Allergy Asthma Immunol Res.  2019 Jan;11(1):16-28. 10.4168/aair.2019.11.1.16.

Biomarkers for Recurrent Wheezing and Asthma in Preschool Children

Affiliations
  • 1Department of Pediatrics, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea.
  • 2Allergy Center, Mie National Hospital, Mie, Japan.
  • 3Asthma and Allergy Center, Inje University Sanggye Paik Hospital, Seoul, Korea. kimck@paik.ac.kr
  • 4SKIMS-BIO Co., Ltd. Seoul, Korea.

Abstract

Wheezing is one of the characteristic symptoms of asthma, but all preschool children with wheezing are not diagnosed with asthma. Preschool children are not cooperative enough to participate in spirometry and invasive tests. Thus, there is no conventional method to diagnose asthma in preschool children. We reviewed studies on non-invasive biomarkers for assessing asthma in preschool children. Specimens that can be easily obtained by non-invasive methods are blood, exhaled breath and urine. Eosinophils, eosinophil cationic protein and eosinophil-derived neurotoxin (EDN) in blood are helpful in evaluating eosinophilic inflammation of the airways. Exhaled breath contains nitric oxide, volatile organic compounds, various cytokines and mediators as analytical components. Fraction of exhaled nitric oxide has been used to assess the degree of eosinophil inflammation and has been standardized in school-age children and adults, but not yet in preschool children. Exhaled breath condensate (EBC) pH and various cytokines/mediators that are detected in EBC seem to be promising biomarkers for assessing asthma, but need more standardization and validation. There are several biomarkers useful for assessing asthma, but none are ideal. Some biomarkers need standardized methods of obtaining samples from uncooperative preschool children for clinical use and require sufficient validation. Recently, another activated eosinophil marker, serum EDN, has shown promising results as a biomarker for recurrent wheezing and asthma in preschool children.

Keyword

Wheezing; asthma; biomarkers; child, preschool; eosinophil-derived neurotoxin

MeSH Terms

Adult
Asthma*
Biomarkers*
Child
Child, Preschool*
Cytokines
Eosinophil Cationic Protein
Eosinophil-Derived Neurotoxin
Eosinophils
Humans
Hydrogen-Ion Concentration
Inflammation
Methods
Nitric Oxide
Respiratory Sounds*
Spirometry
Volatile Organic Compounds
Biomarkers
Cytokines
Eosinophil Cationic Protein
Eosinophil-Derived Neurotoxin
Nitric Oxide
Volatile Organic Compounds

Figure

  • Figure (A) Serum levels of EDN, (B) ECP, and (C) TECs, subgrouped according to asthma severity. Adapted from reference 33 with permission from “J Asthma”. EDN, eosinophil derived neurotoxin; ECP, eosinophil cationic protein; TEC, total eosinophil count; NS, not significant.


Reference

1. 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.
2. Arakawa H, Hamasaki Y, Kohno Y, Ebisawa M, Kondo N, Nishima S, et al. Japanese guidelines for childhood asthma 2017. Allergol Int. 2017; 66:190–204.
Article
3. Ducharme FM, Dell SD, Radhakrishnan D, Grad RM, Watson WT, Yang CL, et al. Diagnosis and management of asthma in preschoolers: a Canadian Thoracic Society and Canadian Paediatric Society position paper. Can Respir J. 2015; 22:135–143.
Article
4. Global Initiative for Asthma. Global strategy for asthma management and prevention [Internet]. place unknown: Global Initiative for Asthma;2018. cite 2018 Jun 6. Available from: www.ginasthma.org.
5. Punekar YS, Sheikh A. Establishing the sequential progression of multiple allergic diagnoses in a UK birth cohort using the General Practice Research Database. Clin Exp Allergy. 2009; 39:1889–1895.
Article
6. Saglani S, Payne DN, Zhu J, Wang Z, Nicholson AG, Bush A, et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med. 2007; 176:858–864.
Article
7. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med. 1994; 88:373–381.
Article
8. Chen YZ, Busse WW, Pedersen S, Tan W, Lamm CJ, O'Byrne PM. Early intervention of recent onset mild persistent asthma in children aged under 11 yrs: the Steroid Treatment As Regular Therapy in early asthma (START) trial. Pediatr Allergy Immunol. 2006; 17:Suppl 17. 7–13.
Article
9. 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; 162:1403–1406.
Article
10. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol. 2012; 130:325–331.
Article
11. Smit HA, Pinart M, Antó JM, Keil T, Bousquet J, Carlsen KH, et al. Childhood asthma prediction models: a systematic review. Lancet Respir Med. 2015; 3:973–984.
Article
12. Gaillard EA, McNamara PS, Murray CS, Pavord ID, Shields MD. Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial? Clin Exp Allergy. 2015; 45:1384–1395.
Article
13. Kim CK, Choi J, Kim HB, Callaway Z, Shin BM, Kim JT, et al. A randomized intervention of montelukast for post-bronchiolitis: effect on eosinophil degranulation. J Pediatr. 2010; 156:749–754.
Article
14. Carraro S, Bozzetto S, Giordano G, El Mazloum D, Stocchero M, Pirillo P, et al. Wheezing preschool children with early-onset asthma reveal a specific metabolomic profile. Pediatr Allergy Immunol. 2018; 29:375–382.
Article
15. Chiu CY, Lin G, Cheng ML, Chiang MH, Tsai MH, Su KW, et al. Longitudinal urinary metabolomic profiling reveals metabolites for asthma development in early childhood. Pediatr Allergy Immunol. 2018; 29:496–503.
Article
16. Lee YJ, Lee HH, Choi BS, Jee HM, Kim KW, Sohn MH, et al. Association between eosinophilic airway inflammation and persistent airflow limitation. J Asthma. 2013; 50:342–346.
Article
17. Castro-Rodriguez JA, Saglani S, Rodriguez-Martinez CE, Oyarzun MA, Fleming L, Bush A. The relationship between inflammation and remodeling in childhood asthma: a systematic review. Pediatr Pulmonol. 2018; 53:824–835.
Article
18. Wagener AH, de Nijs SB, Lutter R, Sousa AR, Weersink EJ, Bel EH, et al. External validation of blood eosinophils, FENO and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015; 70:115–120.
19. Jochmann A, Artusio L, Robson K, Nagakumar P, Collins N, Fleming L, et al. Infection and inflammation in induced sputum from preschool children with chronic airways diseases. Pediatr Pulmonol. 2016; 51:778–786.
Article
20. Nadif R, Siroux V, Oryszczyn MP, Ravault C, Pison C, Pin I, et al. Heterogeneity of asthma according to blood inflammatory patterns. Thorax. 2009; 64:374–380.
Article
21. Just J, Nicoloyanis N, Chauvin M, Pribil C, Grimfeld A, Duru G. Lack of eosinophilia can predict remission in wheezy infants? Clin Exp Allergy. 2008; 38:767–773.
Article
22. Karakoc F, Remes ST, Martinez FD, Wright AL. The association between persistent eosinophilia and asthma in childhood is independent of atopic status. Clin Exp Allergy. 2002; 32:51–56.
Article
23. Hogan SP, Rosenberg HF, Moqbel R, Phipps S, Foster PS, Lacy P, et al. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy. 2008; 38:709–750.
Article
24. Koh GC, Shek LP, Goh DY, Van Bever H, Koh DS. Eosinophil cationic protein: is it useful in asthma? A systematic review. Respir Med. 2007; 101:696–705.
Article
25. Prehn A, Seger RA, Torresani T, Molinari L, Sennhauser FH. Evaluation of a clinical algorithm involving serum eosinophil cationic protein for guiding the anti-inflammatory treatment of bronchial asthma in childhood. Pediatr Allergy Immunol. 2000; 11:87–94.
Article
26. Garcia-Marcos L, Edwards J, Kennington E, Aurora P, Baraldi E, Carraro S, et al. Priorities for future research into asthma diagnostic tools: a PAN-EU consensus exercise from the European asthma research innovation partnership (EARIP). Clin Exp Allergy. 2018; 48:104–120.
Article
27. Kim CK, Callaway Z, Park JS, Kwon E. Utility of serum eosinophil-derived neurotoxin (EDN) measurement by ELISA in young children with asthma. Allergol Int. 2017; 66:70–74.
Article
28. Sedgwick JB, Vrtis RF, Jansen KJ, Kita H, Bartemes K, Busse WW. Peripheral blood eosinophils from patients with allergic asthma contain increased intracellular eosinophil-derived neurotoxin. J Allergy Clin Immunol. 2004; 114:568–574.
Article
29. Hoekstra MO, Grol MH, Hovenga H, Bouman K, Stijnen T, Koëter GH, et al. Eosinophil and mast cell parameters in children with stable moderate asthma. Pediatr Allergy Immunol. 1998; 9:143–149.
Article
30. Morioka J, Kurosawa M, Inamura H, Nakagami R, Mizushima Y, Omura Y, et al. Increased END/EPX in ongoing asthma. Allergy. 2000; 55:1203–1204.
Article
31. Badar A, Hussain MM, Saeed W, Aslam M. Correlation of eosinophil derived neurotoxin with airway resistance in asthmatics. J Pak Med Assoc. 2010; 60:97–101.
32. Kim KW, Lee KE, Kim ES, Song TW, Sohn MH, Kim KE. Serum eosinophil-derived neurotoxin (EDN) in diagnosis and evaluation of severity and bronchial hyperresponsiveness in childhood asthma. Lung. 2007; 185:97–103.
Article
33. Kim CK, Callaway Z, Fletcher R, Koh YY. Eosinophil-derived neurotoxin in childhood asthma: correlation with disease severity. J Asthma. 2010; 47:568–573.
Article
34. Kim CK, Seo JK, Ban SH, Fujisawa T, Kim DW, Callaway Z. Eosinophil-derived neurotoxin levels at 3 months post-respiratory syncytial virus bronchiolitis are a predictive biomarker of recurrent wheezing. Biomarkers. 2013; 18:230–235.
Article
35. Kim CK, Callaway Z, Park JS, Nishimori H, Ogino T, Nagao M, et al. Montelukast reduces serum levels of eosinophil-derived neurotoxin in preschool asthma. Allergy Asthma Immunol Res. 2018; 10:686–697.
Article
36. Idolazzi L, Ridolo E, Fassio A, Gatti D, Montagni M, Caminati M, et al. Periostin: the bone and beyond. Eur J Intern Med. 2017; 38:12–16.
Article
37. Inoue Y, Izuhara K, Ohta S, Ono J, Shimojo N. No increase in the serum periostin level is detected in elementary school-age children with allergic diseases. Allergol Int. 2015; 64:289–290.
Article
38. Song JS, You JS, Jeong SI, Yang S, Hwang IT, Im YG, et al. Serum periostin levels correlate with airway hyper-responsiveness to methacholine and mannitol in children with asthma. Allergy. 2015; 70:674–681.
Article
39. Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994; 78:915–918.
Article
40. Song WJ, Kwon JW, Kim EJ, Lee SM, Kim SH, Lee SY, et al. Clinical application of exhaled nitric oxide measurements in a Korean population. Allergy Asthma Immunol Res. 2015; 7:3–13.
Article
41. American Thoracic Society. European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005; 171:912–930.
42. van der Valk RJ, Caudri D, Savenije O, Koppelman GH, Smit HA, Wijga AH, et al. Childhood wheezing phenotypes and FeNO in atopic children at age 8. Clin Exp Allergy. 2012; 42:1329–1336.
43. Moeller A, Diefenbacher C, Lehmann A, Rochat M, Brooks-Wildhaber J, Hall GL, et al. Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms. J Allergy Clin Immunol. 2008; 121:705–709.
Article
44. Debley JS, Stamey DC, Cochrane ES, Gama KL, Redding GJ. Exhaled nitric oxide, lung function, and exacerbations in wheezy infants and toddlers. J Allergy Clin Immunol. 2010; 125:1228–1234.e13.
Article
45. van der Heijden HH, Brouwer ML, Hoekstra F, van der Pol P, Merkus PJ. Reference values of exhaled nitric oxide in healthy children 1–5 years using off-line tidal breathing. Pediatr Pulmonol. 2014; 49:291–295.
Article
46. Singer F, Luchsinger I, Inci D, Knauer N, Latzin P, Wildhaber JH, et al. Exhaled nitric oxide in symptomatic children at preschool age predicts later asthma. Allergy. 2013; 68:531–538.
Article
47. Sayão LB, de Britto MC, Burity E, Rattes C, Reinaux CM, Fink J, et al. Exhaled nitric oxide as a diagnostic tool for wheezing in preschool children: a diagnostic accuracy study. Respir Med. 2016; 113:15–21.
Article
48. Amann A, Costello BL, Miekisch W, Schubert J, Buszewski B, Pleil J, et al. The human volatilome: volatile organic compounds (VOCs) in exhaled breath, skin emanations, urine, feces and saliva. J Breath Res. 2014; 8:034001.
Article
49. Fens N, van der Schee MP, Brinkman P, Sterk PJ. Exhaled breath analysis by electronic nose in airways disease. Established issues and key questions. Clin Exp Allergy. 2013; 43:705–715.
Article
50. Caldeira M, Barros AS, Bilelo MJ, Parada A, Câmara JS, Rocha SM. Profiling allergic asthma volatile metabolic patterns using a headspace-solid phase microextraction/gas chromatography based methodology. J Chromatogr A. 2011; 1218:3771–3780.
Article
51. Robroeks CM, van Berkel JJ, Jöbsis Q, van Schooten FJ, Dallinga JW, Wouters EF, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J. 2013; 42:98–106.
Article
52. Smolinska A, Klaassen EM, Dallinga JW, van de Kant KD, Jobsis Q, Moonen EJ, et al. Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children. PLoS One. 2014; 9:e95668.
Article
53. van de Kant KD, van Berkel JJ, Jöbsis Q, Lima Passos V, Klaassen EM, van der Sande L, et al. Exhaled breath profiling in diagnosing wheezy preschool children. Eur Respir J. 2013; 41:183–188.
Article
54. Klaassen EM, van de Kant KD, Jöbsis Q, van Schayck OC, Smolinska A, Dallinga JW, et al. Exhaled biomarkers and gene expression at preschool age improve asthma prediction at 6 years of age. Am J Respir Crit Care Med. 2015; 191:201–207.
Article
55. Horváth I, Barnes PJ, Loukides S, Sterk PJ, Högman M, Olin AC, et al. A European Respiratory Society technical standard: exhaled biomarkers in lung disease. Eur Respir J. 2017; 49:1600965.
Article
56. Thomas PS, Lowe AJ, Samarasinghe P, Lodge CJ, Huang Y, Abramson MJ, et al. Exhaled breath condensate in pediatric asthma: promising new advance or pouring cold water on a lot of hot air? A systematic review. Pediatr Pulmonol. 2013; 48:419–442.
Article
57. Ratnawati MJ, Morton J, Henry RL, Thomas PS. Exhaled breath condensate nitrite/nitrate and pH in relation to pediatric asthma control and exhaled nitric oxide. Pediatr Pulmonol. 2006; 41:929–936.
Article
58. Brunetti L, Francavilla R, Tesse R, Strippoli A, Polimeno L, Loforese A, et al. Exhaled breath condensate pH measurement in children with asthma, allergic rhinitis and atopic dermatitis. Pediatr Allergy Immunol. 2006; 17:422–427.
Article
59. Baraldi E, Carraro S, Alinovi R, Pesci A, Ghiro L, Bodini A, et al. Cysteinyl leukotrienes and 8-isoprostane in exhaled breath condensate of children with asthma exacerbations. Thorax. 2003; 58:505–509.
Article
60. Montuschi P, Martello S, Felli M, Mondino C, Barnes PJ, Chiarotti M. Liquid chromatography/mass spectrometry analysis of exhaled leukotriene B4 in asthmatic children. Respir Res. 2005; 6:119.
Article
61. Caballero S, Martorell A, Escribano A, Belda J. Markers of airway inflammation in the exhaled breath condensate of preschool wheezers. J Investig Allergol Clin Immunol. 2013; 23:7–13.
62. van de Kant KD, Jansen MA, Klaassen EM, van der Grinten CP, Rijkers GT, Muris JW, et al. Elevated inflammatory markers at preschool age precede persistent wheezing at school age. Pediatr Allergy Immunol. 2012; 23:259–264.
Article
63. Klaassen EM, van de Kant KD, Jöbsis Q, Høvig ST, van Schayck CP, Rijkers GT, et al. Symptoms, but not a biomarker response to inhaled corticosteroids, predict asthma in preschool children with recurrent wheeze. Mediators Inflamm. 2012; 2012:162571.
Article
64. van de Kant KD, Koers K, Rijkers GT, Lima Passos V, Klaassen EM, Mommers M, et al. Can exhaled inflammatory markers predict a steroid response in wheezing preschool children? Clin Exp Allergy. 2011; 41:1076–1083.
Article
65. Rosias PP, Robroeks CM, van de Kant KD, Rijkers GT, Zimmermann LJ, van Schayck CP, et al. Feasibility of a new method to collect exhaled breath condensate in pre-school children. Pediatr Allergy Immunol. 2010; 21:e235–44.
Article
66. Klonoff-Cohen H, Polavarapu M. Eosinophil protein X and childhood asthma: a systematic review and meta-analysis. Immun Inflamm Dis. 2016; 4:114–134.
67. Chiu CY, Tsai MH, Yao TC, Tu YL, Hua MC, Yeh KW, et al. Urinary LTE4 levels as a diagnostic marker for IgE-mediated asthma in preschool children: a birth cohort study. PLoS One. 2014; 9:e115216.
Article
68. Chawes BL, Bønnelykke K, Bisgaard H. Elevated eosinophil protein X in urine from healthy neonates precedes development of atopy in the first 6 years of life. Am J Respir Crit Care Med. 2011; 184:656–661.
Article
69. Saude EJ, Skappak CD, Regush S, Cook K, Ben-Zvi A, Becker A, et al. Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy. J Allergy Clin Immunol. 2011; 127:757–764.e1.
Article
70. Park YH, Fitzpatrick AM, Medriano CA, Jones DP. High-resolution metabolomics to identify urine biomarkers in corticosteroid-resistant asthmatic children. J Allergy Clin Immunol. 2017; 139:1518–1524.e4.
Article
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