When should fractional exhaled nitric oxide testing be used in the follow‑up of children with asthma aged ≥5 years?

FeNO in Follow-Up of Childhood Asthma

FeNO should be used in follow-up to guide treatment adjustments and predict exacerbations, particularly when measured serially over time, with rising levels (especially ≥25 ppb) indicating inadequate control of eosinophilic inflammation and increased risk of hospitalization.

Current Guideline Context

The available guidelines focus primarily on FeNO's role in diagnosis rather than follow-up monitoring 1, 2, 3. The European Respiratory Society (2021) recommends FeNO ≥25 ppb as supportive of asthma diagnosis in children aged 5-16 years 1. However, this diagnostic threshold provides a foundation for understanding what constitutes elevated airway inflammation during follow-up.

Evidence for FeNO in Monitoring and Follow-Up

Serial Measurements Predict Morbidity

• Rising FeNO levels over time are associated with increased hospitalizations (β = 16.1 for ≥2 hospitalizations in the past year) and higher disease burden in urban minority children with persistent asthma 4.

• Serial FeNO measurements can identify children at risk for asthma-related morbidity, with increases in FeNO correlating with worse outcomes 4.

• FeNO-guided asthma management reduces exacerbations compared to usual care (OR 0.77,95% CI 0.62-0.94) based on meta-analysis of 9 randomized trials including 1,885 children 5.

Baseline FeNO Levels and Disease Severity

• Children with intermediate (25-50 ppb) and high (>50 ppb) FeNO levels show higher rates of lower airway obstruction (54% and 58% respectively) compared to those with low FeNO (<25 ppb, 33%) 4.

• Intermediate FeNO levels are associated with more annual hospitalizations (2.8 ± 6.2) compared to low and high FeNO groups 4.

Practical Application in Follow-Up

When to Measure FeNO During Follow-Up

• At routine follow-up visits to assess adequacy of anti-inflammatory therapy, particularly in children on inhaled corticosteroids 6, 5.

• When considering treatment adjustments, as FeNO adds a dimension beyond traditional tools (symptom scores, spirometry) for assessing asthma control 6.

• For early identification of exacerbation risk, as FeNO can detect worsening eosinophilic inflammation before clinical deterioration 6, 5.

Interpreting FeNO in Follow-Up

• Use 25 ppb as the threshold for clinically significant eosinophilic inflammation in children, consistent with diagnostic recommendations 1, 5.

• Monitor trends over time rather than relying on single measurements, as rising FeNO indicates inadequate control 4.

• Elevated or rising FeNO suggests need for treatment intensification, particularly increasing inhaled corticosteroid dose 6, 5.

Important Caveats and Limitations

What FeNO Does NOT Tell You

• FeNO correlates with total IgE (r = 0.572) but does not correlate with spirometry parameters (FVC, FEV1, FEV1/FVC) or bronchial hyperresponsiveness (PC20) 7.

• FeNO primarily reflects eosinophilic inflammation only—it will not detect non-eosinophilic asthma phenotypes 6, 5.

• The optimal cut-offs for triggering treatment changes remain unclear despite evidence that FeNO-guided care reduces exacerbations 5.

Technical Considerations

• FeNO measurement accuracy varies between devices, with differences equivalent to clinically important thresholds 5.

• FeNO should be measured before spirometry to avoid confounding from forced exhalation 2, 3.

• Children must be at least 4-5 years old to reliably perform FeNO measurements 6, 1.

Clinical Algorithm for FeNO in Follow-Up

For children ≥5 years with established asthma:

1. Measure FeNO at routine follow-up visits (every 3-6 months for persistent asthma) 6, 4.

2. If FeNO ≥25 ppb or rising from previous measurements:

   • Assess adherence to inhaled corticosteroids first 6
   • If adherent, consider increasing anti-inflammatory therapy 6, 5
   • Identify and address potential triggers 4

3. If FeNO <25 ppb and stable:

   • Current anti-inflammatory therapy is likely adequate for eosinophilic control 5
   • Continue monitoring symptoms and lung function, as FeNO alone does not capture all asthma phenotypes 7

4. If FeNO increases by >20% between visits:

   • This signals worsening inflammation and increased exacerbation risk 4
   • Intervene proactively before clinical deterioration 6

Key Pitfall to Avoid

Do not rely on FeNO alone for asthma management decisions—it must be integrated with symptoms, spirometry, and exacerbation history, as FeNO reflects only one dimension of asthma pathophysiology 6, 5, 7.