Suspected asthma with normal spirometry: FeNO thresholds to rule in and rule out

Design

Diagnostic meta-analysis with prospective primary care validation

Population

30 studies (7,141 adults, 989 children); 123 adults in DIVE

Primary outcome

AUC of FeNO and blood eosinophils vs bronchial provocation

Effect

FeNO AUC 0.80 adults; ≥65 ppb PPV 80%; <20 ppb NPV 93%; eosinophils AUC 0.65

A systematic review and meta-analysis in The Lancet Respiratory Medicine (September 2026) pooled 30 diagnostic studies (7,141 adults, 989 children) of exhaled nitric oxide (FeNO) and blood eosinophils in people with suspected asthma and normal spirometry, against bronchial provocation testing. It then replicated the findings prospectively in 123 adults referred from primary care (the DIVE cohort).

FeNO accuracy was good in adults (AUC 0.80, 95% CI 0.73 to 0.85) and fair in children (0.75). In adults at a primary care prevalence of 20%, FeNO of 65 ppb or more gave a positive predictive value of 80%, and under 20 ppb a negative predictive value of 93% — though 18% of asthma would be missed at that rule-out. In children, 30 ppb or more gave a PPV of 80% at the study prevalence. Blood eosinophils performed poorly (AUC 0.65) and added nothing. DIVE reproduced the adult results, with 89% overall accuracy for the thresholds. Accuracy fell within two weeks of inhaled corticosteroid use.

The rule-out threshold was derived post hoc, and the validation cohort was small and single-centre. A middle zone between 20 and 65 ppb still needs further testing.

The change is practical: where bronchial provocation is unavailable, as it is in much of primary care, a FeNO reading before treatment can settle many cases either way.

• Measure FeNO before starting an inhaled steroid in adults with suspected asthma and normal spirometry
• Treat FeNO of 65 ppb or more in an adult as strongly supporting asthma
• Treat FeNO under 20 ppb as making asthma unlikely, but reconsider if symptoms persist
• Refer or test further when FeNO is between 20 and 65 ppb
• Do not use blood eosinophils to diagnose asthma — they added nothing to FeNO

Why it matters

It turns FeNO into a usable diagnostic step for clinics without access to bronchial provocation testing.

Don't overread it

The rule-out threshold was derived post hoc and still misses about one in five cases of asthma.

The statistics, in plain English

Positive predictive value depends on how common asthma is among those tested. At 20% prevalence, a FeNO of 65 ppb or more means about 4 in 5 people have asthma; a FeNO under 20 ppb means about 93 in 100 do not — but because asthma is common, that still misses 18% of cases.

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