Alternative Methods in Identifying Allergic, Nonallergic Type 2 Asthma Endotypes Are Necessary

Issues remain with the current reliance on blood eosinophilic count (BEC) and fractional exhaled nitric oxide (Feno) level to define type 2 (T2)-high severe eosinophilic allergic and nonallergic asthma. Although molecular phenotyping of patients is advancing, clinical definition of true molecular endotypes in clinical practice is limited, wrote the authors of a study published in The Journal of Allergy and Clinical Immunology.¹

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Allergic asthma is when allergens—substances that cause allergic reactions and enter the body when breathed in, swallowed, touched, or injected—trigger a patient's symptoms related to asthma. To fight this, the immune system releases immunoglobulin E (IgE), of which too much can result in inflammation of the airways within the lungs. This inflammation makes it difficult for the patient to breathe, triggering an asthmatic flare-up or attack. It is most common in early childhood and steadily decreases throughout adulthood.² Conversely, nonallergic asthma is triggered by factors other than allergens. These may include viral respiratory infections, irritants in the air, exercise, severe weather, and drugs or certain food additives.2,³

An asthma endotype is a subtype of asthma that is driven by a specific mechanism or mediator, which implies that therapeutic targeting will aid efficacy. In clinical trials, the use of BEC and Feno biomarkers to stratify patients often leads to about a 50% reduction in exacerbation rate, and in some instances, it also improves both asthma control and lung function, with reduced need for oral corticosteroid use. Despite BEC and Feno levels being the current best biomarkers to stratify patients, they do not fully discriminate true molecular disease endotypes, resulting in a reduced capacity to identify patients who will or will not respond to a specific therapy, explained the authors.¹

BEC has remained the major criterion for the selection of patients with asthma and chronic obstructive pulmonary disorder for therapy with an anti-T2 monoclonal antibody. Alternatively, high Feno levels indicate the presence of other allergic diseases, such as allergic rhinitis and eosinophilic chronic bronchitis, and its sensitivity to corticosteroids allows for an increased potential for false-positive and false-negative results in indicating T2 asthma. In addition, differences in true molecular endotypes of inflammation can potentially explain the limited efficacy of T2 biologics in children with allergic and nonallergic asthma with T2-high disease.¹

Further, regarding clinical trials with biologics, the inhaled allergen challenge model must be interpreted carefully, particularly in younger patients who have allergic asthma, the authors explained. There is also the potential for new, noninvasive methods of airway sampling, used alongside methodological developments for quantitation of novel biomarkers. The development of nasal allergen challenge models followed by serial nasosorption sampling allows for investigators to study the molecular basis of an allergic reaction over time.¹

Nasosorption sampling has also proven to be invaluable in the assessment of respiratory viral infections, with precise quantitation of viral load, interferon production, secretory specific immunoglobulin A, and the microbiota. However, in asthma, nasosorption biomarkers require standardization and validation in relation to established blood and sputum biomarkers, as well as comparison with bronchial inflammation.¹

Nasosorption has also been highlighted for its repeated sampling and tracking changes in immune markers such as IL-5 and eosinophil-derived neurotoxin (EDN) over time in individuals during respiratory viral and nasal allergen challenges. While it allows for point-of-care assay development due to high EDN levels, a disadvantage is that the nose might not accurately reflect the asthmatic airways or provide information about the innate T2 response. Further studies that compare nasosorption results with BEC and sputum samples are needed to determine its reliability and discriminatory power, the authors noted.¹

In recent years, the sampling of airways from a variety of compartments by using multiple different sampling methods has been attempted. In addition, an eosinophil peroxidase (EPX) lateral flow assay has recently been developed for rapid sputum analysis, according to the authors. There are also efforts to define specific patterns of urinary metabolites and breath volatiles, which may help the identification and specific treatment of allergic and nonallergic asthma.¹

The authors wrote there is a major challenge for clinicians, pharmaceutical companies, and regulatory bodies in the investigation and validation of these novel methods of airway sampling and the biomarkers that are measured. They noted an international workshop focused on the standardization of sputum methodology as being transformative in understanding T2 asthma, but there is now a need for consensus on standardized protocols for newer methods of sampling and biomarker analysis. Ultimately, the goal is to identify patients with allergic and nonallergic asthma who have a wide range of true molecular endotypes to optimize rational, specific, and anti-inflammatory therapies.¹

REFERENCES

1. Adcock IM, Mumby S, Hansel TT. Identifying allergic and nonallergic type 2 asthma endotypes: Moving beyond blood eosinophil counts and fractional exhaled nitric oxide. J Allergy Clin Immunol. 2025. doi:10.1016/j.jaci.2025.03.003

2. Asthma and Allergy Foundation of America. Allergens and Allergic Asthma. Accessed April 16, 2025. https://aafa.org/asthma/asthma-triggers-causes/allergic-asthma/

3. American College of Allergy, Asthma, & Immunology. Non-Allergic Asthma. Accessed April 16, 2025. https://acaai.org/asthma/types-of-asthma/non-allergic-asthma/