Introduction

Severe asthma is a chronic respiratory condition characterized by persistent airway inflammation and airflow limitation that remains inadequately managed even with optimized therapy (high-dose inhaled corticosteroids (ICS) plus another bronchodilatator), or that deteriorates when high-dose treatment is reduced.1 The development of biologic therapies has revolutionized the management of severe asthma.2 Biologic therapy has shown significant efficacy in improving asthma control, reducing exacerbations, and enhancing lung function.2,3 However, since current- or ex-smokers ≥10 pack-years have been excluded from clinical trials,4–8 there is limited evidence regarding the influence of smoking-related comorbidities, such as emphysema, on the response to biologic therapy in patients with severe asthma. Recent studies have demonstrated that prior smoking exposure does not significantly impact the response to biologic treatments in patients with severe asthma, regardless of the specific biologic therapy used.9–11 Similar findings have been reported in cases of asthma comorbid with chronic obstructive pulmonary disease (COPD).12 However, it is noteworthy that for COPD Dupilumab is the only biologic that has been robustly shown to reduce exacerbations and has recently been approved for this indication.13,14 Pulmonary emphysema, commonly associated with COPD, is also a significant smoking-related comorbidity of asthma associated with increased morbidity and mortality.15–17 Despite its clinical relevance, there is a paucity of research specifically addressing the efficacy of biologic therapies in asthma patients with coexisting emphysema. Therefore, further investigation is warranted to better understand this interaction and to optimize therapeutic strategies for this specific patient population.

This study aimed to quantify the extent of lung emphysema using computer tomography (CT) and investigate its influence on biologic treatment response in asthma patients. By elucidating the impact of emphysema on treatment outcomes, we aim to provide valuable insights into the management of severe asthma patients with concurrent emphysema.

Methods Study Design and Patient Population

This study is a retrospective cohort study conducted at the Department of Internal Medicine II – Pneumology Department, University Hospital Bonn in Germany. The study was approved by the local ethics committee (No. 174/22). All participants provided written informed consent for the register study of the German Asthma Net (GAN).

The study included a total of 86 consecutive patients with a diagnosis of severe asthma, based on the Global Initiative for Asthma recommendations, who were eligible for biologic therapy.1 The inclusion criteria for this study were the presence of a native CT of the thorax, a diagnosis of severe asthma, biologic therapy eligibility and a follow-up after at least 3 months of biologic therapy. Exclusion criteria included patients under 18 years of age. Due to the exploratory nature of this study, all consecutive patients in the given time period were included which fulfilled the inclusion criteria, to obtain the greatest cohort possible. Our hypothesis was that the presence of pulmonary emphysema has no significant influence on the treatment response to biologic therapy.

Assessment of Emphysema

Data for this study were obtained from patient medical records from 2017 to 2022. The extent of lung emphysema was quantified by experienced radiologists using non-contrast chest CT scans obtained as part of routine clinical practice with multidetector CT scanners (≥128 rows). The emphysema analysis was performed using a commercially available software (IMPAX, Agfa HealthCare N.V., Mortsel, Belgium). An example of emphysema quantification on a patient with 32% pulmonary emphysema, visible as red areas, is shown in Figure 1. Consistent with established practice, emphysema was defined as lung parenchyma with attenuation values of less than −950 hounsfield units at inspiration.18–20 For each CT dataset, an emphysema ratio was generated, which is defined as the percentage of lung volume with emphysema divided by total lung volume.

Figure 1 Example of Emphysema Quantification in IMPAX Software. The figure showcases a representative image or screenshot captured within the software interface. This patient was a 65-year-old female with 32 pack years, late onset asthma and a comorbid emphysema occupying 32% of her lungs. The red markings represent areas of emphysematous change within the lungs.

To evaluate treatment response relative to emphysema severity within our cohort, patients were divided into two groups. As no recommendations for a cut-off for clinically meaningful emphysema exists, we chose the 5% threshold based on existing literature21–23 and studies where this specific cutoff has been employed.24,25 We additionally applied a 10% emphysema cut-off for further validation of our results.

Treatment and Outcome Measures

All patients underwent biologic therapy according to the standard treatment guidelines.26 The choice of biologic therapy was based on individual patient characteristics and physician discretion. The outcome measures to assess the effectiveness of the treatment approach included changes in the number of annualized acute exacerbations (AE), reduction of maintenance oral corticosteroid (OCS) doses, asthma control assessed by the Asthma Control Test (ACT) and forced expiratory volume in 1 second (FEV1). The evaluation of treatment response was conducted after the closest possible time point to 6 months (at least 3 months), to adequately address reduction of exacerbations and oral corticosteroid therapy (OCS). The number of acute exacerbations up to the follow-up point was extrapolated to an annualized exacerbation rate in 12 months, to meet standardized end-points as suggested by the ATS/ERS statement on endpoints for asthma trials and clinical practice.27

Additionally, the Biologics Asthma Response Score (BARS) was utilized. BARS incorporates ACT-score, acute exacerbation rate and reduction in OCS dose to evaluate treatment response, allowing for an assessment of whether there was a “good response”, “response” or “inadequate response” overall.28

Asthma remission was defined as an absence of acute exacerbations, the absence of an oral corticosteroid therapy, a good asthma control defined by an ACT score ≥20 points and a stable lung function (FEV1), according to the German guidelines.26

Information on the patient history, eg, comorbidities or allergies (positive sensitization, clinically apparent), were obtained from the patients’ medical history files. Biomarkers, especially blood eosinophil count, were obtained from the closest timepoint before biologic therapy initiation, without the influence of OCS therapy and outside of an exacerbation.

Statistical Analysis

Statistical analysis was performed using SPSS Statistics version 28. Due to the small sample size of the respective groups, non-parametric Mann–Whitney-U-test was used for metric data, if not stated otherwise. Nominal or ordinal-scaled data were analyzed by Pearson’s chi-squared test or Fisher’s exact test when applicable. For some variables data are missing for some patients, the numbers of available data are individually stated in the results table for each variable. The A p-value less than 0.05 was considered statistically significant.

Results Demographic and Clinical Characteristics

A total of 86 patients diagnosed with severe asthma were enrolled in this study, with a mean age of 56.1 ± 12.8 years. Among these, 54 (62.8%) were female. 50% were never-smokers, 50% ex-smokers. No patients were current smokers at the beginning of biologic therapy. Physician-diagnosed COPD was present in 24 patients (27.9%). Patients with a smoking history had an average of 26.9 ± 18.2 pack-years. Additionally, those with a smoking history exhibited a significantly higher amount of emphysema (6.6 ± 8.6%) compared to never-smokers (1.5 ± 1.8%) (p<0.001).

Patients had a native CT Thorax scan within 9 ± 29.5 month of beginning biologic therapy. The range of emphysema severity spanned from 0.0% to 36.1%. Among the patient cohort, the majority (77%) had less than 5% pulmonary emphysema, 10 individuals (11.6%) had ≥10% emphysema, of which 3 (3.48%) displayed ≥20% emphysema, all of whom had a history of smoking (as depicted in Figure 2).

Figure 2 Distribution of Patients Across Emphysema Severity Groups. The pie chart illustrates the distribution of patients categorized into specific groups based on the percentage of emphysema severity. Each segment of the pie represents the percentage of patients falling within defined ranges of emphysema severity.

At the commencement of biologic therapy, nearly all patients were receiving maximal inhaled therapy, including high-dose ICS, LAMA, and LABA. The distribution of used biologics and the exposure to prior biologics were similar in both groups. Among the cohort of 30 patients with previous biologic therapy, 15 patients (17.4%) received one prior biologic, 13 patients (15.1%) two, and two patients (3.5%) received three prior biologics. The assessment of therapy response according to BARS aimed to compare patient parameters post-therapy with those observed prior to previous antibody treatments.

Baseline Characteristics Based on Emphysema Stratification

Within the group with ≥5% emphysema, a significantly higher proportion were ex-smokers compared to the group with <5% emphysema (80.0% vs 40.9%, p=0.002). Furthermore, the ≥5% emphysema group had a significantly greater pack-year history and demonstrated worse pulmonary function, as evidenced by, eg, worse median FEV1 values of 1.34 [1.0;1.6] compared to 1.8 [1.3;2.4] liters (p=0.037), median diffusion capacity (DLCO) of 52 [21;60] vs 78 [61;87] % predicted (p=0.028) or signs of hyperinflation (RV % predicted; 169 [153;181] vs 157 [119;182], p=0.037). Accordingly, the group with emphysema ≥5% included a significantly higher number of patients with pre-diagnosed COPD (50.0% vs 21.1%, p=0.012).

Both groups did not exhibit significant differences in asthma-specific biomarkers like FeNO (37 [14;77] vs 27 [16;66] ppB, p=0.866), blood eosinophil count (300 [129;510] vs 450.0 [210;720] /µL, p=0.627) and IgE-levels (156 [90;382] vs 238 [87;504] U/mL, p=0.588), or asthma comorbidities like chronic rhinosinusitis with nasal polyps or allergies. All baseline characteristics comparing both groups are presented at Table 1.

Table 1 Baseline Characteristics

Treatment Response

After a follow-up time of 7.8 ± 2.5 months, a good treatment response could be shown for both groups, presenting in a reduction of acute exacerbations to 0 [0;2] in both groups (p=0.236), and a reduction of OCS dose to 0 [0;6.5] and 0 [0;5] mg, respectively (p=0.664). ACT score improved similarly, exceeding the minimal-clinical important difference of 3 points.

There were no significant differences in treatment response between the two groups. In detail, there was no difference in the reduction of annualized acute exacerbations (−2.5 [−5;-1] vs −3.0 [−5;-2] n/year, p=0.236), reduction of OCS doses (−4 [−10;0] vs −5 [−10;0] mg, p=0.691), ACT improvement (5 [3;9] vs 4 [0;9], p=0.579) or FEV1 improvement (0.03 [−0.15;0.25] vs 0.23 [−0.5;0.49] L, p=0.052). Results are depicted as boxplots in Figure 3 and at Table 2.

Table 2 Follow-Up

Figure 3 Comparison of Treatment Response Measures Based on Emphysema Severity. Four boxplots representing treatment response measures concerning varying degrees of emphysema severity. Each boxplots displays the change from baseline to follow-up for the specific treatment response parameters, categorized by emphysema severity (<5% and ≥5%). The p-values were acquired with the Mann–Whitney-U test.

Abbreviations: FEV1, Forced Expiratory Volume in 1 second (FEV1) improvement; ACT, Asthma Control Test (ACT) score increase; OCS, Oral Corticosteroid (OCS) use reduction.

Regarding BARS, 60 vs 52% of all patients in each group reached a good therapy response, while 20%, respectively, 12% had an insufficient therapy response (p=0.312, Table 2). The rate of patients who changed or ended biologic therapy due to adverse events or non-efficacy was comparable between patients with ≥5% or <5% emphysema (16.7% vs 20.0%, Table 2).

The rate of asthma remission was comparable with 15.0% in the ≥5% emphysema group and 19.7% in the <5% emphysema group (p=0.753).

Similar results were seen if an emphysema cut-off of 10% was applied, except the reduction in acute exacerbation rate was more pronounced in the group with <10% emphysema (−1.4 [−3.5;-1] vs −3 [−6;-2] n/year, p=0.003, Table 2).

Of the three patients with a pronounced pulmonary emphysema of >20%, two showed a therapy response, while one did show an insufficient therapy response, according to BARS.

Thus, our analysis suggests that patients with severe asthma and comorbid pulmonary emphysema show a similar treatment response compared to those without emphysema.

Discussion

As a central result, we show that the presence of a pulmonary emphysema does not significantly impact the success of biologic therapy in this patient group.

While usually clinical asthma studies exclude patients with >10 pack-years of smoking history, this does not reflect the real-world asthma patient collective. In fact, nearly half of the adult asthmatic population in most developed countries are current or former smokers.16 The GAN (German Asthma Network) study found 2.7% of the asthma patients recruited into the registry in Germany were current smokers and 43.6% ex-smokers.29,30 Existing literature suggests the coexistence of COPD and emphysema in patients with asthma correlates with decreased survival rates and presents clinical challenges.15 Notably, half of the patients in our collective had a smoking history, and, as anticipated, these individuals showed a significantly higher degree of emphysema compared to never-smokers.31 A subset of patients in our study even exhibited a substantial burden of emphysema, with 11.6% presenting with ≥10% emphysema. This in turn underscores the clinical relevance of considering emphysema in the management of severe asthma.

Nonetheless, irrespective of the presence of concurrent emphysema, both patient groups exhibited a similar favorable response to biologic therapy. Additionally, the rates of both remission and treatment discontinuation were comparable. The low rate of patients with asthma remission in the emphysema group may be contributed to persisting symptoms caused by the comorbid emphysema, which cannot be expected to be addressed by biologic therapy.

The fact that the analysis with a 10% emphysema cut-off yielded comparable results, and that two of the three patients with a pulmonary emphysema of >20% showed a response to biologic therapy, supports the notion that biologic therapy was successfully treating the asthma component, regardless of the comorbid emphysema. While it is noteworthy to reiterate the group with ≥10% emphysema showed a significantly lower reduction of acute exacerbations, which may be due to more pronounced comorbid smoking-related lung-injury, it is as important to be cautious whilst interpreting these findings due to the small sample size of this subgroup consisting of only 10 patients. Our previous research had yielded similar outcomes for asthma patients with significant smoking exposure, regardless of the presence of emphysema.10 We attributed this outcome to the careful patient selection process employed to determine eligibility for biologic therapy.

The therapeutic effects of biologic therapy with anti-IL5-/ anti-IL5-receptor-therapy showed only a marginal reduction in exacerbation rates among patients with COPD who did not have concurrent asthma.32,33 In contrast, the recent BOREAS and NOTUS studies demonstrated a 30% and 34% reduction in acute exacerbations of COPD patients with type-2-Inflammation by anti-IL-4/13-therapy, which has now led to the approval of the medication for COPD.13,14 It can be assumed biologic therapy has a favoring effect on type-2-inflammation, regardless of the underlying obstructive disease. In this way, the concept of anti-inflammatory disease-modifying anti-asthmatic drugs (DMAADs) has emerged in asthma therapy, with a clear focus on airway inflammation.34 This raises the question of whether the focus should shift towards detecting treatable traits, such as type-2-inflammation in obstructive lung diseases, rather distinction between asthma and COPD. However, with Tezepelumab there is now an effective therapy option regardless of the presence of type-2-inflammation.34 Moreover, in cases of inadequate therapeutic response, switching to another biologic is an effective and often necessary option in asthma, whereas this option is currently not (yet?) available for COPD.35 Therefore, precise diagnosis and phenotyping remains crucial for optimizing therapy, as does gaining further insights into the efficacy of biologic therapy across different patient groups.

A subgroup analysis regarding the effectiveness of different biologics in our patient population is not feasible due to the small size of the subgroups.

We hence propose that biologic therapy represents a valuable treatment option for individuals with severe asthma, even those with concurrent emphysema, provided that patient selection is conducted carefully. It remains imperative to manage comorbid COPD and emphysema as distinct, but possibly concurrent clinical entities, which also includes designation of the two entities (as opposed to the term “asthma-COPD-overlap (ACO)”.

While the influence of emphysema on treatment response was a central focus of our investigation, it is noteworthy that we observed no significant differences in biomarkers associated with severe asthma among our patient groups. These biomarkers, ie, IgE, FeNO, and blood eosinophil count, are crucial indicators of the underlying inflammatory processes and disease activity.26,36 Previous research has demonstrated varying results regarding airway inflammation markers in relation to smoking status; some studies have reported reduced sputum eosinophil counts and lower levels of fractional exhaled nitric oxide (FeNO) in active smokers. In certain cases, former smokers have exhibited signs of induced type-2 inflammation. Collectively, these findings exhibit an inconsistent nature of the observed associations between smoking and airway inflammation markers.1,37–39 Accordingly, there was no difference in other phenotype defining characteristics, like the presence of allergies or CRSwNP as comorbidities. This suggests that while emphysema may indeed present clinical challenges and complexities in the management of severe asthma, it may not substantially alter the inflammatory pathways, disease activity or comorbidities that are commonly associated with the primary condition. This is a possible explanation for the good therapy response, despite comorbid emphysema. On the other hand, patients with a relevant smoking history and/or the presence of pulmonary emphysema may have been preferably selected to be eligible for biologic therapy, when said inflammation markers or comorbidities were present.

Our findings indicate that the presence of pulmonary emphysema should not hinder biologic therapy in suitable patients with severe asthma. This supports an inclusive approach to treatment eligibility.

Regarding patients with more severe emphysema are needed to fully assess its impact on treatment response and provide more evidence for clinical decision-making.

As this study was conducted at a single center and included only ambulatory patients who had undergone native CT scans, this study had its limitations as it might have introduced preselection bias. Furthermore, the selection of the threshold 5% for clinically relevant emphysema was guided by existing literature.21–25 However, it’s important to note that, to date, universally accepted and validated cut-off values for this purpose remain lacking. Additionally, there were no expiratory CT scans available, therefore the amount of hyperinflation in both asthma and comorbid COPD might have been underestimated. However, the conduction of expiratory CT scans are not part of the clinical routine, and therefore may provide rather theoretical implications.

Furthermore, the study’s sample size was relatively small, and the patient cohort exhibited significant variability in the extent of emphysema. While there was a subset of patients with substantial emphysema, the majority had less severe emphysema. This imbalance in patient distribution might limit the ability to draw robust conclusions about the impact of severe emphysema on treatment response. Additionally, the use of a calculated annualized exacerbation rate does present a potential for error; however, after a median follow-up of nearly 8 moths, we believe that the therapeutic response can be assessed with sufficient accuracy. Remission status on the other hand has to be interpreted with caution, as remission can only be assessed after 12 months by definition. Furthermore, an inadequate choice of biologic may also have influenced the therapy response. However, only a small number of patients discontinued therapy due to lack of efficacy.

The observational nature of the study restricts the ability to establish causality. Retrospective analyses rely on existing data that were collected for various clinical purposes, which may not be as comprehensive or consistent.

Nonetheless, this study possesses several key strengths enhancing the credibility and significance of its findings. The use of real-world data reflects the actual clinical practice and treatment outcomes in a diverse patient population, thereby enhancing the study’s external validity. The quantitative assessment of emphysema extent using computed tomography (CT) enables a standardized and objective measure of emphysema severity.

Conclusion

In conclusion, our study shows a good treatment response to biologic asthma therapy, regardless of the presence of emphysema. Careful patient selection and individualized treatment decisions are crucial in optimizing treatment outcomes in this patient population. Concurrent emphysema should not hinder biologic therapy in suitable patients with severe asthma.

Abbreviations

ACT, Asthma Control Test; ACO, Asthma-COPD-overlap; AE, Acute exacerbations; BARS, Biologic Asthma Response Score; BMI, Body mass index; COPD, Chronic obstructive pulmonary disease; CS, Chronic sinusitis; DLCO, Diffusing capacity of the lungs for carbon monoxide; DLCO/VA, DLCO divided by alveolar volume (transfer coefficient); EGPA, Eosinophilic granulomatosis with polyangiitis; Eos, Eosinophil granulocytes in blood; FeNO, Fractional exhaled nitric oxide; FEV1, Forced expiratory volume in 1 second; FEV1/FVC (Tiffeneau Index), Ratio of the FEV1 to the forced vital capacity of the lungs; GAN, German Asthma Net; GERD, Gastroesophageal reflux disease; ICS, Inhaled Corticosteroid; IgE, Immunoglobulin E serum levels; KCO, Carbon monoxide transfer coefficient; L, liters; LABA, Long-acting beta-agonist; LAMA, Long-acting muscarinic antagonist; OCS, Oral Corticosteroids; pO2, Partial pressure of oxygen; TLC, Total lung capacity; VC, Vital capacity; RV, Residual volume; Rtot, Total airway resistance.

Data Sharing Statement

All Data are available from the corresponding author upon request.

Ethics Approval and Consent

All participants provided written informed consent for the German Asthma Net (GAN) registry. The study was approved by the responsible local ethics committee of the University of Bonn, confirming its adherence to the principles outlined in the Declaration of Helsinki and compliance with all the federal and local requirements (No. 174/22).

Consent for Publications

The authors provide their consent for the publication of the study results.

Acknowledgments

The authors would like to acknowledge the Department of Internal Medicine II – Pneumology Department, University Hospital Bonn, for their support in conducting this study.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Funding

This study was not funded externally.

Disclosure

LB reports personal fees/speaker fees from AstraZeneca, Boehringer Ingelheim, Sanofi, all outside the submitted work. DS reports fees for lectures or consultations from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD, Sanofi, all outside the submitted work. The authors report no other conflicts of interest in this work.

References

1. Venkatesan P. 2023 GINA report for asthma. Lancet Respir Med. 2023;11:589. doi:10.1016/S2213-2600(23)00230-8

2. McGregor MC, Krings JG, Nair P, Castro M. Role of biologics in asthma. Am J Respir Crit Care Med. 2019;199:433–445. doi:10.1164/rccm.201810-1944CI

3. Tourangeau LM, Kavanaugh A, Wasserman SI. The role of monoclonal antibodies in the treatment of severe asthma. Ther Adv Respir Dis. 2011;5:183–194. doi:10.1177/1753465811400489

4. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled Phase 3 trial. Lancet. 2016;388:2115–2127. doi:10.1016/S0140-6736(16)31324-1

5. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486–2496. doi:10.1056/NEJMoa1804092

6. Drick N, Fuge J, Seeliger B, et al. Treatment with interleukin (IL)-5/IL-5 receptor antibodies in patients with severe eosinophilic asthma and COPD. ERJ Open Res. 2022;8:00207–2022. doi:10.1183/23120541.00207-2022

7. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804–811. doi:10.1164/rccm.201208-1414OC

8. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198–1207. doi:10.1056/NEJMoa1403290

9. Baastrup Soendergaard M, Hansen S, Bjerrum A-S, et al. Tobacco exposure and efficacy of biologic therapy in patients with severe asthma: a nationwide study from the Danish severe asthma register. j Allergy Clin Immunol Pract. 2024;12:146–155.e5. doi:10.1016/j.jaip.2023.10.012

10. Morobeid H, Pizarro C, Biener L, et al. Impact of prior smoking exposure and COPD comorbidity on treatment response to monoclonal antibodies in patients with severe asthma. ERJ Open Res. 2021;7:00190–2021. doi:10.1183/23120541.00190-2021

11. Rahman M, Dennison P, Azim A, et al. Past smoking does not influence response to biologic therapy in patients with severe asthma. 0501 - airway pharmacology and treatment [Internet]. Eur Respir Soc. 2022:2214. doi:10.1183/13993003.congress-2022.2214.

12. Lommatzsch M, Mohme SN, Stoll P, Virchow JC. Response to various biologics in patients with both asthma and chronic obstructive pulmonary disease. Respiration. 2023;102:986–990. doi:10.1159/000534922

13. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389:205–214. doi:10.1056/NEJMoa2303951

14. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with blood eosinophil evidence of type 2 inflammation. N Engl J Med. 2024;390:2274–2283. doi:10.1056/NEJMoa2401304

15. Kurashima K, Takaku Y, Ohta C, et al. Smoking history and emphysema in asthma–COPD overlap. COPD. 2017;12:3523–3532. doi:10.2147/COPD.S149382

16. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur Respir J. 2004;24:822–833. doi:10.1183/09031936.04.00039004

17. Thomson NC. Asthma with a smoking history and pre–chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2021;204:109–110. doi:10.1164/rccm.202102-0440LE

18. Wang Z, Gu S, Leader JK, et al. Optimal threshold in CT quantification of emphysema. Eur Radiol. 2013;23:975–984. doi:10.1007/s00330-012-2683-z

19. Coxson HO, Dirksen A, Edwards LD, et al. The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study. Lancet Respir Med. 2013;1:129–136. doi:10.1016/S2213-2600(13)70006-7

20. Heussel CP, Herth FJF, Kappes J, et al. Fully automatic quantitative assessment of emphysema in computed tomography: comparison with pulmonary function testing and normal values. Eur Radiol. 2009;19:2391–2402. doi:10.1007/s00330-009-1437-z

21. Gevenois PA, Koob M-C, Jacobovitz D, De Vuyst P, Yernault J-C, Struyven J. Whole lung sections for computed tomographic–pathologic correlations modified Gough-Wentworth technique: investigative radiology. Investigative Radiology. 1993;28:242–245. doi:10.1097/00004424-199303000-00012

22. Gevenois PA, De Maertelaer V, De Vuyst P, Zanen J, Yernault JC. Comparison of computed density and macroscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med. 1995;152:653–657. doi:10.1164/ajrccm.152.2.7633722

23. Casaburi R, Gorek Dilektasli A, Porszasz J, et al. Establishing clinically meaningful cutoffs for %emphysema and %gas trapping in quantitative chest CT scans. 41 Clinical respiratory physiology, exercise and functional imaging. Eur Respir Soc. 2015; OA2944. doi:10.1183/13993003.congress-2015.OA2944.

24. Park J, Kim E-K, Lee SH, et al. Phenotyping COPD patients with emphysema distribution using quantitative CT measurement; more severe airway involvement in lower dominant emphysema. COPD. 2022;17:2013–2025. doi:10.2147/COPD.S362906

25. Ronit A, Kristensen T, Hoseth VS, et al. Computed tomography quantification of emphysema in people living with HIV and uninfected controls. Eur Respir J. 2018;52:1800296. doi:10.1183/13993003.00296-2018

26. Lommatzsch M, Criée C-P, De Jong CCM, et al. S2k-Leitlinie zur fachärztlichen Diagnostik und Therapie von Asthma 2023: herausgegeben von der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin [S2k guideline for specialist diagnosis and treatment of asthma 2023: published by the German Society for Pneumology and Respiratory Medicine]. V Pneumologie. 2023;77:461–543. German.

27. Reddel HK, Taylor DR, Bateman ED, et al. An official American thoracic society/European respiratory society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180:59–99. doi:10.1164/rccm.200801-060ST

28. Stephanie MKK, Feder C, Fuge J, et al. Criteria for evaluation of response to biologics in severe asthma – the biologics asthma response score (BARS). Pneumologie. 2023. doi:10.1055/a-2102-8128

29. van Bragt JJMH, Adcock IM, Bel EHD, et al. Characteristics and treatment regimens across ERS SHARP severe asthma registries. Eur Respir J. 2020;55:1901163. doi:10.1183/13993003.01163-2019

30. Terzikhan N, Verhamme KMC, Hofman A, Stricker BH, Brusselle GG, Lahousse L. Prevalence and incidence of COPD in smokers and non-smokers: the Rotterdam study. Eur J Epidemiol. 2016;31:785–792. doi:10.1007/s10654-016-0132-z

31. Korn S, Milger K, Skowasch D, et al. The German severe asthma patient: baseline characteristics of patients in the German severe asthma registry, and relationship with exacerbations and control. Respir Med. 2022;195:106793. doi:10.1016/j.rmed.2022.106793

32. Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the prevention of COPD exacerbations. N Engl J Med. 2019;381:1023–1034. doi:10.1056/NEJMoa1905248

33. Pavord ID, Chapman KR, Bafadhel M, et al. Mepolizumab for eosinophil-associated COPD: analysis of METREX and METREO. Int J Chron Obstruct Pulmon Dis. 2021;16:1755–1770. doi:10.2147/COPD.S294333

34. Lommatzsch M, Buhl R, Canonica GW, et al. Pioneering a paradigm shift in asthma management: remission as a treatment goal. Lancet Respir Med. 2024;12:96–99. doi:10.1016/S2213-2600(23)00415-0

35. Biener L, Mümmler C, Hinze CA, et al. Real-world data on tezepelumab in patients with severe asthma in Germany. j Allergy Clin Immunol Pract. 2024;2024:S2213219824006251.

36. Lopez M, White A. SWITCHING BIOLOGICS FOR ASTHMA. Ann Allergy Asthma Immunol. 2022;129:S51.

37. Wan XC, Woodruff PG. Biomarkers in severe asthma. Immunol Allergy Clin North America. 2016;36:547–557. doi:10.1016/j.iac.2016.03.004

38. Oishi K, Matsunaga K, Shirai T, Hirai K, Gon Y. Role of type 2 inflammatory biomarkers in chronic obstructive pulmonary disease. J Clin Med. 2020;9:2670. doi:10.3390/jcm9082670

39. Thomson NC, Chaudhuri R, Heaney LG, et al. Clinical outcomes and inflammatory biomarkers in current smokers and ex smokers with severe asthma. J Allergy Clin Immunol. 2013;131:1008–1016. doi:10.1016/j.jaci.2012.12.1574