Response to Various Biologics in Patients with Both Asthma and Chronic Obstructive Pulmonary Disease

Introduction: Patients can have features of both chronic obstructive pulmonary disease (COPD) and asthma. However, there is still no consensus how to precisely define this patient population. In addition, there are little data on the effectiveness of biologics in these patients. Method: Presence of COPD was defined by a smoking history of ≥10 pack years (PY), a postbronchodilator FEV1/FVC ratio < lower limit of normal (LLN) and FEV1 < 80% predicted, a carbon monoxide diffusion capacity (DLCO) < LLN, and dyspnoea on exertion as a leading symptom. Presence of asthma was defined by high type 2 biomarkers (blood eosinophils ≥300 cells/μL and/or FeNO ≥50 ppb), typical clinical features of asthma (including nocturnal respiratory symptoms), and a documented history of a clinical benefit from inhaled and/or oral glucocorticoid treatment. We analysed data from 20 patients fulfilling the criteria for both COPD and asthma who were newly treated with a biologic due to recurrent exacerbations despite high-dose inhaled triple therapy. Results: Median values before treatment with a biologic were as follows: 40 PY, FEV1 42% predicted, DLCO 45% predicted, 475 eosinophils/μL blood, FeNO 48 ppb. Median duration of biologic treatment (mepolizumab, benralizumab, dupilumab, omalizumab, or tezepelumab) was 12 months. There were significant improvements in exacerbations (most prominent effect), asthma control, and lung function during biologic treatment. Conclusions: Various types of biologics approved for severe asthma treatment can be effective in patients with both COPD and asthma. We propose an easy-to-use definition of these patients for routine clinical practice.


Introduction
It is well-recognised that some patients can have features of both chronic obstructive pulmonary disease (COPD) and asthma [1].Due to the very broad and confusing spectrum of different combinations of these features, the terms asthma-COPD overlap syndrome or asthma-COPD overlap are no longer recommended by international guidelines [2,3].Instead, some authors postulate that patients with a physician's diagnosis of COPD, elevated type 2 biomarkers, and recurrent exacerbations despite inhaled triple therapy (inhaled corticosteroids plus a long-acting beta-agonist [LABA] plus a long-acting muscarinic antagonist [LAMA]) should be termed "COPD with type 2 inflammation" [4].These concepts do not address the fact that severe asthma with a smoking history of ≥10 pack years (PY) [5] is often misclassified as COPD in clinical studies and in real life.More importantly, using the diagnosis "COPD" only can hamper the prescription of highly effective drugs which are approved for asthma only [6].Therefore, current guidelines of the Global Initiative for Asthma (GINA) recommend to diagnose both diseases ("asthma + COPD") in these patients [2].However, there is still no consensus how to precisely define such a patient population.In addition, there are little data on the effectiveness of biologics in these patients [7].Therefore, we here report data on the effectiveness of biologics approved for the treatment of severe asthma in patients with both COPD and asthma, accompanied by a proposed definition of this patient population.

Methods
We defined the presence of COPD by (1) a history of ≥10 PY, (2) a postbronchodilator (PBD) FEV 1 /FVC ratio < lower limit of normal, (3) a PBD FEV 1 < 80% predicted, (4) a carbon monoxide diffusion capacity (DLCO) < lower limit of normal, and (5) presence of dyspnoea on exertion as a leading symptom (Fig. 1).Presence of asthma was defined by (1) high type 2 biomarkers (blood eosinophils ≥300 cells/μL and/or FeNO ≥50 ppb), (2) typical clinical features of asthma (including nocturnal respiratory symptoms), and (3) a documented history of a clinical benefit from treatment with inhaled and/or oral glucocorticoids [8] (Fig. 1).We analysed data from 20 patients presenting routinely to our outpatient clinic in Rostock (Germany) who fulfilled the above mentioned criteria for both COPD and asthma and who were newly treated with a biologic approved for the treatment of severe asthma due to recurrent exacerbations despite inhaled triple therapy (high dose of ICS plus a LABA, plus a LAMA) (Table 1).All patients had inhaled their triple therapies (ICS/LABA/LAMA) within 4 h before lung function testing; therefore, lung function data were classified as PBD values.Due to the pretreatment with inhaled triple therapies, valid reversibility test data (before and after inhalation of a short-acting betaagonist, SABA) could not be obtained.The choice of the biologic was made by the treating physician according to the asthma phenotype of the individual patient and current German asthma guidelines [9].The difference between the 2 time points (baseline vs. last visit) of each parameter was analysed using the Wilcoxon signed rank test, p values <0.05 were regarded as statistically significant.

Results
Patients had a median smoking history of 40 PY, a median PBD FEV 1 of 42% predicted and a median DLCO of 45% predicted, before treatment with a biologic (Table 1).All patients had a history of exacerbations and were characterised by high type 2 biomarkers (median values: 475 eosinophils/μL blood; FeNO 48 ppb) despite inhaled triple therapy (high-dose ICS/LABA/LAMA) (Table 1).The median duration of biologic treatment (from baseline to the last visit) was 12 months (Table 1).There were significant improvements in exacerbations, asthma symptoms, and lung function at the last visit during biologic treatment, as compared with baseline (Table 1; Fig. 2).There were 9 patients with initial OCS maintenance treatment (45% of all patients).In this subgroup, 4 patients stopped and 2 patients reduced OCS maintenance therapy during biologic treatment.In contrast, 3 patients continued to use the initial daily OCS maintenance dose (Table 1).

Discussion
We show, for the first time, that various types of biologics approved for the treatment of severe asthma can be effective in a well-characterised patient population with both COPD and asthma.The most prominent effect of this treatment was the reduction in exacerbations, whereas there was only a minor effect on lung function (due to concomitant COPD).In addition, Asterisks (*) mark significant (p < 0.05, measured using the Wilcoxon signed rank test) differences between the baseline (BL) and the last visit (LV) during biologic treatment.Female (F), male (M), biologic (Biol), diffusion capacity for carbon monoxide (DLCO), oral corticosteroid (OCS), benralizumab (B), dupilumab (D), mepolizumab (M), omalizumab (O), tezepelumab (T), years (yrs), body mass index (BMI), months (mo), forced expiratory volume in the first second of expiration (FEV 1 ), forced vital capacity (FVC), exacerbations (Exac), blood eosinophils (Eos), exhaled nitric oxide (FeNO), asthma control test (ACT), patient (pt), not analysed (NA).# Non-Responder (biologic treatment was discontinued after 7 months).§ If biologic treatment lasted less than 1 year, the number of exacerbations refers to the treatment period with the biologic.

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Respiration 2023;102:986-990 DOI: 10.1159/000534922 Lommatzsch/Mohme/Stoll/Virchow there was a heterogeneous effect on OCS maintenance therapy suggesting that a reduction of maintenance OCS can be challenging in this population of older and multimorbid patients.There is now accumulating evidence from randomised controlled trials that biologics such as dupilumab [4], mepolizumab [10], or benralizumab [11] can be effective in patients who are classified as patients having COPD with elevated type 2 biomarkers.However, these studies do not address and discuss the fact that these patients can have concomitant asthma.Of note, the only difference between the "COPD" population described in the BOREAS trial [4] and a typical population of patients with severe asthma was a smoking history of ≥10 PY (which does not exclude asthma [5]) and a doctor's diagnosis of COPD (which does not exclude the presence of asthma either [12,13]).Our study demonstrates that various types of biologics (and not only one class of biologic) approved for the treatment of asthma [6] can, depending on the respective asthma phenotype, be effective in patients with typical and defined clinical features of both asthma and COPD.
In addition, we propose a new and easy-to-use definition of this patient population (asthma + COPD) for routine clinical practice (Fig. 1).Of note, this definition does not include a lack of SABA reversibility as a COPD criterion.There is now accumulating evidence that SABA reversibility can be absent in asthma [14,15].This is most prominent in patients with severe asthma; more than 65% of all patients with severe asthma lack SABA reversibility [14,15].Furthermore, response to biologics does not depend on SABA reversibility in patients with severe asthma [16,17].In contrast, we included a pathologic DLCO as a COPD criterion because there is evidence that reduced carbon monoxide diffusion capacity can be a marker for emphysema (typical for COPD) among patients with persistent airflow limitation [18].However, our clinical definition of patients with asthma + COPD needs to be validated and tested in future clinical trials.

Statement of Ethics
Not applicable due to the retrospective analysis of deidentified data.

Conflicts of Interest Statement
The authors report no conflicts of interest regarding this report.

Fig. 1 .
Fig.1.Proposed clinical definition of patients with asthma + COPD.Shown are typical features of COPD and asthma (panels on the left and right side), and the proposed criteria for the patient population with asthma + COPD (central panel).Eos, blood eosinophils; DLCO, carbon monoxide diffusion capacity; FEV 1 , forced expiratory volume in the first second of expiration; FVC, forced vital capacity; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; LLN, lower limit of normal; OCS, oral corticosteroid; ppb, parts per billion; PBD, postbronchodilator.

Fig. 2 .
Fig. 2. Clinical effects of various biologics in patients with asthma + COPD.Shown are data from 20 patients from Rostock (Germany) with both COPD and asthma (each dot represents 1 patient), at baseline (before initiation of a treatment with a biologic) and at the last visit in our department.FEV 1 , forced expiratory volume in the first second of expiration; FVC, forced vital capacity; FeNO, fractional exhaled nitric oxide; ppb, parts per billion.

Table 1 .
Patient characteristics and individual treatment response