Relation between serum CC16 levels and asthma predictive index in pre-schoolers with recurrent wheezing
Main Article Content
Keywords
Asthma, Asthma predictive index, CC16, Clara cells, Pre-school, Recurrent wheezing
Abstract
Background: Low levels of serum CC16 were reported in asthmatic adults, but the studies on children were scarce and conflicting. The aim of this study was to compare serum CC16 levels in pre-school children with recurrent wheezing assessed using an asthma predictive index (API).
Methods: We performed a case-control study based on API, with all enrolled pre-school children who had recurrent wheezing episodes (>3 episodes/last year confirmed by a physician) and had presented at one paediatric clinic in Santiago, Chile. The population was divided according to stringent API criteria into positive or negative.
Results: In a one-year period, 60 pre-schoolers were enrolled. After excluding 12, 48 preschoolers remained (27 males, age range from 24 to 71 months) and completed the study; 34 were API positive and 14 were API negative. There were no significant differences in demographics between groups. The level of serum CC16 levels for pre-schoolers with a positive API and negative API were (median 9.2 [7.1-11.5] and 9.4 [5.5-10], p = 0.26, respectively). The area under the curve for the serum CC16 levels to predict a positive API was 0.6, 95% CI [0.43-0.77], p = 0.3. A correlation between serum CC16 levels and age was found (r = 0.36 [0.07-0.59], p = 0.01], but not between serum CC16 levels and peripheral eosinophils blood.
Conclusion: There was no evidence that serum CC16 levels played a role in recurrent wheezing and a positive API in pre-school children. More studies are needed to confirm this finding.
References
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13. Brand PL, Luz Garcia-Garcia M, Morison A, Vermeulen JH, Weber HC. Ciclesonide in wheezy preschool children with a positive asthma predictive index or atopy. Respir Med. 2011;105:1588-95.
14. Li YQ, Xue HY, Chen W, Cao LF. Application of asthma predictive index-based group therapy in wheezing children under 5 years of age. Zhongguo Dang Dai Er Ke Za Zhi. 2014;16:795-9.
15. Expert panel, National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma; 2007. Available from: www.nhlbi.nih.gov/guidelines/asthma/asthgdln htm [accessed March 2017] [updated 2008].
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17. Castro-Rodriguez JA. The necessity of having asthma predictive scores in children. J Allergy Clin Immunol. 2013;132:1311-3.
18. Dierynck I, Bernard A, Roels H, De Ley M. Potent inhibition of both human interferon-gamma production and biologic activity by the Clara cell protein CC16. Am J Respir Cell Mol Biol. 1995;12:205-10.
19. Broeckaert F, Clippe A, Knoops B, Hermans C, Bernard A. Clara cell secretory protein (CC16): features as a peripheral lung biomarker. Ann N Y Acad Sci. 2000;923:68-77.
20. Bernard A. Critical review of Clara cell protein: sound science? Biomarkers. 2008;13:237-43.
21. Broeckaert F, Arsalane K, Hermans C, Bergamaschi E, Brustolin A, Mutti A, et al. Serum clara cell protein: a sensitive biomarker of increased lung epithelium permeability caused by ambient ozone. Environ Health Perspect. 2000;108:533-7.
22. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy. 2000;30:469-75.
23. Schiffmann E, Geetha V, Pencev D, Warabi H, Mato J, Hirata F, et al. Adherence and regulation of leukotaxis. Agents Actions Suppl. 1983;12:106-20.
24. Hayward A. Who’s to blame for asthma? Lancet. 1995;346:1243.
25. Miele L, Cordella-Miele E, Facchiano A, Mukherjee AB. Inhibition of phospholipase A2 by uteroglobin and antiflammin peptides. Adv Exp Med Biol. 1990;279:137-60.
26. Sonar SS, Ehmke M, Marsh LM, Dietze J, Dudda JC, Conrad ML, et al. Clara cells drive eosinophil accumulation in allergic asthma. Eur Respir J. 2012;39:429-38.
27. Van Vyve T, Chanez P, Bernard A, Bousquet J, Godard P, Lauwerijs R, et al. Protein content in bronchoalveolar lavage fluid of patients with asthma and control subjects. J Allergy Clin Immunol. 1995;95 Pt 1:60-8.
28. Shijubo N, Itoh Y, Yamaguchi T, Imada A, Hirasawa M, Yamada T, et al. Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med. 1999;160:930-3.
29. Shijubo N, Itoh Y, Yamaguchi T, Sugaya F, Hirasawa M, Yamada T, et al. Serum levels of Clara cell 10-kDa protein are decreased in patients with asthma. Lung. 1999;177:45-52.
30. Lensmar C, Nord M, Gudmundsson GH, Roquet A, Andersson O, Jörnvall H, et al. Decreased pulmonary levels of the antiinflammatory Clara cell 16 kDa protein after induction of airway inflammation in asthmatics. Cell Mol Life Sci. 2000;57:976-81.
31. Gioldassi XM, Papadimitriou H, Mikraki V, Karamanos NK. Clara cell secretory protein: determination of serum levels by an enzyme immunoassay and its importance as an indicator of bronchial asthma in children. J Pharm Biomed Anal. 2004;34:823-6.
32. Ma YN, Wang J, Lee YL, Ren WH, Lv XF, He QC, et al. Association of urine CC16 and lung function and asthma in Chinese children. Allergy Asthma Proc. 2015;36:59-64.
33. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16- kd protein downregulates T(H)2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol. 2007;120:308-14.
34. Ye Q, Fujita M, Ouchi H, Inoshima I, Maeyama T, Kuwano K, et al. Serum CC-10 in inflammatory lung diseases. Respiration. 2004;71:505-10.
35. de Burbure C, Pignatti P, Corradi M, Malerba M, Clippe A, Dumont X, et al. Uteroglobin-related protein 1 and clara cell protein in induced sputum of patients with asthma and rhinitis. Chest. 2007;131:172-9.
36. Guerra S, Halonen M, Vasquez MM, Spangenberg A, Stern DA, Morgan WJ, et al. Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study. Lancet Respir Med. 2015;3:613-20.
37. Candelaria PV, Backer V, Laing IA, Porsbjerg C, NepperChristensen S, de Klerk N, et al. Association between asthma-related phenotypes and the CC16 A38G polymorphism in an unselected population of young adult Danes. Immunogenetics. 2005;57:25-32.
38. Laing IA, Goldblatt J, Eber E, Hayden CM, Rye PJ, Gibson NA, et al. A polymorphism of the CC16 gene is associated with an increased risk of asthma. J Med Genet. 1998;35:463-7.
39. Sengler C, Heinzmann A, Jerkic SP, Haider A, Sommerfeld C, Niggemann B, et al. Clara cell protein 16 (CC16) gene polymorphism influences the degree of airway responsiveness in asthmatic children. J Allergy Clin Immunol. 2003;111: 515-9.
40. 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;49:665-72.
41. Cheng D, Di H, Xue Z, Zhen G. CC16 gene A38G polymorphism and susceptibility to asthma: an updated meta-analysis. Intern Med. 2015;54:155-62.
42. Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF Jr, Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med. 2004;170:426-32.
43. Ma YN, Qian Z, Wang J, Rodemich E, Lee YL, Lv XF, et al. Environmental tobacco smoke exposure, urine CC-16 levels, and asthma outcomes among Chinese children. Allergy. 2015;70: 295-301.
2. Guilbert TW, Mauger DT, Lemanske RF Jr. Childhood asthma-predictive phenotype. J Allergy Clin Immunol Pract. 2014;2:664-70.
3. Luo G, Nkoy FL, Stone BL, Schmick D, Johnson MD. A systematic review of predictive models for asthma development in children. BMC Med Inform Decis Mak. 2015;28:99.
4. 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 Pt 1:1403-6.
5. Toll DB, Janssen KJ, Vergouwe Y, Moons KG. Validation, updating and impact of clinical prediction rules: a review. J Clin
Epidemiol. 2008;61:1085-94.
6. Caudri D, Wijga A, Scholtens S, Kerkhof M, Gerritsen J, Ruskamp JM, 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.
7. Leonardi NA, Spycher BD, Strippoli MP, Frey U, Silverman M, Kuehni CE. Validation of the Asthma Predictive Index and comparison with simpler clinical prediction rules. J Allergy Clin Immunol. 2011;127, 1466-1472.e6.
8. Rodriguez-Martinez CE, Sossa-Briceno MP, Castro-Rodriguez JA. Discriminative properties of two predictive indices for asthma diagnosis in a sample of preschoolers with recurrent wheezing. Pediatr Pulmonol. 2011;46:1175-81.
9. Balinotti JE, Colom A, Kofman C, Teper A. Association between the Asthma Predictive Index and levels of exhaled nitric oxide in infants and toddlers with recurrent wheezing. Arch Argent Pediatr. 2013;111:191-5.
10. Berankova K, Uhlik J, Honkova L, Pohunek P. Structural changes in the bronchial mucosa of young children at risk of developing asthma. Pediatr Allergy Immunol. 2014;25:136-42.
11. Castro-Rodriguez JA, Sardón O, Pérez-Yarza EG, Korta J, Aldasoro A, Corcuera P, et al. Young infants with recurrent wheezing and positive asthma predictive index have higher levels of exhaled nitric oxide. J Asthma. 2013;50:162-5.
12. Keklikian E, Sanchez-Solis M, Bonina AJ, Meneguzzi A, PastorVivero MD, Mondejar-Lopez P, et al. Do risk factors for persistent asthma modify lung function in infants and young children with recurrent wheeze? Pediatr Pulmonol. 2010;45: 914-8.
13. Brand PL, Luz Garcia-Garcia M, Morison A, Vermeulen JH, Weber HC. Ciclesonide in wheezy preschool children with a positive asthma predictive index or atopy. Respir Med. 2011;105:1588-95.
14. Li YQ, Xue HY, Chen W, Cao LF. Application of asthma predictive index-based group therapy in wheezing children under 5 years of age. Zhongguo Dang Dai Er Ke Za Zhi. 2014;16:795-9.
15. Expert panel, National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma; 2007. Available from: www.nhlbi.nih.gov/guidelines/asthma/asthgdln htm [accessed March 2017] [updated 2008].
16. Global Initiative for Asthma. Global strategy for asthma management and prevention; 2017. Available from: www.ginasthma.org [accessed March 2017].
17. Castro-Rodriguez JA. The necessity of having asthma predictive scores in children. J Allergy Clin Immunol. 2013;132:1311-3.
18. Dierynck I, Bernard A, Roels H, De Ley M. Potent inhibition of both human interferon-gamma production and biologic activity by the Clara cell protein CC16. Am J Respir Cell Mol Biol. 1995;12:205-10.
19. Broeckaert F, Clippe A, Knoops B, Hermans C, Bernard A. Clara cell secretory protein (CC16): features as a peripheral lung biomarker. Ann N Y Acad Sci. 2000;923:68-77.
20. Bernard A. Critical review of Clara cell protein: sound science? Biomarkers. 2008;13:237-43.
21. Broeckaert F, Arsalane K, Hermans C, Bergamaschi E, Brustolin A, Mutti A, et al. Serum clara cell protein: a sensitive biomarker of increased lung epithelium permeability caused by ambient ozone. Environ Health Perspect. 2000;108:533-7.
22. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy. 2000;30:469-75.
23. Schiffmann E, Geetha V, Pencev D, Warabi H, Mato J, Hirata F, et al. Adherence and regulation of leukotaxis. Agents Actions Suppl. 1983;12:106-20.
24. Hayward A. Who’s to blame for asthma? Lancet. 1995;346:1243.
25. Miele L, Cordella-Miele E, Facchiano A, Mukherjee AB. Inhibition of phospholipase A2 by uteroglobin and antiflammin peptides. Adv Exp Med Biol. 1990;279:137-60.
26. Sonar SS, Ehmke M, Marsh LM, Dietze J, Dudda JC, Conrad ML, et al. Clara cells drive eosinophil accumulation in allergic asthma. Eur Respir J. 2012;39:429-38.
27. Van Vyve T, Chanez P, Bernard A, Bousquet J, Godard P, Lauwerijs R, et al. Protein content in bronchoalveolar lavage fluid of patients with asthma and control subjects. J Allergy Clin Immunol. 1995;95 Pt 1:60-8.
28. Shijubo N, Itoh Y, Yamaguchi T, Imada A, Hirasawa M, Yamada T, et al. Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med. 1999;160:930-3.
29. Shijubo N, Itoh Y, Yamaguchi T, Sugaya F, Hirasawa M, Yamada T, et al. Serum levels of Clara cell 10-kDa protein are decreased in patients with asthma. Lung. 1999;177:45-52.
30. Lensmar C, Nord M, Gudmundsson GH, Roquet A, Andersson O, Jörnvall H, et al. Decreased pulmonary levels of the antiinflammatory Clara cell 16 kDa protein after induction of airway inflammation in asthmatics. Cell Mol Life Sci. 2000;57:976-81.
31. Gioldassi XM, Papadimitriou H, Mikraki V, Karamanos NK. Clara cell secretory protein: determination of serum levels by an enzyme immunoassay and its importance as an indicator of bronchial asthma in children. J Pharm Biomed Anal. 2004;34:823-6.
32. Ma YN, Wang J, Lee YL, Ren WH, Lv XF, He QC, et al. Association of urine CC16 and lung function and asthma in Chinese children. Allergy Asthma Proc. 2015;36:59-64.
33. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16- kd protein downregulates T(H)2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol. 2007;120:308-14.
34. Ye Q, Fujita M, Ouchi H, Inoshima I, Maeyama T, Kuwano K, et al. Serum CC-10 in inflammatory lung diseases. Respiration. 2004;71:505-10.
35. de Burbure C, Pignatti P, Corradi M, Malerba M, Clippe A, Dumont X, et al. Uteroglobin-related protein 1 and clara cell protein in induced sputum of patients with asthma and rhinitis. Chest. 2007;131:172-9.
36. Guerra S, Halonen M, Vasquez MM, Spangenberg A, Stern DA, Morgan WJ, et al. Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study. Lancet Respir Med. 2015;3:613-20.
37. Candelaria PV, Backer V, Laing IA, Porsbjerg C, NepperChristensen S, de Klerk N, et al. Association between asthma-related phenotypes and the CC16 A38G polymorphism in an unselected population of young adult Danes. Immunogenetics. 2005;57:25-32.
38. Laing IA, Goldblatt J, Eber E, Hayden CM, Rye PJ, Gibson NA, et al. A polymorphism of the CC16 gene is associated with an increased risk of asthma. J Med Genet. 1998;35:463-7.
39. Sengler C, Heinzmann A, Jerkic SP, Haider A, Sommerfeld C, Niggemann B, et al. Clara cell protein 16 (CC16) gene polymorphism influences the degree of airway responsiveness in asthmatic children. J Allergy Clin Immunol. 2003;111: 515-9.
40. 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;49:665-72.
41. Cheng D, Di H, Xue Z, Zhen G. CC16 gene A38G polymorphism and susceptibility to asthma: an updated meta-analysis. Intern Med. 2015;54:155-62.
42. Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF Jr, Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med. 2004;170:426-32.
43. Ma YN, Qian Z, Wang J, Rodemich E, Lee YL, Lv XF, et al. Environmental tobacco smoke exposure, urine CC-16 levels, and asthma outcomes among Chinese children. Allergy. 2015;70: 295-301.
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Castro-Rodriguez, J., Atton, I., Villarroel, G., & Serrano, C. (2018). Relation between serum CC16 levels and asthma predictive index in pre-schoolers with recurrent wheezing. Allergologia Et Immunopathologia, 46(5), 460-466. https://all-imm.com/index.php/aei/article/view/383
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Castro-Rodriguez, J., Atton, I., Villarroel, G., & Serrano, C. (2018). Relation between serum CC16 levels and asthma predictive index in pre-schoolers with recurrent wheezing. Allergologia Et Immunopathologia, 46(5), 460-466. https://all-imm.com/index.php/aei/article/view/383