Eligibility of C-BIOPRED severe asthma cohort for type-2 biologic therapies.

To the Editor: Patients with severe persistent asthma experience greater morbidity with more impairment in quality of life despite higher use of health care resources and being treated with existing asthma treatments such as inhaled corticosteroids and β-agonists, and sometimes oral corticosteroid (OCS) therapy. Type-2 (T2) high asthma has been identified as a phenotype that responds to targeted T2 biologic therapies such as anti-IgE, anti-interleukin (IL) 5, or anti-IL5Rα and anti-IL4Rα monoclonal antibodies, which are currently available in Europe and North America, and are currently introduced in the rest of the world.[1] Although the prevalence of adult asthma of 4.2% in China is not as high as that in Western countries, severe asthma as defined according to the European Respiratory Society and America Thoracic Society (ERS/ATS) definition is being recognized.[2] The Chinese Biomarkers for the Prediction of Respiratory Disease Outcomes (C-BIOPRED) cohort of 452 severe asthma patients has characterized these patients that share similar features as those reported in cohorts outside China.[3] To understand the potential impact of T2-targeted biologic therapies in China, we have determined the prevalence of T2-high asthma based on the criteria of blood eosinophil count (BEC) of either ≥150/μL or ≥300/μL and/or FeNO ≥20 parts per billion (ppb) (https://ginasthma.org/wp-content/uploads/2021/08/SA-Pocket-guide-v3.0-SCREEN-WMS.pdf). Data are presented as mean (standard deviation) or number of subjects (% of total). P values represent comparison across four groups using Kruskal–Wallis tests for continuous variables or Fisher exact tests for categorical variables. P < 0.05 was considered to be statistically significant. T2-high was present ranging from 55.8% (BEC ≥300 μL) to 75.7% (FeNO ≥20 ppb) of the severe asthma patients, while a combination of BEC ≥150/μL and FeNO ≥20 ppb or BEC ≥300/μL and FeNO ≥20 ppb identified 55.9% and 38.7%, respectively [Supplementary Figure 1, https://links.lww.com/CM9/B402]. In 246 severe asthma patients who were re-assessed at one year, a similar percentage of patients remained T2-high, but 10% to 15% in T2-high or T2-low changed to the alternate class. Sputum eosinophil count (SEC) is a better marker of T2-high asthma,[4] and using a SEC ≥2%,[5] 75% of patients were classified as T2-high. To determine the eligibility for T2 biologic therapies, we used the guidelines of the Global Initiative for Asthma (GINA) (https://ginasthma.org/wp-content/uploads/2021/08/SA-Pocket-guide-v3.0-SCREEN-WMS.pdf), whereby patients diagnosed with severe asthma have had at least two exacerbations in the past year with biomarker cut-offs for different classes of biologic therapies. For anti-IgE antibody, we used the presence of sensitization on skin prick testing or specific IgE to common aeroallergens with total serum IgE and body weight within the dosage range. For anti-IL5 or anti-IL5Rα, BEC of ≥300/μL, and for anti-IL4Rα, BEC ≥150/μL or FeNO ≥25 ppb were used. Among 452 patients with severe asthma, 174 (38.5%) were eligible for one or more of the three biologic treatments [Figure 1]. A total of 51 cases (11.3%) were eligible for anti-IgE treatment, but eight (1.8%) individuals were only eligible for anti-IgE therapy. Similarly, 166 cases (36.7%) were eligible for anti-IL4Rα treatment, but 60 (13.3%) were only eligible for this treatment. There were 87 patients (19.3%) suitable for anti-IL-5/5Rα treatment, but all of whom would also be eligible for anti-IL4Rα treatment [Supplementary Table 1, https://links.lww.com/CM9/B402]. Besides, 63 (13.9%) patients were included for being both eligible for anti-IL4R and anti-IL-5/5Rα groups, and 43 (9.5%) patients were both eligible for anti-IgE and anti-IL4R therapy [Figure 1]. Finally, 24 cases (5.3%) met the three treatment standards for either anti-IgE or anti-IL4R or anti-IL-5/5R antibody.Figure 1: Venn diagram of severe asthmatics eligible for treatment with anti-IgE, or anti-IL5/IL5Rα or anti-IL4Rα monoclonal antibodies. IL: Interleukin.As shown in Supplementary Table 2, [https://links.lww.com/CM9/B402], compared with other groups, patients who would qualify only for anti-IgE had the better controlled asthma, lowest FeNO value (5.61 ppb, P < 0.001), lowest serum BEC, ECP, and total IgE levels, and none required daily OCS therapy. By contrast, those eligible for anti-IL4Rα only had higher BEC (540/μL, P < 0.001), higher FeNO, and highest sputum eosinophilia (33.3%) and comprised of the highest percentage of OCS patients (31.2%). Those eligible for all three biologic treatments had highest total serum IgE (449.75 KU/L, P < 0.001) and ECP levels than the other patients eligible for anti-IgE alone or for anti-IL4Rα alone. Patients not eligible for any biologic treatments were characterized by the highest FeNO (33.2 ppb, P < 0.001), with raised sputum eosinophils and BEC (270/μL) and none received OCS therapy. Because the UK National Health and Care Institute has advocated the use of these biologics using different criteria (https://www.nice.org.uk/guidance/TA751/chapter/1-Recommendations), we have examined these conditions such as the need for having more than four severe exacerbations in the previous year and the combination of BEC ≥150/μL plus FeNO ≥25 ppb for consideration of severe asthma patients for anti-IL4Rα. Thus, extending the cut-off point of 1, 2, 3, or 4 exacerbations in the previous year, those eligible for the biologic therapies would be 58.8%, 38.5%, 23.0%, and 15.3%, respectively [Supplementary Table 1, https://links.lww.com/CM9/B402]. In addition, using the combination of BEC ≥150/μL and FeNO ≥25 ppb instead of BEC ≥150/μL or FeNO ≥25 ppb for anti-IL4Rα allowed for a greater percentage of patients that would be eligible for anti-IgE and anti-IL5/IL5Rα antibody treatments, at the expense of anti-IL4Rα antibody only. Interestingly, those with more than one exacerbation per year and using eligibility for anti-IL4Rα as the combination of BEC ≥150/μL and FeNO ≥25 ppb maximizes the numbers that would be suitable for only one of the three classes of antibodies (anti-IgE: 7.5%, anti-IL5/IL5Rα: 5.3%, and anti-IL4Rα: 10.0%). The T2-high severe asthma phenotype that is relatively stable in up to 80.0% and up to 58.8% of severe asthma would be eligible for biologic therapies, dependent on the criteria used. These definitions are all dependent on the cut-off point of the biomarker used, usually a BEC. The largest group to benefit is that eligible for anti-IL4Rα targeting both IL-4 and IL-13, who have the highest blood and sputum eosinophilia, with a large proportion of atopic patients. Those eligible for IL5/IL5Rα biologic are also eligible for anti-IL-4Rα, which indicates the need for more refined biomarkers that would distinguish eligibility for each specific biologic therapy. Finally, many of the 42.0% of severe asthma patients not eligible for biologic therapies represent those who do not report two or more exacerbations in the previous year, particularly in those with atopy and high BECs. Using the experience of at least four exacerbations, only a minority of severe asthmatics (∼15% only) would be eligible for these biologic therapies. In conclusion, this study reveals that T2-high asthma is the predominant phenotype in patients with severe asthma in the C-BIOPRED cohort and remains relatively stable after a 1-year longitudinal visit. In addition, we found that the proportion of patients for whom different T2 biologic therapies were indicated varied, depending on entry criteria, and that more refined biomarkers that would distinguish eligibility for each specific biologic therapy were needed. Acknowledgements We would like to thank all the members of the C-BIOPRED Study Group who were involved in the design and recruitment of participants into the study. We thank Yicheng Fan, Yujing Liu, Nkouibert Pryseley Assam, Zhaohui Zhou, Wei Jiang, and Jia Wang of Astra-Zeneca for their help in data and statistical analyses and in the preparation of the figures and tables. We also thank all the participants who willingly took part in the C-BIOPRED study. Funding This study was supported by grants from Astra-Zeneca, China, and the National Natural Science Foundation of China (No. 82070026). Conflicts of interest Kian Fan Chung has received honoraria for participating in Advisory Board meetings of GSK, AZ, Roche, Merck, Nocion, and Shionogi regarding treatments for asthma, chronic obstructive pulmonary disease, and chronic cough and has also been remunerated for speaking engagements for AZ. The other authors declare no conflict of interest. Ethics statement The study was approved by the Institutional Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (No. 201525) and written informed consents were obtained from all participants. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request.