Fractional Exhaled Nitric Oxide (FeNO)

Fractional exhaled nitric oxide (FeNO) is a noninvasive biomarker that reflects the amount of nitric oxide (NO) released from the airway epithelium during a controlled exhalation. Because NO production is upregulated by type2 (Th2) inflammation, FeNO has become an important tool in the diagnosis, monitoring, and phenotyping of asthma and other airway diseases.

1. Physiology and Biochemistry of NO in the Airways

Nitric oxide is a gaseous signalling molecule produced by the enzyme nitric oxide synthase (NOS). In the respiratory tract three isoforms exist:

• eNOS (endothelial NOS) constitutively active, regulates vascular tone.
• nNOS (neuronal NOS) involved in neurotransmission.
• iNOS (inducible NOS) expressed in airway epithelial cells, macrophages, and eosinophils in response to cytokines such as IL4 and IL13.

When type2 inflammation is present, iNOS expression is dramatically increased, leading to higher concentrations of NO that diffuse into the lumen of the airway and are expelled during exhalation. The fraction of NO measured in the exhaled breath (parts per billion, ppb) therefore gives a direct estimate of iNOS activity and, by extension, airway eosinophilia.

2. Technical Aspects of FeNO Measurement

2.1 Recommended Procedure

Guidelines from the American Thoracic Society (ATS) and the European Respiratory Society (ERS) outline a standardized method:

1. Patient sits upright, relaxes and performs a slow, steady inhalation to total lung capacity.
2. After a short breathhold (10s), the patient exhales at a constant flow of 50mLs for at least 6seconds.
3. The device records NO concentration continuously and reports the mean value over the last 3seconds.

2.2 Devices

Commercially available handheld analyzers (e.g., NIOX VERO, NObreath) use chemiluminescence or electrochemical detection. Calibration is performed daily, and ambient NO must be recorded to correct for environmental contamination.

2.3 Factors Influencing Results

• **Age** Children typically have lower FeNO values; reference ranges differ from adults.
• **Atopy and allergic rhinitis** elevate FeNO independent of asthma.
• **Smoking** decreases FeNO.
• **Recent intake of nitraterich foods** may cause transient rises.
• **Inhaled corticosteroids (ICS)** produce a dosedependent reduction.

3. Clinical Applications

3.1 Diagnosis of Asthma

Elevated FeNO (>25ppb in adults, >20ppb in children) supports a diagnosis of eosinophilic airway inflammation and can help differentiate asthma from other obstructive disorders such as chronic obstructive pulmonary disease (COPD). A normal value does not exclude asthma; it merely argues against a type2 dominant phenotype.

3.2 Guiding AntiInflammatory Therapy

FeNO can be used to titrate inhaled corticosteroid (ICS) dose:

• **High FeNO (>35ppb)** consider stepping up ICS or adding a leukotriene receptor antagonist.
• **Low FeNO (<20ppb)** may allow safe stepdown or discontinuation.

Several randomized trials have shown that FeNOguided management reduces exacerbation rates and overall steroid exposure compared with symptombased strategies.

3.3 Predicting Response to Biologic Therapies

Patients with higher baseline FeNO are more likely to respond to antiIL4R (dupilumab), antiIL5 (mepolizumab), or antiIgE (omalizumab) agents. FeNO monitoring during therapy can also signal loss of response or the need for dose adjustment.

3.4 Monitoring Adherence

Because FeNO rises rapidly when corticosteroid use is interrupted, a sudden increase can flag poor adherence. This objective cue helps clinicians address behavioral issues without confrontation.

3.5 Occupational and Environmental Health

Elevated FeNO may identify workers exposed to irritants (e.g., isocyanates) who develop subclinical airway inflammation, prompting early intervention.

4. Interpretation of Results Practical Guidance

The following table summarizes common reference ranges and clinical thresholds. Values are expressed in parts per billion (ppb).

Key points for interpretation

• Always compare the result with the patients baseline, not just a population average.
• Consider concomitant atopy, recent infections, or recent changes in medication.
• Use trends over time rather than isolated values to guide therapeutic decisions.

5. Limitations and Pitfalls

• Nontype2 inflammation FeNO is low in neutrophilic asthma, COPD, or bronchiectasis, so a normal value does not rule out disease.
• Technical errors Inadequate exhalation flow, leaks, or device malfunction can produce falsely high or low readings.
• Interindividual variability Genetic polymorphisms in NOS genes affect baseline NO production.
• Cost and accessibility While handheld devices are relatively inexpensive, repeated testing may be limited in lowresource settings.

6. Future Directions

Research is expanding the utility of FeNO beyond asthma:

• Predictive algorithms that combine FeNO with blood eosinophils, periostin, and symptom scores to personalize biologic therapy.
• Exhaled breath condensate analyses that simultaneously measure NO, carbon monoxide, and volatile organic compounds.
• Remote monitoring Smartphonelinked FeNO devices could allow homebased assessment and telemedicine integration.

7. Quick Reference Checklist for Clinicians

1. Verify device calibration and ambient NO level.
2. Ensure a constant exhalation flow of 50mLs.
3. Record at least two acceptable blows and average the results.
4. Compare with agespecific reference ranges.
5. Interpret in the context of clinical history, atopy, and current therapy.
6. Use trends for treatment adjustments and adherence checks.

References: ATS/ERS 2011 FeNO guideline; D. P. P. etal., FeNOguided asthma management, J Allergy Clin Immunol, 2022; GINA 2024 recommendations.