Pediatric asthma phenotypes

Transcription

1 REVIEW C URRENT OPINION Pediatric asthma phenotypes Kelly Cowan and Theresa W. Guilbert Purpose of review There is currently limited ability to identify which infants and young children with recurrent wheezing will ultimately develop persistent asthma. In addition, it is not clear how risk factors influence the development of asthma in later childhood and adulthood. This review will discuss efforts to categorize these children with recurrent wheezing and develop asthma-predictive tools. Recent findings Transient and persistent wheezing phenotypes have been identified with atopy, reduced lung function, and viral and bacterial respiratory infection as major risk factors for persistence of asthma. Children with severe asthma tend to have greater magnitude of atopy and lower lung function than those with mild moderate asthma. These phenotypes and risk factors have been described in previous studies and are supported by the recent literature. Summary Heterogeneity of wheezing phenotypes may account for different responses to treatment and varied outcomes. Overlap in phenotypes and instability over time also add additional challenges to defining discrete groups of children with specific outcomes. Further studies are needed to determine combinations of variables that may improve phenotype designation with the goal of improving asthma prevention and treatment as well as predicting outcomes and understanding the pathogenesis of asthma. Keywords asthma, children, phenotype, wheezing INTRODUCTION Although nearly 50% of children have wheezing with respiratory illnesses in their first year of life, only 20% will have continued wheezing in later childhood [1]. Because of the heterogeneity of the disorder, there is limited ability to identify infants and young children with recurrent wheezing who are at increased risk of developing persistent asthma. In addition, it is not clear how risk factors influence the development of asthma in later childhood and adulthood. Efforts have been made to categorize these children with recurrent wheezing and develop predictive tools to determine who will ultimately develop persistent asthma [2,3,4,5 ]. WHEEZING PHENOTYPES Both epidemiologic and symptom-based phenotypes have been used to describe patterns of wheezing in young children and identify associated risk factors. Epidemiologic phenotypes: transient and persistent wheezing The Tucson Children s Respiratory Study (TCRS) has generated the most well-known wheezing classification. In this prospective longitudinal study of 1246 newborns followed for lower respiratory tract infections, four wheezing phenotypes were identified (Table 1) [1]. (1) Never wheezing (51%) children who never wheezed (2) Early transient wheezing (20%) onset of wheezing before age 3 years with resolution by age 6 years Phenotypes with increased risk of persistent asthma into adolescence and adulthood: (1) Persistent wheezing (14%) onset of wheezing before age 3 years with continued wheezing at age 6 years University of Wisconsin, Madison, Wisconsin, USA Correspondence to Theresa Guilbert, MD, The Department of Pediatrics, University of Wisconsin-Madison, 600 Highland Avenue, K4/944, CSC- 4108, Madison,WI 53716, USA. Tel: ; fax: ; tguilbert@wisc.edu Curr Opin Pediatr 2012, 24: DOI: /MOP.0b013e ab Volume 24 Number 3 June 2012 Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

2 Pediatric asthma phenotypes Cowan and Guilbert KEY POINTS Wheezing phenotypes have been categorized into epidemiologic phenotypes (transient and persistent wheeze) and symptom-based phenotypes (episodic/ viral wheeze and multitrigger wheeze). Major factors that may predict risk of persistent asthma are allergic disease, reduced lung function, and viral respiratory infection and bacterial colonization in infancy. Phenotype heterogeneity, overlap, and instability over time may account for different responses to treatment and varied outcomes. Further studies are needed to determine combinations of variables that may improve phenotype designation with the ultimate goal of improving asthma prevention and treatment as well as predicting outcomes and understanding the pathogenesis of asthma. (2) Late-onset wheezing (15%) children who developed wheezing between 3 and 6 years of age These groups were further characterized into transient infant wheezing, nonatopic persistent wheezing, and IgE-associated/atopic persistent wheezing [6 8]. Transient wheezing begins in the first year of life, resolves by preschool age, and is associated with decreased lung function, smaller airways (low flow rates by lung function testing), maternal tobacco use during pregnancy, having siblings, and daycare attendance. Nonatopic persistent wheezing (lack of allergic sensitization and methacholine hyper-responsiveness) begins in infancy and resolves in mid-childhood. Although IgE-associated/atopic persistent wheezing can begin early in life, it increases in prevalence with age. It is associated with personal and family history of allergic disease, methacholine hyper-responsiveness, and decreased lung function. Children in the IgE-associated/atopic persistent wheezing and lateonset wheezing groups are at increased risk of persistent asthma-like symptoms into adolescence and adulthood. Conversely, the children in the nonatopic persistent wheezing phenotype group experience a decrease in wheezing episodes by early adolescence [9]. On the basis of a study of school-age children, the Italian Studies of Respiratory Disorders in Childhood and the Environment (SIDRIA) classification scheme is similar to the TCRS (Table 1). Two exceptions were an upper age limit for transient early wheezing of 2 years and the frequency of the wheezing phenotypes. In this study, 83% had never wheezed, 7% had transient early wheezing, 4% had persistent wheezing, and 6% had late-onset wheezing [10]. The Avon Longitudinal Study of Parents and Children (ALSPAC) prospective examined maternal report of wheezing in 6265 children [11] using sophisticated statistical methods. With the use of more time points at shorter intervals than the Tucson study combined with objective measures (e.g. lung function and allergen sensitization), two additional phenotypes were identified (Table 1) [12]: (1) Never/infrequent wheeze (59%) (2) Transient early wheeze (16%) wheezing common from 6 to 18 months, but rare to never after 42 months (3) Prolonged early wheeze (9%) wheezing common from 6 to 54 months, but rare to never after 69 months (4) Intermediate-onset wheeze (3%) wheezing rare to never from 6 to 18 months, but common thereafter (5) Late-onset wheeze (6%) infrequent wheezing from 6 to 42 months, but common thereafter (6) Persistent wheeze (7%) wheezing common from 6 months onward Risk factors in all groups included a parental history of asthma (especially maternal) and personal allergic disease. Transient infant wheezing was associated with maternal smoking during pregnancy and having older siblings. Persistent wheezing was associated with prematurity and lower socioeconomic status. The Netherlands Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study is a longitudinal birth cohort study which demonstrated similar wheezing phenotypes in 2810 children (never, infrequent wheeze, transient early wheeze, intermediate-onset wheeze, late-onset wheeze, and persistent wheeze) [13 ] as well as similar associations with asthma, allergic disease, bronchial hyper-responsiveness and lung function (Table 1). Across these epidemiologic studies there are some variations in the age range for phenotypes as well as inconsistencies in associated risk factors. Furthermore, there are also concerns about their usefulness in clinical practice, prospective validity, and potential investigator bias in categorization. Episodic and multitrigger wheezing The European Respiratory Society defined two symptom-based phenotypes: episodic and multitrigger wheeze [14]. Children with episodic (viral) wheeze do so only during discrete periods. Children ß 2012 Wolters Kluwer Health Lippincott Williams Wilkins Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

3 Pulmonology Table 1. Pediatric asthma phenotypes described by longitudinal cohort studies Cohort Population Phenotypes described At risk for persistent asthma in childhood or later Tucson Children s Respiratory Study (TCRS) [1,6 9] 1246 unselected newborns 826 with data at 3 and 6 years 956 with data at 11 years 849 with data at 22 years Never wheeze (51%) Early transient wheeze (20%) Persistent wheezing (14%) Late-onset wheezing (15%) IgE-associated/atopic persistent wheeze and late-onset wheeze (persists into adolescence and adulthood) Nonatopic persistent wheezing (often remits by adolescence) Maternal asthma, maternal smoking, rhinitis apart from colds, eczema during the first year of life, male sex, Hispanic, lower lung function, airway hyper-responsiveness Italian Studies of Respiratory Disorders in Childhood and the Environment (SIDRIA) [10] Population-based study of 6 and 7-year-olds (16 333) Never wheeze (83%) Transient early wheezing (7%) Persistent wheezing (4%) Late-onset wheezing (6%) Parental (esp. maternal) asthma and hay-fever, personal eczema or allergic rhinitis, maternal smoking in pregnancy, male sex, breastfed >6 months British Avon Longitudinal Study of Parents and Children (ALSPAC) [11,12] Netherlands Prevention and Incidence of Asthma and Mite Allergy (PIAMA) Study [13 ] 6265 children from birth cohort Data from 8 time points (birth to 7 years) 2810 children from birth cohort Data from 9 time points (birth to 8 yrs) Never/infrequent wheeze (59%) Transient early wheezing (16%) Prolonged early wheezing (9%) Intermediate-onset wheezing (3%) Late-onset wheezing (6%) Persistent wheeze (7%) Never/infrequent wheeze (75%) Transient early wheeze (17%) Intermediate-onset wheeze (3%) Late-onset wheeze (2%) Persistent wheeze (4%) Atopy, lower lung function, airway hyper-responsiveness, parental asthma (esp. maternal), prematurity, lower socioeconomic status Allergic disease, airway hyper-responsiveness, lower lung function with multitrigger (including viruses, allergens, exercise, and cigarette smoke) wheeze have wheezing both during exacerbations and between episodes and have lower airway function compared with the episodic wheezing phenotype [15 ]. Adding an additional layer of complexity, these phenotypes may not be stable over time. In one study, over half of the children classified into either episodic or multitrigger wheezing phenotypes switched to the other phenotype in the subsequent year [16 ]. SEVERE ASTHMA PHENOTYPE Severe asthma can be differentiated from mild moderate asthma by greater symptom burden, more frequent exacerbations, greater allergic sensitization, more airflow obstruction, and increased fractional exhaled nitric oxide (FeNO) despite higher doses of corticosteroids [17,18 ]. Symptoms may also be identifiable in early life. Historical data from children enrolled in the National Institutes of Health (NIH) Heart, Lung, and Blood Institute Severe Asthma Research Program (NHLBI SARP) showed that children with severe asthma had onset of symptoms in the first 24 months of life compared with 60 months in mild moderate asthma [17]. In addition, children with severe asthma had higher prevalence of atopic dermatitis and positive skin prick testing to aeroallergens by early childhood [17]. Even before the onset of symptoms, asthma may be present. This is illustrated by studies showing that infants with the lowest pulmonary function are those who will go on to have persistent asthma [19,20] and severe bronchial hyper-responsiveness in childhood [19]. In an NHLBI SARP cluster analysis of children with asthma, four clusters were identified, all with varying degrees of allergic disease and a trend of increasing severity [21 ]: late-onset symptomatic asthma with normal lung function, early-onset atopic asthma with normal lung function, earlyonset atopic asthma with mild airflow limitation, and early-onset atopic asthma with advanced airflow limitation. Duration of asthma, number of controller medications, and baseline lung function were major predictors of cluster assignment. Allergic disease, FeNO concentrations, and age of asthma onset were also factors Volume 24 Number 3 June 2012 Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

4 Pediatric asthma phenotypes Cowan and Guilbert Differences in lower airway inflammatory response in severe asthma may also distinguish severe asthma from moderate asthma. In a unique study, by applying a linear discriminant analysis and a supervised method of high-dimensional data reduction to measurements of cytokines and chemokines in bronchoalveolar lavage (BAL) fluid and alveolar macrophage lysate in children with severe asthma, there was a unique molecular phenotype with increased markers of BAL inflammation and alveolar macrophage activation [22 ]. Children with moderate and severe asthma were phenotypically distinct without a clear T(H)1 or T(H)2 pattern. Although neutrophilic, eosinophilic, and mixed airway inflammatory phenotypes have been reported based on BAL and sputum samples from children with severe asthma [23 25], the role of these cells and whether treatment is beneficial in children is unclear. Airway eosinophilia may be present prior to the onset of asthma [26 ]. A study of children who had nonbronchoscopic BAL during elective surgery showed that the BAL eosinophil percentage was significantly increased in children who later developed late-onset childhood wheeze compared with those who never wheezed. Patterns of inflammation are complex and there are likely interactions between cell types, and symptom patterns may not correlate with a particular inflammatory picture. For example, some young adults with asthma in clinical remission have as much eosinophilic inflammation as those with symptomatic asthma [27]. Although the significance of airway neutrophilia remains to be determined, there may be a relevant cause, such as an underlying bacterial infection, and potential benefit from treatment [28 ]. The clinical utility of both epidemiologic and symptom-based phenotypes may be limited due to variability in symptoms and risk factors over time, and overlap of phenotypes. Furthermore, there are no specific therapies targeted to particular phenotypes. Thus, it is unclear if identification of phenotypes and treatment by these phenotypes can modify the course of disease or ultimate outcome. ASTHMA RISK FACTORS The major risk factors for development and persistence of asthma are allergic disease, reduced lung function, and viral and bacterial infections [28,29,30 ]. In addition, numerous genetic, environmental, and developmental factors interact to determine the natural history of asthma in an individual. Allergic disease Numerous phenotype studies have illustrated the relationship between allergic disease and asthma [12,31 33]. For example, in the Tucson cohort, allergic disease was the main risk factor for development of persistent asthma [1]. Children with lateonset and persistent wheezing had a significantly higher rate of allergen sensitization at age 6 years, and alternaria sensitization was associated with a higher rate of asthma at age 22 years [31]. In addition, the intermediate-onset, late-onset, and persistent wheezing phenotypes in the Avon cohort were most strongly associated with allergic disease and childhood asthma [12]. Reduced lung function Children with persistent wheezing phenotypes have a greater degree of lung function impairment compared with other phenotypes [12,32 34,35 ]. In the Avon cohort, phenotypes with prolonged early, intermediate-onset, and persistent wheezing had lowest lung function, and intermediate and lateonset phenotypes had the greatest airway hyperresponsiveness [12]. Different studies have shown abnormal lung function at various ages [1,31,32,35,36 38]. In children who developed persistent wheezing at 6 years of age in the Tucson cohort, lung function was normal in infancy but reduced at 6 years and into adolescence [1]. Also in the Tucson cohort, persistent wheezing in early life and airway hyper-responsiveness and low airway function at 6 years were associated with both chronic and newly diagnosed asthma at 22 years of age [31]. Studies of cohorts from Norway and Australia showed abnormal lung function as young as 1 month of age in children who developed persistent wheeze in later childhood [36,37]. There is also an association with exposure to high levels of perennial allergens early in life and lower lung function during the school years in children with atopic persistent wheezing [39]. Viral infections and bacterial colonization It is unclear whether certain viral respiratory infections cause asthma or if those who wheeze with these illnesses are already predisposed to the development of asthma [40 ]. Nevertheless, viral respiratory infections in infancy (especially with human rhinovirus) are predictive of the development of asthma in later childhood [41]. These infections may amplify the asthma risk with allergic disease and reduced lung function during early childhood [42,43]. A recent study by Bisgaard et al. [30 ] demonstrated that neonates colonized in the hypopharyngeal region with ß 2012 Wolters Kluwer Health Lippincott Williams Wilkins Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

5 Pulmonology Streptococcus pneumonia, Haemophilus influenza, or Moraxella catarrhalis, or with a combination of these organisms, are at increased risk of recurrent preschool wheezing and asthma at age 5. In a recent study by Schwerk et al. [28 ], 42 preschool-aged children with severe persistent wheezing were examined by bronchoscopy and BAL. Eighty-one percent had neutrophilic inflammation and 59% of these had elevated bacterial counts of S. pneumonia, H. influenza, or M. catarrhalis. After 2 6 weeks of antibiotic treatment, 92% of these children demonstrated a marked improvement of symptoms [28 ]. Another possible mechanism for these associations may be that a person with immune function that is biased toward atopy may have altered host defenses that both increase susceptibility to bacterial and viral infections and increase risk of developing asthma [44 48]. ASTHMA-PREDICTIVE TOOLS Various attempts have been made to develop clinical scoring tools to identify children who will continue to wheeze. Asthma-predictive index The most commonly used asthma-predictive scoring system is the asthma-predictive index (API) derived from the Tucson cohort study (Table 2) [4,5,49] to predict future wheezing in children 3 years of age with at least one previous episode of wheezing. Major criteria were clinician-diagnosed eczema and parental asthma. Minor criteria were cliniciandiagnosed allergic rhinitis, wheezing apart from colds, and eosinophilia at least 4%. Children with wheezing and either one major or two minor criteria at 3 years of age were four to seven times more likely to have asthma during later childhood. The API was validated in a population-based birth cohort of 1954 children in Leicester, UK [51 ], with similar results. In addition, results were comparable using a simpler definition. The value of the API may lie in the identification of children who are unlikely to develop persistent asthma. With low sensitivity (15 57%), the API is a poor predictor of development of asthma [4,5,49,51,52 ]. However, with a high negative predictive value, the API can identify children with a low likelihood of developing later asthma when their API is negative [4,5,31]. The US National Asthma Education and Prevention Program Expert Panel Report 3 supports use of a modified API (allergic skin testing replaces clinician-diagnosed allergic rhinitis) in the diagnosis of asthma (Table 1), although the sensitivity and specificity have yet to be determined [53]. The API may help identify preschoolers who respond to inhaled corticosteroids [54,55 ]. For example, in a study of preschool children with recurrent wheeze and a positive API, ciclesonide modestly reduced wheeze exacerbation rates and improved lung function [55 ]. Other asthma risk scores have also been developed [56 58]. Using these scoring systems, combinations of risk factors including recurrent chest infections at 2 years of age, family history of asthma, positive skin prick test to at least one food or inhalant allergen at 4 years of age, and recurrent nasal symptoms at 1 year of age [56], greater severity of obstructive airway disease during the first 2 years of life [57], male sex, post-term delivery, medium/low parental education, wheezing frequency, wheezing/dyspnea apart from colds, parental report of serious infections, and presence of doctor-diagnosed eczema [58] confer significantly greater risk for a preschooler with wheeze to have persistent asthma in later childhood. In one study, for example, children with high scores had 46% risk of later persistent asthma compared with 3% Table 2. Modified API versus original API Modified asthma predictive index Original asthma predictive index Major criteria Major criteria Parental history of asthma Parental history of asthma MD-diagnosed atopic dermatitis MD-diagnosed atopic dermatitis Allergic sensitization to at least one aeroallergen Minor criteria Minor criteria Allergic sensitization to milk, egg, or peanuts MD-diagnosed allergic rhinitis Wheezing unrelated to colds Wheezing unrelated to colds Blood eosinophils 4% Blood eosinophils 4% A history of four or more wheezing episodes with at least one physician diagnosed. In addition, the child must meet at least one of the above major conditions or at least two of the following minor conditions. Differences in indices are made bold. Modified with permission from [50] Volume 24 Number 3 June 2012 Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

6 Pediatric asthma phenotypes Cowan and Guilbert risk of later asthma [58]. The API and other predictive scores have not been validated in diverse populations. Fractional exhaled nitric oxide and specific IgE in prediction of future wheezing In preschool children from the PIAMA study with symptoms suggestive of asthma, higher FeNO and inhalant allergen sensitization (specific IgE) were positively associated with asthma in later childhood, independent of the preschool clinical history. The combination of FeNO, specific IgE, and clinical history improved the prediction of future wheezing [59 ]. Clinical relevance There are many challenges in providing clinical care for young children with recurrent wheezing, especially due to the heterogeneity of asthma in this population. Parents often want to know if their young child will continue to have asthma when they are older. In order to counsel parents as well as aid in management decisions, assessment of risk factors for ongoing persistent asthma in an individual child is useful. This assessment would include a detailed history and physical testing for allergic sensitization and pulmonary function. In contrast to school-aged children and adolescents, preschoolaged children with asthma tend to be exacerbationprone with limited impairment. It is not clear how to apply phenotypes to manage childhood asthma, particularly with nonatopic wheezing. In recent trials, treatment with either daily inhaled corticosteroids [60] or leukotriene receptor antagonists [61] has shown efficacy in preschool-aged children with intermittent wheezing. In addition, intermittent high-dose inhaled corticosteroid therapy is comparable in efficacy to daily low-dose inhaled corticosteroid therapy in high-risk children in this population [62,63,64]. However, there are relatively limited high-quality trials of asthma therapy in preschool-aged children. Therefore, management of these children is largely guided by expert opinion and studies in older children. In older children with persistent asthma, several studies support the use of inhaled corticosteroids, particularly for those with allergic sensitization [65]. CONCLUSION Transient and persistent wheezing phenotypes have been identified, with allergic disease, reduced lung function, and viral respiratory infection in infancy, as major risk factors for persistence of asthma. Refining clinical phenotypes of asthma using a combination of variables, such as inflammatory biomarkers [66,67 71,72 ], cellular and molecular characteristics [22 ], lung imaging [73,74], genetics [75 78], other factors such as medication exposures, nutritional deficiency, and obesity [79 81 ], and statistical techniques [21,22 ] may ultimately help predict outcomes, improve prevention and treatment, and better understand the pathogenesis of asthma. Acknowledgements Kelly Cowan, MD: Funding support for this manuscript: Cystic Fibrosis Foundation First and Second Year Fellowship and DHHS. Theresa Guilbert, MD, MS: Funding support for this manuscript: DHHS (co-investigator). Conflicts of interest Theresa Guilbert: Payment for development of educational presentations: Peerpoint Medical Education Institute (2009 CME course on RSV); Teva (reviewed educational slide deck 2011). Consultancy: Medimmune (2010 research advisor); Teva (2011 research advisor); MAP Pharmaceuticals (2010 research advisor); Glaxo-Smith-Kline (2011 research advisor and DSMB); Astra-Zeneca (2009 research advisor); Merck-Schering-Plough(2009 research advisor); Genetech/Novartis (2009 research advisor). REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995; 332: Spycher BD, Silverman M, Kuehni CE. Phenotypes of childhood asthma: are they real? Clin Exp Allergy 2010; 40: This review discusses research related to childhood asthma phenotypes and highlights the need for a multidimensional approach to refine classical phenotypes. 3. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000; 162 (4 Pt 1): Castro-Rodriguez JA. The Asthma Predictive Index: a very useful tool for predicting asthma in young children [review]. J Allergy Clin Immunol 2010; 126: Castro-Rodriguez JA. The Asthma Predictive Index: early diagnosis of asthma [review]. Curr Opin Allergy Clin Immunol 2011; 11: This study reviews the importance of determining risk of persistent asthma in young children with wheezing and discusses the utility of the API. 6. Stein RT, Holberg CJ, Morgan WJ, et al. Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax 1997; 52: Martinez FD. What have we learned from the Tucson Children s Respiratory Study? [review]. Paediatr Respir Rev 2002; 3: Stein RT, Martinez FD. Asthma phenotypes in childhood: lessons from an epidemiological approach. Paediatr Respir Rev 2004; 5: 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 1999; 354: ß 2012 Wolters Kluwer Health Lippincott Williams Wilkins Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

7 Pulmonology 10. Rusconi F, Galassi C, Corbo GM, et al. Risk factors for early, persistent, and late-onset wheezing in young children. SIDRIA Collaborative Group. Am J Respir Crit Care Med 1999; 160: Sherriff A, Peters TJ, Henderson J, Strachan D. Risk factor associations with wheezing patterns in children followed longitudinally from birth to 3(1/2) years. Int J Epidemiol 2001; 30: Henderson J, Granell R, Heron J, et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax 2008; 63: Savenije OE, Granell R, Caudri D, et al. Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. J Allergy Clin Immunol 2011; 127: e14. Novel wheezing phenotypes identified in the first eight years of life in the ALSPAC study were similar in the PIAMA study. Associations with asthma, atopy, bronchial hyper-responsiveness, and lung function were similar in the two cohorts. This recent study supports classical phenotype studies and expands upon previous findings using objective data and advanced statistical methods. 14. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach [review]. Eur Respir J 2008; 32: Sonnappa S, Bastardo CM, Wade A, et al. Symptom-pattern phenotype and pulmonary function in preschool wheezers. J Allergy Clin Immunol 2010; 126: e1 7. This study is the first to demonstrate abnormal pulmonary function associated with the multiple-trigger wheezing phenotype in preschoolers. 16. Schultz A, Devadason SG, Savenije OE, et al. The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze. Acta Paediatrica 2010; 99: This study highlights the instability of wheezing phenotypes. 17. Fitzpatrick AM, Gaston BM, Erzurum SC, Teague WG. Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide. J Allergy Clin Immunol 2006; 118: Fitzpatrick AM, Teague WG. Severe asthma in children: insights from the National Heart, Lung, and Blood Institute s Severe Asthma Research Program. Pediatr Allergy Immunol Pulmonol 2010; 23: This review highlights recent insights into severe asthma in children derived from the National Heart, Lung, and Blood Institute s Severe Asthma Research Program (SARP). 19. Haland G, Carlsen KC, Sandvik L, et al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med 2006; 355: Stern DA, Morgan WJ, Wright AL, et al. Poor airway function in early infancy and lung function by age 22 years: a nonselective longitudinal cohort study. Lancet 2007; 370: Fitzpatrick AM, Teague WG, Meyers DA, et al. Heterogeneity of severe asthma inchildhood: confirmation by clusteranalysisofchildreninthenationalinstitutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol 2011; 127: e1 13. This unique study demonstrates the utility of using an unsupervised cluster analysis to determine asthma phenotypes in school-aged children with persistent asthma across a range of severities. Children in these clusters had various degrees of atopy. Other major determinants of cluster assignment were duration of asthma, number of controller medications, and baseline lung function. FeNO concentrations and age of asthma onset were also factors. 22. Fitzpatrick AM, Higgins M, Holguin F, et al. The molecular phenotype of severe asthma in children. J Allergy Clin Immunol 2010; 125: e18. This study applied linear discriminant analysis, a supervised method of highdimensional data reduction, to cytokines and chemokines measured in the BAL fluid and alveolar macrophage lysate to differentiate children with severe asthma from mild moderate asthma. This illustrates a method that may be helpful in improving classification of children with asthma. 23. de Blic J, Tillie-Leblond I, Tonnel AB, et al. Difficult asthma in children: an analysis of airway inflammation. J Allergy Clin Immunol 2004; 113: Lex C, Payne DN, Zacharasiewicz A, et al. Sputum induction in children with difficult asthma: safety, feasibility, and inflammatory cell pattern. Pediatr Pulmonol 2005; 39: Gibson PG, Norzila MZ, Fakes K, et al. Pattern of airway inflammation and its determinants in children with acute severe asthma. Pediatr Pulmonol 1999; 28: Thavagnanam S, Williamson G, Ennis M, et al. Does airway allergic inflammation preexist before late onset wheeze in children? Pediatr Allergy Immunol 2010; 21: This study compared cellular and cytokine data from BAL performed in children who later developed persistent wheeze and those who never wheezed, showing that airway inflammation preceded development of clinical symptoms. 27. van den Toorn LM, Overbeek SE, de Jongste JC, et al. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001; 164: Schwerk N, Brinkmann F, Soudah B, et al. Wheeze in preschool age is associated with pulmonary bacterial infection and resolves after antibiotic therapy. PLoS One 2011; 6:e This study highlights the contribution of bacterial infections to persistent wheezing and airway neutrophilia in preschool children. The majority of children with severe persistent wheeze and bacterial infection had improvement in symptoms after antibiotics. 29. Covar RA, Strunk R, Zeiger RS, et al. Predictors of remitting, periodic, and persistent childhood asthma. J Allergy Clin Immunol 2010; 125: e Bisgaard H, Hermansen MN, Bonnelykke K, et al. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ 2010; 341:c4978. This prospective birth cohort study showed that acute wheezy episodes in young children were significantly associated with bacterial infections similar to but independent of the association with viral infections. This supports the association between respiratory infections and wheezing. 31. Stern DA, Morgan WJ, Halonen M, et al. Wheezing and bronchial hyperresponsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet 2008; 372: Lowe LA, Simpson A, Woodcock A, et al. Wheeze phenotypes and lung function in preschool children. Am J Respir Crit Care Med 2005; 171: Kurukulaaratchy RJ, Fenn MH, Waterhouse LM, et al. Characterization of wheezing phenotypes in the first 10 years of life. Clin Exp Allergy 2003; 33: Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995; 332: Oostveen E, Dom S, Desager K, et al. Lung function and bronchodilator response in 4-year-old children with different wheezing phenotypes. Eur Respir J 2010; 35: This study was unique in that it examined the association between pre and postbronchodilator lung function and the wheezing phenotype in preschool children. 36. Haland G, Carlsen KC, Sandvik L, et al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med 2006; 355: Turner SW, Palmer LJ, Rye PJ, et al. The relationship between infant airway function, childhood airway responsiveness, and asthma. Am J Respir Crit Care Med 2004; 169: Morgan WJ, Stern DA, Sherrill DL, et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med 2005; 172: Illi S, von Mutius E, Lau S, et al. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study. Lancet 2006; 368: Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma? J Allergy Clin Immunol 2010; 125: This review discusses the link between early viral lower respiratory infections and later asthma. 41. Martinez FD. The connection between early life wheezing and subsequent asthma: the viral march. Allergol Immunopathol 2009; 37: Holt PG, Upham JW, Sly PD. Contemporaneous maturation of immunologic and respiratory functions during early childhood: implications for development of asthma prevention strategies. J Allergy Clin Immunol 2005; 116:16 24; quiz Holt PG, Sly PD. Prevention of allergic respiratory disease in infants: current aspects and future perspectives [review]. Curr Opin Allergy Clin Immunol 2007; 7: Kusel MM, de Klerk NH, Kebadze T, et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 2007; 119: Korppi M, Kotaniemi-Syrjanen A, Waris M, et al. Rhinovirus-associated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis. Pediatr Infect Dis J 2004; 23: Jartti T, Korppi M, Ruuskanen O. The clinical importance of rhinovirusassociated early wheezing. Eur Respir J 2009; 33: ; author reply Hartert TV. Are persons with asthma at increased risk of pneumococcal infections, and can we prevent them? J Allergy Clin Immunol 2008; 122: Juhn YJ, Kita H, Yawn BP, et al. Increased risk of serious pneumococcal disease in patients with asthma. J Allergy Clin Immunol 2008; 122: Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000; 162: Guilbert TW, Morgan WJ, Zeiger RS, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol 2004; 114: Leonardi NA, Spycher BD, Strippoli MP, et al. Validation of the asthma predictive index and comparison with simpler clinical prediction rules. J Allergy Clin Immunol 2011; 127: e6. This study validated the API developed in the Tucson cohort in children from the population-based Leicester Respiratory Cohort, and also showed that a similar prediction could be made using simpler rules. 52. Brand PL. The Asthma Predictive Index: not a useful tool in clinical practice [letter]. J Allergy Clin Immunol 2011; 127: This article discusses the low sensitivity of the API in identifying those who will develop persistent asthma, and the challenges of applying this to clinical practice. 53. Expert Panel Report 3 (EPR-3). Guidelines for the diagnosis and management of asthma: Summary Report J Allergy Clin Immunol 2007; 120(5 Suppl):S94 S Volume 24 Number 3 June 2012 Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

8 Pediatric asthma phenotypes Cowan and Guilbert 54. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006; 354: Brand PL, Luz Garcia-Garcia M, Morison A, et al. Ciclesonide in wheezy preschool children with a positive asthma predictive index or atopy. Respir Med 2011; 105: This is one of the few large-scale studies that have examined inhaled corticosteroid treatment in preschool children with recurrent wheeze. In preschool children with recurrent wheeze and a positive API, ciclesonide reduced wheeze exacerbation rates and improved lung function. A large placebo response and unexpected selection of patients with mild disease may have affected outcomes, highlighting the heterogeneity of preschool wheezing disorders. 56. Kurukulaaratchy RJ, Matthews S, Holgate ST, Arshad SH. Predicting persistent disease among children who wheeze during early life. Eur Respir J 2003; 22: Devulapalli CS, Carlsen KC, Haland G, et al. Severity of obstructive airways diseaseby age 2yearspredictsasthma at10years of age. Thorax2008; 63: Caudri D, Wijga A, A Schipper CM, et al. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol 2009; 124: e Caudri D, Wijga AH, Hoekstra MO, et al. Prediction of asthma in symptomatic preschool children using exhaled nitric oxide, Rint and specific IgE. Thorax 2010; 65: Evaluation studies in children from the PIAMA birth cohort with preschool wheezing. Both FeNO and specific IgE measured at 4 years of age improved the prediction of asthma symptoms until the age of 8 years, independent of clinical history. 60. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006; 354: Bisgaard H, Zielen S, Garcia-Garcia ML, et al. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 2005; 171: Ducharme FM, Lemire C, Noya FJ, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med 2009; 360: Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med 2011; 365: This study demonstrates that a daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations in children who had a positive modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year. 64. Papi A, Nicolini G, Boner AL, et al. Short term efficacy of nebulized beclomethasone in mild-to-moderate wheezing episodes in preschool children. Ital J Pediatr 2011; 37: National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma: clinical practice guidelines. Bethesda (MD): NIH/National Heart, Lung, and Blood Institute. 2007; Gordon ED, Sidhu SS, Wang ZE, et al. A protective role for periostin and TGFbeta in IgE-mediated allergy and airway hyperresponsiveness. Clin Exp Allergy 2012; 42: This study explores the role of periostin in airway hyper-responsiveness in mice. 67. Stern DA, Guerra S, Halonen M, et al. Low IFN-gamma production in the first year of life as a predictor of wheeze during childhood. J Allergy Clin Immunol 2007; 120: Krawiec ME, Westcott JY, Chu HW, et al. Persistent wheezing in very young children is associated with lower respiratory inflammation. Am J Respir Crit Care Med 2001; 163: Saglani S, Malmstrom K, Pelkonen AS, et al. Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction. Am J Respir Crit Care Med 2005; 171: Saglani S, Payne DN, Zhu J, et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med 2007; 176: Barbato A, Turato G, Baraldo S, et al. Epithelial damage and angiogenesis in the airways of children with asthma. Am J Respir Crit Care Med 2006; 174: Rothers J, Halonen M, Stern DA, et al. Adaptive cytokine production in early life differentially predicts total IgE levels and asthma through age 5 years. J Allergy Clin Immunol 2011; 128: e2. This study examined whether IgE levels and asthma might differ in their relation to early life cytokine production. 73. Hoshino M, Matsuoka S, Handa H, et al. Correlation between airflow limitation and airway dimensions assessed by multidetector CT in asthma. Respir Med 2010; 104: This study assessed the relationship between airflow limitation and airway dimensions in asthma using multidetector-row computed tomography. 74. Aysola RS, Hoffman EA, Gierada D, et al. Airway remodeling measured by multidetector CT is increased in severe asthma and correlates with pathology. Chest 2008; 134: Hall IP, Wheatley A, Christie G, et al. Association of CCR5 delta32 with reduced risk of asthma. Lancet 1999; 354: O Donnell AR, Toelle BG, Marks GB, et al. Age-specific relationship between CD14 and atopy in a cohort assessed from age 8 to 25 years. Am J Respir Crit Care Med 2004; 169: Khoo SK, Hayden CM, Roberts M, et al. Associations of the IL12B promoter polymorphism in longitudinal data from asthmatic patients 7 to 42 years of age. J Allergy Clin Immunol 2004; 113: Basu K, Palmer CN, Lipworth BJ, et al. Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults. Allergy 2008; 63: McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics 2011; 128: This review discusses the epidemiologic association of acetominophen use with asthma prevalence and severity, and potential mechanisms for this association. 80. Paul G, Brehm J, Alcorn JF, et al. Vitamin D and asthma. Am J Respir Crit Care Med 2012; 185: This review examines the current literature related to vitamin D supplementation for asthma treatment or prevention. 81. Rastogi D, Canfield SM, Andrade A, et al. Obesity-associated asthma in children: a distinct entity. Chest [Epub ahead of print] This study examined pulmonary function and serum cytokines and showed that pediatric obesity-associated asthma differed from atopic asthma and was characterized by Th1 polarization ß 2012 Wolters Kluwer Health Lippincott Williams Wilkins Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.