Nitric oxide (NO) is a well-recognized biological mediator. It is produced in the human lung and is present in the exhaled breath. NO is felt to play a key role in the airways as a vasodilator, bronchodilator, neurotransmitter, and inflammatory mediator. NO is created by several isoforms of the enzyme nitric oxide synthase (NOS). At least one form of NOS is inducible by inflammatory cytokines and inhibited by glucocorticoids. Exhaled NO levels rise in association with acute airway inflammation, sputum eosinophila, viral upper respiratory infections and other parameters associated with asthma control. However, it is not completely clear whether exhaled NO is a cause of inflammation or simply a marker of inflammation.
Measurement of fractional nitric oxide concentration in exhaled breath (FeNO) is a quantitative, non-invasive and safe method to measure airway inflammation. Repeat measurements can be easily made. Conventional testing such as FEV1 reversibility or bronchial provocation testing is only indirectly associated with airway inflammation. FeNO offers the advantage of detecting eosinophilic airway inflammation. It has also been correlated with the likelihood of corticosteroid responsiveness and therefore may help determine the potential need for inhaled steroid therapy. FeNO measurement can also reveal otherwise unsuspected non-compliance with inhaled steroid therapy.
The American Thoracic Society published Guidelines in 2011 recommending the use of FeNO in the diagnosis of eosinophilic airway inflammation. A low FeNO level (below 25 parts per billion) indicates that eosinophilic inflammation and responsiveness to steroids are less likely, whereas a FeNO greater than 50 ppb in adults is strongly correlated with eosinophilic inflammation and also correlates with responsiveness to steroid therapy. FeNO values between 25 and 50 parts per billion in adults are indeterminate. When the FeNO level is above 50 a change of greater than 20% is recommended to indicate a significant change in FeNO values. When the FeNO level is below 50 parts per billion, a change of 10 ppb should be considered significant.
It should be noted that in children below 12 years of age, the reference ranges are different with a FeNO level of less than 20 ppb indicative of lack of eosinophilic inflammation,a level of greater than 35 ppb indicative of eosinophilic inflammation and the range between 20 and 35 ppb being indeterminate.
FeNO levels tend to be a bit lower in current smokers than in ex-smokers, with highest levels in non-smokers. FeNO can also be low in patients with pulmonary hypertension,hypothermia, caffeine and alcohol use, and menstruating women. Certain drugs such as enalapril can increase FeNO levels, as can ingestion of arginine rich foods, air pollution exposure, and upper respiratory tract infections. FeNO values can affected by measurement technique, exhalation flow rate, nasal NO contamination, height and other factors. Persistently high FeNO levels could be consistent with continued allergen exposure.
FeNO testing adds a new dimension to the tools which have traditionally been available, such as history, physical exam, and pulmonary function testing. FeNO testing can also be used to determine whether airway inflammation is contributing to poor asthma control (versus other causes such as reflux, anxiety, continued allergen exposure, etc). FeNO measurement has been shown in some studies to reduce maintenance doses of inhaled steroids without compromising asthma control.
The American Thoracic Society Practice Guidelines report that if a patient is symptomatic (in terms of chronic cough, wheezing, or shortness of breath), for at least six weeks at the time of initial presentation, and the FeNO level is low (below 25 ppb in an adult) the patient would be unlikely to benefit from a trial of inhaled steroids. Certainly, in this setting a patient could have non-eosinophilic asthma, or other disease entities, such as post viral bronchial hyper-responsiveness syndrome, reflux, etc.
FeNO measurement may prove helpful in pulmonary diseases other than asthma as well. Although FeNO measurement may be helpful in determining steroid responsiveness in patients with COPD, there has not been enough research in this area to make conclusive statements. FeNO has been shown to be elevated in non-cystic fibrosis related bronchiectasis and sarcoidosis, but reduced in children with cystic fibrosis. FeNO has a 95 percent negative predictive value for detecting Non-asthmatic eosinophilic bronchitis.
The American Thoracic Society Clinical Practice Guidelines recommends using evidence based cut points rather than reference ranges for interpretation of FeNO. In an individual patient with asthma, a “personal best” value is felt to be more helpful than a normal value. For clinical decision making, it is important to distinguish between the use of FeNO for diagnosis of asthma versus monitoring a patient with established asthma. It is also important to consider the presence or absence of symptoms (see table). More research is needed to clearly define the use of FeNO measurement in different clinical settings. However, it appears likely that this test will be increasingly used in the diagnosis and management of asthma and other respiratory illnesses.
By Daniel T. Layish MD