Allergy Asthma Respir Dis.  2014 May;2(2):85-90. 10.4168/aard.2014.2.2.85.

Phenotype and endotype in pediatric asthma

• Yang HJ
• Kim BS
• Kim WK
• Kim J
• Kim JT
• Suh DI
• Koh YY
• Shin YH
• Lee SY
• Lim DH
• Choung JT
• Kim HB
• Asthma Study Group in Preschool Children

• KMID: 2261741
• DOI: http://doi.org/10.4168/aard.2014.2.2.85

Abstract

Asthma is not a homogeneous disease presenting variable clinical features, but a complex disorder consisting of many different disease entities characterized by variable air-flow limitation. To date, there are little effective preventive-strategies for the development of asthma, and it has been emphasized that early identification and intervention are the best ways to reduce the associated morbidities, quality of life, and socioeconomic burden. Predicting the natural course of asthma is still difficult, although various phenotypic approaches and predictive scores are developed and widely used. The present phenotypes and predictive scores may be reliable in the population, but those appear to be unreliable in each individual in real practice. Either undertreatment or overtreatment in childhood asthma is an important issue, because they are associated with poor compliance, increments of socioeconomic burdens, and poor quality of life. There is no doubt about the clinical efficacy of inhaled corticosteroid (ICS) in childhood asthma, but the negative effect of long-term use of ICS on the height is emerging. Therefore general physicians should consider an individualized management using specific phenotypes and endotypes, and regularly re-evaluate the drug-response, level of control, and adherence/compliance to avoid inadequate treatment.

Keyword

Phenotype; Endotype; Asthma; Child

MeSH Terms

Asthma*
Child
Compliance
Humans
Phenotype*
Quality of Life

Reference

1. Bisgaard H, Bonnelykke K. Long-term studies of the natural history of asthma in childhood. J Allergy Clin Immunol. 2010; 126:187–197.

2. Anandan C, Nurmatov U, van Schayck OC, Sheikh A. Is the prevalence of asthma declining? Systematic review of epidemiological studies. Allergy. 2010; 65:152–167.

3. 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. 1995; 332:133–138.

4. Yunginger JW, Reed CE, O'Connell EJ, Melton LJ 3rd, O'Fallon WM, Silverstein MD. A community-based study of the epidemiology of asthma. Incidence rates, 1964-1983. Am Rev Respir Dis. 1992; 146:888–894.

5. Grad R, Morgan WJ. Long-term outcomes of early-onset wheeze and asthma. J Allergy Clin Immunol. 2012; 130:299–307.

6. Bacharier LB, Guilbert TW. Diagnosis and management of early asthma in preschool-aged children. J Allergy Clin Immunol. 2012; 130:287–296.

7. Caudri D, Wijga AH, Smit HA, Koppelman GH, Kerkhof M, Hoekstra MO, et al. Asthma symptoms and medication in the PIAMA birth cohort: evidence for under and overtreatment. Pediatr Allergy Immunol. 2011; 22:652–659.

8. Holt PG, Sly PD. Prevention of allergic respiratory disease in infants: current aspects and future perspectives. Curr Opin Allergy Clin Immunol. 2007; 7:547–555.

9. Szefler SJ. Advances in pediatric asthma in 2011: moving forward. J Allergy Clin Immunol. 2012; 129:60–68.

10. Szefler SJ. Early asthma: stepping closer to primary prevention. J Allergy Clin Immunol. 2012; 130:308–310.

11. Campo P, Rodriguez F, Sanchez-Garcia S, Barranco P, Quirce S, Perez-Frances C, et al. Phenotypes and endotypes of uncontrolled severe asthma: new treatments. J Investig Allergol Clin Immunol. 2013; 23:76–88.

12. Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011; 127:355–360.

13. Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes. Allergy. 2012; 67:835–846.

14. Spycher BD, Silverman M, Kuehni CE. Phenotypes of childhood asthma: are they real? Clin Exp Allergy. 2010; 40:1130–1141.

15. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008; 372:1107–1119.

16. Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, 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; 63:974–980.

17. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD. Tucson Children's Respiratory Study: 1980 to present. J Allergy Clin Immunol. 2003; 111:661–675.

18. Spycher BD, Silverman M, Brooke AM, Minder CE, Kuehni CE. Distinguishing phenotypes of childhood wheeze and cough using latent class analysis. Eur Respir J. 2008; 31:974–981.

19. Just J, Gouvis-Echraghi R, Couderc R, Guillemot-Lambert N, Saint-Pierre P. Novel severe wheezy young children phenotypes: boys atopic multiple-trigger and girls nonatopic uncontrolled wheeze. J Allergy Clin Immunol. 2012; 130:103–110.e8.

20. Weinmayr G, Keller F, Kleiner A, du Prel JB, Garcia-Marcos L, Batlles-Garrido J, et al. Asthma phenotypes identified by latent class analysis in the ISAAC phase II Spain study. Clin Exp Allergy. 2013; 43:223–232.

21. Herr M, Just J, Nikasinovic L, Foucault C, Le Marec AM, Giordanella JP, et al. Risk factors and characteristics of respiratory and allergic phenotypes in early childhood. J Allergy Clin Immunol. 2012; 130:389–396.e4.

22. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008; 32:1096–1110.

23. Zhang G, Goldblatt J, LeSouef P. The era of genome-wide association studies: opportunities and challenges for asthma genetics. J Hum Genet. 2009; 54:624–628.

24. Runyon RS, Cachola LM, Rajeshuni N, Hunter T, Garcia M, Ahn R, et al. Asthma discordance in twins is linked to epigenetic modifications of T cells. PLoS One. 2012; 7:e48796.

25. Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol. 2010; 126:453–465.

26. Agache IO. From phenotypes to endotypes to asthma treatment. Curr Opin Allergy Clin Immunol. 2013; 13:249–256.

27. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010; 363:1211–1221.

28. Holloway JW, Yang IA, Holgate ST. Genetics of allergic disease. J Allergy Clin Immunol. 2010; 125:2 Suppl 2. S81–S94.

29. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007; 448:470–473.

30. Bisgaard H, Bonnelykke K, Sleiman PM, Brasholt M, Chawes B, Kreiner-Moller E, et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med. 2009; 179:179–185.

31. Blekic M, Kljaic Bukvic B, Aberle N, Marinho S, Hankinson J, Custovic A, et al. 17q12-21 and asthma: interactions with early-life environmental exposures. Ann Allergy Asthma Immunol. 2013; 110:347–353.e2.

32. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006; 38:441–446.

33. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006; 118:214–219.

34. Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H, et al. Filaggrin null mutations are associated with increased asthma severity in children and young adults. J Allergy Clin Immunol. 2007; 120:64–68.

35. Song GG, Kim JH, Lee YH. Association between ADAM33 S2 and ST+4 polymorphisms and susceptibility to asthma: a meta-analysis. Gene. 2013; 524:72–78.

36. Basu K, Palmer CN, Tavendale R, Lipworth BJ, Mukhopadhyay S. Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. J Allergy Clin Immunol. 2009; 124:1188–1194.e3.

37. Giubergia V, Gravina L, Castanos C, Chertkoff L. Influence of β(2)-adrenergic receptor polymorphisms on asthma exacerbation in children with severe asthma regularly receiving salmeterol. Ann Allergy Asthma Immunol. 2013; 110:156–160.

38. Chen LC, Tseng HM, Wu CJ, Kuo ML, Wu CJ, Gao PS, et al. Evaluation of a common variant of the gene encoding clara cell 10 kd protein (CC10) as a candidate determinant for asthma severity and steroid responsiveness among Chinese children. J Asthma. 2012; 49:665–672.

39. Cortessis VK, Thomas DC, Levine AJ, Breton CV, Mack TM, Siegmund KD, et al. Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response relationships. Hum Genet. 2012; 131:1565–1589.

40. Kabesch M, Michel S, Tost J. Epigenetic mechanisms and the relationship to childhood asthma. Eur Respir J. 2010; 36:950–961.

41. Fu A, Leaderer BP, Gent JF, Leaderer D, Zhu Y. An environmental epigenetic study of ADRB2 5'-UTR methylation and childhood asthma severity. Clin Exp Allergy. 2012; 42:1575–1581.

42. Li LB, Leung DY, Martin RJ, Goleva E. Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid-resistant asthma. Am J Respir Crit Care Med. 2010; 182:877–883.

43. Rehan VK, Liu J, Naeem E, Tian J, Sakurai R, Kwong K, et al. Perinatal nicotine exposure induces asthma in second generation offspring. BMC Med. 2012; 10:129.

44. Tezza G, Mazzei F, Boner A. Epigenetics of allergy. Early Hum Dev. 2013; 89:Suppl 1. S20–S21.

45. Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006; 11:54–61.

46. Berry M, Morgan A, Shaw DE, Parker D, Green R, Brightling C, et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007; 62:1043–1049.

47. Lee YJ, Kim KW, Choi BS, Sohn MH, Kim KE. Clinical characteristics of eosinophilic and noneosinophilic asthma in children. Acta Paediatr. 2013; 102:53–57.

48. Lopuhaä CE, Out TA, Jansen HM, Aalberse RC, van der Zee JS. Allergen-induced bronchial inflammation in house dust mite-allergic patients with or without asthma. Clin Exp Allergy. 2002; 32:1720–1727.

49. 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; 23:131–138.

50. Rao CK, Moore CG, Bleecker E, Busse WW, Calhoun W, Castro M, et al. Characteristics of perimenstrual asthma and its relation to asthma severity and control: data from the Severe Asthma Research Program. Chest. 2013; 143:984–992.

51. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002; 418:426–430.

52. Goleva E, Li LB, Eves PT, Strand MJ, Martin RJ, Leung DY. Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 2006; 173:607–616.

53. Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin Exp Allergy. 2012; 42:650–658.

54. The Global Initiative for Asthma. GINA Report, Global strategy for asthma management and prevention. Updated 2012 [Internet]. The Global Initiative for Asthma;c2012. cited 2013 Jul 10. Available from: http://www.ginasthma.org/documents/4.

55. Castro-Rodríguez 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):1403–1406.

56. Kurukulaaratchy RJ, Matthews S, Holgate ST, Arshad SH. Predicting persistent disease among children who wheeze during early life. Eur Respir J. 2003; 22:767–771.

57. Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, Krawiec M, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol. 2004; 114:1282–1287.

58. Castro-Rodriguez JA. The Asthma Predictive Index: a very useful tool for predicting asthma in young children. J Allergy Clin Immunol. 2010; 126:212–216.

59. Caudri D, Wijga A, Schipper CM, Hoekstra M, Postma DS, Koppelman GH, et al. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol. 2009; 124:903–910.e1-7.