Jacqueline Ross, MD, a physician at Allergy Partners of New Jersey.

Jacqueline Ross, MD

This episode, "Both Upper and Lower Airway Diseases," features the panel on the patients they consider their sickest.

Managing Both Upper and Lower Airway Diseases

Dr. Chupp notes patients with both upper and lower disease can be the sickest, and asks Dr. Ross how aspirin desensitization fits in the biologic era. It has changed, she says. In fellowship it was weekly, done post-surgically, and cumbersome, requiring multiple consecutive days. Biologics now reduce mediators enough that a patient with cardiac risk factors may tolerate aspirin without exacerbating. She notes a partial revival: high prostaglandin D2 patients may respond well to desensitization. Still, once patients learn the alternative is lifelong high-dose aspirin with its own risks, they choose biologics.

Dr. Wechsler frames upper airway disease as one of the comorbidities that makes asthma difficult to control. He looks for it deliberately and treats both if he can, noting some therapies favor the upper airway, some the lower, and some work in both, which makes it a real decision point.

Dr. Hanania says his group stopped aspirin desensitization entirely, because the biologic literature is now convincing. Anti-IL-5, anti-TSLP, and anti-IL-4 all work in polyposis, and polyposis itself may predict better response to anti-IL-5. He co-manages with rhinologists and allergists, images with CT sinuses, and notes most patients who have surgery continue to have polyposis.

Dr. Chupp reports the same shift at his center, with a monthly ENT conference and review of surgical pathology for eosinophil levels, which guide agent choice alongside practical differences in dosing. The biggest impact, he says, has been a drop in sinonasal surgery. Dr. Ross adds that in her area ENTs now use biologics before surgery to reduce polyp burden and improve outcomes, and observes that as a solo allergist she lacks the multispecialty access her colleagues describe.

Up next, in " Biologics for Severe Asthma: Targets, Timing, and Outcomes," Dr. Wechsler lays out the full toolbox.

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Biologics have displaced a procedure that once filled the fellowship schedule. The panel weighs what replaced aspirin desensitization, and how sinus surgery rates changed with it.

"Unified Airway Disease Presentation in Clinic," takes up a question that looks different from every specialty's waiting room.

Unified Airway Disease Presentation in Clinic

Dr. Chupp asks Dr. Ross what percentage of patients presenting with nasal polyps actually have allergic sensitization, noting the field increasingly recognizes two phenotypes: the systemically allergic patient, and the patient without sensitization. Dr. Ross reaches for eosinophilic esophagitis as a parallel. She sees individuals who test positive for absolutely everything and others with identical findings who test negative to every test run. No tool yet distinguishes them. The consolation, she says, is that treatment options now exist for either end result. She estimates about 75% of her patients have some allergy driving their phenotype, while conceding her office is skewed; her non-allergic patients likely land in the ENT office instead.

Dr. Wechsler says the distinction is genuinely hard, and clinicians often treat for one, then the other. Patients referred to him with asthma and sinus disease frequently arrive after a course of antibiotics that may not have helped what is actually a type 2 inflammatory problem. Around 30% to 40% of his asthma patients have concomitant upper airway disease, and treating it aggressively pays off in both directions.

Dr. Ross argues specialists must go beyond the presenting complaint, because a good history teases out polyps, sinus issues, repeat surgeries, and antibiotics. Dr. Wechsler adds that it is not difficult: ask about sense of smell, the best single indicator of upper airway disease.

Dr. Hanania reports his CRS and polyp patients skew non-allergic with late-onset asthma and significant polyposis, and roughly 15% have aspirin or NSAID-exacerbated disease. He describes starting multidisciplinary discussions with rhinology and allergy, calling cross-specialty communication an area still raw in practice.

In "Managing Both Upper and Lower Airway Diseases," the panel will ask what happens to aspirin desensitization once biologics arrive.

Not every patient with nasal polyps is allergic, and no test reliably separates those who are. The panel discusses how referral patterns skew what each specialist believes.

In "The Unified Airway: Linking Severe Asthma and Sinus Disease," our experts turn from the lower airway to the whole of it.

The Unified Airway: Linking Severe Asthma and Sinus Disease

Dr. Chupp notes the discussion has focused on asthma, though sinus disease is a large part of the equation, and asks how each panelist defines the unified airway. Dr. Ross says it is really one airway, artificially separated in the past. Look at the biology at the epithelial surface, she argues, and the two sites look alike: exposed to the same pathogens, allergens, viruses, and occupational irritants, with the same early alarmin responses through TSLP, IL-33, and IL-25. Both show mucus hypersecretion, goblet cell hyperplasia, potential polyp growth, and ciliary dysfunction. She highlights nerve hyper-responsiveness at both sites, producing anosmia above and bronchoconstriction below. Patients with a respiratory complaint usually report an upper airway complaint at the same time, so treatment must run from the sinuses to the lungs.

Dr. Wechsler frames it as a systemic inflammatory process rather than mere anatomical proximity, predominantly type 2, with the same cytokines, the same cells, the same epithelial barrier dysfunction, fibrotic elements, and mucus. Because bad sinuses worsen asthma and bad asthma worsens sinuses, he treats systemically, blocking TSLP or IL-4 and IL-13 to benefit both. Dr. Ross adds that the dual presentations cluster: nasal polyps with asthma, aspirin-exacerbated respiratory disease, allergic rhinitis with asthma. She argues these should be understood as combined phenotypes.

Dr. Hanania supplies the evidence base. The hypothesis was propagated years ago and is supported epidemiologically, pathophysiologically, immunologically, and functionally. About 70% of patients with CRS with nasal polyps have asthma, and about 40% of asthma patients, especially type 2, have CRS with nasal polyps. Compare a nasal polyp cross-section with an airway biopsy, he says, and the infiltration, mucus, and remodeling match. It is a two-way highway.

Our next episode, "Unified Airway Disease Presentation in Clinic," presses Dr. Ross on an assumption about who those polyp patients really are.

Anatomy separated the sinuses from the lungs, and specialty training reinforced the split. The panel makes the case that the evidence describes a single organ with one disease process.

This episode, "Low T2 Asthma: What Anti-TSLP Data Show in Low-Eosinophil Patients," features Dr. Wechsler testing a widely held assumption against the data.

Low T2 Asthma: What Anti-TSLP Data Show in Low-Eosinophil Patients

Dr. Chupp raises low T2 asthma, describing patients with low biomarkers who may be neutrophilic or polygranulocytic depending on the defining study. The prevailing view is that anti-TSLP therapies work better in these patients than the high T2 biologics. He asks Dr. Wechsler why.

Dr. Wechsler's answer complicates the premise. He says the field is still learning TSLP biology and does not have good data on anti-TSLP in broad non-type 2 patients. The drug works well in low-eosinophil patients in asthma, he notes, but low eosinophils are not the same as non-type 2. A patient can have low eosinophils alongside high nitric oxide, or an allergic phenotype. Data in pure non-type 2 asthma are still awaited.

He then walks the evidence. Anti-TSLP performed well in low-eosinophil asthma, with a 39% reduction in exacerbations. In the COPD trial, however, there was minimal effect in the low-eosinophil group. In the more recent SUNRISE study of oral steroid-dependent patients randomized against placebo, the drug reduced both steroid dose and exacerbations, but that finding sat primarily in patients with background eosinophilia. A study of a TSLP receptor-targeted agent in a broad asthma population showed the same pattern: major efficacy in patients with elevated eosinophils, no significant exacerbation reduction in the low-eosinophil group, though lung function did improve in those patients.

His conclusion is that much remains unknown about the exact role of TSLP and epithelial cytokines in non-type 2 asthma. He points to where the answer may come from: TSLP has receptors on airway smooth muscle and on mast cells, and studying where TSLP binds may explain the pattern. Dr. Chupp adds that anti-IL-33 therapies are in development with some successful clinical data.

Up next, in "The Unified Airway: Linking Severe Asthma and Sinus Disease," the experts move above the lungs.

The assumption that anti-alarmin therapy is the answer for low T2 disease meets the trial evidence. Dr. Wechsler walks through where the efficacy signal actually concentrates.

Jacqueline Ross, MD

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