- Email: [email protected]
Drug, genes and asthma: when variability matters
Oral Presentations / Paediatric Respiratory Reviews 14S2 (2013) S1–S53
correspondence arising from published manuscripts and research letters – and the bar is high for the latter, they are not a repository for inadequate research. We also welcome suggestions for themed issues – we have had recent ones on TB (for world TB day) and cystic fibrosis. Writing a good paper: Far too many manuscripts fall at the first hurdle because of basic errors. Basic organisation is often lacking. Introduction – why you did it: This needs to summarise the background literature, and tell the reader why the subject is important. The two most important questions to answer are ‘what for?’ and ‘so what?’ – if you have not managed this at the end of the introduction, the paper must fail. Methods – what you did: Be prepared to use the on-line supplement for detailed descriptions. Use CONSORT (http://www.consortstatement.org/) and STROBE (http://www.strobe-statement.org/) diagrams if appropriate. The reader should be able to reproduce what you have done. Results – what you found: Start with the patient population; keep tables and graphs simple, be prepared to put more detailed tables on-line. Discussion – what it means: Do NOT repeat the introduction. Many people find structuring the discussion (Box 2) is helpful. Box 2. How to structure the discussion section • Statement of Principal Findings • Strengths and weaknesses of the study – There are always some problems! • Strengths and weaknesses with respect to other studies – Discrepant results? • Meaning of the study • Unanswered questions and future research Special issues: Genetic studies: There are particular pitfalls to avoid. These include reporting SNPs with no biological readout and no idea whether they affect gene expression; reporting mere association with no biological plausibility or validation elsewhere, e.g. animal studies; no second validation population; or the validation population replicates different SNPs in the same gene. Generally, editors are sceptical about genetic studies, because so many have fallen by the wayside having not been replicated. Case reports: Everyone likes talking about their interesting cases, but editors have little interest in publishing them, because they are not cited. Absolutely key is that there must be a take-home message: SO WHAT! is the inevitable cry of the referee. Other case reports to avoid include the 17th case of a rarity in the literature; the first report of a rarity in your country; and first report of an association between two rarities. All this is mere stamp-collecting. Opportunities for young investigators: First and most important, send us your good work! Consider writing a journal review for Lung Alerts, a feature in which interesting papers from other journals are discussed. Consider becoming a reviewer; probably best to start helping your mentor with a review before expecting to fly solo. Think about writing a review article; but send us a pre-submission proposal, and have a big-hitting co-author. Conclusion: Thorax is the journal for the bright, up and coming young investigator. Introduce yourself to us, and let’s work together to move the speciality forward! AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London References [1] Udwadia ZF. MDR, XDR, TDR tuberculosis: ominous progression. Thorax. 2012; 67: 286–8.
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Spanish Sessions SPA-1 Genetics and genomics of asthma, a step towards . . . where? C. Sanz, M. Isidoro Garc´ıa, S. de Arriba, F. Lorente, I. Davila. ´ Allergy Service, University Hospital of Salamanca, Salamanca, Spain Asthma is increasing worldwide at an alarming rate and its prevalence makes it the most common chronic disease in childhood and adolescence. Therefore, the governments, their health institutions and citizens must consider the study and treatment of this disease as a social and health priority [1]. As a multifactorial disease, several genes contribute to its development. This fact, associated to the diversity of asthma phenotypes and environmental influences have made difficult to obtain a clear pattern of inheritance. With the huge development of molecular genetics technologies, candidate gene studies are giving way to different types of studies at the genomic point of view. All these approaches are allowing the identification of several genes associated with asthma [2,3]. However, in these studies there are some conflicting results between different populations and there is still a lack of knowledge about the actual influence of these gene variants. Some confounding factors are inappropriate sample size, population stratification, differences in the phenotype classification, or inadequate gene coverage [4]. To confirm the real effect of the reported associations it will be necessary to consider the genetic environment and to perform functional studies that explain the molecular mechanisms that mediate between the emergence of a gene variant and the development of the disease [5]. The increasing development of experimental techniques opens a new horizon that will allow the identification of major genetic factors of susceptibility to asthma and the resulting classification of the populations groups based on their genetic characteristics, enabling the application of specific and highly efficient treatments [4]. References [1] Call for Global Action on Chronic Respiratory Diseases organized by the World Health Organization and the European Federation of Allergy and Airways Diseases (Rome, 11 June 2009). http://www.efanet.org/enews/ press.html/, http://www.who.int/respiratory/gard/en/. [2] Binia A and Kabesch M. Respiratory medicine – genetic base for allergy and asthma. Swiss med Weekly. 2012; 142: 1–11. [3] Moffatt M.F., Phil D., Gut I.D., Demenais F., et al. A Large-Scale, Consortium-Based Genome wide Association Study of Asthma. N Eng J Med. 2010; 363: 1211–21. [4] Isidoro-Garc´ıa M. and Davila ´ I. Genetica ´ en el asma. Espacioasma. 2013; 6(1): 8–12. [5] Isidoro-Garc´ıa M., Sanz C., Garc´ıa-Solaesa V., Pascual M., et al. PTGDR gene in asthma: a functional, genetic, and epigenetic study. Allergy. 2011; 66;12: 1553–62.
SPA-2 Drug, genes and asthma: when variability matters I. Davila, ´ C. Sanz, M. Isidoro Garc´ıa. Allergy Service, University Hospital, Salamanca, Spain It is estimated that 20–95% of the variability in drug responses is due to genetic factors [1]. In asthma a high inter-subject variability in the responses to the main drugs used in the treatment of asthma has been described. Thus, for example, a great variability in the response to fluticasone and montelukast has been observed in children [2]. Genetic studies have been performed with the main asthma drugs. In the case of bronchodilators, most studies have focused on the ADRB2, and some association of bronchodilator response and tachyphylaxis has been described, particularly with polymorphisms located on position 16 [3]. Related to corticosteroids
S44
Oral Presentations / Paediatric Respiratory Reviews 14S2 (2013) S1–S53
several genes have been implicated in the response in asthma. The most important of them are CRH1 (corticotropin-releasing hormone receptor 1), TBX21 (nuclear transcription factor T-bet) and FCER2 (low affinity IgE receptor) [4]. Finally, in the leukotriene pathway, the main pharmacogenetics studies have involved the ALOX5 (5-lipoxygenase), CYSLTR2 (cysteinyl leukotriene receptor 2) and LTC4S (leukotriene C4 synthase) genes. Nevertheless, most of the studies are limited by small sample sizes and a lack of replication studies. Although little is known about the effect of genes in the response to asthma drugs, the door is open for a personalized medicine, capable to minimize adverse effect and lead to a more cost-effective care. References [1] Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets, and side effects. N Engl J Med. 2003 Feb 6; 348(6): 538–49. [2] Szefler SJ, Phillips BR, Martinez FD, et al. Characterization of withinsubject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol. 2005 Feb; 115(2): 233–42. [3] Ortega VE, Hawkins GA, Peters SP, Bleecker ER. Pharmacogenetics of the beta 2-adrenergic receptor gene. Immunol Allergy Clin North Am. 2007 Nov; 27(4): 665–84; vii. [4] Lima JJ, Blake KV, Tantisira KG, Weiss ST. Pharmacogenetics of asthma. Curr Opin Pulm Med. 2009 Jan; 15(1): 57–62. [5] Tantisira KG, Drazen JM. Genetics and pharmacogenetics of the leukotriene pathway. J Allergy Clin Immunol. 2009 Sep; 124(3): 422–7.
SPA-3 Epigenetics in asthma: a master key? M. Pascual. University of Pamplona, Spain Asthma belongs to a group of complex and multifactorial diseases that are not the obvious result of a single mutation or an environmental aggression. Several studies have explored the genetic dimension of these diseases, but have proved to be insufficient to fully understand their prevalence and patterns of heritability [1]. Indeed, the quick rise in prevalence of asthma and other related diseases has motivated a tremendous interest in their epigenetic dimension, leading to the identification of environmental conditions and aggressions that might be responsible for epigenetic remodeling [2]. Under the term epigenetics a wide variety of mechanisms are included, which result in stable and heritable molecular patterns that exert long-term regulation of gene expression without altering the underlying DNA sequence [3]. Epigenetics has been proposed to hold the key to understand the intricate connections between external environmental aggressions and asthma onset and progression. References [1] Vercelli D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol. 2008; 8(18301422): 169–82. [2] Pascual M, Roa S. Epigenetic approaches to allergy research. Springer Briefs in genetics. ISBN: 978-1-4614-6365-8. [3] Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nature reviews Genetics. 2008 Jun; 9(6): 465–76.
SPA-5 “New therapeutic targets for children wheezing and asthma” – When should we use palivizumab? A Spanish consensus M. Gaboli. University Hospital of Salamanca, University of Salamanca, Salamanca, Spain Traditionally, the risk of severe respiratory infection due to respiratory syncytial virus (RSV) has been related to prematurity and presence of congenital cardiac disease. Therefore, several studies have focused on showing the usefulness and the effectiveness of RSV infection prophylaxis with monoclonal antibodies in the most susceptible patients [1–3]. It seems well established that RSV bronchiolitis in infancy is associated with recurrent wheezing and asthma during the first decade of life [4–5]. In some children, wheezing after early lower airway infection with RSV is transient. In many others it represents
the onset of asthma. However, the association between RSV early infection with the risk of development of atopy or asthma later in life is still debated. On the one hand, several results indicate that severe RSV bronchiolitis in young children may shift the T-helper Th1/Th2 balance in favor of a Th2 cytokine pattern, leading to the development of allergic sensitization and persistent asthma [6–7]. According to this hypothesis, a prospective multicentric study was conducted to assess the impact of palivizumab prophylaxis administered during the first year of life on the rates of recurrent wheezing. This study showed that preterm infants with no family history of asthma and atopy were significantly protected from recurrent wheezing from 2 to 5 year of life, which was not observed in children who had a history of asthma or atopy [8]. On the other hand, the majority of the studies that relate recurrent wheezing and asthma to impaired pulmonary function later in life in children that have suffered a severe RSV bronchiolitis are observational. Therefore, several authors consider that the causality is not demonstrated [9]. They suggest the possibility that inherited anomalies and underlying diseases may predispose the infant to develop a more severe infection of the lower respiratory tract, the RSV being in this case associated with the onset of severe lung sequelae with obstructive airway disease and wheezing that eventually give reason of the impaired lung function later in life [10–12]. More recently, interest has been put in assessing the risk factor for severe RSV infection [13–17]. It seems that patients suffering of underlying systemic disease (immunodeficiency, syndromes due to chromosomal abnormality, neuromuscular impairment) as well as primary lung disease or airway abnormalities (cystic fibrosis, severe respiratory tract malacia, sequelae of congenital diaphragmatic hernia, etc.) are at significant risk of more severe RSV infection and recurrent wheezing. This observation, together with the data regarding the benefits of RSV prevention in infants born prematurely or in young children with significant cardiovascular alteration, raised the question whether a specific prophylaxis in these groups of patients should be recommended. Up to now, data available in the literature about the use of palivizumab in patients with conditions excluded by indication from clinical trials are very heterogeneous and the cost and risk-benefit relationships are still a matter of debate [18–23]. To achieve a consensus of opinion regarding the adequacy of the off-label use of palivizumab for some pediatric patients with severe respiratory diseases or underlying conditions which are known to impair lung function later on in life, a study using the Delphi method was conducted in Spain among an expert group of pediatric pulmonologists (Gaboli et al., submitted). The Delphi technique is a well-established consensus method to gather and refine expert opinion on any given issue. It should be noticed that only a grade C recommendation can be made based on expert opinion and panel consensus. In the absence of studies with a higher degree of evidence, consensus-driven clinical guidelines represent a starting point to design new prospective studies; these should aim to achieve a better knowledge on the actual effect of preventing RSV infection with palivizumab in small children with severe respiratory disorders. References [1] Resch B et al. Cost-effectiveness of palivizumab for respiratory syncytial virus infection in high-risk children, based on long-term epidemiologic data from Austria. Pediatr Infect Dis J 2012; 31: e1-e8. [2] The IMpact-RSV Study Group. Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. Pediatrics 1998; 102: 531–537. [3] Feltes TF et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr 2003; 143: 532–540.
correspondence arising from published manuscripts and research letters – and the bar is high for the latter, they are not a repository for inadequate research. We also welcome suggestions for themed issues – we have had recent ones on TB (for world TB day) and cystic fibrosis. Writing a good paper: Far too many manuscripts fall at the first hurdle because of basic errors. Basic organisation is often lacking. Introduction – why you did it: This needs to summarise the background literature, and tell the reader why the subject is important. The two most important questions to answer are ‘what for?’ and ‘so what?’ – if you have not managed this at the end of the introduction, the paper must fail. Methods – what you did: Be prepared to use the on-line supplement for detailed descriptions. Use CONSORT (http://www.consortstatement.org/) and STROBE (http://www.strobe-statement.org/) diagrams if appropriate. The reader should be able to reproduce what you have done. Results – what you found: Start with the patient population; keep tables and graphs simple, be prepared to put more detailed tables on-line. Discussion – what it means: Do NOT repeat the introduction. Many people find structuring the discussion (Box 2) is helpful. Box 2. How to structure the discussion section • Statement of Principal Findings • Strengths and weaknesses of the study – There are always some problems! • Strengths and weaknesses with respect to other studies – Discrepant results? • Meaning of the study • Unanswered questions and future research Special issues: Genetic studies: There are particular pitfalls to avoid. These include reporting SNPs with no biological readout and no idea whether they affect gene expression; reporting mere association with no biological plausibility or validation elsewhere, e.g. animal studies; no second validation population; or the validation population replicates different SNPs in the same gene. Generally, editors are sceptical about genetic studies, because so many have fallen by the wayside having not been replicated. Case reports: Everyone likes talking about their interesting cases, but editors have little interest in publishing them, because they are not cited. Absolutely key is that there must be a take-home message: SO WHAT! is the inevitable cry of the referee. Other case reports to avoid include the 17th case of a rarity in the literature; the first report of a rarity in your country; and first report of an association between two rarities. All this is mere stamp-collecting. Opportunities for young investigators: First and most important, send us your good work! Consider writing a journal review for Lung Alerts, a feature in which interesting papers from other journals are discussed. Consider becoming a reviewer; probably best to start helping your mentor with a review before expecting to fly solo. Think about writing a review article; but send us a pre-submission proposal, and have a big-hitting co-author. Conclusion: Thorax is the journal for the bright, up and coming young investigator. Introduce yourself to us, and let’s work together to move the speciality forward! AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London References [1] Udwadia ZF. MDR, XDR, TDR tuberculosis: ominous progression. Thorax. 2012; 67: 286–8.
S43
Spanish Sessions SPA-1 Genetics and genomics of asthma, a step towards . . . where? C. Sanz, M. Isidoro Garc´ıa, S. de Arriba, F. Lorente, I. Davila. ´ Allergy Service, University Hospital of Salamanca, Salamanca, Spain Asthma is increasing worldwide at an alarming rate and its prevalence makes it the most common chronic disease in childhood and adolescence. Therefore, the governments, their health institutions and citizens must consider the study and treatment of this disease as a social and health priority [1]. As a multifactorial disease, several genes contribute to its development. This fact, associated to the diversity of asthma phenotypes and environmental influences have made difficult to obtain a clear pattern of inheritance. With the huge development of molecular genetics technologies, candidate gene studies are giving way to different types of studies at the genomic point of view. All these approaches are allowing the identification of several genes associated with asthma [2,3]. However, in these studies there are some conflicting results between different populations and there is still a lack of knowledge about the actual influence of these gene variants. Some confounding factors are inappropriate sample size, population stratification, differences in the phenotype classification, or inadequate gene coverage [4]. To confirm the real effect of the reported associations it will be necessary to consider the genetic environment and to perform functional studies that explain the molecular mechanisms that mediate between the emergence of a gene variant and the development of the disease [5]. The increasing development of experimental techniques opens a new horizon that will allow the identification of major genetic factors of susceptibility to asthma and the resulting classification of the populations groups based on their genetic characteristics, enabling the application of specific and highly efficient treatments [4]. References [1] Call for Global Action on Chronic Respiratory Diseases organized by the World Health Organization and the European Federation of Allergy and Airways Diseases (Rome, 11 June 2009). http://www.efanet.org/enews/ press.html/, http://www.who.int/respiratory/gard/en/. [2] Binia A and Kabesch M. Respiratory medicine – genetic base for allergy and asthma. Swiss med Weekly. 2012; 142: 1–11. [3] Moffatt M.F., Phil D., Gut I.D., Demenais F., et al. A Large-Scale, Consortium-Based Genome wide Association Study of Asthma. N Eng J Med. 2010; 363: 1211–21. [4] Isidoro-Garc´ıa M. and Davila ´ I. Genetica ´ en el asma. Espacioasma. 2013; 6(1): 8–12. [5] Isidoro-Garc´ıa M., Sanz C., Garc´ıa-Solaesa V., Pascual M., et al. PTGDR gene in asthma: a functional, genetic, and epigenetic study. Allergy. 2011; 66;12: 1553–62.
SPA-2 Drug, genes and asthma: when variability matters I. Davila, ´ C. Sanz, M. Isidoro Garc´ıa. Allergy Service, University Hospital, Salamanca, Spain It is estimated that 20–95% of the variability in drug responses is due to genetic factors [1]. In asthma a high inter-subject variability in the responses to the main drugs used in the treatment of asthma has been described. Thus, for example, a great variability in the response to fluticasone and montelukast has been observed in children [2]. Genetic studies have been performed with the main asthma drugs. In the case of bronchodilators, most studies have focused on the ADRB2, and some association of bronchodilator response and tachyphylaxis has been described, particularly with polymorphisms located on position 16 [3]. Related to corticosteroids
S44
Oral Presentations / Paediatric Respiratory Reviews 14S2 (2013) S1–S53
several genes have been implicated in the response in asthma. The most important of them are CRH1 (corticotropin-releasing hormone receptor 1), TBX21 (nuclear transcription factor T-bet) and FCER2 (low affinity IgE receptor) [4]. Finally, in the leukotriene pathway, the main pharmacogenetics studies have involved the ALOX5 (5-lipoxygenase), CYSLTR2 (cysteinyl leukotriene receptor 2) and LTC4S (leukotriene C4 synthase) genes. Nevertheless, most of the studies are limited by small sample sizes and a lack of replication studies. Although little is known about the effect of genes in the response to asthma drugs, the door is open for a personalized medicine, capable to minimize adverse effect and lead to a more cost-effective care. References [1] Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets, and side effects. N Engl J Med. 2003 Feb 6; 348(6): 538–49. [2] Szefler SJ, Phillips BR, Martinez FD, et al. Characterization of withinsubject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol. 2005 Feb; 115(2): 233–42. [3] Ortega VE, Hawkins GA, Peters SP, Bleecker ER. Pharmacogenetics of the beta 2-adrenergic receptor gene. Immunol Allergy Clin North Am. 2007 Nov; 27(4): 665–84; vii. [4] Lima JJ, Blake KV, Tantisira KG, Weiss ST. Pharmacogenetics of asthma. Curr Opin Pulm Med. 2009 Jan; 15(1): 57–62. [5] Tantisira KG, Drazen JM. Genetics and pharmacogenetics of the leukotriene pathway. J Allergy Clin Immunol. 2009 Sep; 124(3): 422–7.
SPA-3 Epigenetics in asthma: a master key? M. Pascual. University of Pamplona, Spain Asthma belongs to a group of complex and multifactorial diseases that are not the obvious result of a single mutation or an environmental aggression. Several studies have explored the genetic dimension of these diseases, but have proved to be insufficient to fully understand their prevalence and patterns of heritability [1]. Indeed, the quick rise in prevalence of asthma and other related diseases has motivated a tremendous interest in their epigenetic dimension, leading to the identification of environmental conditions and aggressions that might be responsible for epigenetic remodeling [2]. Under the term epigenetics a wide variety of mechanisms are included, which result in stable and heritable molecular patterns that exert long-term regulation of gene expression without altering the underlying DNA sequence [3]. Epigenetics has been proposed to hold the key to understand the intricate connections between external environmental aggressions and asthma onset and progression. References [1] Vercelli D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol. 2008; 8(18301422): 169–82. [2] Pascual M, Roa S. Epigenetic approaches to allergy research. Springer Briefs in genetics. ISBN: 978-1-4614-6365-8. [3] Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nature reviews Genetics. 2008 Jun; 9(6): 465–76.
SPA-5 “New therapeutic targets for children wheezing and asthma” – When should we use palivizumab? A Spanish consensus M. Gaboli. University Hospital of Salamanca, University of Salamanca, Salamanca, Spain Traditionally, the risk of severe respiratory infection due to respiratory syncytial virus (RSV) has been related to prematurity and presence of congenital cardiac disease. Therefore, several studies have focused on showing the usefulness and the effectiveness of RSV infection prophylaxis with monoclonal antibodies in the most susceptible patients [1–3]. It seems well established that RSV bronchiolitis in infancy is associated with recurrent wheezing and asthma during the first decade of life [4–5]. In some children, wheezing after early lower airway infection with RSV is transient. In many others it represents
the onset of asthma. However, the association between RSV early infection with the risk of development of atopy or asthma later in life is still debated. On the one hand, several results indicate that severe RSV bronchiolitis in young children may shift the T-helper Th1/Th2 balance in favor of a Th2 cytokine pattern, leading to the development of allergic sensitization and persistent asthma [6–7]. According to this hypothesis, a prospective multicentric study was conducted to assess the impact of palivizumab prophylaxis administered during the first year of life on the rates of recurrent wheezing. This study showed that preterm infants with no family history of asthma and atopy were significantly protected from recurrent wheezing from 2 to 5 year of life, which was not observed in children who had a history of asthma or atopy [8]. On the other hand, the majority of the studies that relate recurrent wheezing and asthma to impaired pulmonary function later in life in children that have suffered a severe RSV bronchiolitis are observational. Therefore, several authors consider that the causality is not demonstrated [9]. They suggest the possibility that inherited anomalies and underlying diseases may predispose the infant to develop a more severe infection of the lower respiratory tract, the RSV being in this case associated with the onset of severe lung sequelae with obstructive airway disease and wheezing that eventually give reason of the impaired lung function later in life [10–12]. More recently, interest has been put in assessing the risk factor for severe RSV infection [13–17]. It seems that patients suffering of underlying systemic disease (immunodeficiency, syndromes due to chromosomal abnormality, neuromuscular impairment) as well as primary lung disease or airway abnormalities (cystic fibrosis, severe respiratory tract malacia, sequelae of congenital diaphragmatic hernia, etc.) are at significant risk of more severe RSV infection and recurrent wheezing. This observation, together with the data regarding the benefits of RSV prevention in infants born prematurely or in young children with significant cardiovascular alteration, raised the question whether a specific prophylaxis in these groups of patients should be recommended. Up to now, data available in the literature about the use of palivizumab in patients with conditions excluded by indication from clinical trials are very heterogeneous and the cost and risk-benefit relationships are still a matter of debate [18–23]. To achieve a consensus of opinion regarding the adequacy of the off-label use of palivizumab for some pediatric patients with severe respiratory diseases or underlying conditions which are known to impair lung function later on in life, a study using the Delphi method was conducted in Spain among an expert group of pediatric pulmonologists (Gaboli et al., submitted). The Delphi technique is a well-established consensus method to gather and refine expert opinion on any given issue. It should be noticed that only a grade C recommendation can be made based on expert opinion and panel consensus. In the absence of studies with a higher degree of evidence, consensus-driven clinical guidelines represent a starting point to design new prospective studies; these should aim to achieve a better knowledge on the actual effect of preventing RSV infection with palivizumab in small children with severe respiratory disorders. References [1] Resch B et al. Cost-effectiveness of palivizumab for respiratory syncytial virus infection in high-risk children, based on long-term epidemiologic data from Austria. Pediatr Infect Dis J 2012; 31: e1-e8. [2] The IMpact-RSV Study Group. Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. Pediatrics 1998; 102: 531–537. [3] Feltes TF et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr 2003; 143: 532–540.