Clinical Reviews in Allergy & Immunology

, Volume 56, Issue 2, pp 129–138 | Cite as

Fractional Exhaled Nitric Oxide for the Diagnosis of Childhood Asthma: a Systematic Review and Meta-analysis

  • Songqi Tang
  • Yiqiang Xie
  • Conghu Yuan
  • Xiaoming Sun
  • Yubao CuiEmail author


The gold standard for diagnosing asthma in children is based on clinical history of respiratory symptoms, physical examination, and respiratory function testing. Recent advances indicate that a non-invasive measure of airway inflammation, fractional exhaled nitric oxide (FeNO), provides objective data for use in asthma diagnosis. However, the diagnostic performance of FeNO in children with asthma has not been clearly defined. This systematic review and meta-analysis aimed to evaluate the diagnostic accuracy of FeNO in the clinical determination of asthma in children. Databases of PubMed, the Cochrane Library, EMBASE, MEDION, and Web of Science were searched for relevant articles through March 31, 2016. A bivariate model was used for pooling estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary receiver operating curves (SROC) as the main diagnostic measures. In total, eight studies met the inclusion criteria, which included 2933 subjects. The pooled estimates of sensitivity, specificity, and DOR for the detection of asthma in children were 0.79 [95 % confidence interval (CI), 0.64–0.89], 0.81 (95 % CI, 0.66–0.90), and 16.52 (95 % CI, 7.64–35.71). The SROC was 0.87 (95 % CI, 0.84–0.90). In brief, FeNO achieves a moderate diagnostic performance in the detection of asthma in children.


Fractional exhaled nitric oxide (FeNO) Childhood asthma Diagnosis 



We would like to thank Dr. Wen Wu, Department of cardiovascular medicine, Nanjing First Hospital, Affiliated to Nanjing Medical University (Nanjing, China), for helping us in STATA software techniques. This work was supported by the National Natural Science Foundation of China (NSFC 81473668, NSFC 81473618, NSFC31272369, and NSFC31572319).


  1. 1.
    Rao DR, Phipatanakul W (2016) An overview of fractional exhaled nitric oxide and children with asthma. Expert Rev Clin Immunol 12(5):521–530CrossRefGoogle Scholar
  2. 2.
    Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, Haahtela T, Hurd SS, Inoue H, de Jongste JC, Lemanske RF Jr, Levy ML, O’Byrne PM, Paggiaro P, Pedersen SE, Pizzichini E, Soto-Quiroz M, Szefler SJ, Wong GW, FitzGerald JM (2015) A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J 46(3):622–639CrossRefGoogle Scholar
  3. 3.
    Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329(27):2002–2012CrossRefGoogle Scholar
  4. 4.
    Alving K, Weitzberg E, Lundberg JM (1993) Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 6(9):1368–1370Google Scholar
  5. 5.
    Hanson JR, De Lurgio SA, Williams DD, Dinakar C (2013) Office-based exhaled nitric oxide measurement in children 4 years of age and older. Ann Allergy Asthma Immuno 111(5):358–363CrossRefGoogle Scholar
  6. 6.
    Silkoff PE, Carlson M, Bourke T, Katial R, Ogren E, Szefler SJ (2004) The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma. J Allergy Clin Immunol 114(5):1241–1256CrossRefGoogle Scholar
  7. 7.
    Balinotti JE, Colom A, Kofman C, Teper A (2013) Association between the Asthma Predictive Index and levels of exhaled nitric oxide in infants and toddlers with recurrent wheezing. Arch Argent Pediatr 111(3):191–195Google Scholar
  8. 8.
    Paraskakis E, Brindicci C, Fleming L, Krol R, Kharitonov SA, Wilson NM, Barnes PJ, Bush A (2006) Measurement of bronchial and alveolar nitric oxide production in normal children and children with asthma. Am J Respir Crit Care Med 174(3):260–267CrossRefGoogle Scholar
  9. 9.
    van der Valk RJ, Caudri D, Savenije O, Koppelman GH, Smit HA, Wijga AH, Postma DS, Kerkhof M, Brunekreef B, de Jongste JC (2012) Childhood wheezing phenotypes and FeNO in atopic children at age 8. Clin Exp Allergy 42(9):1329–1336CrossRefGoogle Scholar
  10. 10.
    Elmasri M, Romero KM, Gilman RH, Hansel NN, Robinson CL, Baumann LM, Cabrera L, Hamilton RG, Checkley W, Pura Study Investigators (2014) Longitudinal assessment of high versus low levels of fractional exhaled nitric oxide among children with asthma and atopy. Lung 192(2):305–312CrossRefGoogle Scholar
  11. 11.
    Jouaville LF, Annesi-Maesano I, Nguyen LT, Bocage AS, Bedu M, Caillaud D (2003) Interrelationships among asthma, atopy, rhinitis and exhaled nitric oxide in a population-based sample of children. Clin Exp Allergy 33(11):1506–1511CrossRefGoogle Scholar
  12. 12.
    Guo Z, Wang Y, Xing G, Wang X (2016) Diagnostic accuracy of fractional exhaled nitric oxide in asthma: a systematic review and meta-analysis of prospective studies. J Asthma 53(4):404–412CrossRefGoogle Scholar
  13. 13.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700CrossRefGoogle Scholar
  14. 14.
    Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM, QUADAS-2 Group (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155(8):529–536CrossRefGoogle Scholar
  15. 15.
    Menke J (2013) Bivariate random-effects meta-analysis of sensitivity and specificity with the Bayesian SAS PROC MCMC: methodology and empirical evaluation in 50 meta-analyses. Med Decis Making 33(5):692–701CrossRefGoogle Scholar
  16. 16.
    Devillé WL, Buntinx F, Bouter LM, Montori VM, de Vet HC, van der Windt DA, Bezemer PD (2002) Conducting systematic reviews of diagnostic studies: didactic guidelines. BMC Med Res Methodol 2:9CrossRefGoogle Scholar
  17. 17.
    Deeks JJ, Macaskill P, Irwig L (2005) The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol 58(9):882–893CrossRefGoogle Scholar
  18. 18.
    Caraguel CG, Vanderstichel R (2013) The two-step Fagan’s nomogram: ad hoc interpretation of a diagnostic test result without calculation. Evid Based Med 18(4):125–128CrossRefGoogle Scholar
  19. 19.
    Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH (2005) Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol 58(10):982–990CrossRefGoogle Scholar
  20. 20.
    Sivan Y, Gadish T, Fireman E, Soferman R (2009) The use of exhaled nitric oxide in the diagnosis of asthma in school children. J Pediatr 155(2):211–216CrossRefGoogle Scholar
  21. 21.
    Sachs-Olsen C, Lødrup Carlsen KC, Mowinckel P, Håland G, Devulapalli CS, Munthe-Kaas MC, Carlsen KH (2010) Diagnostic value of exhaled nitric oxide in childhood asthma and allergy. Pediatr Allergy Immunol 21(1Pt2):e213–221CrossRefGoogle Scholar
  22. 22.
    Pérez Tarazona S, Martínez Camacho RM, Alfonso Diego J, Escolano Serrano S, Talens Gandía J (2011) Diagnostic value of exhaled nitric oxide measurement in mild asthma. An Pediatr (Barc) 75(5):320–328CrossRefGoogle Scholar
  23. 23.
    Yao T, Ou L, Lee W, Yeh K, Chen L, Huang J (2011) Exhaled nitric oxide discriminates children with and without allergic sensitization in a population-based study. Clin Exp Allergy 41(4):556–564CrossRefGoogle Scholar
  24. 24.
    Woo SI, Lee JH, Kim H, Kang JW, Sun YH, Hahn YS (2012) Utility of fractional exhaled nitric oxide (FENO) measurements in diagnosing asthma. Respir Med 106(8):1103–1109CrossRefGoogle Scholar
  25. 25.
    Jerzyńska J, Majak P, Janas A, Stelmach R, Stelmach W, Smejda K, Stelmach I (2014) Predictive value of fractional nitric oxide in asthma diagnosis-subgroup analyses. Nitric Oxide 40:87–91CrossRefGoogle Scholar
  26. 26.
    Zhu H, Yu X, Hao C, Wang Y, Yang X, Lu Y, Sun H, Luo W, Lai K (2015) The diagnostic value of the fractional exhaled nitric oxide for cough variant asthma in children. Zhonghua Jie He He Hu Xi Za Zhi 38(5):352–355 (In Chinese) Google Scholar
  27. 27.
    An SH, Tian WQ, Li JY (2015) Utility of fractional exhaled nitric oxide in children with asthma. Zhongguo Dang Dai Er Ke Za Zhi 17(8):134–137Google Scholar
  28. 28.
    Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, Plummer AL, Taylor DR, American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications (2011) An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 184(5):602–615CrossRefGoogle Scholar
  29. 29.
    Pohunek P, Warner JO, Turzíková J, Kudrmann J, Roche WR (2005) Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma. Pediatr Allergy Immunol 16(1):43–51CrossRefGoogle Scholar
  30. 30.
    Malmberg LP, Pelkonen AS, Haahtela T, Turpeinen M (2003) Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma. Thorax 58(6):494–499CrossRefGoogle Scholar
  31. 31.
    Bae JM (2014) An overview of systematic reviews of diagnostic tests accuracy. Epidemiol Health 36:e2014016CrossRefGoogle Scholar
  32. 32.
    Lee J, Kim KW, Choi SH, Huh J, Park SH (2015) Systematic review and meta-analysis of studies evaluating diagnostic test accuracy: a practical review for clinical researchers—part II. Statistical methods of meta-analysis. Korean J Radiol 16(6):1188–1196CrossRefGoogle Scholar
  33. 33.
    Ricciardolo FL, Silvestri M, Pistorio A, Strozzi MM, Tosca MA, Bellodi SC, Battistini E, Gardella C, Rossi GA (2010) Determinants of exhaled nitric oxide levels (FeNO) in childhood atopic asthma: evidence for neonatal respiratory distress as a factor associated with low FeNO levels. J Asthma 47(7):810–816CrossRefGoogle Scholar
  34. 34.
    Baraldi E, Azzolin NM, Zanconato S, Dario C, Zacchello F (1997) Corticosteroids decrease exhaled nitric oxide in children with acute asthma. J Pediatr 131(3):381–385CrossRefGoogle Scholar
  35. 35.
    Filippone M, Bonetto G, Corradi M, Frigo AC, Baraldi E (2012) Evidence of unexpected oxidative stress in airways of adolescents born very pre-term. Eur Respir J 40(5):1253–1259CrossRefGoogle Scholar
  36. 36.
    Lu M, Wu B, Che D, Qiao R, Gu H (2015) FeNO and asthma treatment in children: a systematic review and meta-analysis. Medicine (Baltimore) 94(4):e347CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.College of Traditional Chinese MedicineHainan Medical UniversityHaikouChina
  2. 2.The Third People’s Hospital of Yancheng, Affiliated Yancheng Hospital, School of MedicineSoutheast UniversityYanchengPeople’s Republic of China
  3. 3.School of Preclinical MedicineXuzhou Medical UniversityXuzhouPeople’s Republic of China
  4. 4.Department of Clinical Laboratory, The Third People’s Hospital, Affiliated Yancheng Hospital, School of MedicineSoutheast UniversityYanchengPeople’s Republic of China

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