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Current Respiratory Medicine Reviews

Editor-in-Chief

ISSN (Print): 1573-398X
ISSN (Online): 1875-6387

Review Article

Towards Precision Medicine in Pediatric Severe Asthma: An Update on Current and Emerging Biomarkers

Author(s): Amelia Licari, Riccardo Castagnoli, Enrica Manca, Martina Votto, Alexander Michev and Gian Luigi Marseglia*

Volume 15, Issue 3, 2019

Page: [187 - 194] Pages: 8

DOI: 10.2174/1573398X15666190423150227

Abstract

Pediatric severe asthma is actually considered a rare disease with a heterogeneous nature. Recent cohort studies focusing on children with severe asthma identified different clinical presentations (phenotypes) and underlying pathophysiological mechanisms (endotypes). Phenotyping and endotyping asthma represent the current approach to patients with severe asthma and consist in characterizing objectively measurable and non-invasive indicators (biomarkers) capable of orienting diagnosis, management and personalized treatment, as advocated by the Precision Medicine approach. The aim of this review is to provide a practical overview of current and emerging biomarkers in pediatric severe asthma.

Keywords: Biomarkers, eosinophils, fractional exhaled nitric oxide, IgE, neutrophils, pediatric, periostin, severe asthma.

Graphical Abstract
[1]
Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43(2): 343-73.
[http://dx.doi.org/10.1183/09031936.00202013] [PMID: 24337046]
[2]
Bush A, Fleming L, Saglani S. Severe asthma in children. Respirology 2017; 22(5): 886-97.
[http://dx.doi.org/10.1111/resp.13085] [PMID: 28543931]
[3]
Licari A, Manca E, Rispoli GA, Mannarino S, Pelizzo G, Marseglia GL. Congenital vascular rings: A clinical challenge for the pediatrician. Pediatr Pulmonol 2015; 50(5): 511-24.
[http://dx.doi.org/10.1002/ppul.23152] [PMID: 25604054]
[4]
Licari A, Castagnoli R, Denicolò CF, Rossini L, Marseglia A, Marseglia GL. The nose and the lung: United airway disease? Front Pediatr 2017; 5: 44.
[http://dx.doi.org/10.3389/fped.2017.00044] [PMID: 28316969]
[5]
Licari A, Brambilla I, De Filippo M, Poddighe D, Castagnoli R, Marseglia GL. The role of upper airway pathology as a co-morbidity in severe asthma. Expert Rev Respir Med 2017; 11(11): 855-65.
[http://dx.doi.org/10.1080/17476348.2017.1381564] [PMID: 28918658]
[6]
Licari A, Caimmi S, Bosa L, Marseglia A, Marseglia GL, Caimmi D. Rhinosinusitis and asthma: A very long engagement. Int J Immunopathol Pharmacol 2014; 27(4): 499-508.
[http://dx.doi.org/10.1177/039463201402700405] [PMID: 25572729]
[7]
Licari A, Brambilla I, Marseglia A, De Filippo M, Paganelli V, Marseglia GL. Difficult vs. severe asthma: Definition and limits of asthma control in the pediatric population. Front Pediatr 2018; 6: 170.
[http://dx.doi.org/10.3389/fped.2018.00170] [PMID: 29971223]
[8]
Chipps BE, Parikh NG, Maharaj SK. Severe asthma in children. Curr Allergy Asthma Rep 2017; 17(4): 21.
[http://dx.doi.org/10.1007/s11882-017-0688-z] [PMID: 28353215]
[9]
Ramratnam SK, Bacharier LB, Guilbert TW. Severe asthma in children. J Allergy Clin Immunol Pract 2017; 5(4): 889-98.
[http://dx.doi.org/10.1016/j.jaip.2017.04.031] [PMID: 28689839]
[10]
Chipps BE, Haselkorn T, Rosén K, Mink DR, Trzaskoma BL, Luskin AT. Asthma exacerbations and triggers in children in TENOR: impact on quality of life. J Allergy Clin Immunol Pract 2018; 6(1): 169-176.e2.
[http://dx.doi.org/10.1016/j.jaip.2017.05.027] [PMID: 28803186]
[11]
Montalbano L, Cilluffo G, Montella S, et al. Neuropsychological and Quality of life (QoL) assessment in children with severe asthma (SA) and moderate persistent asthma (MPA): a case-control study.Proceedings of the ERS International Congress. 2018 Sep; 15-9. Paris, France 2018. PA4674
[http://dx.doi.org/10.1183/13993003.congress-2018.PA4674]
[12]
Tai A, Tran H, Roberts M, Clarke N, Wilson J, Robertson CF. The association between childhood asthma and adult chronic obstructive pulmonary disease. Thorax 2014; 69(9): 805-10.
[http://dx.doi.org/10.1136/thoraxjnl-2013-204815] [PMID: 24646659]
[13]
Fitzpatrick AM. Severe asthma in children: lessons learned and future directions. J Allergy Clin Immunol Pract 2016; 4(1): 11-9.
[http://dx.doi.org/10.1016/j.jaip.2015.10.008] [PMID: 26772923]
[14]
Fleming L, Murray C, Bansal AT, et al. U-BIOPRED Study Group. The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts. Eur Respir J 2015; 46(5): 1322-33.
[http://dx.doi.org/10.1183/13993003.00780-2015] [PMID: 26405287]
[15]
Licari A, Castagnoli R, Brambilla I, et al. Asthma endotyping and biomarkers in childhood asthma. Pediatr Allergy Immunol Pulmonol 2018; 31(2): 44-55.
[http://dx.doi.org/10.1089/ped.2018.0886] [PMID: 30069422]
[16]
Licari A, Castagnoli R, Brambilla I, et al. New approaches for identifying and testing potential new anti-asthma agents. Expert Opin Drug Discov 2018; 13(1): 51-63.
[http://dx.doi.org/10.1080/17460441.2018.1396315] [PMID: 29077521]
[17]
Samitas K, Zervas E, Gaga M. T2-low asthma: Current approach to diagnosis and therapy. Curr Opin Pulm Med 2017; 23(1): 48-55.
[http://dx.doi.org/10.1097/MCP.0000000000000342] [PMID: 27798418]
[18]
Licari A, Marseglia GL. Current and future challenges in pediatric severe asthma. Curr Med Res Opin 2018; 34(5): 943-4.
[http://dx.doi.org/10.1080/03007995.2018.1439463] [PMID: 29421950]
[19]
Just J, Bourgoin-Heck M, Amat F. Clinical phenotypes in asthma during childhood. Clin Exp Allergy 2017; 47(7): 848-55.
[http://dx.doi.org/10.1111/cea.12939] [PMID: 28422351]
[20]
Teague WG, Phillips BR, Fahy JV, et al. Baseline features of the severe asthma research program (SARP III) cohort: Differences with age. J Allergy Clin Immunol Pract 2018; 6(2): 545-554.e4.
[http://dx.doi.org/10.1016/j.jaip.2017.05.032] [PMID: 28866107]
[21]
Robinson D, Humbert M, Buhl R, et al. Revisiting Type 2-high and Type 2-low airway inflammation in asthma: Current knowledge and therapeutic implications. Clin Exp Allergy 2017; 47(2): 161-75.
[http://dx.doi.org/10.1111/cea.12880] [PMID: 28036144]
[22]
Hirose K, Iwata A, Tamachi T, Nakajima H. Allergic airway inflammation: key players beyond the Th2 cell pathway. Immunol Rev 2017; 278(1): 145-61.
[http://dx.doi.org/10.1111/imr.12540] [PMID: 28658544]
[23]
Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol 2015; 16(1): 45-56.
[http://dx.doi.org/10.1038/ni.3049] [PMID: 25521684]
[24]
Agache I, Rogozea L. Asthma biomarkers: Do they bring precision medicine closer to the clinic? Allergy Asthma Immunol Res 2017; 9(6): 466-76.
[http://dx.doi.org/10.4168/aair.2017.9.6.466] [PMID: 28913985]
[25]
Carr TF, Kraft M. Use of biomarkers to identify phenotypes and endotypes of severe asthma. Ann Allergy Asthma Immunol 2018; 1081-1206(18): 30615-X.
[26]
Bossley CJ, Fleming L, Gupta A, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol 2012; 129(4): 974-82.e13.
[http://dx.doi.org/10.1016/j.jaci.2012.01.059] [PMID: 22385633]
[27]
Saglani S, Lloyd CM. Eosinophils in the pathogenesis of paediatric severe asthma. Curr Opin Allergy Clin Immunol 2014; 14(2): 143-8.
[http://dx.doi.org/10.1097/ACI.0000000000000045] [PMID: 24500296]
[28]
Nair P. What is an “eosinophilic phenotype” of asthma? J Allergy Clin Immunol 2013; 132(1): 81-3.
[http://dx.doi.org/10.1016/j.jaci.2013.05.007] [PMID: 23727039]
[29]
Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): A multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380(9842): 651-9.
[http://dx.doi.org/10.1016/S0140-6736(12)60988-X] [PMID: 22901886]
[30]
Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med 2013; 13: 11.
[http://dx.doi.org/10.1186/1471-2466-13-11] [PMID: 23442497]
[31]
Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: Eosinophilic airway inflammation in nonallergic asthma. Nat Med 2013; 19(8): 977-9.
[http://dx.doi.org/10.1038/nm.3300] [PMID: 23921745]
[32]
Casciano J, Krishnan JA, Small MB, et al. Value of peripheral blood eosinophil markers to predict severity of asthma. BMC Pulm Med 2016; 16(1): 109.
[http://dx.doi.org/10.1186/s12890-016-0271-8] [PMID: 27473851]
[33]
Price D, Wilson AM, Chisholm A, et al. Predicting frequent asthma exacerbations using blood eosinophil count and other patient data routinely available in clinical practice. J Asthma Allergy 2016; 9: 1-12.
[PMID: 26793004]
[34]
Cowan DC, Taylor DR, Peterson LE, et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 2015; 135(4): 877-83.e1.
[http://dx.doi.org/10.1016/j.jaci.2014.10.026] [PMID: 25488689]
[35]
Fitzpatrick AM, Jackson DJ, Mauger DT, et al. NIH/NHLBI AsthmaNet. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol 2016; 138(6): 1608-1618.e12.
[http://dx.doi.org/10.1016/j.jaci.2016.09.028] [PMID: 27777180]
[36]
Licari A, Castagnoli R, Panfili E, Marseglia A, Brambilla I, Marseglia GL. An Update on Anti-IgE Therapy in Pediatric Respiratory Diseases. Curr Respir Med Rev 2017; 13(1): 22-9.
[http://dx.doi.org/10.2174/1573398X13666170616110738] [PMID: 29290750]
[37]
Poddighe D, Brambilla I, Licari A, Marseglia GL. Omalizumab in the therapy of pediatric asthma. Recent Pat Inflamm Allergy Drug Discov 2018; 12(2): 103-9.
[http://dx.doi.org/10.2174/1872213X12666180430161351] [PMID: 29714140]
[38]
Massanari M, Holgate ST, Busse WW, Jimenez P, Kianifard F, Zeldin R. Effect of omalizumab on peripheral blood eosinophilia in allergic asthma. Respir Med 2010; 104(2): 188-96.
[http://dx.doi.org/10.1016/j.rmed.2009.09.011] [PMID: 19846286]
[39]
Busse W, Spector S, Rosén K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol 2013; 132(2): 485-6.e11.
[http://dx.doi.org/10.1016/j.jaci.2013.02.032] [PMID: 23591271]
[40]
Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013; 187(8): 804-11.
[http://dx.doi.org/10.1164/rccm.201208-1414OC] [PMID: 23471469]
[41]
Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med 2016; 4(7): 549-56.
[http://dx.doi.org/10.1016/S2213-2600(16)30031-5] [PMID: 27177493]
[42]
Yancey SW, Keene ON, Albers FC, et al. Biomarkers for severe eosinophilic asthma. J Allergy Clin Immunol 2017; 140(6): 1509-18.
[http://dx.doi.org/10.1016/j.jaci.2017.10.005] [PMID: 29221581]
[43]
Mukherjee M, Aleman Paramo F, Kjarsgaard M, et al. Weight-adjusted Intravenous Reslizumab in Severe Asthma with Inadequate Response to Fixed-Dose Subcutaneous Mepolizumab. Am J Respir Crit Care Med 2018; 197(1): 38-46.
[http://dx.doi.org/10.1164/rccm.201707-1323OC] [PMID: 28915080]
[44]
Ullmann N, Bossley CJ, Fleming L, Silvestri M, Bush A, Saglani S. Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma. Allergy 2013; 68(3): 402-6.
[http://dx.doi.org/10.1111/all.12101] [PMID: 23347007]
[45]
Wagener AH, de Nijs SB, Lutter R, et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax 2015; 70(2): 115-20.
[http://dx.doi.org/10.1136/thoraxjnl-2014-205634] [PMID: 25422384]
[46]
Vizmanos-Lamotte G, Moreno-Galdó A, Muñoz X, Gómez-Ollés S, Gartner S, Cruz MJ. Induced sputum cell count and cytokine profile in atopic and non-atopic children with asthma. Pediatr Pulmonol 2013; 48(11): 1062-9.
[http://dx.doi.org/10.1002/ppul.22769] [PMID: 23401467]
[47]
Toyran M, Bakirtas A, Dogruman-Al F, Turktas I. Airway inflammation and bronchial hyperreactivity in steroid naive children with intermittent and mild persistent asthma. Pediatr Pulmonol 2014; 49(2): 140-7.
[http://dx.doi.org/10.1002/ppul.22810] [PMID: 23798479]
[48]
Woodruff PG, Khashayar R, Lazarus SC, et al. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J Allergy Clin Immunol 2001; 108(5): 753-8.
[http://dx.doi.org/10.1067/mai.2001.119411] [PMID: 11692100]
[49]
Hastie AT, Moore WC, Meyers DA, et al. National Heart, Lung, and Blood Institute Severe Asthma Research Program. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 2010; 125(5): 1028-1036.e13.
[http://dx.doi.org/10.1016/j.jaci.2010.02.008] [PMID: 20398920]
[50]
Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med 2000; 161(1): 64-72.
[http://dx.doi.org/10.1164/ajrccm.161.1.9809100] [PMID: 10619799]
[51]
Bjerregaard A, Laing IA, Backer V, et al. High fractional exhaled nitric oxide and sputum eosinophils are associated with an increased risk of future virus-induced exacerbations: A prospective cohort study. Clin Exp Allergy 2017; 47(8): 1007-13.
[http://dx.doi.org/10.1111/cea.12935] [PMID: 28390083]
[52]
van Rensen EL, Straathof KC, Veselic-Charvat MA, Zwinderman AH, Bel EH, Sterk PJ. Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax 1999; 54(5): 403-8.
[http://dx.doi.org/10.1136/thx.54.5.403] [PMID: 10212103]
[53]
Pizzichini MM, Pizzichini E, Clelland L, et al. Sputum in severe exacerbations of asthma: Kinetics of inflammatory indices after prednisone treatment. Am J Respir Crit Care Med 1997; 155(5): 1501-8.
[http://dx.doi.org/10.1164/ajrccm.155.5.9154849] [PMID: 9154849]
[54]
Fleming L, Wilson N, Regamey N, Bush A. Use of sputum eosinophil counts to guide management in children with severe asthma. Thorax 2012; 67(3): 193-8.
[http://dx.doi.org/10.1136/thx.2010.156836] [PMID: 21825081]
[55]
Petsky HL, Li A, Chang AB. Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev 2017. 8CD005603
[http://dx.doi.org/10.1002/14651858.CD005603.pub3] [PMID: 28837221]
[56]
Ciprandi G, Marseglia GL, Castagnoli R, et al. From IgE to clinical trials of allergic rhinitis. Expert Rev Clin Immunol 2015; 11(12): 1321-33.
[http://dx.doi.org/10.1586/1744666X.2015.1086645] [PMID: 26358006]
[57]
Lemanske RF Jr. The childhood origins of asthma (COAST) study. Pediatr Allergy Immunol 2002; 13(s15)(Suppl. 15): 38-43.
[http://dx.doi.org/10.1034/j.1399-3038.13.s.15.8.x] [PMID: 12688623]
[58]
Szefler SJ, Wenzel S, Brown R, et al. Asthma outcomes: biomarkers. J Allergy Clin Immunol 2012; 129(3)(Suppl.): S9-S23.
[http://dx.doi.org/10.1016/j.jaci.2011.12.979] [PMID: 22386512]
[59]
Licari A, Marseglia A, Caimmi S, et al. Omalizumab in children. Paediatr Drugs 2014; 16(6): 491-502.
[http://dx.doi.org/10.1007/s40272-014-0107-z] [PMID: 25404353]
[60]
Licari A, Marseglia G, Castagnoli R, Marseglia A, Ciprandi G. The discovery and development of omalizumab for the treatment of asthma. Expert Opin Drug Discov 2015; 10(9): 1033-42.
[http://dx.doi.org/10.1517/17460441.2015.1048220] [PMID: 25979110]
[61]
Licari A, Castagnoli R, Denicolò C, et al. Omalizumab in childhood asthma italian study group. omalizumab in children with severe allergic asthma: The italian real-life experience. Curr Respir Med Rev 2017; 13(1): 36-42.
[http://dx.doi.org/10.2174/1573398X13666170426094536] [PMID: 29213221]
[62]
Chapurlat RD, Confavreux CB. Novel biological markers of bone: From bone metabolism to bone physiology. Rheumatology (Oxford) 2016; 55(10): 1714-25.
[http://dx.doi.org/10.1093/rheumatology/kev410] [PMID: 26790456]
[63]
Bobolea I, Barranco P, Del Pozo V, et al. Sputum periostin in patients with different severe asthma phenotypes. Allergy 2015; 70(5): 540-6.
[http://dx.doi.org/10.1111/all.12580] [PMID: 25631525]
[64]
Jia G, Erickson RW, Choy DF, et al. Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) Study Group. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 2012; 130(3): 647-654.e10.
[http://dx.doi.org/10.1016/j.jaci.2012.06.025] [PMID: 22857879]
[65]
Sidhu SS, Yuan S, Innes AL, et al. Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci USA 2010; 107(32): 14170-5.
[http://dx.doi.org/10.1073/pnas.1009426107] [PMID: 20660732]
[66]
Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018; 378(26): 2486-96.
[http://dx.doi.org/10.1056/NEJMoa1804092] [PMID: 29782217]
[67]
Manka LA, Wechsler ME. Selecting the Right Biologic for Your Patients with Severe Asthma. Ann Allergy Asthma Immunol 2018 Jul; 261081-1206(18): 30619-7.
[http://dx.doi.org/10.1016/j.anai.2018.07.033]
[68]
Maxfield AZ, Landegger LD, Brook CD, et al. Periostin as a biomarker for nasal polyps in chronic rhinosinusitis. Otolaryngol Head Neck Surg 2018; 158(1): 181-6.
[http://dx.doi.org/10.1177/0194599817737967] [PMID: 29040053]
[69]
Sung M, Lee KS, Ha EG, et al. An association of periostin levels with the severity and chronicity of atopic dermatitis in children. Pediatr Allergy Immunol 2017; 28(6): 543-50.
[http://dx.doi.org/10.1111/pai.12744] [PMID: 28631851]
[70]
James A, Hedlin G. Biomarkers for the phenotyping and monitoring of asthma in children. Curr Treat Options Allergy 2016; 3(4): 439-52.
[http://dx.doi.org/10.1007/s40521-016-0106-0] [PMID: 27942431]
[71]
Song JS, You JS, Jeong SI, et al. Serum periostin levels correlate with airway hyper-responsiveness to methacholine and mannitol in children with asthma. Allergy 2015; 70(6): 674-81.
[http://dx.doi.org/10.1111/all.12599] [PMID: 25703927]
[72]
Inoue T, Akashi K, Watanabe M, et al. Periostin as a biomarker for the diagnosis of pediatric asthma. Pediatr Allergy Immunol 2016; 27(5): 521-6.
[http://dx.doi.org/10.1111/pai.12575] [PMID: 27062336]
[73]
Baraldi E, de Jongste JC. European Respiratory Society/American Thoracic Society (ERS/ATS) Task Force. Measurement of exhaled nitric oxide in children, 2001. Eur Respir J 2002; 20(1): 223-37.
[http://dx.doi.org/10.1183/09031936.02.00293102] [PMID: 12166573]
[74]
Ferraro V, Carraro S, Bozzetto S, Zanconato S, Baraldi E. Exhaled biomarkers in childhood asthma: old and new approaches. Asthma Res Pract 2018; 4: 9.
[http://dx.doi.org/10.1186/s40733-018-0045-6] [PMID: 30094051]
[75]
Baraldi E, Scollo M, Zaramella C, Zanconato S, Zacchello F. A simple flow-driven method for online measurement of exhaled NO starting at the age of 4 to 5 years. Am J Respir Crit Care Med 2000; 162(5): 1828-32.
[http://dx.doi.org/10.1164/ajrccm.162.5.2002014] [PMID: 11069821]
[76]
Dweik RA, Boggs PB, Erzurum SC, 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(5): 602-15.
[http://dx.doi.org/10.1164/rccm.9120-11ST] [PMID: 21885636]
[77]
Pijnenburg MW, De Jongste JC. Exhaled nitric oxide in childhood asthma: a review. Clin Exp Allergy 2008; 38(2): 246-59.
[http://dx.doi.org/10.1111/j.1365-2222.2007.02897.x] [PMID: 18076708]
[78]
Gabriele C, Jaddoe VW, van Mastrigt E, et al. Exhaled nitric oxide and the risk of wheezing in infancy: the Generation R Study. Eur Respir J 2012; 39(3): 567-72.
[http://dx.doi.org/10.1183/09031936.00151010] [PMID: 21920894]
[79]
Kotaniemi-Syrjänen A, Malmberg LP, Malmström K, Pelkonen AS, Mäkelä MJ. Factors associated with elevated exhaled nitric oxide fraction in infants with recurrent respiratory symptoms. Eur Respir J 2013; 41(1): 189-94.
[http://dx.doi.org/10.1183/09031936.00019811] [PMID: 22743669]
[80]
Fang LC, Shyur SD, Wang JY, Kao YH, Yang CH, Yu YT. Exhaled nitric oxide helps discriminating asthmatic children with and without positive specific IgE to aero-allergens. Asian Pac J Allergy Immunol 2017.
[http://dx.doi.org/10.12932/AP-270717-0126] [PMID: 29223148]
[81]
Spahn JD, Malka J, Szefler SJ. Current application of exhaled nitric oxide in clinical practice. J Allergy Clin Immunol 2016; 138(5): 1296-8.
[http://dx.doi.org/10.1016/j.jaci.2016.09.002] [PMID: 27664377]
[82]
Gomersal T, Harnan S, Essat M, et al. A systematic review of fractional exhaled nitric oxide in the routine management of childhood asthma. Pediatr Pulmonol 2016; 51(3): 316-28.
[http://dx.doi.org/10.1002/ppul.23371] [PMID: 26829581]
[83]
Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev 2016; 11 CD011439
[http://dx.doi.org/10.1002/14651858.CD011439.pub2] [PMID: 27825189]
[84]
Carraro S, Baraldi E. Exhaled breath condensate in children: present knowledge and future prospects. J Breath Res 2008; 2(3) 037003
[http://dx.doi.org/10.1088/1752-7155/2/3/037003] [PMID: 21386164]
[85]
Horváth I, Barnes PJ, Loukides S, et al. A European Respiratory Society technical standard: exhaled biomarkers in lung disease. Eur Respir J 2017; 49(4) 1600965
[http://dx.doi.org/10.1183/13993003.00965-2016] [PMID: 28446552]
[86]
Davis MD, Montpetit AJ. Exhaled Breath Condensate: An Update. Immunol Allergy Clin North Am 2018; 38(4): 667-78.
[http://dx.doi.org/10.1016/j.iac.2018.06.002]
[87]
Glowacka E, Jedynak-Wasowicz U, Sanak M, Lis G. Exhaled eicosanoid profiles in children with atopic asthma and healthy controls. Pediatr Pulmonol 2013; 48(4): 324-35.
[http://dx.doi.org/10.1002/ppul.22615] [PMID: 22782807]
[88]
Formanek 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(3): 487-91.
[http://dx.doi.org/10.1183/09031936.02.00101202] [PMID: 11936527]
[89]
Zanconato 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(2): 257-63.
[http://dx.doi.org/10.1016/j.jaci.2003.10.046] [PMID: 14767439]
[90]
Samitas K, Chorianopoulos D, Vittorakis S, et al. Exhaled cysteinyl-leukotrienes and 8-isoprostane in patients with asthma and their relation to clinical severity. Respir Med 2009; 103(5): 750-6.
[http://dx.doi.org/10.1016/j.rmed.2008.11.009] [PMID: 19110408]
[91]
Tenero L, Zaffanello M, Piazza M, Piacentini G. Measuring airway inflammation in asthmatic children. Front Pediatr 2018; 6: 196.
[http://dx.doi.org/10.3389/fped.2018.00196] [PMID: 30035104]
[92]
Moschino L, Zanconato S, Bozzetto S, Baraldi E, Carraro S. Childhood asthma biomarkers: present knowledge and future steps. Paediatr Respir Rev 2015; 16(4): 205-12.
[PMID: 26100359]
[93]
Neerincx AH, Vijverberg SJH, Bos LDJ, et al. Breathomics from exhaled volatile organic compounds in pediatric asthma. Pediatr Pulmonol 2017; 52(12): 1616-27.
[http://dx.doi.org/10.1002/ppul.23785] [PMID: 29082668]
[94]
Rufo JC, Madureira J, Fernandes EO, Moreira A. Volatile organic compounds in asthma diagnosis: A systematic review and meta-analysis. Allergy 2016; 71(2): 175-88.
[http://dx.doi.org/10.1111/all.12793] [PMID: 26476125]
[95]
de Vries R, Dagelet YWF, Spoor P, et al. Clinical and inflammatory phenotyping by breathomics in chronic airway diseases irrespective of the diagnostic label. Eur Respir J 2018; 51(1)1701817
[http://dx.doi.org/10.1183/13993003.01817-2017] [PMID: 29326334]
[96]
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(7): 705-15.
[http://dx.doi.org/10.1111/cea.12052] [PMID: 23786277]
[97]
Robroeks CM, van Berkel JJ, Jöbsis Q, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J 2013; 42(1): 98-106.
[http://dx.doi.org/10.1183/09031936.00010712] [PMID: 23645402]
[98]
Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160(3): 1001-8.
[http://dx.doi.org/10.1164/ajrccm.160.3.9812110] [PMID: 10471631]
[99]
European Network for Understanding Mechanisms of Severe Asthma. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J 2003; 22(3): 470-7.
[http://dx.doi.org/10.1183/09031936.03.00261903] [PMID: 14516137]
[100]
Schleich F, Brusselle G, Louis R, et al. Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir Med 2014; 108(12): 1723-32.
[http://dx.doi.org/10.1016/j.rmed.2014.10.007] [PMID: 25456708]
[101]
Moore WC, Hastie AT, Li X, et al. National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol 2014; 133(6): 1557-63.e5.
[http://dx.doi.org/10.1016/j.jaci.2013.10.011] [PMID: 24332216]
[102]
Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanović R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000; 161(1): 9-16.
[http://dx.doi.org/10.1164/ajrccm.161.1.9802048] [PMID: 10619791]
[103]
Licari A, Manti S, Castagnoli R, et al. Immunomodulation in Pediatric Asthma. Front Pediatr 2019; 7: 289. Published 2019 Jul 12
[http://dx.doi.org/10.3389/fped.2019.00289]
[104]
Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol 2007; 119(5): 1043-52.
[http://dx.doi.org/10.1016/j.jaci.2007.02.042] [PMID: 17472810]
[105]
Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002; 57(10): 875-9.
[http://dx.doi.org/10.1136/thorax.57.10.875] [PMID: 12324674]
[106]
Lex C, Payne DN, Zacharasiewicz A, et al. Sputum induction in children with difficult asthma: safety, feasibility, and inflammatory cell pattern. Pediatr Pulmonol 2005; 39(4): 318-24.
[http://dx.doi.org/10.1002/ppul.20159] [PMID: 15678506]
[107]
Ordoñez CL, Shaughnessy TE, Matthay MA, Fahy JV. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance. Am J Respir Crit Care Med 2000; 161(4 Pt 1): 1185-90.
[http://dx.doi.org/10.1164/ajrccm.161.4.9812061] [PMID: 10764310]
[108]
Jochmann A, Artusio L, Robson K, et al. Infection and inflammation in induced sputum from preschool children with chronic airways diseases. Pediatr Pulmonol 2016; 51(8): 778-86.
[http://dx.doi.org/10.1002/ppul.23366] [PMID: 26678320]
[109]
Chung KF. Airway microbial dysbiosis in asthmatic patients: A target for prevention and treatment? J Allergy Clin Immunol 2017; 139(4): 1071-81.
[http://dx.doi.org/10.1016/j.jaci.2017.02.004] [PMID: 28390574]
[110]
Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: Evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001; 119(5): 1329-36.
[http://dx.doi.org/10.1378/chest.119.5.1329] [PMID: 11348936]
[111]
Sadik CD, Kim ND, Luster AD. Neutrophils cascading their way to inflammation. Trends Immunol 2011; 32(10): 452-60.
[http://dx.doi.org/10.1016/j.it.2011.06.008] [PMID: 21839682]
[112]
Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest 2012; 142(1): 86-93.
[http://dx.doi.org/10.1378/chest.11-1838] [PMID: 22345378]
[113]
Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999; 160(5 Pt 1): 1532-9.
[http://dx.doi.org/10.1164/ajrccm.160.5.9806170] [PMID: 10556116]

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