- Email: [email protected]
RSV and asthma: the chicken or the egg?
S6
Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
obese prepubertal children. Am J Respir Crit Care Med 2008; 177: 1142– 1149. [5] Bhattacharjee R, Kim J, Kheirandish-Gozal L, Gozal D. Obesity and obstructive sleep apnea syndrome in children: A tale of inflammatory cascades. Pediatr Pulmonol. 2011; 46(4): 313–23.
II.5 RSV and asthma: the chicken or the egg? T.V. Hartert. Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Nashville, TN 37232–8300, USA Correspondence: Tina V. Hartert, M.D., M.P.H. Division of Allergy, Pulmonary and Critical Care Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Vanderbilt University School of Medicine, Nashville, TN 37232–8300, USA. Phone: +1 615 322 3412; fax: +1 615 936 1269. E-mail: [email protected] Keywords: Respiratory syncytial virus, lower respiratory tract infection, bronchiolitis, asthma, recurrent wheezing
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections (LRTIs), during infancy, and almost all children have been infected at least once by age 2 years. By age 2, almost all children have been infected with RSV and most have been infected twice. The initial RSV infection is usually the most severe, causing LRTI, such as bronchiolitis, in 20–30% of infants. However, for reasons that are not fully understood, the immune response to RSV is incomplete and reinfection with RSV occurs throughout the life. There are well established links between RSV illness and asthma. First, it is well established that among infants who require hospitalization for RSV bronchiolitis, as many as 20–40% in various studies develop asthma by age 13 years. Second, viral infections are the most frequent and important cause of asthma exacerbations in children, implicated in up to 85% of disease exacerbations. While these data convincingly demonstrate that infants who develop viral-associated bronchiolitis have a high risk of developing asthma, and animal studies demonstrate biologically plausible mechanisms through which RSV may contribute to asthma, these studies can not answer the question of whether RSV contributed to asthma inception or was merely the first manifestation of reactive airway disease in a genetically predisposed child. The aims of this overview are to review the evidence of the relationship between RSV infection and subsequent asthma. Studies of the influence of RSV infection on the risk and severity of childhood asthma: The occurrence of recurrent wheezing after RSV LRTI has been recognized for decades. We and others have demonstrated that children hospitalized for RSV bronchiolitis during infancy are more likely to have subsequent episodes of wheezing and asthma during the first decade of life compared with children without a history of a bronchiolitis hospitalization during infancy [1–7]. Whether this risk persists throughout adolescence and into adult life is less clear, as longitudinal studies suffer from significant patient drop-out. Those studies which follow children longitudinally past 10 years suggest that RSV may no longer be significantly associated with asthma risk. The association of increased asthma risk among infants with RSV LRTI during infancy is consistent in most studies, and most pronounced during the first 6 years of life. Two ongoing longitudinal studies of infants with RSV bronchiolitis suggest that RSV infection does increase the risk of wheezing and later childhood asthma [1,2]. Sigurs and colleagues reported an increased prevalence of asthma or recurrent wheezing and allergic sensitization in children with RSV bronchiolitis at multiples timepoints, including at age 18, where 39% of the children who had suffered from RSV bronchiolitis in infancy were documented to have asthma or recurrent wheezing compared to only 9% in the control group. Somewhat different results were obtained in the Tucson Children’s Respiratory Study which prospectively enrolled
1246 infants born between 1980 to 1984 [1]. In this study, LRTI with confirmed RSV infection was associated with increased risks of infrequent and frequent wheezing at age 6, but the risk was reduced as children became older, and was not statistically significant by age 13 years. Taken together, these studies demonstrate that severe RSV bronchiolitis is associated with a 30 to 40% increased risk of subsequent asthma, at least within the first decade of life. The difference in asthma risk after the first decade of life between the two studies might be simply due to the differences in the populations studied, as well as the severity of infant RSV infection between the two groups. Recently, follow up of the children at age 22 years in the Tucson Children’s Respiratory Study has been reported. Asthma at age 22 years has been found to be associated with recurrent wheezing at age 6 years [7]. Although the relationship between RSV infection in early childhood and later asthma development was not significant at age 13 years in this cohort of children, a revisit of the association of asthma at age 22 years with RSV infection during early childhood will provide insights into the importance of this early life event. The causal relationship of RSV infection on the development of wheezing and asthma: Is the increased association of asthma following infant RSV infection an epiphenomenon due to enhanced airway inflammation and injury among those genetically predisposed to develop asthma, or does RSV alter the host defense, lung and/or immunity and truly cause asthma? A few recent studies have been aimed to address this question. We identified a dosedependent relationship between increasing infant bronchiolitis severity and both increased asthma risk and increased asthma severity among a population-based cohort of children covered under a US state-based health insurance plan, the TABS (Tennessee Asthma & Bronchiolitis Study) cohort [4,8]. This has been replicated using data from a managed care organization by Escobar and colleagues [6]. In the TABS study, we specifically evaluated the causal role of winter viral respiratory epidemics in the development of asthma among nearly 100,000 infants in a retrospective birth cohort [8]. We did this by investigating the relationship between infant age at the first winter viral peak following birth and subsequent asthma risk during the fifth to sixth year of life. Infants who were 4 months old at the peak of winter viral season were more likely to develop both clinical bronchiolitis and childhood asthma. Despite the winter viral peak shifting by nearly two months over the six winter viral seasons studied, the risk of asthma shifted in any given year with the shift in the peak of the winter viral peak such that infants born approximately 4 months prior to the first winter viral peak they encountered following birth were at the highest risk of developing childhood asthma. This strongly suggests a causal role of early RSV infection on asthma development. Three additional studies provide evidence, however, to dispute RSV causality. In a population based study among Denmark twins [9]. Thomsen and colleagues fitted genetic variance components and direction of causation models to over 8,000 twin pairs [9]. A model in which RSV hospitalization causes asthma was rejected, whereas one in which asthma causes RSV hospitalization was not. In another attempt to detect the causality between RSV and asthma, Stensballe and colleagues reported that the effect of RSV hospitalization on asthma was only short term (2 months after RSV hospitalization) and no longer significant 1 year later [10]. Lastly, a study of 37 monozygotic twin pairs discordant for severe RSV bronchiolitis in infancy indicated no differential effect of severity of RSV infection on the development of asthma [11]. All three twin studies utilized RSV bronchiolitis information from patient registries. Twins who were discordant for RSV hospitalization were highly likely to be concordant for RSV infection given the known high infectivity. Therefore, any conclusion about causality suffers from the misclassification of twins not hospitalized with RSV infection to an uninfected group. In addition, asthma was defined at an early age in two of the three twin studies. Children were considered as having asthma as early as infancy or by age 3 years,
Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
which may well reflect children with “transient early wheezing” but not asthma. The impact of prevention or treatment of RSV on asthma risk: Ultimately to address the question of whether RSV infection during infancy causes asthma, showing that prevention or delay in infant infection prevents asthma will be necessary. There is very limited data, in the form of two small studies, which suggest that RSV immunoprophylaxis may lower the likelihood for the development of asthma. The first is a small investigation of 13 children identified retrospectively as having received RSV immunoprophylaxis, showing that receipt of RSV immunoprophylaxis during infancy may have long-term effects on respiratory and immunologic parameters relevant to the development of asthma [12]. The second study is an industrysponsored investigation of open-label compassionate-use RSV immunoprophylaxis among a European cohort of preterm infants showing decreased wheezing outcomes among infants receiving immunoprophylaxis. There are substantial limitations to the design and selection of subjects, including use of RSV immunoprophylaxis on a compassionate use basis with no delineated indications nor standard recommendations for use in each child [13]. In addition, the age of the children in this investigation at follow-up was only 19–43 months. Lastly, an open-label study assessing the impact of treating (not preventing) active RSV bronchiolitis with the antiviral agent ribavirin showed a reduction of the risk of asthma and allergic sensitization at age 6 years among children 2 years and less who did and did not receive ribavirin for RSV bronchiolitis [14]. This study also has limitations, in that those who did and did not receive ribavirin differed significantly in age of RSV bronchiolitis, prematurity and disease severity. Summary: To summarize the evidence in support of a role of RSV in asthma causation there is: (1) Ecological evidence of increasing rates of infant bronchiolitis in the last ten years mirroring the 5-year offset increases in asthma at age 5 years among these same children; (2) Dose-response relationship with a positive severity-dependent association with both asthma risk and asthma morbidity; (3) Known common host immune factors for both diseases, with persons with asthma known to be at increased risk for viral infections and invasive bacterial infections; (4) Genetic evidence with genes predisposing to asthma also linked to susceptibility and severity of RSV infection; and lastly (5) Causal evidence with demonstration for the first time that timing of birth in relationship to when RSV circulates independently predicts asthma development, with birth timing conferring a nearly 30% increase in risk of early childhood asthma. Ultimately, however, showing that prevention or delay in infant infection prevents asthma will definitively answer the question of whether RSV causes asthma, and potentially provide an important primary asthma prevention strategy. References [1] Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 354(9178), 541–545 (1999). [2] Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 161(5), 1501–1507 (2000). [3] Sigurs N, Aljassim F, Kjellman B, et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax 65(12), 1045–1052 (2010). [4] Carroll KN, Wu P, Gebretsadik T, et al. The severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. J Allergy Clin Immunol. 123(5), 1055–61, 1061 (2009). [5] Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 332(3), 133–138 (1995). [6] Escobar GJ, Ragins A, Li SX, Prager L, Masaquel AS, Kipnis P. Recurrent wheezing in the third year of life among children born at 32 weeks’ gestation or later: relationship to laboratory-confirmed, medically
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
S7
attended infection with respiratory syncytial virus during the first year of life. Arch Pediatr Adolesc Med 164(10), 915–922 (2010). Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet 372(9643), 1058–1064 (2008). Wu P, Dupont WD, Griffin MR, et al. Evidence of a causal role of winter virus infection during infancy in early childhood asthma. Am.J.Respir.Crit Care Med. 178(11), 1123–1129 (2008). Thomsen SF, van der SS, Stensballe LG, et al. Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study. Am.J Respir.Crit Care Med. 179(12), 1091–1097 (2009). Stensballe LG, Simonsen JB, Thomsen SF, et al. The causal direction in the association between respiratory syncytial virus hospitalization and asthma. J Allergy Clin Immunol. 123(1), 131–137 (2009). Poorisrisak P, Halkjaer LB, Thomsen SF, et al. Causal direction between respiratory syncytial virus bronchiolitis and asthma studied in monozygotic twins. Chest 138(2), 338–344 (2010). Wenzel SE, Gibbs RL, Lehr MV, Simoes EA. Respiratory outcomes in high-risk children 7 to 10 years after prophylaxis with respiratory syncytial virus immune globulin. Am.J.Med. 112(8), 627–633 (2002). Simoes EA, Groothuis JR, Carbonell-Estrany X, et al. Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. J Pediatr 151(1), 34–42, 42 (2007). Chen CH, Lin YT, Yang YH, et al. Ribavirin for respiratory syncytial virus bronchiolitis reduced the risk of asthma and allergen sensitization. Pediatr Allergy Immunol 19(2), 166–172 (2008).
II.6 2012 – The year in preview B.K. Rubin. Department of Pediatrics,Virginia Commonwealth University, and Children’s Hospital of Richmond, Richmond, VA, USA A highlight of many international meetings is a review of pertinent literature in a specific field that has been published in the preceding year. Although such “year in review” presentations are important, at CIPP we are pleased to present the news that has not yet happened. In this presentation which is a combination of science and fiction, I will present the very best research that has not yet been conducted but will be published sometime in the year 2012. This research will cover all aspects of pediatric pulmonary disease. Any resemblance to real research that is actually published during this time period is strictly coincidental and the product of a very fertile imagination. The hope of this presentation is to stimulate the audience to think about possibilities and to give insight into how scientists think about developing new research projects.
III. Obstructive Lung Disease III.1. Obstructive Lung Disease – Where genome meets environmentome III.1.1 The clinical relevance of asthma genetics F. Martinez. Regents’ Professor, Director, BIO5 Institute, Director, Arizona Respiratory Center, Swift-McNear Professor of Pediatrics, University of Arizona, USA There different approaches have been attempted to elucidate the genetic basis of asthma and other complex diseases. Initially, most studies consisted of assessment of association between polymorphisms in candidate genes and asthma and asthma-related traits. These studies provided replicated evidence for association in many different genes [1]. Simultaneously, other studies applied a second approach, namely, linkage analysis between asthma and highly polymorphic markers distributed in a roughly uniform way in the genome. Although these latter studies yielded some promising results [2], they proved relatively insensitive to identifying areas of
Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
obese prepubertal children. Am J Respir Crit Care Med 2008; 177: 1142– 1149. [5] Bhattacharjee R, Kim J, Kheirandish-Gozal L, Gozal D. Obesity and obstructive sleep apnea syndrome in children: A tale of inflammatory cascades. Pediatr Pulmonol. 2011; 46(4): 313–23.
II.5 RSV and asthma: the chicken or the egg? T.V. Hartert. Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Nashville, TN 37232–8300, USA Correspondence: Tina V. Hartert, M.D., M.P.H. Division of Allergy, Pulmonary and Critical Care Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Vanderbilt University School of Medicine, Nashville, TN 37232–8300, USA. Phone: +1 615 322 3412; fax: +1 615 936 1269. E-mail: [email protected] Keywords: Respiratory syncytial virus, lower respiratory tract infection, bronchiolitis, asthma, recurrent wheezing
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections (LRTIs), during infancy, and almost all children have been infected at least once by age 2 years. By age 2, almost all children have been infected with RSV and most have been infected twice. The initial RSV infection is usually the most severe, causing LRTI, such as bronchiolitis, in 20–30% of infants. However, for reasons that are not fully understood, the immune response to RSV is incomplete and reinfection with RSV occurs throughout the life. There are well established links between RSV illness and asthma. First, it is well established that among infants who require hospitalization for RSV bronchiolitis, as many as 20–40% in various studies develop asthma by age 13 years. Second, viral infections are the most frequent and important cause of asthma exacerbations in children, implicated in up to 85% of disease exacerbations. While these data convincingly demonstrate that infants who develop viral-associated bronchiolitis have a high risk of developing asthma, and animal studies demonstrate biologically plausible mechanisms through which RSV may contribute to asthma, these studies can not answer the question of whether RSV contributed to asthma inception or was merely the first manifestation of reactive airway disease in a genetically predisposed child. The aims of this overview are to review the evidence of the relationship between RSV infection and subsequent asthma. Studies of the influence of RSV infection on the risk and severity of childhood asthma: The occurrence of recurrent wheezing after RSV LRTI has been recognized for decades. We and others have demonstrated that children hospitalized for RSV bronchiolitis during infancy are more likely to have subsequent episodes of wheezing and asthma during the first decade of life compared with children without a history of a bronchiolitis hospitalization during infancy [1–7]. Whether this risk persists throughout adolescence and into adult life is less clear, as longitudinal studies suffer from significant patient drop-out. Those studies which follow children longitudinally past 10 years suggest that RSV may no longer be significantly associated with asthma risk. The association of increased asthma risk among infants with RSV LRTI during infancy is consistent in most studies, and most pronounced during the first 6 years of life. Two ongoing longitudinal studies of infants with RSV bronchiolitis suggest that RSV infection does increase the risk of wheezing and later childhood asthma [1,2]. Sigurs and colleagues reported an increased prevalence of asthma or recurrent wheezing and allergic sensitization in children with RSV bronchiolitis at multiples timepoints, including at age 18, where 39% of the children who had suffered from RSV bronchiolitis in infancy were documented to have asthma or recurrent wheezing compared to only 9% in the control group. Somewhat different results were obtained in the Tucson Children’s Respiratory Study which prospectively enrolled
1246 infants born between 1980 to 1984 [1]. In this study, LRTI with confirmed RSV infection was associated with increased risks of infrequent and frequent wheezing at age 6, but the risk was reduced as children became older, and was not statistically significant by age 13 years. Taken together, these studies demonstrate that severe RSV bronchiolitis is associated with a 30 to 40% increased risk of subsequent asthma, at least within the first decade of life. The difference in asthma risk after the first decade of life between the two studies might be simply due to the differences in the populations studied, as well as the severity of infant RSV infection between the two groups. Recently, follow up of the children at age 22 years in the Tucson Children’s Respiratory Study has been reported. Asthma at age 22 years has been found to be associated with recurrent wheezing at age 6 years [7]. Although the relationship between RSV infection in early childhood and later asthma development was not significant at age 13 years in this cohort of children, a revisit of the association of asthma at age 22 years with RSV infection during early childhood will provide insights into the importance of this early life event. The causal relationship of RSV infection on the development of wheezing and asthma: Is the increased association of asthma following infant RSV infection an epiphenomenon due to enhanced airway inflammation and injury among those genetically predisposed to develop asthma, or does RSV alter the host defense, lung and/or immunity and truly cause asthma? A few recent studies have been aimed to address this question. We identified a dosedependent relationship between increasing infant bronchiolitis severity and both increased asthma risk and increased asthma severity among a population-based cohort of children covered under a US state-based health insurance plan, the TABS (Tennessee Asthma & Bronchiolitis Study) cohort [4,8]. This has been replicated using data from a managed care organization by Escobar and colleagues [6]. In the TABS study, we specifically evaluated the causal role of winter viral respiratory epidemics in the development of asthma among nearly 100,000 infants in a retrospective birth cohort [8]. We did this by investigating the relationship between infant age at the first winter viral peak following birth and subsequent asthma risk during the fifth to sixth year of life. Infants who were 4 months old at the peak of winter viral season were more likely to develop both clinical bronchiolitis and childhood asthma. Despite the winter viral peak shifting by nearly two months over the six winter viral seasons studied, the risk of asthma shifted in any given year with the shift in the peak of the winter viral peak such that infants born approximately 4 months prior to the first winter viral peak they encountered following birth were at the highest risk of developing childhood asthma. This strongly suggests a causal role of early RSV infection on asthma development. Three additional studies provide evidence, however, to dispute RSV causality. In a population based study among Denmark twins [9]. Thomsen and colleagues fitted genetic variance components and direction of causation models to over 8,000 twin pairs [9]. A model in which RSV hospitalization causes asthma was rejected, whereas one in which asthma causes RSV hospitalization was not. In another attempt to detect the causality between RSV and asthma, Stensballe and colleagues reported that the effect of RSV hospitalization on asthma was only short term (2 months after RSV hospitalization) and no longer significant 1 year later [10]. Lastly, a study of 37 monozygotic twin pairs discordant for severe RSV bronchiolitis in infancy indicated no differential effect of severity of RSV infection on the development of asthma [11]. All three twin studies utilized RSV bronchiolitis information from patient registries. Twins who were discordant for RSV hospitalization were highly likely to be concordant for RSV infection given the known high infectivity. Therefore, any conclusion about causality suffers from the misclassification of twins not hospitalized with RSV infection to an uninfected group. In addition, asthma was defined at an early age in two of the three twin studies. Children were considered as having asthma as early as infancy or by age 3 years,
Oral Presentations / Paediatric Respiratory Reviews 12S1 (2011) S1–S66
which may well reflect children with “transient early wheezing” but not asthma. The impact of prevention or treatment of RSV on asthma risk: Ultimately to address the question of whether RSV infection during infancy causes asthma, showing that prevention or delay in infant infection prevents asthma will be necessary. There is very limited data, in the form of two small studies, which suggest that RSV immunoprophylaxis may lower the likelihood for the development of asthma. The first is a small investigation of 13 children identified retrospectively as having received RSV immunoprophylaxis, showing that receipt of RSV immunoprophylaxis during infancy may have long-term effects on respiratory and immunologic parameters relevant to the development of asthma [12]. The second study is an industrysponsored investigation of open-label compassionate-use RSV immunoprophylaxis among a European cohort of preterm infants showing decreased wheezing outcomes among infants receiving immunoprophylaxis. There are substantial limitations to the design and selection of subjects, including use of RSV immunoprophylaxis on a compassionate use basis with no delineated indications nor standard recommendations for use in each child [13]. In addition, the age of the children in this investigation at follow-up was only 19–43 months. Lastly, an open-label study assessing the impact of treating (not preventing) active RSV bronchiolitis with the antiviral agent ribavirin showed a reduction of the risk of asthma and allergic sensitization at age 6 years among children 2 years and less who did and did not receive ribavirin for RSV bronchiolitis [14]. This study also has limitations, in that those who did and did not receive ribavirin differed significantly in age of RSV bronchiolitis, prematurity and disease severity. Summary: To summarize the evidence in support of a role of RSV in asthma causation there is: (1) Ecological evidence of increasing rates of infant bronchiolitis in the last ten years mirroring the 5-year offset increases in asthma at age 5 years among these same children; (2) Dose-response relationship with a positive severity-dependent association with both asthma risk and asthma morbidity; (3) Known common host immune factors for both diseases, with persons with asthma known to be at increased risk for viral infections and invasive bacterial infections; (4) Genetic evidence with genes predisposing to asthma also linked to susceptibility and severity of RSV infection; and lastly (5) Causal evidence with demonstration for the first time that timing of birth in relationship to when RSV circulates independently predicts asthma development, with birth timing conferring a nearly 30% increase in risk of early childhood asthma. Ultimately, however, showing that prevention or delay in infant infection prevents asthma will definitively answer the question of whether RSV causes asthma, and potentially provide an important primary asthma prevention strategy. References [1] Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 354(9178), 541–545 (1999). [2] Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 161(5), 1501–1507 (2000). [3] Sigurs N, Aljassim F, Kjellman B, et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax 65(12), 1045–1052 (2010). [4] Carroll KN, Wu P, Gebretsadik T, et al. The severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. J Allergy Clin Immunol. 123(5), 1055–61, 1061 (2009). [5] Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 332(3), 133–138 (1995). [6] Escobar GJ, Ragins A, Li SX, Prager L, Masaquel AS, Kipnis P. Recurrent wheezing in the third year of life among children born at 32 weeks’ gestation or later: relationship to laboratory-confirmed, medically
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
S7
attended infection with respiratory syncytial virus during the first year of life. Arch Pediatr Adolesc Med 164(10), 915–922 (2010). Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet 372(9643), 1058–1064 (2008). Wu P, Dupont WD, Griffin MR, et al. Evidence of a causal role of winter virus infection during infancy in early childhood asthma. Am.J.Respir.Crit Care Med. 178(11), 1123–1129 (2008). Thomsen SF, van der SS, Stensballe LG, et al. Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study. Am.J Respir.Crit Care Med. 179(12), 1091–1097 (2009). Stensballe LG, Simonsen JB, Thomsen SF, et al. The causal direction in the association between respiratory syncytial virus hospitalization and asthma. J Allergy Clin Immunol. 123(1), 131–137 (2009). Poorisrisak P, Halkjaer LB, Thomsen SF, et al. Causal direction between respiratory syncytial virus bronchiolitis and asthma studied in monozygotic twins. Chest 138(2), 338–344 (2010). Wenzel SE, Gibbs RL, Lehr MV, Simoes EA. Respiratory outcomes in high-risk children 7 to 10 years after prophylaxis with respiratory syncytial virus immune globulin. Am.J.Med. 112(8), 627–633 (2002). Simoes EA, Groothuis JR, Carbonell-Estrany X, et al. Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. J Pediatr 151(1), 34–42, 42 (2007). Chen CH, Lin YT, Yang YH, et al. Ribavirin for respiratory syncytial virus bronchiolitis reduced the risk of asthma and allergen sensitization. Pediatr Allergy Immunol 19(2), 166–172 (2008).
II.6 2012 – The year in preview B.K. Rubin. Department of Pediatrics,Virginia Commonwealth University, and Children’s Hospital of Richmond, Richmond, VA, USA A highlight of many international meetings is a review of pertinent literature in a specific field that has been published in the preceding year. Although such “year in review” presentations are important, at CIPP we are pleased to present the news that has not yet happened. In this presentation which is a combination of science and fiction, I will present the very best research that has not yet been conducted but will be published sometime in the year 2012. This research will cover all aspects of pediatric pulmonary disease. Any resemblance to real research that is actually published during this time period is strictly coincidental and the product of a very fertile imagination. The hope of this presentation is to stimulate the audience to think about possibilities and to give insight into how scientists think about developing new research projects.
III. Obstructive Lung Disease III.1. Obstructive Lung Disease – Where genome meets environmentome III.1.1 The clinical relevance of asthma genetics F. Martinez. Regents’ Professor, Director, BIO5 Institute, Director, Arizona Respiratory Center, Swift-McNear Professor of Pediatrics, University of Arizona, USA There different approaches have been attempted to elucidate the genetic basis of asthma and other complex diseases. Initially, most studies consisted of assessment of association between polymorphisms in candidate genes and asthma and asthma-related traits. These studies provided replicated evidence for association in many different genes [1]. Simultaneously, other studies applied a second approach, namely, linkage analysis between asthma and highly polymorphic markers distributed in a roughly uniform way in the genome. Although these latter studies yielded some promising results [2], they proved relatively insensitive to identifying areas of