What does a high Fractional exhaled Nitric Oxide (FeNO) level indicate in asthma and how is it managed?

High FeNO in Asthma: Significance and Management

High fractional exhaled nitric oxide (FeNO) levels in asthma indicate the presence of eosinophilic airway inflammation and predict likely responsiveness to corticosteroid therapy. This biomarker provides valuable information about the underlying inflammatory process that drives asthma symptoms and exacerbations.

What FeNO Measures and Interpretation

FeNO is a non-invasive biomarker that measures the concentration of nitric oxide in exhaled breath. In asthma, it primarily reflects:

• T-helper 2 (Th2) cell-driven inflammation
• Eosinophilic airway inflammation
• Upregulation of inducible nitric oxide synthase (NOS2) in airway epithelial cells 1

Interpretation of FeNO Values

The American Thoracic Society (ATS) guidelines recommend the following cut-off values:

Category	Adults (ppb)	Children (ppb)
Low	<25	<20
Intermediate	25-50	20-35
High	>50	>35

1, 2

Clinical Significance of High FeNO

1. Indicates Eosinophilic Inflammation: High FeNO (>50 ppb in adults, >35 ppb in children) strongly correlates with eosinophilic airway inflammation 1, 3. Studies show subjects with high FeNO have significantly higher percentages of eosinophils in bronchoalveolar lavage (BAL) compared to those with normal FeNO levels 3.

2. Predicts Steroid Responsiveness: High FeNO levels predict likely responsiveness to inhaled corticosteroids (ICS) with strong predictive value 1, 4. This makes FeNO particularly useful for determining who might benefit from steroid treatment.

3. Identifies Risk of Exacerbations: Elevated FeNO is associated with increased risk of asthma exacerbations and loss of control when inhaled steroids are reduced or withdrawn 1, 5.

4. Reflects Allergic/Atopic Status: High FeNO is strongly associated with atopy, regardless of asthma diagnosis 6. Patients with both asthma and atopy typically have the highest FeNO levels 6.

5. Supports Asthma Diagnosis: While not diagnostic on its own, high FeNO provides supportive evidence for asthma diagnosis when combined with clinical symptoms 1, 7.

Management Implications of High FeNO

1. Initiating or Adjusting Corticosteroid Therapy

• High FeNO (>50 ppb) strongly predicts steroid responsiveness 1
• Even intermediate FeNO levels (25-50 ppb) are associated with significant improvement in asthma control after starting ICS treatment 4
• Consider initiating or increasing ICS dose in patients with elevated FeNO and uncontrolled symptoms

2. Monitoring Treatment Response

The ATS recommends:

• A significant response to anti-inflammatory therapy is indicated by a reduction of at least 20% in FeNO for values over 50 ppb or more than 10 ppb for values lower than 50 ppb 1
• Serial measurements help determine trends and monitor treatment efficacy

3. Assessing Adherence

• FeNO typically decreases within days to weeks after starting ICS therapy 1
• Persistently high FeNO despite prescribed ICS therapy may indicate poor adherence or incorrect inhaler technique 1, 7

4. Allergen Exposure Management

• FeNO increases with allergen exposure in sensitized patients 1
• Consider allergen avoidance strategies for patients with elevated FeNO and known allergic triggers
• FeNO levels decrease when allergic asthmatic children are removed from allergen exposure 1

Important Caveats and Considerations

1. Not the Sole Diagnostic Tool: FeNO should not be used in isolation for diagnosis or management decisions but integrated with clinical assessment and other tests 2, 7

2. Confounding Factors: Several factors can affect FeNO levels:

   • Age (higher in children)
   • Atopy (increases FeNO independent of asthma)
   • Smoking (decreases FeNO)
   • Recent respiratory infections
   • Diet (nitrate-rich foods can increase FeNO)

3. Phenotype Considerations: Not all asthma is associated with high FeNO:

   • Non-eosinophilic/neutrophilic asthma may have normal FeNO
   • Patients may have normal FeNO when asymptomatic or after steroid treatment

4. Monitoring Algorithm:

   • Establish baseline FeNO before starting ICS
   • Recheck 4-8 weeks after initiating or changing therapy
   • If FeNO remains high despite therapy, assess: a) Adherence to medication b) Inhaler technique c) Ongoing allergen exposure d) Need for step-up therapy

In conclusion, high FeNO in asthma represents an important biomarker of Th2-driven eosinophilic inflammation that helps guide treatment decisions, particularly regarding corticosteroid therapy. Regular monitoring of FeNO can improve asthma management by providing objective evidence of underlying inflammation that may not be apparent from symptoms or lung function tests alone.