FeNO Helps Doctors Manage Asthma Treatment Accurately

QUICK OVERVIEW

I. The Imperative for Precision Phenotyping in Mild Asthma

1.1 What is Asthma Heterogeneity, and Why is Phenotyping Important?

The Global Initiative for Asthma (GINA) defines asthma as a heterogeneous disease. Chronic airway inflammation characterizes it, impacting approximately 358 million individuals worldwide. Consequently, the disorder is clinically complex. It exhibits numerous distinct phenotypes and endotypes, such as Type 2 helper T-cell high (Th2-high) and Th2-low disease, necessitating a move toward personalized medicine. Specifically, cytokines like Interleukin-13 (IL-13) primarily drive Type 2 (T2) inflammation, making it a crucial targetable trait. Therefore, Fractional exhaled nitric oxide (FeNO) has emerged as a significant element in achieving precision medicine. It rapidly and non-invasively characterizes these underlying disease phenotypes and endotypes.

1.2 What is the Unique Diagnostic Challenge in Mild Disease?

Clinicians fundamentally rely on demonstrating recurrent, at least partially reversible, airway obstruction to diagnose asthma. However, this demonstration can be particularly challenging in patients with mild asthma. Airflow obstruction may not be evident during routine spirometry. Thus, clinicians must often resort to more complex or resource-intensive modalities. These include serial peak flow measurements or time-intensive, costly bronchial provocation testing. Furthermore, specialized laboratories often restrict these tests.

1.2.1 How does FeNO Help Characterize Underlying T2 Inflammation in Mild Asthma?

A critical consideration in this cohort is the high prevalence of underlying inflammation. Indeed, T2 inflammation is prevalent in a large proportion of asthmatics. Clinicians find it in up to 80% of those who are corticosteroid-naïve. Consequently, for patients presenting with suspicious symptoms but lacking definitive functional evidence of variable obstruction, FeNO’s utility is magnified. Its value confirms the presence of the T2 inflammatory mechanism (endotype) that often underlies the symptomatic presentation of mild asthma. Crucially, it does not confirm the clinical disease definition. This ability to rapidly assess the biological driver provides essential objective evidence. Therefore, it guides the decision to initiate appropriate anti-inflammatory therapy, such as inhaled corticosteroids (ICS), even when physiological testing is inconclusive.

1.3 What is the Rationale for FeNO Assessment in Mild Asthma?

FeNO is a non-invasive, cost-effective, and point-of-care biomarker used to detect T2 airway inflammation. International guidelines, including the American Thoracic Society (ATS) and the National Institute for Health and Care Excellence (NICE), propose measuring FeNO as an adjunct during diagnostic evaluation. They also propose it for subsequent monitoring of airway inflammation in individuals suspected of having asthma. For instance, longitudinal phenotyping studies, such as the ADEPT cohort, consistently identify mild, Type 2, early-onset disease with preserved lung function. This supports the systematic use of FeNO. Ultimately, the early identification of this stable, treatable T2 trait confirms that mild asthma is frequently a stable biological entity. It requires consistent endotype-specific management rather than representing simply a transient illness.

II. Pathophysiology, Methodology, and Clinical Cut-Points of FeNO

2.1 What is the Biochemical Basis of FeNO Elevation?

Nitric oxide (NO) is a biological messenger. It acts as a smooth muscle relaxing agent and neurotransmitter at low concentrations, but it functions as an inflammatory mediator at high concentrations within the lung. The fractional concentration of exhaled NO (FeNO) measures NO concentration in the exhaled breath. Clinicians detect elevated FeNO levels in asthmatic patients. Specifically, these levels primarily result from the increased expression of inducible nitric oxide synthase (iNOS) within the airway epithelial cells, driven mainly by the T2 cytokine Interleukin-13 (IL-13). Therefore, the standardized, non-invasive measurement of FeNO provides a complementary tool for assessing airways disease.

2.2 What are the Standardized Clinical Cut-Points for Interpreting FeNO (ATS/ERS Consensus)?

Clinical guidelines utilize standardized cut-points to interpret FeNO results. In fact, these cut-points aid in diagnostic evaluation and treatment stratification. These cut-points are crucial for assigning an objective measure of T2 inflammatory burden:

2.2.1 How are High FeNO Levels Interpreted?

High FeNO (Elevated): Levels exceeding 50 parts per billion (ppb) in adults and 35 ppb in children are considered high. Crucially, this range strongly supports an asthma diagnosis driven by significant eosinophilic inflammation. It indicates a high likelihood of responsiveness to corticosteroid therapy. For example, one recommendation suggests a 50 ppb cut-off point. This offers high specificity (greater than 90%) and supports an asthma diagnosis. This high degree of certainty allows clinicians to confidently assign a T2 endotype, providing a strong evidence base for selecting ICS as the optimal initial therapy.

2.2.2 How are Intermediate and Low FeNO Levels Interpreted?

Intermediate FeNO (Indeterminate): Concentrations ranging between 25 and 50 ppb in adults, and 20 and 35 ppb in children, are considered intermediate. Therefore, interpretation in this range requires clinicians to carefully integrate the result with the overall clinical context and other assessment metrics. Clinicians may need to dynamically track FeNO levels over time to reveal an underlying or emerging asthma diagnosis. Consequently, they should not rely on a single, isolated measurement.

Low FeNO: Values below 25 ppb in adults and 20 ppb in children suggest that significant eosinophilic airway inflammation is unlikely. Alternatively, they also suggest that medication successfully suppresses existing inflammation.

Table 1 summarizes the consensus clinical cut-points clinicians use for FeNO interpretation in asthma management.

2.3 What are the Interpretation Limitations, and What is the Non-Eosinophilic Asthma Paradox?

While highly useful, FeNO is not a perfect diagnostic tool. It has lower sensitivity, meaning it is not effective for ruling out asthma. This limitation, in turn, reflects asthma’s fundamental heterogeneity. Specifically, approximately 50% of patients, including those with mild-to-moderate disease, exhibit a Non-Eosinophilic Asthma (NEA) phenotype. NEA can be neutrophilic or paucigranulocytic. Therefore, a low FeNO reading in a persistently symptomatic patient is highly informative. It directs the clinician away from a T2-targeting strategy and toward investigating alternative non-T2 inflammatory pathways.

In addition, confounding factors can also influence FeNO measurements. For example, smoking is known to suppress FeNO levels, which complicates the assessment of underlying T2 inflammation in current smokers. Furthermore, conditions such as viral respiratory infections and active bronchoconstriction cause FeNO values to fluctuate.

III. Diagnostic Stratification and Predictive Performance in Mild Asthma

3.1 What do Quantitative Performance Metrics Reveal about FeNO’s Utility?

Studies evaluating FeNO’s diagnostic performance, often in general asthma populations including mild cases, highlight its utility in identifying elevated inflammatory states. For instance, in one cohort comparing asthmatic and non-asthmatic groups, the median FeNO concentration was significantly higher in the asthma group (49.5 ppb) than in the non-asthma group (23 ppb). This demonstrates a strong difference in inflammatory burden ($p<0.001$).

However, the choice of cut-off dramatically affects utility. When assessing the predictive value for diagnosis, a low 25 ppb cut-off yielded a sensitivity of 75.4% but only a 47.9% specificity. Conversely, high FeNO levels (such as the 50 ppb threshold) are highly specific for T2 inflammation. These quantitative findings confirm FeNO’s principal value in mild asthma. Specifically, it confirms the high-end T2 inflammatory burden rather than serving as a general rule-out test.

3.2 How does FeNO Facilitate Identification of the T2-High Phenotype?

FeNO recognizes and confirms the eosinophilic asthma phenotype. In general, Eosinophilic infiltration characterizes T2-high asthma. It typically involves elevated levels of both FeNO and peripheral Blood Eosinophil Counts (BEC). Population surveys weighted toward mild disease demonstrated clear relationships. Participants with allergic asthma (especially never or former smokers) exhibited significantly higher FeNO values compared to those without allergic asthma. Consequently, this stratification capacity allows for targeted early intervention. It helps patients whose asthma is confirmed to be driven by T2 inflammatory mechanisms.

3.3 What is FeNO’s Prognostic Value in Risk Stratification?

Beyond diagnosis, high FeNO levels provide significant prognostic information. Higher levels associate with increased risk for future asthma exacerbations and overall lower lung function. Data suggest combining elevated FeNO levels with BEC offers a higher odds ratio for predicting lower lung function than using either measure alone. Moreover, a FeNO cutoff of $\ge 57$ ppb specifically associated with a more rapid trajectory of lung function decline in cohorts of adults newly diagnosed with asthma.

Generally, asthma management in routine practice often relies heavily on subjective symptom scores, such as the Asthma Control Test (ACT). Nevertheless, objective testing has shown abnormal lung function (spirometry) or raised FeNO ($\ge 35$ ppb) remains common in 54% of children who otherwise report good asthma control. This dissonance between patient perception and objective biological status demonstrates a risk: specifically, relying exclusively on symptoms risks overlooking individuals at high biological risk of future severe asthma attacks. FeNO is therefore a necessary tool for objective risk assessment. It provides a crucial biological corrective to symptom-based evaluations.

IV. FeNO’s Therapeutic Utility: Monitoring and Adjusting ICS Regimens

4.1 How Does FeNO Predict Inhaled Corticosteroid (ICS) Response?

FeNO is one of the most established predictors of therapeutic response to inhaled corticosteroids. The overall low quality of the evidence base across all asthma management strategies led an expert panel to deliver a conditional recommendation. They suggested FeNO measurement is beneficial and should be used in conjunction with usual care when clinicians consider treatment for asthmatic patients. Ultimately, this recommendation affirms FeNO’s role as a practical clinical guide for initiating therapy.

4.2 How is FeNO Used to Monitor Treatment Adherence and Effectiveness?

The dynamic monitoring of FeNO is central to ensuring optimal control in mild asthma. In short, FeNO measurably confirms how effectively the daily ICS regimen suppresses airway inflammation. Longitudinal studies confirm this utility. They show significant decreases in mean FeNO levels across mild, moderate, and moderately severe asthmatic groups following ICS treatment. Thus, the magnitude of the FeNO decrement upon commencing ICS therapy supports its clinical value. It monitors ongoing airway inflammation and gauges the rate of therapeutic response and adherence.

A disparity sometimes exists: a patient reports symptomatic improvement quickly, yet an objective signal, such as a high FeNO level, persists. FeNO ensures clinicians sustain treatment until they control the underlying pathophysiology. Consequently, this reduces the risk of rapid relapse and ensures the long-term goal of preventing future exacerbations.

4.3 How is FeNO Incorporated into Management Algorithms for ICS Dosing?

Clinicians successfully integrate FeNO measurements into specific management algorithms designed to adjust ICS dosing. In certain protocols, clinicians escalate the ICS dose when FeNO levels exceed a high cut-point. Conversely, the ICS dose may be carefully reduced when FeNO levels fall below a low cut-point. This strategy is particularly important in mild asthma. Minimizing cumulative corticosteroid exposure is a core goal here, mirroring the precision principles applied in severe asthma management. Therefore, FeNO supports confident de-escalation of therapy when clinicians confirm the biological activity as low, providing an objective measure of inflammatory control.

4.4 Can FeNO Prognosticate Response to Biologic Therapies?

Clinicians generally reserve biologics for severe asthma. Nevertheless, foundational evidence supports using FeNO to predict responsiveness to anti-T2 biologics (such as dupilumab or omalizumab). This validates FeNO’s reliability as a robust T2 endotype marker across the disease spectrum. Specifically, higher baseline FeNO values associate with greater asthma control and reduced exacerbation risk in patients receiving these targeted anti-T2 therapies.

V. Comparative Biomarker Analysis: FeNO versus Eosinophil Metrics

5.1 Why is Sputum Eosinophil Analysis Impractical in Mild Asthma?

Sputum eosinophil analysis has traditionally been the gold standard for defining eosinophilic airway inflammation and guiding treatment in clinical trials. Studies consistently show a reduction in sputum eosinophil counts after treatment with ICS and specific anti-eosinophil agents. However, the complex procedure of sputum induction and analysis necessitates specialist expertise. This makes it impractical and inaccessible for routine primary care management of mild asthma. Consequently, FeNO and Blood Eosinophil Counts (BEC) serve as the necessary, practical, non-invasive surrogates.

5.2 What is the Synergy and Discordance Between FeNO and Blood Eosinophil Counts (BEC)?

Both FeNO and BEC are established biomarkers that characterize T2-high asthma. FeNO reflects localized inflammation, primarily driven by IL-13 activity in the airway epithelium. In contrast, BEC reflects the systemic eosinophil burden; IL-5 production primarily drives it.

The relationship between these markers is complex. They often show synergy—combining elevated FeNO and BEC yields higher predictive value for assessing adverse outcomes, such as lower lung function, than either measure alone —but they do not always correlate. This discordance provides valuable information about the localized versus systemic nature and severity of the T2 drive. For example, patients receiving anti-IL-5 therapy for severe asthma showed greater improvements in lung function and inflammatory markers when they had both high BEC and high FeNO, compared to those with high FeNO but low BEC.

Furthermore, systemic or high-dose ICS highly suppresses BEC levels. This can mask the underlying T2 nature of the disease, especially in a variable condition like severe asthma. Mild asthma with intermittent ICS use also carries this suppression risk. Therefore, FeNO provides a complementary, localized signal less prone to this suppression, underscoring the need for a multi-biomarker approach for robust T2 classification in mild disease.

VI. Dynamic Phenotyping and Longitudinal Assessment

6.1 Why are Static (Cross-Sectional) Phenotyping Studies Insufficient?

Asthma is inherently variable. Triggers like viral infections and environmental allergens influence it. However, most initial phenotyping and omics studies have been cross-sectional. They rely on a single time point assessment. Crucially, this methodological limitation fails to capture the evolution or stability of disease characteristics and gene expression over time. It carries the intrinsic risk of misclassifying transient inflammatory states as stable, persistent disease.

6.2 Why is Longitudinal Validation Essential for Mild Phenotypes?

Advanced studies underscore the importance of longitudinal data. The ADEPT study, for instance, validated adult asthma clusters longitudinally, using clinical and biomarker characteristics. This research successfully identified stable clusters, including the “mild, type 2, early-onset disease and preserved lung function” phenotype. Consequently, longitudinal assessment is essential to define the stability and clinical significance of phenotypes identified in mild asthmatic populations.

6.3 How is FeNO Used for Tracking Temporal Variability in Mild Asthma?

FeNO is invaluable for dynamic phenotyping. Tracking its concentration over time is often more reliable than using an isolated positive test to reveal an underlying or ongoing asthma diagnosis.

FeNO concentration demonstrates significant temporal variability in mild allergic asthmatic children. Exposure to airborne allergens, such as pollens during grass pollen season, leads to measurable FeNO increases. Subsequently, these return to pre-seasonal baseline values. This observation demonstrates FeNO can distinguish between intermittent, transient inflammation linked to specific exposures and stable, persistent T2 disease. Ultimately, this ability allows clinicians to precisely tie controller usage to periods of biological activity. Therefore, for patients exhibiting highly seasonal or intermittent FeNO increases, the objective FeNO signal provides the rationale they need to implement episodic controller therapy. This customizes the treatment duration based on inflammatory burden rather than adhering to a potentially unnecessary fixed daily regimen.

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VII. Algorithmic Frameworks: Conceptual Adaptation from Severe to Mild Asthma

7.1 What is the Eosinophilic Gradient Algorithm in Severe Asthma?

The International Severe Asthma Registry (ISAR) is a major initiative. It focuses on collecting longitudinal, real-life data for patients with severe asthma. ISAR research has proven critical in characterizing severe asthma phenotypes. It led to the development of a consensus-driven, multicomponent eosinophilic gradient algorithm. This algorithm utilizes readily accessible variables, including FeNO and BEC concentrations. In short, it rigorously characterizes T2 inflammation in severe asthmatics, informing the selection of targeted biologic treatments.

7.2 How can Gradient Principles be Applied to Mild Asthma Phenotyping?

The rigorous, multi-component, and longitudinal framework established by ISAR is conceptually transferable. It is highly relevant for improving precision phenotyping in mild asthma. While the therapeutic goal in mild asthma is not biologic selection but precision prevention, an adapted T2 gradient algorithm could, however, create a highly accurate system for risk stratification. This system would integrate quantitative FeNO, BEC, and clinical characteristics (such as atopy and age of onset).

This algorithmic approach addresses single-point assessment’s fundamental weakness: intermittent ICS use in mild asthma can transiently suppress BEC, masking a high T2 status. Instead, clinicians adopt the ISAR principle—using multiple, repeated measures of both localized (FeNO) and systemic (BEC) inflammation—to prevent misclassifying a patient with persistent T2 burden as non-T2. Thus, this ensures accurate identification of high-risk T2-high mild asthmatics. They immediately receive the appropriate GINA Step 2 or 3 controller therapy, preventing disease progression and subsequent functional decline.

7.3 How Does FeNO Contribute to Precision Guideline Implementation?

Major international guidelines, including ATS and NICE, recommend FeNO testing for initial diagnosis and subsequent monitoring of airway inflammation. Its utility ensures objective, quantifiable measures of T2 burden guide therapeutic decisions, such as the escalation to a daily controller regimen. In essence, FeNO is beneficial when clinicians contemplate treatment. It provides the clinical rationale for initiating or adjusting ICS therapy, moving management beyond purely empirical decisions based solely on poorly controlled symptom scores.

VIII. Future Research Directions

FeNO has an indispensable role in the management and phenotyping of mild asthma. As a non-invasive, objective biomarker, it provides reliable, quantitative evidence of the underlying T2 endotype. This allows clinicians to make evidence-based decisions regarding diagnosis, ICS initiation and titration, monitoring treatment adherence, and comprehensive future risk stratification. Specifically, FeNO’s high specificity at elevated levels is critical. It allows confident assignment of the treatable T2 trait, maximizing the probability of a positive therapeutic outcome with ICS.

However, significant gaps remain in applying precision medicine to asthma. The data consistently show approximately 50% of mild asthmatics exhibit a non-eosinophilic phenotype. Unfortunately, FeNO is ineffective in characterizing this large subgroup. Their inflammatory drivers (neutrophilic or paucigranulocytic) are likely non-responsive to ICS. Therefore, future research must prioritize identifying and validating accessible biomarkers suitable for routine clinical use. This will accurately phenotype the non-eosinophilic population and guide alternative, non-ICS therapeutic strategies.

Furthermore, leveraging the rigorous methodological principles established by registries like ISAR is paramount. Researchers need to develop and longitudinally validate simplified, multi-biomarker T2 risk stratification algorithms tailored specifically for mild asthma cohorts. Ultimately, these algorithms must systematically integrate FeNO measurements with other clinical and biological data. This will optimize the timing, frequency, and overall utility of FeNO testing in routine primary care and specialist practice.

REFERENCE

NATURE: npj primary care respiratory medicine

Refining mild asthma phenotyping with FeNO: a population-based evaluation

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