Review
The analysis of volatile organic compounds in exhaled breath and biomarkers in exhaled breath condensate in children – clinical tools or scientific toys?
E. van Mastrigt,
J. C. de Jongste,
M. W. Pijnenburg,
E. van Mastrigt
Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
Search for more papers by this authorJ. C. de Jongste
Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
Search for more papers by this authorCorresponding Author
M. W. Pijnenburg
Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
Correspondence: M. W. H. Pijnenburg, Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Sp 3435, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
E-mail: [email protected]
Search for more papers by this authorE. van Mastrigt,
J. C. de Jongste,
M. W. Pijnenburg,
E. van Mastrigt
Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
Search for more papers by this authorJ. C. de Jongste
Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
Search for more papers by this authorCorresponding Author
M. W. Pijnenburg
Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
Correspondence: M. W. H. Pijnenburg, Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Sp 3435, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
E-mail: [email protected]
Search for more papers by this authorSummary
Current monitoring strategies for respiratory diseases are mainly based on clinical features, lung function and imaging. As airway inflammation is the hallmark of many respiratory diseases in childhood, noninvasive methods to assess the presence and severity of airway inflammation might be helpful in both diagnosing and monitoring paediatric respiratory diseases. At present, the measurement of fractional exhaled nitric oxide is the only noninvasive method available to assess eosinophilic airway inflammation in clinical practice. We aimed to evaluate whether the analysis of volatile organic compounds (VOCs) in exhaled breath (EB) and biomarkers in exhaled breath condensate (EBC) is helpful in diagnosing and monitoring respiratory diseases in children. An extensive literature search was conducted in Medline, Embase and PubMed on the analysis and applications of VOCs in EB and EBC in children. We retrieved 1165 papers, of which nine contained original data on VOCs in EB and 84 on biomarkers in EBC. These were included in this review. We give an overview of the clinical applications in childhood and summarize the methodological issues. Several VOCs in EB and biomarkers in EBC have the potential to distinguish patients from healthy controls and to monitor treatment responses. Lack of standardization of collection methods and analysis techniques hampers the introduction in clinical practice. The measurement of metabolomic profiles may have important advantages over detecting single markers. There is a lack of longitudinal studies and external validation to reveal whether EB and EBC analysis have added value in the diagnostic process and follow-up of children with respiratory diseases. In conclusion, the use of VOCs in EB and biomarkers in EBC as markers of inflammatory airway diseases in children is still a research tool and not validated for clinical use.
References
- 1Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993; 6: 1368–70.
- 2Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343: 133–5.
- 3Pauling L, Robinson AB, Teranishi R, Cary P. Quantitative analysis of urine vapor and breath by gas-liquid partition chromatography. Proc Natl Acad Sci USA 1971; 68: 2374–6.
- 4Buszewski B, Kesy M, Ligor T, Amann A. Human exhaled air analytics: biomarkers of diseases. Biomed Chromatogr 2007; 21: 553–66.
- 5Barker M, Hengst M, Schmid J et al. Volatile organic compounds in the exhaled breath of young patients with cystic fibrosis. Eur Respir J 2006; 27: 929–36.
- 6Dragonieri S, Schot R, Mertens BJ et al. An electronic nose in the discrimination of patients with asthma and controls. J Allergy Clin Immunol 2007; 120: 856–62.
- 7Raymer JH, Thomas KW, Cooper SD, Whitaker DA, Pellizzari ED. A device for sampling of human alveolar breath for the measurement of expired volatile organic compounds. J Anal Toxicol 1990; 14: 337–44.
- 8Wallace L, Buckley T, Pellizzari E, Gordon S. Breath measurements as volatile organic compound biomarkers. Environ Health Perspect 1996; 104(Suppl 5): 861–9.
- 9Schubert JK, Spittler KH, Braun G, Geiger K, Guttmann J. CO(2)-controlled sampling of alveolar gas in mechanically ventilated patients. J Appl Physiol 2001; 90: 486–92.
- 10Schubert JK, Miekisch W, Birken T, Geiger K, Noldge-Schomburg GF. Impact of inspired substance concentrations on the results of breath analysis in mechanically ventilated patients. Biomarkers 2005; 10: 138–52.
- 11Martin AN, Farquar GR, Jones AD, Frank M. Human breath analysis: methods for sample collection and reduction of localized background effects. Anal Bioanal Chem 2010; 396: 739–50.
- 12Gordon SM, Wallace LA, Brinkman MC, Callahan PJ, Kenny DV. Volatile organic compounds as breath biomarkers for active and passive smoking. Environ Health Perspect 2002; 110: 689–98.
- 13Lechner M, Moser B, Niederseer D et al. Gender and age specific differences in exhaled isoprene levels. Respir Physiol Neurobiol 2006; 154: 478–83.
- 14Phillips M, Cataneo RN, Greenberg J, Gunawardena R, Rahbari-Oskoui F. Increased oxidative stress in younger as well as in older humans. Clin Chim Acta 2003; 328: 83–6.
- 15Birken T, Schubert J, Miekisch W, Noldge-Schomburg G. A novel visually CO2 controlled alveolar breath sampling technique. Technol Health Care 2006; 14: 499–506.
- 16Deykin A, Massaro AF, Drazen JM, Israel E. Exhaled nitric oxide as a diagnostic test for asthma: online versus offline techniques and effect of flow rate. Am J Respir Crit Care Med 2002; 165: 1597–601.
- 17Robroeks CMHHT, Van Berkel JJBN, Dallinga JW et al. Metabolomics of volatile organic compounds in cystic fibrosis patients and controls. Pediatr Res 2010; 68: 75–80.
- 18Van Berkel JJ, Dallinga JW, Moller GM et al. Development of accurate classification method based on the analysis of volatile organic compounds from human exhaled air. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 861: 101–7.
- 19Lazar Z, Fens N, van der Maten J et al. Electronic nose breathprints are independent of acute changes in airway caliber in asthma. Sensors (Basel) 2010; 10: 9127–38.
- 20van der Schee MP, Fens N, Brinkman P et al. Effect of transportation and storage using sorbent tubes of exhaled breath samples on diagnostic accuracy of electronic nose analysis. J Breath Res 2013; 7: 016002.
- 21Fens N, Zwinderman AH, van der Schee MP et al. Exhaled breath profiling enables discrimination of chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2009; 180: 1076–82.
- 22Fens N, 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: 705–15.
- 23Dallinga JW, Robroeks CMHHT, Van Berkel JJBN et al. Volatile organic compounds in exhaled breath as a diagnostic tool for asthma in children. Clin Exp Allergy 2010; 40: 68–76.
- 24Caldeira M, Barros AS, Bilelo MJ, Parada A, Camara JS, Rocha SM. Profiling allergic asthma volatile metabolic patterns using a headspace-solid phase microextraction/gas chromatography based methodology. J Chromatogr A 2011; 1218: 3771–80.
- 25Caldeira M, Perestrelo R, Barros AS et al. Allergic asthma exhaled breath metabolome: a challenge for comprehensive two-dimensional gas chromatography. J Chromatogr A 2012; 1254: 87–97.
- 26Robroeks CM, van Berkel JJ, Jobsis Q et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J 2013; 42: 98–106.
- 27Van De Kant KDG, Van Berkel JJBN, Jobsis Q et al. Exhaled breath profiling in diagnosing wheezy preschool children. Eur Respir J 2013; 41: 183–8.
- 28Paff T, van der Schee MP, Daniels JMA et al. Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia. J Cyst Fibrosis 2013; Sep; 12(5): 454–60.
- 29Mutlu GM, Garey KW, Robbins RA, Danziger LH, Rubinstein I. Collection and analysis of exhaled breath condensate in humans. Am J Respir Crit Care Med 2001; 164: 731–7.
- 30Leung TF, Li CY, Yung E, Liu EKH, Lam CWK, Wong GWK. Clinical and technical factors affecting pH and other biomarkers in exhaled breath condensate. Pediatr Pulmonol 2006; 41: 87–94.
- 31Vaughan J, Ngamtrakulpanit L, Pajewski TN et al. Exhaled breath condensate pH is a robust and reproducible assay of airway acidity. Eur Respir J 2003; 22: 889–94.
- 32Paget-Brown AO, Ngamtrakulpanit L, Smith A et al. Normative data for pH of exhaled breath condensate. Chest 2006; 129: 426–30.
- 33Glowacka E, Jedynak-Wasowicz U, Sanak M, Lis G. Exhaled eicosanoid profiles in children with atopic asthma and healthy controls. Pediatr Pulmonol 2013; 48: 324–35.
- 34Horvath I, Hunt J, Barnes PJ et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 2005; 26: 523–48.
- 35Horvath I, de Jongste J. Exhaled biomarkers. Eur Resp Soc Monogr 2010; 49: 1–31.
- 36Thomas PS, Lowe AJ, Samarasinghe P 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: 419–42.
- 37Jobsis Q, Raatgeep HC, Schellekens SL, Hop WCJ, Hermans PWM, De Jongste JC. Hydrogen peroxide in exhaled air of healthy children: reference values. Eur Respir J 1998; 12: 483–5.
- 38Brooks SM, Haight RR, Gordon RL. Age does not affect airway pH and ammonia as determined by exhaled breath measurements. Lung 2006; 184: 195–200.
- 39Cunningham S, McColm JR, Ho LP, Greening AP, Marshall TG. Measurement of inflammatory markers in the breath condensate of children with cystic fibrosis. Eur Respir J 2000; 15: 955–7.
- 40Formanek W, Inci D, Lauener RP, Wildhaber JH, Frey U, Hall GL. Elevated nitrite in breath condensates of children with respiratory disease. Eur Respir J 2002; 19: 487–91.
- 41Cap P, Chladek J, Pehal F et al. Gas chromatography/mass spectrometry analysis of exhaled leukotrienes in asthmatic patients. Thorax 2004; 59: 465–70.
- 42Cruz MJ, Sanchez-Vidaurre S, Romero PV, Morell F, Munoz X. Impact of age on pH, 8-isoprostane, and nitrogen oxides in exhaled breath condensate. Chest 2009; 135: 462–7.
- 43Kotz D, van de Kant K, Jobsis Q, van Schayck CP. Effects of tobacco exposure on lung health and pulmonary biomarkers in young, healthy smokers aged 12-25 years: a systematic review. Expert Rev Respir Med 2007; 1: 403–18.
- 44Doniec Z, Nowak D, Tomalak W, Pisiewicz K, Kurzawa R. Passive smoking does not increase hydrogen peroxide (H2O 2) levels in exhaled breath condensate in 9-year-old healthy children. Pediatr Pulmonol 2005; 39: 41–5.
- 45Kullmann T, Barta I, Antus B, Horvath I. Drinking influences exhaled breath condensate acidity. Lung 2008; 186: 263–8.
- 46Barreto M, Villa MP, Olita C, Martella S, Ciabattoni G, Montuschi P. 8-Isoprostane in exhaled breath condensate and exercise-induced bronchoconstriction in asthmatic children and adolescents. Chest 2009; 135: 66–73.
- 47Bonsignore MR, La Grutta S, Cibella F et al. Effects of exercise training and montelukast in children with mild asthma. Med Sci Sports Exerc 2008; 40: 405–12.
- 48Alessio HM, Hagerman AE, Fulkerson BK, Ambrose J, Rice RE, Wiley RL. Generation of reactive oxygen species after exhaustive aerobic and isometric exercise. Med Sci Sports Exerc 2000; 32: 1576–81.
- 49Czebe K, Barta I, Antus B, Valyon M, Horvath I, Kullmann T. Influence of condensing equipment and temperature on exhaled breath condensate pH, total protein and leukotriene concentrations. Respir Med 2008; 102: 720–5.
- 50Rosias PP, Robroeks CM, Niemarkt HJ et al. Breath condenser coatings affect measurement of biomarkers in exhaled breath condensate. Eur Respir J 2006; 28: 1036–41.
- 51Tufvesson E, Bjermer L. Methodological improvements for measuring eicosanoids and cytokines in exhaled breath condensate. Respir Med 2006; 100: 34–8.
- 52Franklin P, Moeller A, Hall GL, Horak F Jr, Patterson H, Stick SM. Variability of nitric oxide metabolites in exhaled breath condensate. Respir Med 2006; 100: 123–9.
- 53McCafferty JB, Bradshaw TA, Tate S, Greening AP, Innes JA. Effects of breathing pattern and inspired air conditions on breath condensate volume, pH, nitrite, and protein concentrations. Thorax 2004; 59: 694–8.
- 54Muller WG, Morini F, Eaton S, Peters M, Jaffe A. Safety and feasibility of exhaled breath condensate collection in ventilated infants and children. Eur Respir J 2006; 28: 479–85.
- 55Vogelberg C, Wurfel C, Knoetzsch A, Kahlert A, Range U, Leupold W. Exhaled breath condensate pH in infants and children with acute and recurrent wheezy bronchitis. Pediatr Pulmonol 2007; 42: 1166–72.
- 56Effros RM, Biller J, Foss B et al. A simple method for estimating respiratory solute dilution in exhaled breath condensates. Am J Respir Crit Care Med 2003; 168: 1500–5.
- 57Dwyer TM. Sampling airway surface liquid: non-volatiles in the exhaled breath condensate. Lung 2004; 182: 241–50.
- 58Effros RM, Hoagland KW, Bosbous M et al. Dilution of respiratory solutes in exhaled condensates. Am J Respir Crit Care Med 2002; 165: 663–9.
- 59Esther CR Jr, Boysen G, Olsen BM et al. Mass spectrometric analysis of biomarkers and dilution markers in exhaled breath condensate reveals elevated purines in asthma and cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 2009; 296: L987–93.
- 60Prieto L, Ferrer A, Palop J, Domenech J, Llusar R, Rojas R. Differences in exhaled breath condensate pH measurements between samples obtained with two commercial devices. Respir Med 2007; 101: 1715–20.
- 61Vogelberg C, Kahlert A, Wurfel C et al. Exhaled breath condensate nitrite – methodological problems of sample collection. Med Sci Monit 2008; 14: CR416–22.
- 62Bloemen K, Van Den Heuvel R, Govarts E et al. A new approach to study exhaled proteins as potential biomarkers for asthma. Clin Exp Allergy 2011; 41: 346–56.
- 63Profita M, La Grutta S, Carpagnano E et al. Noninvasive methods for the detection of upper and lower airway inflammation in atopic children. J Allergy Clin Immunol 2006; 118: 1068–74.
- 64Carpagnano GE, Barnes PJ, Francis J, Wilson N, Bush A, Kharitonov SA. Breath condensate pH in children with cystic fibrosis and asthma: a new noninvasive marker of airway inflammation? Chest 2004; 125: 2005–10.
- 65Carraro S, Folesani G, Corradi M, Zanconato S, Gaston B, Baraldi E. Acid-base equilibrium in exhaled breath condensate of allergic asthmatic children. Allergy 2005; 60: 476–81.
- 66Brunetti L, Francavilla R, Tesse R et al. Exhaled breath condensate pH measurement in children with asthma, allergic rhinitis and atopic dermatitis. Pediatr Allergy Immunol 2006; 17: 422–7.
- 67Brunetti L, Francavilla R, Tesse R et al. Exhaled breath condensate cytokines and pH in pediatric asthma and atopic dermatitis. Allergy Asthma Proc 2008; 29: 461–7.
- 68Rosias PPR, Dompeling E, Dentener MA et al. Childhood asthma: exhaled markers of airway inflammation, asthma control score, and lung function tests. Pediatr Pulmonol 2004; 38: 107–14.
- 69MacGregor G, Ellis S, Andrews J et al. Breath condensate ammonium is lower in children with chronic asthma. Eur Respir J 2005; 26: 271–6.
- 70 Ratnawati, 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: 929–36.
- 71Nicolaou NC, Lowe LA, Murray CS, Woodcock A, Simpson A, Custovic A. Exhaled breath condensate pH and childhood asthma: unselected birth cohort study. Am J Respir Crit Care Med 2006; 174: 254–9.
- 72Kullmann T, Barta I, Lázár Z et al. Exhaled breath condensate pH standardised for CO2 partial pressure. Eur Respir J 2007; 29: 496–501.
- 73Robroeks CMHHT, Van De Kant KDG, Jobsis Q et al. Exhaled nitric oxide and biomarkers in exhaled breath condensate indicate the presence, severity and control of childhood asthma. Clin Exp Allergy 2007; 37: 1303–11.
- 74Bloemen K, Koppen G, Govarts E et al. Application of non-invasive biomarkers in a birth cohort follow-up in relation to respiratory health outcome. Biomarkers 2010; 15: 583–93.
- 75Van De Kant KD, Koers K, Rijkers GT et al. Can exhaled inflammatory markers predict the response to inhaled corticosteroids in wheezing preschool children? Am J Respir Crit Care Med 2011; 183: 1076–83.
- 76Zetterquist W, Marteus H, Hedlin G, Alving K. Increased exhaled nitrite in children with allergic asthma is not related to nitric oxide formation. Clin Respir J. 2008; 2: 166–74.
- 77Baraldi E, Giordano G, Pasquale MF et al. 3-Nitrotyrosine, a marker of nitrosative stress, is increased in breath condensate of allergic asthmatic children. Allergy Eur J Allergy Clin Immunol 2006; 61: 90–6.
- 78Bodini A, Peroni DG, Zardini F et al. Flunisolide decreases exhaled nitric oxide and nitrotyrosine levels in asthmatic children. Mediators Inflamm 2006; 2006: 31919.
- 79Zacharasiewicz A, Wilson N, Lex C et al. Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med 2005; 171: 1077–82.
- 80Straub DA, Ehmann R, Hall GL et al. Correlation of nitrites in breath condensates and lung function in asthmatic children. Pediatr Allergy Immunol 2004; 15: 20–5.
- 81Celio S, Troxler H, Durka SS et al. Free 3-nitrotyrosine in exhaled breath condensates of children fails as a marker for oxidative stress in stable cystic fibrosis and asthma. Nitric Oxide Biol Chem 2006; 15: 226–32.
- 82Caballero S, Martorell A, Escribano A, Belda J. Markers of airway inflammation in the exhaled breath condensate of preschool wheezers. J Invest Allergol Clin Immunol 2013; 23: 7–13.
- 83Horak F Jr, Moeller A, Singer F et al. Longitudinal monitoring of pediatric cystic fibrosis lung disease using nitrite in exhaled breath condensate. Pediatr Pulmonol 2007; 42: 1198–206.
- 84Jobsis Q, Raatgeep HC, Hermans PWM, De Jongste JC. Hydrogen peroxide in exhaled air is increased in stable asthmatic children. Eur Respir J 1997; 10: 519–21.
- 85Dohlman AW, Black HR, Royall JA. Expired breath hydrogen peroxide is a marker of acute airway inflammation in pediatric patients with asthma. Am Rev Respir Dis 1993; 148: 955–60.
- 86Caffarelli C, Calcinai E, Rinaldi L, Povesi Dascola C, Terracciano L, Corradi M. Hydrogen peroxide in exhaled breath condensate in asthmatic children during acute exacerbation and after treatment. Respiration. 2012; 84: 291–298.
- 87Trischler J, Merkel N, Konitzer S, Muller CM, Unverzagt S, Lex C. Fractionated breath condensate sampling: H(2)O(2) concentrations of the alveolar fraction may be related to asthma control in children. Respir Res 2012; 13: 14.
- 88Robroeks CMHHT, van Vliet D, Jobsis Q et al. Prediction of asthma exacerbations in children: results of a one-year prospective study. Clin Exp Allergy 2012; 42: 792–8.
- 89Latzin P, Griese M. Exhaled hydrogen peroxide, nitrite and nitric oxide in healthy children: decrease of hydrogen peroxide by atmospheric nitric oxide. Eur J Med Res 2002; 7: 353–8.
- 90Carraro S, Giordano G, Piacentini G et al. Asymmetric dimethylarginine (Adma) in exhaled breath condensate and serum of asthmatic children. Chest 2013; Aug; 144(2): 405–10.
- 91Dut R, Dizdar EA, Birben E et al. Oxidative stress and its determinants in the airways of children with asthma. Allergy 2008; 63: 1605–9.
- 92Corradi M, Folesani G, Andreoli R et al. Aldehydes and glutathione in exhaled breath condensate of children with asthma exacerbation. Am J Respir Crit Care Med 2003; 167: 395–9.
- 93Celik M, Tuncer A, Soyer OU, Sackesen C, Tanju Besler H, Kalayci O. Oxidative stress in the airways of children with asthma and allergic rhinitis. Pediatr Allergy Immunol. 2012; 23: 556–561.
- 94Shahid SK, Kharitonov SA, Wilson NM, Bush A, Barnes PJ. Exhaled 8-isoprostane in childhood asthma. Respir Res 2005; 6 Jul 21; 6: 79.
- 95Baraldi E, Carraro S, Alinovi R et al. Cysteinyl leukotrienes and 8-isoprostane in exhaled breath condensate of children with asthma exacerbations. Thorax 2003; 58: 505–9.
- 96Baraldi E, Ghiro L, Piovan V et al. Increased exhaled 8-isoprostane in childhood asthma. Chest 2003; 124: 25–31.
- 97Zanconato S, Carraro S, Corradi M et al. Leukotrienes and 8-isoprostane in exhaled breath condensate of children with stable and unstable asthma. J Allergy Clin Immunol 2004; 113: 257–63.
- 98Caballero Balanza S, Martorell Aragones A, Cerda Mir JC et al. Leukotriene B4 and 8-isoprostane in exhaled breath condensate of children with episodic and persistent asthma. J Investig Allergol Clin Immunol 2010; 20: 237–43.
- 99Carraro S, Cogo PE, Isak I et al. EIA and GC/MS analysis of 8-isoprostane in EBC of children with problematic asthma. Eur Respir J 2010; 35: 1364–9.
- 100Hasan RA, O'Brien E, Mancuso P. Lipoxin A(4) and 8-isoprostane in the exhaled breath condensate of children hospitalized for status asthmaticus. Pediatr Crit Care Med 2012; 13: 141–5.
- 101Montuschi P, Corradi M, Ciabattoni G, Nightingale J, Kharitonov SA, Barnes PJ. Increased 8-isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. Am J Respir Crit Care Med 1999; 160: 216–20.
- 102Mondino C, Ciabattoni G, Koch P et al. Effects of inhaled corticosteroids on exhaled leukotrienes and prostanoids in asthmatic children. J Allergy Clin Immunol 2004; 114: 761–7.
- 103Shibata A, Katsunuma T, Tomikawa M et al. Increased leukotriene E4 in the exhaled breath condensate of children with mild asthma. Chest 2006; 130: 1718–22.
- 104Carraro S, Corradi M, Zanconato S et al. Exhaled breath condensate cysteinyl leukotrienes are increased in children with exercise-induced bronchoconstriction. J Allergy Clin Immunol 2005; 115: 764–70.
- 105Csoma Z, Kharitonov SA, Balint B, Bush A, Wilson NM, Barnes PJ. Increased leukotrienes in exhaled breath condensate in childhood asthma. Am J Respir Crit Care Med 2002; 166: 1345–9.
- 106Debley JS, Hallstrand TS, Monge T, Ohanian A, Redding GJ, Zimmerman J. Methods to improve measurement of cysteinyl leukotrienes in exhaled breath condensate from subjects with asthma and healthy controls. J Allergy Clin Immunol 2007; 120: 1216–7.
- 107Kielbasa B, Moeller A, Sanak M et al. Eicosanoids in exhaled breath condensates in the assessment of childhood asthma. Pediatr Allergy Immunol 2008; 19: 660–9.
- 108Montuschi P, Mondino C, Koch P, Barnes PJ, Ciabattoni G. Effects of a leukotriene receptor antagonist on exhaled leukotriene E4 and prostanoids in children with asthma. J Allergy Clin Immunol 2006; 118: 347–53.
- 109Steiss JO, Rudloff S, Landmann E, Ruckes-Nilges C, Zimmer KP, Lindemann H. Effect of inhaled corticosteroid treatment on exhaled breath condensate leukotriene E4 in children with mild asthma. Allergy Asthma Proc 2008; 29: 371–5.
- 110Sachs-Olsen C, Sanak M, Lang AM, Gielicz A, Mowinckel P, Lodrup Carlsen KC, Carlsen KH, Szczeklik A. Eoxins: a new inflammatory pathway in childhood asthma. J Allergy Clin Immunol. 2010; 126: 859–867.e859.
- 111Debley JS, Cochrane ES, Redding GJ, Carter ER. Lung function and biomarkers of airway inflammation during and after hospitalization for acute exacerbations of childhood asthma associated with viral respiratory symptoms. Ann Allergy Asthma Immunol 2012; 109: 114–120.e112.
- 112Lex C, Zacharasiewicz A, Payne DNR, Wilson NM, Nicholson AG, Kharitonov SA, Barnes PJ, Bush A. Exhaled breath condensate cysteinyl leukotrienes and airway remodeling in childhood asthma: a pilot study. Respir Res. 2006; Apr 7; 7: 63.
- 113Montuschi 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 Oct 19; 6: 119.
- 114Karakoc GB, Yukselen A, Yilmaz M, Altintas DU, Kendirli SG. Exhaled breath condensate MMP-9 level and its relationship with asthma severity and interleukin-4/10 levels in children. Ann Allergy Asthma Immunol 2012; 108: 300–4.
- 115Leung TF, Wong GW, Ko FW, Lam CW, Fok TF. Increased macrophage-derived chemokine in exhaled breath condensate and plasma from children with asthma. Clin Exp Allergy 2004; 34: 786–91.
- 116Shahid SK, Kharitonov SA, Wilson NM, Bush A, Barnes PJ. Increased interleukin-4 and decreased interferon-gamma in exhaled breath condensate of children with asthma. Am J Respir Crit Care Med 2002; 165: 1290–3.
- 117van de Kant KD, Klaassen EM, Jobsis Q et al. Wheezing in preschool children is associated with increased levels of cytokines/chemokines in exhaled breath condensate. J Allergy Clin Immunol 2010; 126: 669–71.
- 118van de Kant KDG, Jansen MA, Klaassen EMM et al. Elevated inflammatory markers at preschool age precede persistent wheezing at school age. Pediatr Allergy Immunol 2012; 23: 259–64.
- 119Robroeks CMHHT, Rijkers GT, Jobsis Q et al. Increased cytokines, chemokines and soluble adhesion molecules in exhaled breath condensate of asthmatic children. Clin Exp Allergy 2010; 40: 77–84.
- 120Klaassen EMM, Van De Kant KDG, Jobsis Q et al. Symptoms, but not a biomarker response to inhaled corticosteroids, predict asthma in preschool children with recurrent wheeze. Mediators Inflamm 2012; 2012:Volume 2012, Article ID 162571, 7 pages doi:10.1155/2012/162571.
- 121Bodini A, D'Orazio C, Peroni D et al. Biomarkers of neutrophilic inflammation in exhaled air of cystic fibrosis children with bacterial airway infections. Pediatr Pulmonol 2005; 40: 494–9.
- 122Bodini A, D'Orazio C, Peroni DG et al. IL-8 and pH values in exhaled condensate after antibiotics in cystic fibrosis children. Int J Immunopathol Pharmacol 2007; 20: 467–72.
- 123Newport S, Amin N, Dozor AJ. Exhaled breath condensate pH and ammonia in cystic fibrosis and response to treatment of acute pulmonary exacerbations. Pediatr Pulmonol 2009; 44: 866–72.
- 124Ojoo JC, Mulrennan SA, Kastelik JA, Morice AH, Redington AE. Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma and in cystic fibrosis. Thorax 2005; 60: 22–6.
- 125Robroeks CMHHT, Rosias PPR, Van Vliet D et al. Biomarkers in exhaled breath condensate indicate presence and severity of cystic fibrosis in children. Pediatr Allergy Immunol 2008; 19: 652–9.
- 126Zetterquist W, Marteus H, Kalm-Stephens P et al. Oral bacteria–the missing link to ambiguous findings of exhaled nitrogen oxides in cystic fibrosis. Respir Med 2009; 103: 187–93.
- 127Marteus H, Tornberg DC, Weitzberg E, Schedin U, Alving K. Origin of nitrite and nitrate in nasal and exhaled breath condensate and relation to nitric oxide formation. Thorax 2005; 60: 219–25.
- 128Jobsis Q, Raatgeep HC, Schellekens SL, Kroesbergen A, Hop WCJ, De Jongste JC. Hydrogen peroxide and nitric oxide in exhaled air of children with cystic fibrosis during antibiotic treatment. Eur Respir J 2000; 16: 95–100.
- 129Rosias PPR, Den Hartog GJM, Robroeks CMHHT et al. Free radicals in exhaled breath condensate in cystic fibrosis and healthy subjects. Free Radic Res 2006; 40: 901–9.
- 130Lucidi V, Ciabattoni G, Bella S, Barnes PJ, Montuschi P. Exhaled 8-isoprostane and prostaglandin E2 in patients with stable and unstable cystic fibrosis. Free Radic Biol Med 2008; 45: 913–9.
- 131Esther CR Jr, Olsen BM, Lin FC, Fine J, Boucher RC. Exhaled breath condensate adenosine tracks lung function changes in cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 2013; 304: L504–9.
- 132Karakoc GB, Inal A, Yilmaz M, Altintas DU, Kendirli SG. Exhaled breath condensate MMP-9 levels in children with bronchiectasis. Pediatr Pulmonol 2009; 44: 1010–6.
- 133Zihlif N, Paraskakis E, Tripoli C, Lex C, Bush A. Markers of airway inflammation in primary ciliary dyskinesia studied using exhaled breath condensate. Pediatr Pulmonol 2006; 41: 509–14.
- 134Filippone M, Bonetto G, Corradi M, Frigo AC, Baraldi E. Evidence of unexpected oxidative stress in airways of adolescents born very pre-term. Eur Respir J 2012; 40: 1253–9.
- 135Carraro S, Andreola B, Alinovi R et al. Exhaled leukotriene B4 in children with community acquired pneumonia. Pediatr Pulmonol 2008; 43: 982–6.
- 136Carraro S, Giordano G, Reniero F et al. Asthma severity in childhood and metabolomic profiling of breath condensate. Allergy 2013; 68: 110–7.
- 137Greenwald R, Fitzpatrick AM, Gaston B, Marozkina NV, Erzurum S, Teague WG. Breath formate is a marker of airway S-nitrosothiol depletion in severe asthma. PLoS One 2010: 5: Jul 30; 5(7): e11919.
- 138Montuschi P, Paris D, Melck D et al. NMR spectroscopy metabolomic profiling of exhaled breath condensate in patients with stable and unstable cystic fibrosis. Thorax 2012; 67: 222–8.
- 139von Jagwitz M, Pessler F, Akmatov M, Li J, Range U, Vogelberg C. Reduced breath condensate pH in asymptomatic children with prior wheezing as a risk factor for asthma. J Allergy Clin Immunol 2011; 128: 50–5.
- 140Walsh BK, Mackey DJ, Pajewski T, Yu Y, Gaston BM, Hunt JF. Exhaled-breath condensate pH can be safely and continuously monitored in mechanically ventilated patients. Respir Care 2006; 51: 1125–31.
- 141Dodig S, Cepelak I, Vlasic Z, Topic RZ, Banovic S. Urates in exhaled breath condensate of children with asthma. Lab Med 2010; 41: 728–30.
- 142Bodini A, Peroni D, Vicentini L et al. Exhaled breath condensate eicosanoids and sputum eosinophils in asthmatic children: a pilot study. Pediatr Allergy Immunol 2004; 15: 26–31.
- 143Profita M, Montuschi P, Bonanno A et al. Novel perspectives in the detection of oral and nasal oxidative stress and inflammation in pediatric united airway diseases. Int J Immunopathol Pharmacol 2010; 23: 1211–9.
- 144Leung TF, Wong GWK, Ko FWS, Lam CWK, Fok TF. Clinical and atopic parameters and airway inflammatory markers in childhood asthma: a factor analysis. Thorax 2005; 60: 822–6.
- 145van de Kant KD, Klaassen EM, van Aerde KJ et al. Impact of bacterial colonization on exhaled inflammatory markers in wheezing preschool children. J Breath Res 2012; 6: 046001.
- 146Van De Kant K, Jobsis Q, Klaassen E et al. Wheezing in preschool children is associated with increased levels of inflammatory markers in exhaled breath condensate. Allergy Eur J Allergy Clin Immunol 2010; 65: 16–7.
- 147Robroeks CMHHT, Jobsis Q, Damoiseaux JGMC et al. Cytokines in exhaled breath condensate of children with asthma and cystic fibrosis. Ann Allergy Asthma Immunol 2006; 96: 349–55.
- 148Leung TF, Wong GWK, Ko FWS et al. Analysis of growth factors and inflammatory cytokines in exhaled breath condensate from asthmatic children. Int Arch Allergy Immunol 2005; 137: 66–72.
- 149Esther CR Jr, Alexis NE, Clas ML et al. Extracellular purines are biomarkers of neutrophilic airway inflammation. Eur Respir J 2008; 31: 949–56.
- 150Dodig S, Vlasic Z, Cepelak I, Zrinski Topic R, Turkalj M, Nogalo B. Magnesium and calcium in exhaled breath condensate of children with asthma and gastroesophageal reflux disease. J Clin Lab Anal 2009; 23: 34–39.
- 151Delfino RJ, Gong H, Linn WS, Hu Y, Pellizzari ED. Respiratory symptoms and peak expiratory flow in children with asthma in relation to volatile organic compounds in exhaled breath and ambient air. J Expo Anal Environ Epidemiol 2003 Sep 13; 13(5): 348–63.
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