Fractional exhaled nitric oxide as a determinant for the clinical course of asthma: a systematic review

ABSTRACT Background: Precision medicine means linking the right patient to the right management strategy including best possible pharmacological therapy, considering the individual variability of the disease characteristics, type of inflammation, genes, environment, and lifestyle. For heterogenous diseases such as asthma, reliable biomarkers are needed to facilitate the best possible disease control and reduce the risk of side effects. The present review examines fractional exhaled nitric oxide (FeNO) as a guide for the management strategy of asthma and predictor of its clinical course. Method: The literature included was identified by searching the PubMed database using specific key words and MeSH terms. Studies were not excluded based on their design alone. The search resulted in 212 hits, of which 35 articles were included in this review. Results: Several studies support a potential role for high FeNO levels as a prognostic biomarker for accelerated lung function decline in adults with newly diagnosed asthma. Furthermore, studies report an association between high FeNO levels and excess decline in FEV1 in adults with long-standing moderate to severe asthma despite optimised therapy, whereas the findings for patients with less severe disease are conflicting. Applying a FeNO-based management algorithm reduces the exacerbation rate in adults with asthma. Similar observations are seen in children, though based on fewer studies. The available studies provide evidence that the level of FeNO may be useful as a predictor of subsequent loss of asthma control in adults, though the evidence is somewhat conflicting in children and young adults. Conclusion: The present review provides evidence of the prognostic value of FeNO as a surrogate biomarker for type 2 inflammation in the airways. FeNO is likely to emerge as an important biomarker in monitoring and tailoring modern asthma treatment, either alone or in combination with other biomarkers.

[1]  I. Pavord,et al.  Predictive value of blood eosinophils and exhaled nitric oxide in adults with mild asthma: a prespecified subgroup analysis of an open-label, parallel-group, randomised controlled trial. , 2020, The Lancet. Respiratory medicine.

[2]  D. Jarvis,et al.  Determinants of fractional exhaled nitric oxide in healthy men and women from the European Community Respiratory Health Survey III , 2019, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[3]  M. Pijnenburg.  The Role of FeNO in Predicting Asthma , 2019, Front. Pediatr..

[4]  S. Srivastava,et al.  Disconnect of type 2 biomarkers in severe asthma; dominated by FeNO as a predictor of exacerbations and periostin as predictor of reduced lung function. , 2018, Respiratory medicine.

[5]  C. Leone,et al.  Can inflammatory markers in induced sputum be used to detect phenotypes and endotypes of pediatric severe therapy‐resistant asthma? , 2018, Pediatric pulmonology.

[6]  H. Makita,et al.  Prospective predictors of exacerbation status in severe asthma over a 3‐year follow‐up , 2018, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[7]  H. Ortega,et al.  Asthma Exacerbations Associated with Lung Function Decline in Patients with Severe Eosinophilic Asthma. , 2018, The journal of allergy and clinical immunology. In practice.

[8]  M. Weatherall,et al.  Type 2 Biomarkers and Prediction of Future Exacerbations and Lung Function Decline in Adult Asthma. , 2018, The journal of allergy and clinical immunology. In practice.

[9]  W. Tam,et al.  Trajectory of spirometric and exhaled nitric oxide measurements in Chinese schoolchildren with asthma , 2018, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[10]  A. Zwinderman,et al.  Predictors of accelerated decline in lung function in adult-onset asthma , 2018, European Respiratory Journal.

[11]  Richard Beasley,et al.  After asthma: redefining airways diseases , 2017, The Lancet.

[12]  E. Israel,et al.  Severe and Difficult‐to‐Treat Asthma in Adults , 2017, The New England journal of medicine.

[13]  P. Nair,et al.  Regulation of human airway smooth muscle cell migration and relevance to asthma , 2017, Respiratory Research.

[14]  Y. Hahn,et al.  Combined use of fractional exhaled nitric oxide and bronchodilator response in predicting future loss of asthma control among children with atopic asthma , 2017, Respirology.

[15]  Á. Cruz,et al.  Revisiting Type 2‐high and Type 2‐low airway inflammation in asthma: current knowledge and therapeutic implications , 2017, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[16]  N. Visitsunthorn,et al.  Association between levels of fractional exhaled nitric oxide and asthma exacerbations in Thai children , 2017, Respirology.

[17]  E. Konozy,et al.  Fractional exhaled nitric oxide along with a reduced force expiratory volume are conclusive prognostic biomarkers to alert for asthma exacerbation , 2017 .

[18]  C. Janson,et al.  Simultaneously increased fraction of exhaled nitric oxide levels and blood eosinophil counts relate to increased asthma morbidity. , 2016, The Journal of allergy and clinical immunology.

[19]  K. Kostikas,et al.  Sputum interleukin‐13 as a biomarker for the evaluation of asthma control , 2016, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[20]  A. Chang,et al.  Exhaled nitric oxide levels to guide treatment for adults with asthma. , 2016, The Cochrane database of systematic reviews.

[21]  T. Hirano,et al.  Persistently high exhaled nitric oxide and loss of lung function in controlled asthma. , 2016, Allergology international : official journal of the Japanese Society of Allergology.

[22]  Antonio Molino,et al.  Fractional exhaled nitric oxide-measuring devices: technology update , 2016, Medical devices.

[23]  M. Ogasawara,et al.  Fractional exhaled nitric oxide levels as a predictor of long-term prognoses in patients with mild asthma. , 2016, Respiratory investigation.

[24]  W. Assendelft,et al.  Identifying patients at risk for severe exacerbations of asthma: development and external validation of a multivariable prediction model , 2016, Thorax.

[25]  Q. Jöbsis,et al.  Association between exhaled inflammatory markers and asthma control in children , 2016, Journal of breath research.

[26]  R. Jörres,et al.  Influence of the practice setting on diagnostic prediction rules using FENO measurement in combination with clinical signs and symptoms of asthma , 2015, BMJ Open.

[27]  P. Montuschi,et al.  The Combined Impact of Exhaled Nitric Oxide and Sputum Eosinophils Monitoring in Asthma Treatment: A Prospective Cohort Study. , 2015, Current pharmaceutical design.

[28]  Joohyun Park,et al.  Association of longitudinal fractional exhaled nitric oxide measurements with asthma control in atopic children. , 2015, Respiratory medicine.

[29]  I. Pavord,et al.  Current evidence and future research needs for FeNO measurement in respiratory diseases. , 2014, Respiratory medicine.

[30]  M. Sears.  Trends in the prevalence of asthma. , 2014, Chest.

[31]  N. Visitsunthorn,et al.  Is fractional exhaled nitric oxide (FeNO) associated with asthma control in children? , 2013, Asian Pacific journal of allergy and immunology.

[32]  D. Jacobs,et al.  Adult-onset asthma becomes the dominant phenotype among women by age 40 years. the longitudinal CARDIA study. , 2013, Annals of the American Thoracic Society.

[33]  S. Wenzel.  Asthma phenotypes: the evolution from clinical to molecular approaches , 2012, Nature Medicine.

[34]  T. Kawayama,et al.  Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics , 2012, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[35]  E. Nizankowska-Mogilnicka,et al.  Frequent exacerbators – a distinct phenotype of severe asthma , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[36]  M. Ferrer,et al.  Is it necessary to treat all asthmatic children with raised levels of exhaled nitric oxide?: treating the patient or the data. , 2011, Allergologia et immunopathologia.

[37]  W. Crawford,et al.  Elevated exhaled nitric oxide is a clinical indicator of future uncontrolled asthma in asthmatic patients on inhaled corticosteroids. , 2011, The Journal of allergy and clinical immunology.

[38]  R. Marthan,et al.  Control maintenance can be predicted by exhaled NO monitoring in asthmatic patients. , 2011, Respiratory medicine.

[39]  G. Redding,et al.  Exhaled nitric oxide predicts persistence of wheezing, exacerbations, and decline in lung function in wheezy infants and toddlers , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[40]  D. Curran‐Everett,et al.  Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. , 2010, American journal of respiratory and critical care medicine.

[41]  M. Fujimura,et al.  Evaluation of airway hyperresponsiveness and exhaled nitric oxide as risk factors for airway remodeling in patients with stable asthma. , 2009, Allergy and Asthma Proceedings.

[42]  D. Jarvis,et al.  Rhinitis and onset of asthma: a longitudinal population-based study , 2008, The Lancet.

[43]  Mike Thomas,et al.  Cluster analysis and clinical asthma phenotypes. , 2008, American journal of respiratory and critical care medicine.

[44]  K. Rabe,et al.  Exhaled nitric oxide predicts lung function decline in difficult-to-treat asthma , 2008, European Respiratory Journal.

[45]  A. Michils,et al.  Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients , 2008, European Respiratory Journal.

[46]  D. Postma,et al.  Severe exacerbations predict excess lung function decline in asthma , 2007, European Respiratory Journal.

[47]  D. Taylor,et al.  Exhaled nitric oxide measurements: clinical application and interpretation , 2006, Thorax.

[48]  N. Zamel,et al.  Role of spirometry and exhaled nitric oxide to predict exacerbations in treated asthmatics. , 2006, Chest.

[49]  P. Sterk,et al.  Bronchial CD8 cell infiltrate and lung function decline in asthma. , 2005, American journal of respiratory and critical care medicine.

[50]  S. Peters,et al.  Airway remodeling contributes to the progressive loss of lung function in asthma: an overview. , 2005, The Journal of allergy and clinical immunology.

[51]  J. Cowan,et al.  Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. , 2005, The New England journal of medicine.

[52]  N. Wilson,et al.  Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. , 2005, American journal of respiratory and critical care medicine.

[53]  W. Hop,et al.  Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission , 2005, Thorax.

[54]  D. Knight,et al.  Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath , 2004, Thorax.

[55]  N. Kissoon,et al.  Exhaled nitric oxide reflects asthma severity and asthma control , 2004, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[56]  D. Postma,et al.  Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up. , 2003, Thorax.

[57]  R. Hancox,et al.  The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. , 2001, American journal of respiratory and critical care medicine.

[58]  J Vestbo,et al.  A 15-year follow-up study of ventilatory function in adults with asthma. , 1998, The New England journal of medicine.

[59]  R. Pauwels,et al.  GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION , 1996 .

[60]  E. Weitzberg,et al.  Increased amount of nitric oxide in exhaled air of asthmatics. , 1993, The European respiratory journal.

[61]  P. Ilmarinen,et al.  Age-specific incidence of new asthma diagnoses in Finland. , 2017, The journal of allergy and clinical immunology. In practice.

[62]  R. Katial,et al.  Exhaled nitric oxide. , 2012, Immunology and allergy clinics of North America.

[63]  T. Tsuburai,et al.  Markers for step-down of inhaled corticosteroid therapy in adult asthmatics. , 2012, Allergology international : official journal of the Japanese Society of Allergology.

[64]  S. Willsie.  An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (FeNO) for Clinical Applications , 2012 .

[65]  I. Oguzulgen,et al.  Asthma in obese women: outcomes and factors involved. , 2011, Journal of investigational allergology & clinical immunology.

[66]  Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. , 2007, The Journal of allergy and clinical immunology.

[67]  S. Wenzel,et al.  Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. , 2004, The Journal of allergy and clinical immunology.