of influenza deaths, which mainly occur in elderly people. Less than a third of people consulting with influenzalike illness had received a vaccine, which suggests substantial scope for prevention through widened vaccine usage. An additional advantage of this type of clinical and virological surveillance is that vaccine efficacy can be estimated by the test-negative casecontrol design, which can compare vaccine uptake in individuals who test positive for influenza and those who test negative. This approach is used in the Influenza Monitoring Vaccine Effectiveness (I-MOVE) network in Europe.3 Combined data from Europe and the USA would provide much larger numbers of individuals,
Published Online August 21, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00327-6 See Articles page 709
Science Picture Co/Science Photo Library
In their analysis of the Influenza Incidence Surveillance Project, Ashley Fowlkes and colleagues1 provide the first comprehensive assessment of the contribution of influenza to outpatient consultations in the USA. They compare the incidence of consultations during four consecutive influenza seasons, starting in October 2009, during the emergence of the H1N1 influenza pandemic. Important features of this surveillance system include its wide geographical coverage, information about the population base from which the consultations arise to enable calculation of consultation rates, use of standardised case definitions for influenza-like illness, and systematic investigation of cases for identification of influenza virus and virus subtype. The investigators also collected data about vaccination history and use of rapid influenza diagnostic tests (RIDTs) and antivirals. By combining incidence of influenza-like illness with the proportion of cases that were confirmed, the investigators were able to calculate incidence rates for influenza-associated visits. This rate could not be measured fully for the 2009–10 season because surveillance only started in October. Outside the 2009–10 pandemic season, the highest incidence of influenza-associated visits was 10·7 per 1000 people (95% CI 10·3–11·1) in 2012–13 and the lowest was 1·9 per 1000 people (1·8–2·0) in 2011–12. However, in the interpretation of clinic-based surveillance data, consultations represent only the tip of the iceberg of community infections. For example, a community study in England reported about 46 PCR-confirmed influenza cases per 1000 people during a typical influenza season and even higher incidence of serologically-confirmed infection at roughly 180 cases per 1000 people.2 Fowlkes and colleagues’ study shows the importance of children in influenza epidemiology, with those aged
667
antibodies. A phase 3 study might be needed to show a significant cost-benefit ratio, in view of the likelihood of tralokinumab being an add-on drug, and to make this treatment a viable option for patients with asthma, and two randomised trials are underway. Because of the diversity of statistical methods that are being applied to the study of biological control in patients with asthma, and the differing outcome variables used, the comparison of one biological drug to another is at times difficult, if not impossible. As noted in several expert panel position papers, 9,10 it would help both the asthma practitioner and the pharmaceutical industry to have one, well defined set of outcome variables by which to compare newly emerging therapies as well as head-to-head trials. Additionally, the COMET initiative could provide a standardised platform for analysis of asthma studies, and these studies should concentrate on changes in variables that are clinically relevant, and not just statistically significant. Moreover, because many of the upcoming biological therapies are directed at the same target, such a platform would enable direct comparison of these drugs even if they are not included in the same study.
*Phillip E Korenblat, H James Wedner Division of Allergy and Clinical Immunology, Washington University School of Medicine, St Louis, MO 63141, USA [email protected] We declare no conflicts of interest. 1 2
3 4
5
6 7
8 9
10
Kau AL, Korenblat P. Anti-interleukins 4 and 13 for asthma in era of endotypes. Curr Opinion Allergy Clin Immunol 2014; 6: 570–75. Jia G, Erickson RW, Choy DF, et al. Periostin a systemic biomarker of eosinophilic airway inflammation in asthma patients. J Allergy Clin Immunol 2012; 130: 647–54. Ortega HG, Liu MC, Pavord DM, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371: 1198–207. Castro M, Wenzel S, Bleecker E, et al. Benrolizumab, an anti-interlukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014; 11: 879–90. Noonan M, Korenblat P, Mosesova S, et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol 2013; 132: 567–74. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistant asthma with elevated eosinophil levels. N Engl J Med 2013; 368: 2455–66. Brightling C, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in patients with uncontrolled severe asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015; published online July 29. http://dx.doi.org/10.1016/S2213-2600(15)00197-6. Corren J, Lemanski CJ, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: 1088–98. Reddel HK, Taylor DR, Bateman ED. An Official American Thoracic Society/ European Respiratory Society Statement: asthma control and exacerbations. Standardizing endpoints for clinical asthma and clinical practice. Am J Resp Crit Care Med 2009; 180: 59–99. Busse WW, Morgan WJ, Taggart V, Togias A. Asthma outcomes workshop: overview. JACI 2012; 129: s1–s8.
For the COMET initiative see http://www.comet-initiative. org/
Inhaled epinephrine does not shorten hospital stay for infants with bronchiolitis destined to develop repeated bronchospasm Recent studies have added to the evidence for lack of efficacy of bronchodilators for infants admitted to hospital with viral bronchiolitis. Bronchiolitis is a leading cause of hospital admission for infants, and many organisations have reported variation in care and published guidelines to improve management of this common condition.1–3 In a multicentre, randomised trial from Norway, Skjerven and colleagues4 found that administration of inhaled epinephrine on an asneeded basis was no different than normal saline control treatment in improving hospital length of stay or other outcomes. Furthermore, infants receiving a fixed schedule of regular epinephrine treatments had worse outcomes than those receiving it as-needed. In that trial, presence of atopic eczema, a previous episode of wheezing, or family history of atopy did not affect the treatment response to epinephrine. www.thelancet.com/respiratory Vol 3 September 2015
In The Lancet Respiratory Medicine, Skjerven and colleagues5 extend their previous findings by following these same infants to 2 years of age. Similar to findings in other studies, a substantial proportion (143 [48·6%] of 294 patients) of these children who had been admitted to hospital for bronchiolitis continued to have recurrent bronchial obstruction at follow-up. The investigators assessed the hypothesis that infants destined for recurrent bronchial obstruction, atopy, or allergic sensitisation might have responded better to epinephrine at the time of their initial admission to hospital for bronchiolitis. A future tendency towards these conditions is often used by clinicians to justify treatment with bronchodilators for infants with bronchiolitis. Contrary to this hypothesis, infants with subsequent obstruction did not have a differential response to epinephrine at the time of the
Published Online August 26, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00333-1 See Articles page 702
665
Ian Boddy/Science Photo Library
Comment
initial trial procedure, and infants with later atopy or allergic sensitisation who received epinephrine had a longer length of stay in the hospital compared with infants who did not go on to develop atopy or allergic sensitisation. This study informs about the pathophysiology of bronchiolitis rather than suggesting that clinicians alter practice from current recommendations. None of these factors measured at the time of hospital admission predicted any differential response to epinephrine to guide management decisions. These studies support international guidelines that recommend against use of bronchodilators for infants admitted to hospital with bronchiolitis.1,2 Additionally, there are important limitations of this study that could affect the findings. Hospital length of stay has shortcomings as an outcome measure of response to therapy because timing of discharge might involve other factors such as family readiness, staff routines, and time of day. More importantly, this was a study of infants admitted to hospital, not a population-based study, and it is possible that bronchodilators could have a differential response in some subgroups of infants that prevented hospital admission in the first place. However, such speculation runs contrary to the overwhelming body of evidence studying bronchiolitis in many settings and finding negligible effect of bronchodilators.6 Acknowledging these limitations, this study does add some additional information about one of the classic chicken or egg questions of paediatrics.7 We 666
know that hospital admission with bronchiolitis increases the risk of subsequent wheezing for an infant, but is this a result of the bronchial viral infection, or does the virus unmask an existing pre-disposition in the infant towards wheezing?8 This study would add to the literature suggesting that the infants are similar at the time of hospital admission with bronchiolitis, and traits leading to recurrent wheezing and bronchodilator response develop later. Recent investigations have found that preventing bronchiolitis by passive immunisation for respiratory syncytial virus with palivizumab in premature infants without lung disease does reduce the risk of recurrent wheezing, suggesting the virus plays a part in the development of this phenotype.9 However, other studies have found evidence of host factors existing before bronchiolitis that predict both bronchiolitis and recurrent wheezing, including lung function, bronchial hyper-responsiveness, genetic, and immunological predictors.8 Progression from bronchiolitis to recurrent wheezing is probably a multifactorial process that will be further elucidated by future cohort studies. For now, clinicians can continue to focus on supportive care rather than prescription of epinephrine or bronchodilators for infants admitted with bronchiolitis. They can counsel parents that there is an increased risk of recurrent wheezing for these infants, but there does not seem to be a useful relation between how the infants respond at time of hospital admission and the development of these future characteristics. Joseph J Zorc Perelman School of Medicine, University of Pennsylvania and The Children’s Hospital of Philadelphia, Philadelphia, PA, USA [email protected] I declare no competing interests. 1 2
3
4
5
Scottish Intercollegiate Guidelines Network. Bronchiolitis in children. 2006. http://wwwsignacuk/pdf/sign91pdf (accessed Aug 14, 2015). Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical Practice Guideline: The diagnosis, management, and prevention of bronchiolitis. Pediatrics 2014; 134: e1474–e502. Paediatric Society New Zealand. Guidelines. Wheeze and chest infection in children under 1 year. http://wwwpaediatricsorgnz/files/guidelines/ Wheezeendorsedpdf (accessed Aug 14, 2015). Skjerven HO, Hunderi JO, Brugmann-Pieper SK, et al. Racemic adrenaline and inhalation strategies in acute bronchiolitis. N Engl J Med 2013; 368: 2286–93. Skjerven HO, Rolfsjord LB, Berents TL, et al. Allergic diseases and the effect of inhaled epinephrine in children with acute bronchiolitis: follow-up from the randomised, controlled, double-blind, Bronchiolitis ALL trial. Lancet Respir Med 2015; published online Aug 26. http://dx.doi. org/10.1016/S2213-2600(15)00319-7.
www.thelancet.com/respiratory Vol 3 September 2015
Comment
6 7
Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2014; 6: CD001266. Bont LL, Ramilo, O. The relationship between RSV bronchiolitis and recurrent wheeze: the chicken and the egg. Early Hum Dev 2011; 87 (suppl 1): S51–54.
8 9
Gidaris D, Urquhart D, Anthracopoulos MB. ‘They said it was bronchiolitis; is it going to turn into asthma doctor?’. Respirology 2014; 19: 1158–64. Blanken M, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze. N Engl J Med 2013; 369: 782–83.
First comprehensive assessment of the burden of consultations for influenza in the USA
www.thelancet.com/respiratory Vol 3 September 2015
2–17 years consistently having the highest incidence of influenza consultations. Additionally, low levels of influenza consultation were reported in adults older than 65 years. This age pattern is highly consistent with data from other surveillance systems internationally and with community studies of influenza, but contrasts sharply with the distribution of influenza deaths, which mainly occur in elderly people. Less than a third of people consulting with influenzalike illness had received a vaccine, which suggests substantial scope for prevention through widened vaccine usage. An additional advantage of this type of clinical and virological surveillance is that vaccine efficacy can be estimated by the test-negative casecontrol design, which can compare vaccine uptake in individuals who test positive for influenza and those who test negative. This approach is used in the Influenza Monitoring Vaccine Effectiveness (I-MOVE) network in Europe.3 Combined data from Europe and the USA would provide much larger numbers of individuals,
Published Online August 21, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00327-6 See Articles page 709
Science Picture Co/Science Photo Library
In their analysis of the Influenza Incidence Surveillance Project, Ashley Fowlkes and colleagues1 provide the first comprehensive assessment of the contribution of influenza to outpatient consultations in the USA. They compare the incidence of consultations during four consecutive influenza seasons, starting in October 2009, during the emergence of the H1N1 influenza pandemic. Important features of this surveillance system include its wide geographical coverage, information about the population base from which the consultations arise to enable calculation of consultation rates, use of standardised case definitions for influenza-like illness, and systematic investigation of cases for identification of influenza virus and virus subtype. The investigators also collected data about vaccination history and use of rapid influenza diagnostic tests (RIDTs) and antivirals. By combining incidence of influenza-like illness with the proportion of cases that were confirmed, the investigators were able to calculate incidence rates for influenza-associated visits. This rate could not be measured fully for the 2009–10 season because surveillance only started in October. Outside the 2009–10 pandemic season, the highest incidence of influenza-associated visits was 10·7 per 1000 people (95% CI 10·3–11·1) in 2012–13 and the lowest was 1·9 per 1000 people (1·8–2·0) in 2011–12. However, in the interpretation of clinic-based surveillance data, consultations represent only the tip of the iceberg of community infections. For example, a community study in England reported about 46 PCR-confirmed influenza cases per 1000 people during a typical influenza season and even higher incidence of serologically-confirmed infection at roughly 180 cases per 1000 people.2 Fowlkes and colleagues’ study shows the importance of children in influenza epidemiology, with those aged
667