In an adult or pediatric patient with suspected or established asthma, how should fractional exhaled nitric oxide (FeNO) be used to diagnose eosinophilic airway inflammation and guide inhaled corticosteroid therapy?

Use of FeNO in Asthma Management

FeNO should be used to diagnose eosinophilic airway inflammation and predict inhaled corticosteroid responsiveness, with specific cutoff values guiding clinical decisions: values <25 ppb in adults (<20 ppb in children) indicate eosinophilic inflammation is unlikely and ICS therapy will probably not help, while values >50 ppb in adults (>35 ppb in children) indicate eosinophilic inflammation is present and ICS therapy is likely to be beneficial. 1

Diagnostic Applications

Primary Diagnostic Uses

FeNO serves three key diagnostic functions according to the American Thoracic Society guidelines:

• Diagnosing eosinophilic airway inflammation (strong recommendation, moderate quality evidence) 1
• Determining likelihood of steroid responsiveness in patients with chronic respiratory symptoms possibly due to airway inflammation (strong recommendation, low quality evidence) 1
• Supporting asthma diagnosis when objective evidence is needed (weak recommendation, moderate quality evidence) 1

Critical Caveat About Asthma Diagnosis

Asthma is a clinical diagnosis and FeNO is NOT a standalone diagnostic test for asthma. 1 Not all asthma is eosinophilic—there are neutrophilic, mixed, and paucigranulocytic phenotypes where FeNO may be low despite active asthma. 1 FeNO specifically identifies the eosinophilic phenotype, which is the steroid-responsive type. 2, 3

Interpretation Algorithm

Age-Specific Cutoff Values

Adults:

• Low FeNO: <25 ppb - Eosinophilic inflammation unlikely, steroid responsiveness unlikely 1
• Intermediate FeNO: 25-50 ppb - Interpret cautiously with clinical context 1
• High FeNO: >50 ppb - Eosinophilic inflammation present, steroid responsiveness likely 1

Children (<12 years):

• Low FeNO: ≤20 ppb - Eosinophilic inflammation unlikely 1
• Intermediate FeNO: 20-35 ppb - Interpret cautiously 1
• High FeNO: ≥35 ppb - Eosinophilic inflammation present 1

Age must be accounted for in children under 12 years (strong recommendation, high quality evidence). 1

Clinical Decision-Making Based on FeNO Levels

Low FeNO (<25 ppb adults; <20 ppb children)

In symptomatic patients presenting initially:

• Eosinophilic airway inflammation is unlikely 1
• Patient is unlikely to benefit from ICS trial 1
• Consider alternative diagnoses: vocal cord dysfunction, anxiety-hyperventilation, bronchiectasis, cardiac disease, rhinosinusitis, GERD 1
• Consider noneosinophilic asthma (probably steroid unresponsive) 1

Recent high-quality evidence supports this: a 2021 randomized controlled trial demonstrated that steroid-naïve patients with suspected asthma and FeNO ≤27 ppb showed no clinically meaningful benefit from ICS treatment over 3 months compared to placebo. 4

In established asthma patients with low FeNO:

• Implies adequate ICS dosing and good adherence 1
• ICS dose may be reduced (repeat FeNO in 4 weeks to confirm; if remains low, relapse is unlikely) 1
• If symptomatic despite low FeNO: consider alternative diagnoses, poor adherence, or steroid resistance 1

High FeNO (>50 ppb adults; >35 ppb children)

In symptomatic patients presenting initially:

• Eosinophilic inflammation is present 1
• Patient is likely to benefit from ICS trial 1
• Consider atopic asthma, eosinophilic bronchitis, or COPD with mixed inflammatory phenotype 1

In established asthma patients with high FeNO:

If symptomatic:

• High persistent allergen exposure 1
• ICS delivery problems: poor adherence, poor inhaler technique, proximal drug deposition with untreated distal inflammation 1
• Inadequate ICS dose 1
• Risk for exacerbation 1

If asymptomatic:

• Do not change ICS dosing initially; monitor FeNO trend over time 1
• Withdrawing ICS is likely to be followed by relapse 1
• Consider increasing therapy as high FeNO may be a risk factor for upcoming exacerbation even without symptoms 1
• Note: "high" FeNO may be normal in certain percent of population (particularly atopic individuals) 1

Intermediate FeNO (25-50 ppb adults; 20-35 ppb children)

Interpret cautiously with clinical context (strong recommendation, low quality evidence). 1

• Monitor change in FeNO over time 1
• Consider persistent allergen exposure 1
• Consider inadequate ICS dose 1
• Serial measurements are more informative than single values 1

Monitoring Airway Inflammation

FeNO should be used to monitor airway inflammation in established asthma (strong recommendation, low quality evidence). 1

Defining Significant Changes

Significant increase in FeNO:

• >20% increase when baseline value is >50 ppb, OR
• >10 ppb absolute increase when baseline value is <50 ppb 1

Significant decrease (response to anti-inflammatory therapy):

• ≥20% reduction when baseline value is >50 ppb, OR
• ≥10 ppb absolute reduction when baseline value is <50 ppb 1

The change in FeNO following corticosteroid intervention may be more valid than the absolute value. 1

Specific Clinical Applications

Assessing ICS Adherence

High FeNO in a patient on ICS therapy strongly suggests:

• Poor medication adherence 1
• Poor inhaler technique 1
• Inadequate dosing 1

This is one of the most practical uses of FeNO—unmasking otherwise unsuspected non-adherence to corticosteroid therapy. 3

Guiding ICS Dose Adjustments

FeNO can guide:

• Step-down dosing 1
• Step-up dosing 1
• Discontinuation of anti-inflammatory medications 1

Important limitation: While guidelines support this use, a 2013 pediatric randomized controlled trial found that FeNO-guided ICS titration did not reduce corticosteroid usage or exacerbation frequency compared to standard management. 5 This suggests that FeNO-driven management algorithms may need refinement, and FeNO levels may relate to atopy as much as to asthma control. 5

Phenotyping for Biologic Therapy

FeNO identifies T2 (Type 2) allergic inflammation phenotype, which is crucial for selecting patients who will respond to biologic treatments targeting IL-4/IL-13 pathways. 2, 3 This represents an emerging and important application in severe asthma management. 3

Factors Affecting FeNO Interpretation

Factors That Increase FeNO

• Persistent and/or high allergen exposure (strong recommendation, moderate quality evidence) 1
• Atopy (even without active asthma) 1
• Tall stature 1
• Male sex 1

Factors That Decrease FeNO

• Smoking 6
• Recent spirometry 6
• ICS therapy 1

Factors to Control During Measurement

• Avoid nitrate-rich diet before testing 6
• Avoid contamination from nasal NO 6
• Standardized measurement at 50 mL/s flow rate 6

Common Pitfalls to Avoid

1. Do not use FeNO as the sole diagnostic test for asthma—it identifies eosinophilic inflammation, not asthma per se. 1

2. Do not ignore clinical context with intermediate values—these require serial monitoring and correlation with symptoms, lung function, and other clinical factors. 1

3. Do not assume all asthma patients will have elevated FeNO—neutrophilic and paucigranulocytic phenotypes exist. 1

4. Do not overlook alternative diagnoses when FeNO is high—eosinophilic bronchitis and some COPD patients also have elevated FeNO. 1, 6

5. Account for atopy—atopic individuals without asthma may have elevated FeNO as their baseline normal. 1

6. Establish individual baseline during clinical stability—serial measurements using the patient as their own control ("personal best") is more informative than single values. 1