Not Everything That Wheezes Is Asthma: Comorbidities, Mimickers, and the Right Time to Escalate

Biologic therapy has fundamentally reshaped the management of severe asthma over the past 2 decades, moving from a single approved agent — omalizumab — to a portfolio of 7 biologics targeting distinct inflammatory pathways with growing long-term safety and efficacy data. The composite biomarker framework underlying this approach has itself matured: the ORACLE2 meta-analysis, a patient-level analysis of 22 randomized controlled trial control groups including more than 6,000 patients, confirmed that elevated blood eosinophils and fractional exhaled nitric oxide (FeNO) are synergistically predictive of asthma attack risk and independently identify treatable T2 inflammation — establishing a quantitative basis for combining these biomarkers in clinical decision-making.¹

More recently, the twice-yearly anti-IL-5 biologic depemokimab received FDA approval in December 2025 based on the SWIFT-1 and SWIFT-2 trials,² and the NIMBLE non-inferiority trial published in the American Journal of Respiratory and Critical Care Medicine in 2026 provided the first evidence that patients already responding to mepolizumab or benralizumab can switch to depemokimab without loss of exacerbation control.³ In chronic obstructive pulmonary disease (COPD), dupilumab and mepolizumab have expanded the field into eosinophilic inflammatory phenotyping, with the BOREAS, NOTUS, and MATINEE trials establishing the evidentiary basis for add-on biologic therapy in patients who continue to exacerbate despite triple inhaled therapy.⁴˒⁵˒⁶

Against this backdrop, HCPLive convened a virtual clinical forum moderated by Nicola Hanania, MD, MS, Director of the Airways Clinical Research Center at Baylor College of Medicine and Chief of Pulmonary Critical Care at Ben Taub Hospital in Houston — a clinician investigator with firsthand experience in the pivotal biologic trials that have shaped both the asthma and COPD fields. Notably, Hanania served as a site investigator on the BOREAS and NOTUS dupilumab COPD trials and is a named contributor to the ORACLE2 consortium. The panel comprised 11 pulmonary and critical care physicians drawn from academic centers and community practices across Texas and Oklahoma, including fellows in training, program directors, and at least one community hospital pulmonologist practicing in a predominantly rural setting — a composition that grounded the discussion in the breadth of real-world implementation challenges.

The forum convened at a moment when the biologic treatment paradigm in both asthma and COPD is expanding faster than clinical infrastructure and payer systems have adapted. Depemokimab's approval has introduced a twice-yearly IL-5 option that addresses adherence barriers but has generated new clinical questions about the manageability of 6-month dosing intervals.² Mucus plug scoring — validated by CT-based data from the VESTIGE and CASCADE trials — is emerging as a candidate third biomarker for predicting biologic response in asthma, one that the moderator has already implemented in multicenter research protocols.⁷˒⁸ And GOLD 2026's formal endorsement of biologic escalation in eosinophilic COPD has elevated practitioner interest at a moment when most clinicians are still gaining comfort with the patient selection criteria.⁹ The group's discussion — spanning biomarker implementation, OCS stewardship, shared decision-making, biologic selection, and the frontier of COPD biologics — captured both the scientific momentum and the persistent practical friction that define this field in mid-2026.

First discussing asthma management, panelists have broadly adopted biomarker-driven prescribing but continues to navigate meaningful implementation gaps. Panelists across practice settings described FeNO as clinically valuable but inconsistently available — with academic sites integrating it into PFT workflows and county or community practices lacking equipment or trained staff. The composite biomarker approach endorsed by ORACLE and ORACLE2 — combining eosinophils and FeNO for synergistic risk stratification — resonated with Hanania, who described measuring all 3 T2 biomarkers (eosinophil count, FeNO, and IgE) as standard intake practice for new asthma patients at UT Health Houston. Biologic selection was described as a multifactorial process in which clinical phenotype and biomarkers provide the initial framework, but insurance formulary placement frequently determines the final agent. The group was broadly positive about dupilumab across age groups, with pediatric panelists noting strong adherence in teenagers due to co-improvement of atopic dermatitis and rhinitis, and adult clinicians describing durable OCS elimination and rare patients achieving clinical remission. Hanania identified the absence of formal step-down or inhaler discontinuation protocols as a significant unmet need — patients are achieving remission with no guideline to guide what comes next. Depemokimab drew split opinion: panelists from rural settings valued the logistical relief of twice-yearly dosing, while others expressed concern about managing clinical deterioration or adverse events over a 6-month interval without recourse to dose timing. Mucus plug data from VESTIGE and CASCADE — novel to roughly half the panel — was acknowledged as mechanistically explanatory but not currently practice-changing.

The COPD discussion was anchored by Hanania's direct trial experience. His observation that ~40% of BOREAS/NOTUS participants dropped below the ≥300 eos threshold between screening and randomization — yet showed comparable efficacy — raises the real-world question of how strictly to apply the label's cutoff in clinical practice, a point he framed as hypothesis-generating rather than practice-changing without confirmatory data. Panelists described routine eosinophil monitoring in COPD patients but acknowledged that pre-steroid measurement is difficult in practice, as most exacerbating patients have already received systemic steroids before their CBC is drawn. Real-world experience with mepolizumab in COPD was described as promising, with Brimah noting that the lower eosinophil eligibility threshold (≥150 cells/µL within the prior year) makes it easier to obtain insurance approval than dupilumab. Polling results from the COPD segment were notably consistent with prior forums in this series: clearer patient selection algorithms and payer support remained the most urgently needed improvements. Unmet needs raised in the closing discussion included the absence of approved targeted therapies for non-T2 COPD — a gap Hanania is actively investigating through trials at Baylor — and the untested but clinically observed possibility that early biologic intervention in eosinophilic COPD could attenuate long-term FEV1 decline, an outcome that only multi-year prospective data can confirm.

“Just like when these biologics started rolling out for asthma, they were really reserved for those very severe, uncontrolled asthmatics... And it seems like this is where we're starting with COPD, especially, with the GOLD guidelines aligning with that. And with asthma, we started seeing kind of a, let's start evaluating these patients earlier, getting them on biologics earlier [approach]. I feel like at 1 point, we will start noticing that these COPD patients, especially those type 2 inflammatory COPD patients, will benefit with a sooner approach,” a panelist said. “I feel like that's where we will be headed. It's really just trying to catch these patients earlier, before we have the exacerbations and hospitalizations to align with the guidelines.”

References

1. Meulmeester FL, Mailhot-Larouche S, Celis-Preciado C, et al; ORACLE2 Consortium. Inflammatory and clinical risk factors for asthma attacks (ORACLE2): a patient-level meta-analysis of control groups of 22 randomised trials. Lancet Respir Med. 2025;13(6):505-516. doi:10.1016/S2213-2600(25)00037-2

2. Jackson DJ, Wechsler ME, Menzies-Gow A, et al; SWIFT-1 and SWIFT-2 Investigators. Twice-yearly depemokimab in severe asthma with an eosinophilic phenotype. N Engl J Med. 2024;391(24):2337-2349. doi:10.1056/NEJMoa2406673

3. Chupp G, Nagase H, Skowasch D, et al; NIMBLE Study Investigators. Switching to twice-yearly depemokimab from mepolizumab/benralizumab in severe asthma: a multicenter, randomized, double-blind, phase 3A clinical trial (NIMBLE). Am J Respir Crit Care Med. Published online 2026. doi:10.1093/ajrccm/aamag031

4. Bhatt SP, Rabe KF, Hanania NA, et al; BOREAS Investigators. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389(3):205-214. doi:10.1056/NEJMoa2303951

5. Bhatt SP, Rabe KF, Hanania NA, et al; NOTUS Investigators. Dupilumab for COPD with blood eosinophil evidence of type 2 inflammation. N Engl J Med. 2024;390(24):2274-2283. doi:10.1056/NEJMoa2401304

6. Criner GJ, Celli BR, Bhatt SP, et al. Mepolizumab for COPD with exacerbations and eosinophilia. N Engl J Med. 2023;389(23):2127-2138. doi:10.1056/NEJMoa2303120

7. Porsbjerg CM, Dunican EM, Lugogo NL, et al. Effect of dupilumab on mucus burden in patients with moderate-to-severe asthma: the VESTIGE trial. Am J Respir Crit Care Med. Published online October 27, 2025. doi:10.1164/rccm.202410-1894OC

8. Diver S, McDowell PJ, Siddiqui S, et al. Tezepelumab and mucus plugs in patients with moderate-to-severe asthma. NEJM Evid. 2024;3(3):EVIDoa2300135. doi:10.1056/EVIDoa2300135

9. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for Prevention, Diagnosis and Management of COPD: 2026 Report. GOLD; 2026. https://goldcopd.org. Accessed April 25, 2026.