Nicola Hanania, MD, MS

"Navigating Severe Asthma Management Without Direct TSLP Biomarkers" takes up the question of what clinicians cannot currently measure.

Navigating Severe Asthma Management Without Direct TSLP Biomarkers

Dr. Chupp puts two questions to Dr. Hanania. Do particular biomarker patterns change how he treats a patient? And given that alarmins are now considered important targets, is there any biomarker for them, or anything on the horizon? Dr. Hanania first adds a use his colleagues did not mention. Beyond prediction and pharmacodynamic response, he uses biomarkers prognostically, to identify patients at risk of exacerbation, and notes emerging data suggesting composite biomarkers may predict that risk better than single ones.

On alarmins, his answer is direct: no specific biomarker exists, particularly for TSLP. But he offers a workaround rooted in the pathway. Because TSLP drives downstream signaling, blocking it lowers IgE, eosinophils, and FeNO. So while FeNO reflects the IL-13 pathway specifically, a master regulator sitting above all three pathways is reflected, indirectly, in all three of the biomarkers already available. He knows of nothing in the pipeline specific to TSLP or IL-33, and notes these cytokines are not easily measured, so clinicians cannot identify a high-TSLP patient and target accordingly.

He then returns to the non-type 2 gap. Epithelial cytokines act on that pathway too, but the measurement tools are poor. Airway neutrophils have been examined and are not as good as sputum or blood eosinophils. He calls biomarkers reflecting non-type 2 inflammation a major unmet need, made more pressing precisely because TSLP influences that pathway.

Dr. Hanania closes by agreeing with the overlap point. Isolated high eosinophils with a predominant IL-5 pathway occur, but in allergic and non-allergic type 2 asthma all the markers are often elevated together. Deciding which pathway predominates, he admits, is usually a guessing game.

In "Low T2 Asthma: What Anti-TSLP Data Show in Low-Eosinophil Patients," the panel will examine what the trial data show in patients whose biomarkers stay low.

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Alarmins are now leading therapeutic targets, yet no biomarker measures them. Dr. Hanania explains what blocking TSLP reveals downstream, and where the real measurement gap lies.

In "Asthma Biomarkers: Using Eosinophils, FeNO, and IgE to Guide Therapy," the panel gets specific about the three biomarkers in routine use.

Asthma Biomarkers: Using Eosinophils, FeNO, and IgE to Guide Therapy

Dr. Chupp asks Dr. Wechsler how he uses biomarkers when a patient shows several at once. Dr. Wechsler names the three currently in use: eosinophils in blood or sputum, exhaled nitric oxide, and IgE. Each can serve as a predictive biomarker, a response biomarker, or both. He draws the distinction concretely. Eosinophils fall when anti-IL-5 therapy is given, while IgE levels may not fall with anti-IgE therapy, making IgE a poor response marker.

His approach is to check all of them and build a full picture, alongside asthma severity judged by exacerbation frequency and decrement in lung function. More than one biomarker is elevated at least two thirds of the time, he says; isolated elevation is rare. So he looks for a dominant marker, one wildly out of proportion to the others, such as an eosinophil count of 1,000 or a nitric oxide level of 200. That happens occasionally and can guide therapy directly.

When no marker dominates, he turns to phenotypic features and comorbidities. Atopic dermatitis might steer him toward anti-IL-4 therapy, chronic sinusitis with nasal polyps toward another agent, and an eosinophilic granulomatosis with polyangiitis phenotype toward a different one again. Beyond that, he integrates patient-centered factors: dosing frequency, where the drug is administered, and what insurance will cover.

Dr. Ross agrees the tools are limited and says she would welcome gene-related options. Her population skews allergic, so an eosinophil count of 1,000 with atopic dermatitis, or an IgE of 3,000, does not necessarily implicate asthma. She asks how many conditions she can treat at once. For the purely asthmatic patient with no comorbidities, biomarkers carry far more weight.

Our next episode, " Navigating Severe Asthma Management Without Direct TSLP Biomarkers," puts the harder question to Dr. Hanania: what do you do when the marker you need does not exist?

Dr. Wechsler and Dr. Ross describe how they read overlapping results and what they weigh when no single marker dominates.

In "Treatable Traits in Asthma: Targeting Comorbidities Beyond the Lung," our experts turn to what the treatable traits framework looks like at the bedside.

Treatable Traits in Asthma: Targeting Comorbidities Beyond the Lung

Dr. Chupp asks Dr. Hanania for a concrete example, listing the candidates on the table: nitric oxide levels, blood eosinophils, allergic sensitization on skin testing, and specific IgE on blood testing. Which of these, he asks, actually counts as a treatable trait? Dr. Hanania offers allergic asthma as one, with the upper airway to be taken up later in the program. He notes some clinicians use eosinophilic asthma as a treatable trait, then immediately concedes the problem. Others would call it an endotype, and others still a phenotype. He admits the framework is not foolproof and that people argue about it.

He then widens the lens. Treatable traits have been applied across other pulmonary diseases, and the framework distinguishes pulmonary traits from extrapulmonary ones. That distinction carries his main clinical point. Even though he and Dr. Wechsler are pulmonologists trained to focus on the lung, these patients arrive with a long list of comorbidities that sit outside it. He names sleep apnea and gastroesophageal reflux as examples of extrapulmonary traits that need addressing alongside the airway.

Dr. Ross says this falls squarely into her camp. Allergists tend to see patients head to toe, and her patients carry the traits of allergic sensitization and a type 2 background: atopic dermatitis, eosinophilic esophagitis, and nasal polyps. Those traits, she argues, genuinely guide what a given patient is likely to respond to.

Dr. Chupp closes with the recurring challenge. There is tremendous overlap between the biomarkers and the clinical features in any individual patient. Even so, he says, the biomarkers available can still be used to personalize the approach.

Up next, in "Asthma Biomarkers: Using Eosinophils, FeNO, and IgE to Guide Therapy," Dr. Wechsler walks through how he reads the three biomarkers clinicians actually have.

A treatable trait is easier to endorse than to define. The panel works through what qualifies, and why extrapulmonary traits deserve the same attention as the airway itself.

"Asthma Phenotypes and Endotypes: Defining the Terms" takes up a vocabulary problem the field has never fully settled.

Asthma Phenotypes and Endotypes: Defining the Terms

Dr. Chupp notes that recognizing the epithelium as part of the immune system has forced clinicians to confront the disease's complexity, and that this complexity now shows up clinically as multiple subtypes. He asks each panelist to define the terms. Dr. Wechsler calls a phenotype the outward manifestation of a disease process, something a patient can describe: smoker or non-smoker, frequent exacerbator or not. Endotype refers to the underlying mechanism, which a patient cannot describe but a biomarker can reveal. He gives examples. Eosinophils identify an IL-5-driven eosinophilic endotype. High nitric oxide points to an IL-13-mediated process. Broadly, he says, there are two endotypes: type 2, mediated by IL-4, IL-5, and IL-13 and identified by allergies, eosinophils, or nitric oxide, and non-type 2, defined by the absence of those biomarkers and often neutrophilic or polygranulocytic. Phenotypes are useful because they point to endotypes; chronic rhinosinusitis with nasal polyps is a phenotype that flags type 2 biology.

Dr. Chupp presses on the disagreement, noting some clinicians classify eosinophils differently. Dr. Ross sees crossover rather than a clean line, using the phenotype as a marker for the biology underneath. She describes allergic asthma patients with very high IgE and seasonal presentation, and notes eosinophilic patients respond exceptionally well to steroid courses despite frequent exacerbations.

Dr. Hanania offers an iceberg analogy- above the water sits the clinical phenotype: early or late onset, allergic, smoke-related, obesity-related, exacerbation-prone. Below sits the endotype. He adds a third term, treatable traits, and argues it appeals to clinicians precisely because the available biomarkers remain limited and imperfect.

In "Treatable Traits in Asthma: Targeting Comorbidities Beyond the Lung," the panel will press Dr. Hanania for a concrete example of what a treatable trait actually is.

Phenotype, endotype, and treatable trait are used loosely and often interchangeably. The panel defines each term and tests where the boundaries between them break down.

Nicola Hanania, MD, MS

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