What conditions and factors can cause an elevated fractional exhaled nitric oxide (FeNO) level?

Causes of Elevated FeNO

Elevated FeNO primarily reflects eosinophilic airway inflammation, with asthma being the most common cause, but atopy, allergen exposure, and certain respiratory conditions also raise levels independent of asthma diagnosis. 1

Primary Pathophysiologic Causes

Eosinophilic Airway Inflammation

• Asthma is the predominant cause of elevated FeNO, with levels correlating moderately well with eosinophilic inflammatory pathways in central and peripheral airways 2
• FeNO >50 ppb (≥35 ppb in children) indicates eosinophilic inflammation is likely present and predicts corticosteroid responsiveness 1
• The relationship between FeNO and eosinophilia persists in steroid-naïve patients but may be altered by inhaled corticosteroid therapy 1
• Mucosal eosinophil count and eosinophil activation (evidenced by major basic protein deposition) correlate with FeNO levels in bronchial biopsies 1

Poorly Controlled or Untreated Asthma

• Loss of asthma control when inhaled corticosteroids are withdrawn causes FeNO to increase significantly 1
• Patients in apparent clinical remission from atopic asthma may still have raised FeNO with underlying eosinophilic inflammation on biopsy 1
• FeNO increases by approximately 60% during late-phase allergen responses in atopic asthma 1

Host Factors That Elevate FeNO

Atopy and Allergic Sensitization

• Atopy is often associated with higher FeNO levels even in the absence of asthma 1
• Atopic males (nonsmokers) have FeNO values of 11.2-56.5 ppb compared to 9.5-47.4 ppb in non-atopic males 3
• The American Thoracic Society recommends accounting for persistent and/or high allergen exposure as a factor associated with higher FeNO 1

Demographic Factors

• Males have FeNO values 20-30% higher than females 1, 3
• Age affects FeNO in children younger than 12 years, with higher levels observed with increasing age 1
• The menstrual cycle may influence FeNO levels in females 1

Environmental and Exposure-Related Causes

Allergen Exposure

• FeNO levels increase in grass-pollen allergic patients during pollen season, even without significant changes in airway function 1
• Mite-allergic asthmatic children show prompt FeNO increases after short periods of natural re-exposure to mites 1
• Moving to allergen-free environments (e.g., mite-free mountain settings) causes prompt FeNO decreases 1

Air Pollution

• Air pollution is an environmental determinant that may contribute to elevated FeNO and the high prevalence of allergic disease 4

Other Respiratory Conditions

Eosinophilic COPD

• In eosinophilic COPD, each 50 cells/μL higher blood eosinophil count is associated with a 3.2% increase in FeNO 5
• Asthma history in COPD patients is associated with 29.1% higher FeNO 5
• FeNO ≥25 ppb in COPD correlates with higher exacerbation events and poor clinical outcomes 6

Allergic Rhinitis

• Allergic rhinitis is a clinical determinant of increased FeNO levels in children 4

Important Clinical Caveats

Factors That Lower FeNO (Creating False Negatives)

• Current smoking significantly reduces FeNO by approximately 20-40%, which can mask underlying eosinophilic inflammation 1, 3, 2
• Passive smoking causes only transient (≈30 minutes) FeNO reduction 1
• Corticosteroid treatment reduces FeNO two- to fourfold, with effects potentially visible as early as 3 days 1

Scope for False Positives and Negatives

• The American Thoracic Society acknowledges significant scope for both false positives and false negatives when using FeNO as a surrogate for clinically relevant eosinophilia 1
• Important dissociation exists between eosinophilic airway inflammation and symptoms/disordered airway function in some asthma phenotypes 1
• FeNO values between 25-50 ppb (20-35 ppb in children) should be interpreted cautiously with reference to clinical context 1