Biologics are emerging for selected COPD patients with frequent exacerbations despite optimal therapy. Blood eosinophil counts (BEC) predict response to biologics targeting type 2 (T2) airway inflammation. The role of fractional exhaled nitric oxide (FeNO) remains to be clarified, although a post hoc analysis suggested greater benefit of anti-IL4/13R in patients with increased FeNO 1. Observational studies report elevated BEC (≥ 300 cells/μL) and FeNO (≥ 20 ppb) in up to 37% and 32% of COPD patients, respectively 2, 3. However, the prevalence of T2 inflammation in patients with moderate or severe COPD exacerbations in a real-world setting remains unclear. In this retrospective observational study, we aimed to estimate the prevalence of T2 inflammation in exacerbating COPD patients despite optimal inhalation therapy, at Franciscus Hospital Rotterdam, the Netherlands, between April 2022 and April 2024. COPD was identified by the national healthcare product code (DBC 1241) and FEV1/FVC ratio < 0.7. Patients with a primary diagnosis of asthma were excluded. Comorbid asthma was retained, based on the discretion of the treating physician. Moderate exacerbations were defined as increased symptoms requiring oral corticosteroids (3–14 days) with or without antibiotics; severe exacerbations required hospitalization. Optimal inhalation therapy was defined as triple therapy, or dual bronchodilators if BEC < 100 cells/μL, consistent with the 2026 GOLD report. T2 inflammation was defined as BEC ≥ 300 cells/μL and/or FeNO ≥ 30 ppb, assessed in the subset of patients with both biomarkers available (n = 174). Biomarkers were analyzed over a 5-year period. For the main analysis, the highest recorded biomarker values were used, irrespective of clinical state. Prevalence estimates were extrapolated to country level, assuming our real-world cohort represents the Dutch secondary-care population. The ethics committee approved the study as not subject to medical research regulations; consent was waived. Of 2278 identified COPD patients, 776 (34%) had exacerbations (≥ 2 moderate/≥ 1 severe exacerbations in the past 12 months). After exclusions for suboptimal therapy (n = 152) and missing data (n = 6), 618 (27%) remained in the study cohort of whom 34% were current smokers (Tables S1–S3). Elevated BEC was found in 213 (34%) of patients (Figure 1; Table S1). Among patients with ≥ 2 BEC measurements (n = 497), 14 (3%) had ≥ 300 cells/μL at all measurements, and 96 (19%) had ≥ 300 cells/μL at ≥ 2 measurements (Figure S1). In the subset with both BEC and FeNO data, 84 of 174 patients (48%) had T2-high biomarkers (30 (17%) BEC and FeNO-high, 41 (24%) FeNO-high, and 73 (42%) BEC-high) (Figures 1 and 2; Tables S2 and S3). Current smoking was independently associated with lower FeNO levels (β = −0.34, p = 0.001), corresponding to a 29% reduction compared with non-smokers. BEC did not differ significantly (p = 0.27). Our cohort represents 2.9% of the Dutch secondary care COPD population (n = 78,980 in 2022) 4. Extrapolating to national population yields n = 21,483 (95% CI 20,038–22,928) patients with exacerbations despite optimal therapy, n = 7639 (95% CI 6816–8463) with elevated BEC, and n = 5062 (95% CI 3707–6417) for FeNO. This study shows that T2 inflammation biomarkers are present in a significant proportion of optimally treated COPD patients with frequent exacerbations. These patients may represent a target for specific biologics. The strength of this study is the real-world design of COPD patients in a secondary care cohort. Nevertheless, the retrospective design, incomplete data on optimal management, and possible selection bias in FeNO testing may overestimate the true prevalence of T2 inflammation in this population. On the other hand, FeNO levels may have been underestimated due to the large proportion of current smokers (34%). Therefore, the national estimate for elevated FeNO has considerable uncertainty. Our finding of elevated BEC and FeNO in 17% of patients is slightly lower than the BOREAS post hoc analysis (26%) 1, with differences likely due to inclusion criteria of the randomized controlled trial. Similarly, Roche et al. reported 21% of patients in a retrospective mixed-care French cohort had frequent exacerbations on triple therapy 5. The higher proportion of exacerbations despite optimal therapy in our exclusively secondary care cohort may reflect a more severe population. Notably, 15% of patients with exacerbations and eosinophilia were GOLD stage 4, versus 9% in the total cohort, highlighting a higher exacerbation risk. Although excluded from dupilumab trials, they constitute a substantial subgroup who may benefit from biologics. In our study population, asthma comorbidity was documented in 11% of patients, based on physicians' documentation (Tables S1–S3). This may have led to an overestimation of T2 inflammation. However, this also reflects real-world clinical practice. Our study showed a significant, modest correlation (ρ = 0.27, p = 0.003) between FeNO and BEC (Figure 2). The modest correlation may reflect non-synchronous sampling, or reduced FeNO values due to smoking-related effects. In addition, resident and inflammatory subtypes of eosinophils with different roles have been described in chronic airway disease 6. Possible higher occurrence of resident eosinophils in COPD as compared to asthma could be one of the explanations for the less pronounced effect of T2 biologics in COPD studies to date (Table S4). To enhance classification of eosinophilic COPD, we used the highest recorded BEC value to account for variability 7. Only 3% of patients had persistently elevated BEC. Given variability in the number and timing of measurements, which were evaluated irrespective of clinical state, and the inability to exclude measurements during oral corticosteroid treatment, the proportion of patients with ≥ 2 elevated measurements (19%) likely provides a more robust estimate. This is consistent with the 18% reported by Baraldi et al. 7 In clinical practice, repeated biomarker assessment, especially during symptoms or exacerbations, together with clinical context may help determine whether the disease is T2 driven. In summary, one-third to half of COPD patients with frequent exacerbations despite optimal inhalation therapy had T2 inflammatory profiles. These findings suggest a potential role for biologics, warranting further prospective evaluation, particularly regarding the role of FeNO in clinical decision-making. M.C.M., M.D., and P.-P.W.H. developed the original concept for this work and study design. Acquisition and analysis of the data were performed by J.C.C.M.V., M.C.M., M.D., and P.-P.W.H. All authors contributed to the interpretation of the data. The first draft of the manuscript was written by M.C.M. D.-J.S., F.M.E.F., J.C.C.M.V., M.D., and P.-P.W.H. provided intellectual feedback, critically reviewed the manuscript, and approved the final version of the manuscript to be published. All authors agree to be accountable for all aspects of the manuscript. The current study was investigator initiated by the Franciscus Gasthuis the collection, analysis, or interpretation of the data; the writing or review of the manuscript; and did not read the manuscript prior to submission. M.C.M.: Personal speaker fee from AstraZeneca. J.C.C.M.V.: Unrestricted grants paid to institution from AstraZeneca, Chiesi, Teva, GSK, Sanofi, and Medical Delta. Personal fees for advisory board participation from Chiesi and AstraZeneca. D.-J.S.: Grants for clinical trial expenses from Pulmonx Corp (USA), PulmAir (USA), Apreo (USA), FreeFlowMedical, MoreAir (USA), and Nuvaira (USA). Consulting fees paid to institution from Nuvaira (USA), MoreAir (USA), Apreo (USA), and PulmonX (USA). Speaker fees paid to institution from PulmonX (USA), and Nuvaira (USA). F.M.E.F.: Personal Consulting fees from Sanofi and MSD. Personal speaker fees from AstraZeneca, Chiesi, GKS, Sanofi, Pfizer. Support fees for attending meetings paid to institution from AstraZeneca. M.D.: speaker fees to institution from GKS and Sanofi. Fee paid to institution for participation on Advisory Board GSK. P.-P.W.H.: personal speaker fees from GSK and Chiesi. Personal fee for advisory board participation from GSK, Sanofi. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1: all70300-sup-0001-DataS1.docx. 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Melles et al. (Tue,) studied this question.