The Use of Fraction of Exhaled Nitric Oxide in Pulmonary Practice Kaiser G. Lim, MD, FCCP; and Carl Mottram, RRT, RPFT CHEST 2008; 133:1232–124 Jeung Eun Park

Asthma Definition Reversible bronchospasm, bronchial hyperresponsiveness, and airway inflammation Treatment Antiinflammatory treatment Accurate assessment and monitoring of the underlying inflammatory state of the airways No point-of-service test available to assess airway inflammation in asthma.

FeNO To assess airway inflammation in asthma patients Normative reference equations and values Highly reproducible Responsive to changes in the underlying disease state Predictive of response to treatment with antiinflammatory medications

Nitric oxide A widely distributed endogenous regulatory molecule in the body synthesized from L-arginine by the enzyme NO synthase (NOS). NO in the airway is measured by its reaction with ozone, which is detected by chemiluminescence. Three isoforms of NOS Asthma : the inducible calcium-independent NOS(NOS2A)

Nitric oxide The level of FeNO in patients with asthma Elevated The inducible calcium-independent NOS15 in the airway epithelium of the bronchial wall with possible contribution from inflammatory T cells and macrophages. NOS is up-regulated transcriptionally by inflammatory cytokines in the airways.

The Level of FeNO Correlates With Markers of Airway Inflammation The degree of bronchial hyperresponsiveness, bronchodilator reversibility, and atopy Blood eosinophilia Airway inflammation Sputum eosinophils Mucosal eosinophilia BAL eosinophilia

The Level of FeNO Correlates With Markers of Airway Inflammation FeNO decreases quickly after the start of antiinflammatory therapy, with improvement in airway inflammation, and increases when airway inflammation worsens. Asthma, atopy, allergic rhinitis, and eosinophilic bronchitis without asthma. FeNO is an excellent noninvasive measure of eosinophilic airway inflammation.

Clinical Application of FeNO

Diagnosis In the presence of compatible respiratory symptoms and airflow limitation, an elevated FeNO has high sensitivity and specificity for diagnosing asthma. a specificity 90% and a positive predictive value of > 90% Chest. 2003;123:

Clinical Application of FeNO The FeNO may be within normal limits. Mild nonatopic asthmatic patients Patients already receiving ICS therapy Differentiate between different grades of asthma severity of correlate with FEV1  No Differentiate between COPD and asthma  Yes

Clinical Application of FeNO Therapy Predict the response to therapy with oral corticosteroids and ICSs in patients with asthma, COPD, cough, and otherwise nonspecific respiratory symptoms. ICSs, antileukotriene therapy : FeNO ↓ Nedocromil, theophylline : FeNO → FeNO Dose-response relationship with ICSs Useful in titrating antiinflammatory medication in asthma patients while maintaining asthma control Predicting outcome

Clinical Application of FeNO FeNO has been predictive of asthma exacerbations. FeNO > 22 ppb : sixfold greater risk of losing asthma control FeNO > 49 ppb : predicting relapse Each doubling of the FeNO level increased the risk of an asthma relapse by threefold. Monitor adherence to antiinflammatory medication FeNO increases quickly once medication is stopped There is no correlation between FeNO and quality of life.

Clinical Application of FeNO Interpretation of Results In 2005, both the ATS and ERS recommended using 50 mL/s as the standard flow rate. FeNO > 35 ppb in a steroid-naïve patient : asthma FeNO > 38 ppb in patients with chronic cough : predictive of a response to ICS therapy Asthmatic patient receiving ICSs + persistent symptoms + FeNO > 35 ppb : atopy, persistent airway inflammation, or nonadherence to therapy Asthmatic patient receiving ICSs + persistent symptoms + FeNO < 35 ppb : comorbidities

NIOX FLEX NIOX MINI NIOX; Aerocrine; Solna, Sweden

COST NIOX system in a Start package : $43,000 A computer, software, monitor, keyboard, calibration gas, installation, and training Gas regulator : $1,500 Replace the NO scrubber : $94, every 6 months Calibration gas : $1,400, every 12 months The NIOX system : $3,000, serviced every 18 months A disposable mouthpiece filter : $4, each test A single test costs : $165

Summary The measurement of FeNO was never meant to be used in isolation, but in conjunction with clinical history and lung function testing FeNO : status of eosinophilic inflammation of the bronchial mucosa The only test for airway inflammation that can be performed conveniently and serially at the point of service FDA- approved device

Summary The information obtained is predictive of future disease status. Predicting asthma relapse, maintaining asthma control, adherence to medication, and loss of asthma control, especially in children The clinician can titrate or withdraw therapy with ICSs based on the FeNO.

Conclusion The measurement of FeNO is useful in the diagnosis and management of patients with asthma. The availability of predictive equations will further refine the clinical application of FeNO not only in patients with asthma, but also in those with chronic cough, COPD, and other respiratory problems. The current equipment is patient-user friendly but expensive.