Value of bronchial reversibility to salbutamol, exhaled nitric oxide and responsiveness to methacholine to corroborate the diagnosis of asthma in children

Main Article Content

Javier Mallol
Carlos Riquelme
Viviana Aguirre
Marcela Martínez
Alejandro Gallardo
Carlos Sánchez
Pablo Córdova

Keywords

Asthma tests, FENO, Methacholine, Bronchial reversibility

Abstract

Introduction and Objectives: Functional and inflammatory measures have been recommended to corroborate asthma diagnosis in schoolchildren, but the evidence in this regard is conflicting. We aimed to determine, in real-life clinical situation, the value of spirometry, spirometric bronchial reversibility to salbutamol (BDR), bronchial responsiveness to methacholine (MCT) and fractional exhaled nitric oxide (FENO), to corroborate the diagnosis of asthma in children on regular inhaled corticosteroids (ICS) referred from primary care.


Methods: One hundred and seventy-seven schoolchildren with mild-moderate persistent asthma, on treatment with regular ICS, participated in the study. Abnormal tests were defined as FENO ≥ 27 ppb, BDR (FEV1 ≥ 12%) and methacholine PC20 ≤ 4 mg/mL.


Results: The proportions of positive BDR, FENO and MCT, were 16.4%, 33.3%, and 87.0%, respectively. MCT was associated with FENO (p < 0.03) and BDR (p = 0.001); FENO was associated with BDR (p = 0.045), family history of asthma (p = 0.003) and use of asthma medication in the first two years of life (p = 0.004). BDR was significantly related with passive tobacco exposure (p = 0.003).


Conclusions: Spirometry, BDR and BDR had a poor performance for corroborating diagnosis in our asthmatic children on ICS treatment; on the contrary, MCT was positive in most of them, which agrees with previous reports. Although asthma tests are useful to corroborate asthma when positive, clinical diagnosis remains the best current approach for asthma diagnosis, at least while better objective and feasible measurements at the daily practice are available. At present, these tests may have a better role for assessing the management and progression of the condition.

Abstract 54 | PDF Downloads 46

References

1. Global Asthma Report 2018. http://globalasthmareport.org/ (accessed on May 2019).

2. NICE Guideline. https://www.nice.org.uk/guidance/NG80, 2017 (accessed on March 2019.

3. GINA 2018. https://ginasthma.org/wp-content/uploads/2018/04/wms-GINA-2018-report-tracked v1.3.pdf (accessed on May 2019).

4. Moeller A, Carlsen KH, Sly PD, Baraldi E, Piacentini G, Pavord I, et al. Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation. Eur Respir Rev. 2015;24:204-15, http://dx.doi.org/10.1183/16000617.00003914.

5. Murray C, Foden P, Lowe L, Durrington H, Custovic A, Simpson A. Diagnosis of asthma in symptomatic children based on measures of lung function: an analysis of data from a population-based birth cohort study. Lancet Child Adolesc Health. 2017;1:114-23,
http://dx.doi.org/10.1016/S2352-4642(17)30008-1.

6. Tse SM, Gold DR, Sordillo JE, Hoffman EB, Gillman MW, RifasShiman SL, et al. Diagnostic accuracy of the bronchodilator response in children. J Allergy Clin Immunol. 2013;132:554-9, http://dx.doi.org/10.1016/j.jaci.2013.03.031, e5.

7. Green RJ, Klein M, Becker P, Halkas A, Lewis H, Kitchin O, et al. Disagreement among common measures of asthma control in children. Chest. 2013;143:117-22, http://dx.doi.org/10.1378/chest.12-1070.

8. Thomas B, Chay OM, Allen JC Jr, Chiang AS, Pugalenthi A, Goh A, et al. Concordance between bronchial hyperresponsiveness, fractional exhaled nitric oxide, and asthma control in children. Pediatr Pulmonol. 2016;51:1004-9, http://dx.doi.org/10.1002/ppul.23426.

9. Boulay ME, Boulet LP. Discordance between asthma control clinical, physiological and inflammatory parameters in mild asthma. Respir Med. 2013;107:511-8, http://dx.doi.org/10.1016/j.rmed.2012.12.015.

10. Mallol J, Aguirre V, Gallardo A, Cortez E, Sánchez C, Riquelme C, et al. Effect of once-daily generic ciclesonide on exhaled nitric oxide in atopic children with persistent asthma. Allergol Immunopathol (Madr). 2016;44:106-12, http://dx.doi.org/10.1016/j.aller.2015.01.011.

11. Park GM, Han HW, Kim JY, Lee E, Cho HJ, Yoon J, et al. Association of symptom control with changes in lung function, bronchial hyperresponsiveness, and exhaled nitric oxide after inhaled corticosteroid treatment in children with asthma. Allergol Int. 2016;65:439-43, http://dx.doi.org/10.1016/j.alit.2016.03.011.

12. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184:602-15, http://dx.doi.org/10.1164/rccm.9120-11ST.

13. Mallol J, Aguirre V, Córdova P, Cortez E, Gallardo A, Riquelme C. Fraction of exhaled nitric oxide in healthy Chilean schoolchildren aged 8-15 years. Allergol Immunopathol (Madr). 2015;43:528-32, http://dx.doi.org/10.1016/j.aller.2014.07.003.

14. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983;127:725-34.

15. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948-68.

16. Mallol J, Castro-Rodriguez JA, Cortez E, Aguirre V, Aguilar P, Barrueto L. Heightened bronchial hyperresponsiveness in the absence of heightened atopy in children with current wheezing and low-income status. Thorax. 2008;63:167-71.

17. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines for methacholine and exercise challenge testing-1999. Am J Respir Crit Care Med. 2000;161:309-29.

18. Mazi A, Lands LC. Effect of lowering methacholine challenge test cut-off in children. Ann Allergy Asthma Immunol. 2014;113:393-7, http://dx.doi.org/10.1016/j.anai.2014.06.024. Epub 2014 Aug 1.

19. Rao DR, Gaffin JM, Baxi SN, Sheehan WJ, Hoffman EB, Phipatanakul W. The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity. J Asthma. 2012;49:586-92, http://dx.doi.org/10.3109/02770903.2012.690481.

20. Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. The N Engl J Med. 2000;343:1054-63.

21. Coates AL, Wanger J, Cockcroft DW, Culver BH, the Bronchoprovocation Testing Task Force. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017;49, http://dx.doi.org/10.1183/13993003.01526-2016, pii: 1601526.

22. Sumino K, Sugar EA, Irvin CG, Kaminsky DA, Shade D, Wei CY, et al. American Lung Association Asthma Clinical Research Centers. Methacholine challenge test: diagnostic characteristics in asthmatic patients receiving controller medications. J Allergy Clin Immunol. 2012;130(69), http://dx.doi.org/10.1016/j.jaci.2012.02.025. Erratum in: J Allergy Clin Immunol. 2012 Nov;130:1084.

23. Mallol J, Aguirre V. Once versus twice-daily budesonide metered dose in halerin children with mild to moderate asthma: effect on symptoms and bronchial responsiveness. Allergol Immunopathol (Madr). 2007;35:25-31.

24. Nuijsink M, Vaessen-Verberne AA, Hop WC, Sterk PJ, Duiverman EJ, de Jongste JC, et al. Long-term follow-up after two years of asthma treatment guided by airway responsiveness in children. Respir Med. 2013;107:981-6, http://dx.doi.org/10.1016/j.rmed.2013.03.008.

25. Suh DI, Lee JK, Kim CK, Koh YY. Bronchial hyperresponsiveness to methacholine/AMP and the bronchodilator response in asthmatic children. Eur Respir J. 2011;37:800-5, http://dx.doi.org/10.1183/09031936.00049610.

26. Carlsten C, Dimich-Ward H, Ferguson A, Becker A, Dybuncio A, Chan-Yeung M. Airway hyperresponsiveness to methacholine in 7-year-old children: sensitivity and specificity for pediatric allergist-diagnosed asthma. Pediatr Pulmonol. 2011;46:175-8, http://dx.doi.org/10.1002/ppul.21347.

27. Nishio K, Odajima H, Motomura C, Nakao F, Nishima S. Effect of inhaled steroid therapy on exhaled nitric oxide and bronchial responsiveness in children with asthma. J Asthma. 2006;43:739-43.

28. Riiser A, Hovland V, Carlsen KH, Mowinckel P, Lødrup Carlsen KC. Does bronchial hyperresponsiveness in childhood predict active asthma in adolescence? Am J Respir Crit Care Med. 2012;186:493-500, http://dx.doi.org/10.1164/rccm.201112-2235OC.

29. Rao DR, Phipatanakul W. An overview of fractional exhaled nitric oxide and children with asthma. Expert Rev Clin Immunol. 2016;12:521-30, http://dx.doi.org/10.1586/1744666X.2016.1141049.

30. Brooks CR, van Dalen CJ, Zacharasiewicz A, Simpson JL, Harper JL, Le Gros G, et al. Absence of airway inflammation in a large proportion of adolescents with asthma. Respirology. 2016;21:460-6, http://dx.doi.org/10.1111/resp.12701.

31. Tang S, Xie Y, Yuan C, Sun X, Cui Y. Fractional exhaled nitric oxide for the diagnosis of childhood asthma: a systematic review and meta-analysis. Clin Rev Allergy Immunol. 2019;56:129-38, http://dx.doi.org/10.1007/s12016-016-8573-4.

32. Galant SP, Morphew T, Newcomb RL, Hioe K, Guijon O, Liao O. The relationship of the bronchodilator response phenotype to poor asthma control in children with normal spirometry. J Pediatr. 2011;158:953-9, http://dx.doi.org/10.1016/j.jpeds.2010.11.029, e1.

33. Dundas I, Chan EY, Bridge PD, McKenzie SA. Diagnostic accuracy of bronchodilator responsiveness in wheezy children. Thorax. 2005;60:13-6.

34. Busse WW. What is the best pulmonary diagnostic approach for wheezing patients with normal spirometry? Respir Care. 2012;57:39-46, http://dx.doi.org/10.4187/respcare.01449, discussion 47-9.

35. Ferrer Galván M, Javier Álvarez Gutiérrez F, Romero Falcón A, Romero Romero B, Sáez A, Medina Gallardo JF. Is the bronchodilator test a useful tool to measure asthma control? Respir Med. 2017;126:26-31, http://dx.doi.org/10.1016/j.rmed.2017.03.008.

36. Heffler E, Crimi C, Campisi R, Sichili S, Nicolosi G, Porto M, et al. Bronchodilator response as a marker of poor asthma control. Respir Med. 2016;112:45-50, http://dx.doi.org/10.1016/j.rmed.2016.01.012.


37. Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF Jr, Szefler SJ, et al. Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values. J Allergy Clin Immunol. 2010;126:527-34, http://dx.doi.org/10.1016/j.jaci.2010.05.016, e1-8.

38. Dufetelle E, Bokov P, Delclaux C, Beydon N. Should reversibility be assessed in all asthmatic children with normal spirometry? Eur Respir J. 2018;52:1800373, http://dx.doi.org/10.1183/13993003.00373-2018.

39. Latzin P, Fuchs O. Asthma diagnosis in children: more evidence needed. Lancet Child Adolesc Health. 2017;1:83-5, http://dx.doi.org/10.1016/S2352-4642(17)30019-6.