From Eosinophils to Image Biomarkers: The Evolving Science of Biologic Selection in Asthma and COPD

The emergence of targeted biologic therapies in severe asthma has fundamentally altered the treatment paradigm for a disease once managed almost exclusively through inhaled corticosteroids and bronchodilators. Across a growing portfolio of approved agents — omalizumab, mepolizumab, benralizumab, reslizumab, dupilumab, tezepelumab, and most recently depemokimab — the identification of type 2 (T2) inflammation via blood eosinophil count and fractional exhaled nitric oxide (FeNO) has enabled a precision medicine approach that was unimaginable a decade ago. Real-world registry data from the International Severe Asthma Registry (ISAR), now encompassing nearly 35,000 patients across 28 countries, indicate that approximately 30–50% of biologic-treated patients achieve clinical remission when defined by elimination of exacerbations, OCS discontinuation, normalized lung function, and symptom control — a target outcome once considered unattainable in severe disease.¹ In chronic obstructive pulmonary disease (COPD), the landscape has evolved more recently but is generating comparable enthusiasm: dupilumab and mepolizumab have both received regulatory approval as add-on therapies for patients with eosinophilic COPD who continue to exacerbate despite triple inhaled therapy, based on the BOREAS/NOTUS and MATINEE trial programs respectively.²

Against this backdrop, HCPLive convened a virtual clinical forum in April 2026 moderated by Antonio Anzueto, MD, emeritus professor at the University of Texas San Antonio and a member of the GOLD Guidelines Committee — bringing a clinical trialist's perspective to both guideline context and emerging evidence. The panel comprised seven pulmonary and critical care physicians based across Texas, in San Antonio, Houston, Dallas, and Plano, representing a mix of academic medical centers, county hospital systems, and private practice settings. The geographic and practice-setting diversity of the panel grounded the discussion in real-world challenges of biologic access and patient management in a state with high asthma burden and significant populations affected by COPD driven by biofuel and occupational exposures.

The forum convened at a moment when several concurrent developments are reshaping clinical practice in both diseases. The December 2025 FDA approval of depemokimab — the first twice-yearly biologic for severe eosinophilic asthma — has expanded the IL-5 class while introducing new questions about dosing interval management and real-world adherence.3 Publication of mucus plug scoring data from the VESTIGE trial in the American Journal of Respiratory and Critical Care Medicine and the CASCADE analysis in NEJM Evidence has introduced CT-based mucus plug quantification as a potential third biomarker for asthma biologic response, one the moderator argued will be routinely incorporated into practice within the coming years.4,5 Foundational data from the COPDGene cohort demonstrating that airway-occluding mucus plugs are independently associated with excess all-cause mortality and exacerbations in COPD have further elevated this imaging phenotype as a therapeutic target.6 And the GOLD 2026 report has formally incorporated biologics into the COPD escalation algorithm while strengthening the recommendation for baseline CT chest in all patients with COPD.7

The most substantive discussion in the asthma segment centered on biologic selection and the practical limitations clinicians face in applying biomarker-driven decision-making. Panelists confirmed broad biologic adoption, with dupilumab as the most commonly initiated agent and eosinophil count as the primary selection driver, followed by FeNO where clinic access permitted. Availability of FeNO testing varied considerably across the group — some practices had integrated it into standard spirometry workflows, while county hospital systems lacked the equipment entirely. Anzueto described a practical model for cost justification through billing code development, noting the machine typically offsets its cost within the first several days of use in high-volume asthma practices. Polling results identified biomarkers as the leading clinical selection driver, but panelists consistently noted that insurance formulary placement and prior authorization requirements often determine the actual agent prescribed, effectively overriding clinical reasoning.

The 2019 decision by GINA and GOLD to retire the asthma-COPD overlap (ACOS) classification was cited as a concrete example of how labeling can affect access — that reclassification was partly motivated by the recognition that ACOS designation was blocking biologic eligibility for patients who fundamentally had asthma. Depemokimab's six-month dosing interval was viewed as conceptually appealing for adherence-challenged patients, but insurance non-coverage was the primary barrier at forum time, and panelists raised questions about how patients and clinicians would recognize suboptimal disease control across such an extended interval. Combination biologic therapy — an approach occasionally attempted anecdotally in very severe OCS-dependent cases — was confirmed to have no supporting clinical trial data.

The mucus plug discussion represented the most scientifically forward-looking segment of the forum. Drawing on COPDGene's standardized CT methodology and biologic trial data from VESTIGE and CASCADE, Anzueto presented mucus plug scoring as an emerging third biomarker for asthma that could eventually predict biologic response alongside eosinophils and FeNO. In VESTIGE, patients with high baseline mucus plug scores (≥4) showed disproportionate improvements in pre-bronchodilator FEV1 at weeks 4, 12, and 24 with dupilumab, while low-score patients demonstrated no meaningful lung function benefit — suggesting mucus plug burden identifies a mechanistically responsive subgroup.4 CASCADE data with tezepelumab showed a parallel pattern.5 The moderator flagged an active randomized trial of dupilumab vs. placebo in chronic bronchitis COPD with mucus plug assessment as a primary endpoint, and noted that software tools for integrating mucus scoring into routine radiology reads are already in commercial development. Panelists were largely unfamiliar with this data, and several expressed interest in how it might eventually stratify biologic candidates in moderate disease below the current exacerbation-based threshold.

“I think what we need to do is we need to have our eyes open because these are going to be an area that we're going to see a lot of activity in the near future. Stratifying the patient's severity, not only based on the biomarkers that are traditionally eosinophils, the FeNO, the oral corticosteroids, until we can identify, oh, that's a severe individual. At 1 point, we'll be able to identify those patients based on the mucus plugs,” Anzueto said.

In the COPD segment, the panel reflected a field at an earlier stage of biologic integration, with greater uncertainty about patient selection and more significant access barriers. All panelists reported routinely checking eosinophil counts in new COPD patients — some reviewing historical CBCs retrospectively — but Anzueto noted that many automated panels do not include eosinophil differentials, leaving a practical data gap particularly relevant in county and safety-net settings. Real-world experience with dupilumab in COPD was described as mixed: exacerbation reduction was the most consistent finding, while FVC improvement was less reliably replicated outside the trial setting, particularly at borderline eosinophil thresholds.

Anzueto contextualized declining apparent effect sizes in recent mepolizumab COPD trials — noting that baseline exacerbation rates in MATINEE (~1.01/year) were substantially lower than in earlier METREX/METREO studies (~1.7/year) as a direct consequence of optimized triple therapy raising the performance floor.2 Polling revealed that payer support and reimbursement guidance was the factor panelists most wanted to improve biologic integration in COPD, followed by clearer patient selection algorithms. Anzueto closed by reinforcing GOLD 2026's strong recommendation for baseline CT in all patients diagnosed with COPD — citing data showing that 60% of one cohort had significant coronary calcifications that had gone undetected, underscoring CT's value beyond pulmonary phenotyping — and predicting that AI-driven quantification of mucus plugs, emphysema burden, and small airway disease will ultimately define the next generation of COPD biomarkers.7

References

1. Larenas-Linnemann D, Rhee CK, Altraja A, et al. International Severe Asthma Registry (ISAR): 2017–2024 status and progress update. Tuberc Respir Dis (Seoul). 2025;88(2):193-215. doi:10.4168/trd.2024.0208

2. 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

3. 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

4. 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

5. 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

6. Diaz AA, Orejas JL, Grumley S, et al. Airway-occluding mucus plugs and mortality in patients with chronic obstructive pulmonary disease. JAMA. 2023;329(21):1832-1839. doi:10.1001/jama.2023.2065

7. 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 10, 2026.