01 / About FeNO

FeNO testing identifies airway inflammation severity

 

Nitric oxide

It took until the late 1980s to discover that the human body has complex enzymes, NO synthases, that synthesize a ubiquitous gaseous mediator, nitric oxide (NO), that diffuses and acts locally on cells to mediate physiologic responses1. Perhaps the best known of these is the effect of NO on smooth muscle in the vasculature, resulting in relaxation and vasodilation. Similarly, in the airway, NO results in bronchodilation.  NO acts through binding to receptors on smooth muscle called soluble guanylate cyclase which raises intracellular cyclic GMP, that inhibits the entry of calcium to the cell and relaxes the muscle. The Nobel prize was awarded in 1998 to 3 researchers, Murad, Ignarro, and Furchgott, for their role in elucidating the mechanisms of action of NO².

 

NO and inflammation

Of relevance to asthma, NO is an inflammatory mediator that is produced in large amounts during inflammatory conditions e.g. sepsis. NO is a reactive species that in large amounts increases oxidative stress, and also results in vasodilation in areas of inflammation. In asthma, there is inflammation of the airways with infiltration of inflammatory cells e.g. eosinophils, and the production of inflammatory mediators including NO.

 

Exhaled NO

It was first in 1991 that nitric oxide (NO) was identified in the breath of humans and mammals3. There is now a vast body of literature (in excess of 11,000 peer reviewed articles)  that include exhaled NO (FeNO) in the abstract. Here we provide some essential facts about FeNO that may be of interest and then survey emerging knowledge about this remarkable biomarker.

NO produced in the airway mucosa by NO synthases, diffuses into the airway lumen and is exhaled. Everyone exhales NO due to physiologic production, but in asthma when there is allergic asthmatic inflammation e.g. infiltration of eosinophils, FeNO levels are elevated compared to non-allergic asthmatic controls.

The elevated FeNO in asthma and the fall after ICS underpin the utility of FeNO in asthma and have led to its widespread application.

 

Essential facts about FeNO

1. FeNO is elevated in allergic asthmatics4 and elevations are driven by allergic inflammation (Type 2 or Th2) characterized by eosinophilic infiltration, and high IgE levels. On the reverse side of the coin, there is a large proportion of asthmatics who are non-allergic and do not have an elevated FeNO. An elevated FeNO is associated with infiltration of eosinophils in the airways5,6.

2. FeNO falls after treatment with anti-inflammatory medications e.g. inhaled steroids (ICS)7, and biologics e.g. the anti- IgE monoclonal antibody, omalizumab8,9, but is not reduced by bronchodilators.

3. An elevated FeNO predicts a good response to corticosteroids10.

4. In a new patient with symptoms suggestive of asthma, an elevated FeNO can be used to diagnose asthma with high positive and negative predictive values11.

5. In an allergic asthmatic, FeNO can be used to detect non-adherence with ICS treatment which is a widespread issue12.

6. A progressively rising FeNO is an early sign of worsening asthmatic inflammation e.g due to allergen exposure13,  and could be used to drive proactive preventive measures to prevent asthma worsening.

7. When combined with other management tools, FeNO can assist in managing difficult to control asthma14,15.

Airway inflammation severity by method of assessment16

asthma control test

16. LaForce C, et al. Ann Allergy Asthma Immunol. 2014;113(6):619–623.

02 / Current guidelines

International guidelines support FeNO

FeNO is recognised in ATS and NICE guidelines as a complementary tool to other ways of assessing airway diseases, including asthma.

Summary of current global guidelines supporting FeNO use.

• ATS/ERS- guidelines issued in 199917, and revised in 200518. Clinical guidelines issued by ATS in 2011 and are of great use for the practicing clinician19.

• ERS guidelines were jointly issued with ATS as above. Subsequent ERS taskforce has developed a technical standard for exhaled biomarkers in lung disease including FENO in 201720

• The UK National Health Service NICE guidelines on FENO 2014 endorse the use of FeNO in clinical practice (https://www.nice.org.uk/guidance/dg12)

asthma guidelines

1. Culotta E, Koshland DE, Jr. NO news is good news. Science. 1992;258(5090):1862-1865.

2. Smith O. Nobel Prize for NO research. Nat Med. 1998;4(11):1215.

3. Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun. 1991;181(2):852-857.

4. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet. 1994;343(8890):133-135.

5. Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax. 1998;53(2):91-95.

6. Berlyne GS, Parameswaran K, Kamada D, Efthimiadis A, Hargreave FE. A comparison of exhaled nitric oxide and induced sputum as markers of airway inflammation. J Allergy Clin Immunol. 2000;106(4):638-644.

7. Jatakanon A, Lim S, Chung KF, Barnes PJ. An inhaled steroid improves markers of airway inflammation in patients with mild asthma. Eur Respir J. 1998;12(5):1084-1088.

8. Hanania NA, Wenzel S, Rosen 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): 804-811.

9. Silkoff PE, Romero FA, Gupta N, Townley RG, Milgrom H. Exhaled nitric oxide in children with asthma receiving Xolair (omalizumab), a monoclonal anti-immunoglobulin E antibody. Pediatrics. 2004;113(4):e308-312.

10. Little SA, Chalmers GW, MacLeod KJ, McSharry C, Thomson NC. Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma. Thorax. 2000;55(3): 232-234.

11. Smith AD, Cowan JO, Filsell S, et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med. 2004;169(4):473-478.

12. Beck-Ripp J, Griese M, Arenz S, Koring C, Pasqualoni B, Bufler P. Changes of exhaled nitric oxide during steroid treatment of childhood asthma. Eur Respir J. 2002;19(6):1015-1019.

13. Vahlkvist S, Sinding M, Skamstrup K, Bisgaard H. Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure. J Allergy Clin Immunol. 2006;117(6):1272-1276.

14. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005;352(21):2163-2173.

15. Powell H, Murphy VE, Taylor DR, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet. 2011;378(9795):983-990.

16. LaForce C, et al. Ann Allergy Asthma Immunol. 2014;113(6):619–623.

17. Recommendations for standardized procedures for the on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 1999;160(6):2104-2117.

18. American Thoracic S, European Respiratory S. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171(8):912-930.

19. Dweik RA, Boggs PB, Erzurum SC, et al. 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):602-615.

20. Horvath I, Barnes PJ, Loukides S, et al. A European Respiratory Society technical standard: exhaled biomarkers in lung disease. Eur Respir J. 2017;49(4).

03 / Interpreting FeNO

General outline for FeNO interpretation

FeNO < 25ppb

(<20 ppb in children)

FeNO 25-50 ppb

(20-35 ppb in children)

FeNO > 50 ppb

(>35 ppb in children)

Diagnosis

Symptoms* present
during past 6+ wk

  • Eosinophilic airway inflammation unlikely
  • Alternative diagnoses
  • Unlikely to benefit from ICS
  • Be cautious
  • Evaluate clinical context
  • Monitor change in FeNO over time
  • Eosinophilic airway inflammation present
  • Likely to benefit from ICS

Monitoring (in Patients with Diagnosed Asthma)

Symptoms* present

  • Possible alternative diagnoses
  • Unlikely to benefit from increase in ICS
  • Persistent allergen exposure
  • Inadequate ICS dose
  • Poor adherence
  • Steroid resistance
  • Persistent allergen exposure
  • Poor adherence or inhaler technique
  • Inadequate ICS dose
  • Risk for exacerbation
  • Steriod resistance

Symptoms* absent

  • Adequate ICS dose
  • Good adherence
  • ICS taper
  • Adequate ICS dosing
  • Good adherence
  • Monitor change in FeNO
  • ICS withdrawal or dose reduction may result in relapse
  • Poor adherence or inhaler technique

*Symptoms refer to cough and/or wheeze and/or shortness of breath.

Definition of abbreviations: FeNO = fraction of exhaled nitric oxide; ICS = inhaled corticosteroid.

The interpretation of FeNO is an adjunct measure to history, physical exam, and lung function assessment.

1. R. A. Dweik, et. al, Am. J. Respir., 2011; vol. 184, pp. 602–615.

Download the interpretation guide as PDF

Download the interpretation guide as PDF

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