贝那利珠单抗治疗重度嗜酸性粒细胞性哮喘期间的急性发作特征（BenRex研究）：一项多中心前瞻性队列研究
2026/09/09
摘要
背景：贝那利珠单抗是一种白细胞介素-5受体α拮抗剂，可耗竭血液嗜酸性粒细胞；与安慰剂相比，可使重度哮喘急性发作减少约50%。本研究旨在阐明贝那利珠单抗治疗期间仍发生急性发作的潜在机制。
方法：BenRex是一项多中心前瞻性队列研究，招募符合国家关于贝那利珠单抗用于哮喘的许可标准的参与者。研究在英国15家重度哮喘中心开展。收集基线数据后，给予开放标签贝那利珠单抗治疗12-18个月。发生急性发作时，参与者在开始治疗前到研究中心接受医疗评估，并检测呼出气一氧化氮分数（FeNO）、进行肺功能检查和哮喘控制问卷评估，同时采集血液和痰液标本。
结果：2019年9月30日至2024年4月23日期间，在156名参与者中评估了121次急性发作事件。90名参与者（58%）为女性，66名（42%）为男性；147名（94%）参与者自我认定为白人。急性发作时血嗜酸性粒细胞计数中位数为0个/μL（IQR 0-0）。在有痰液标本的急性发作中，55%存在气道中性粒细胞增多（27/49）。C反应蛋白（CRP）中位数由基线时的3.00 mg/L（1.00-6.00）升至急性发作时的9.00 mg/L（3.00-17.00；p=0.0067）。39份痰液标本中，8份（20.5%）检出具有临床意义的病毒病原体，而病毒总检出率为22/39（56.4%）。最常见的病毒病原体为甲型流感病毒、人偏肺病毒和鼻病毒，三者均在39份标本中的2份（5.1%）检出。新获得的细菌包括卡他莫拉菌〔3/22（13.6%）〕、流感嗜血杆菌〔4/22（18.2%）〕和肺炎链球菌〔2/22（9.1%）〕。从基线到急性发作期，DNA-中性粒细胞弹性蛋白酶复合物（p=0.0080）和天青杀素-1（p=0.012）浓度升高。在111次接受评估的急性发作中，56次（50.5%）的FeNO≥50 ppb，并与细菌检出可能性降低相关。FeNO与CRP或痰液中性粒细胞均无相关性。
结论：研究结果提示，患者接受贝那利珠单抗治疗期间发生的急性发作并不涉及嗜酸性粒细胞性炎症。气道中性粒细胞增多、病毒病原体及痰微生物组改变均提示感染是急性发作最主要的原因。这一观察结果有望改善贝那利珠单抗治疗下仍发生哮喘急性发作的精准管理。
Asthma exacerbation profile of benralizumab for severe eosinophilic asthma (the BenRex study): a multicentre, prospective cohort study
Jennifer Logan, Kirsty Martin, Lynsey Gillespie, Alex McConnachie, Wai-Ting Nicola Lee, Hassan Burhan, Thomas Brown, Shoaib Faruqi, David J Jackson, Ramesh Kurukulaaratchy, Adel H Mansur, Dinesh Saralaya, Stephen J Fowler, Pujan Patel, James Brown, James Lordan, Salman Siddiqui, Steven James Smith, Peer Ameen Shah, Koirobi Haldar, Spyridon Megremis, Sophie A Harrison, Rhys Brown, Charlotte Nelson, Vijay Mistry, Vanessa Brown, James D Chalmers, Ratko Djukanovic, Ian D Pavord, Liam G Heaney, Christopher E Brightling, Rekha Chaudhuri
Abstract
BACKGROUND:
Benralizumab, an interleukin-5 receptor α antagonist, depletes blood eosinophils, reducing exacerbations of severe asthma by approximately 50% versus placebo. In this study, we aimed to characterise mechanisms underlying exacerbations occurring on benralizumab.
METHODS:
BenRex, a multicentre, prospective cohort study, recruited participants meeting national licensing criteria for benralizumab for asthma. The study was conducted in 15 UK severe asthma centres. After collecting baseline data, open-label benralizumab was administered for 12–18 months. At exacerbation, participants attended for medical review before initiating treatment, fractional exhaled nitric oxide (FeNO), spirometry, asthma control questionnaire, and blood and sputum sampling.
RESULTS:
Between Sept 30, 2019, and April 23, 2024, 121 exacerbation events were assessed in 156 individuals. 90 participants (58%) were female and 66 (42%) were male; 147 (94%) of participants identified as White. Median blood eosinophil counts at exacerbation were 0 (IQR 0–0) cells per μL. Airway neutrophilia was present in 55% of exacerbations where sputum was available (27/49). Median C-reactive protein (CRP) increased from 3.00 mg/L (1.00–6.00) at baseline to 9.00 mg/L (3.00–17.00) at exacerbation (p=0.0067). Clinically relevant viral pathogens were seen in eight (20.5%) of 39 sputum samples; although viruses were detected in 22 (56.4%) of 39 samples. Influenza A, metapneumovirus, and rhinovirus were the most common viral pathogens (each found in 2 [5.1%] of 39 samples). New acquisitions of Moraxella catarrhalis (3 [13·6%] of 22), Haemophilus influenzae (4 [18·2%] of 22), and Streptococcus pneumoniae (2 [9·1%] of 22) occurred. DNA-neutrophil elastase complexes (p=0.0080) and azurocidin-1 (p=0.012) concentrations rose from baseline to exacerbation. FeNO was ≥50 parts per billion in 56 (50.5%) of 111 assessed exacerbations and was associated with reduced odds of bacterial detection. FeNO did not correlate with CRP or sputum neutrophils.
CONCLUSION:
Our findings suggested that eosinophilic inflammation is not involved in exacerbations when a patient is being treated with benralizumab. Airway neutrophilia, viral pathogens, and alteration of the sputum microbiome point to infection as the most prominent causes of exacerbations. This observation should improve precision management of asthma exacerbations occurring despite treatment with benralizumab.
背景：贝那利珠单抗是一种白细胞介素-5受体α拮抗剂，可耗竭血液嗜酸性粒细胞；与安慰剂相比，可使重度哮喘急性发作减少约50%。本研究旨在阐明贝那利珠单抗治疗期间仍发生急性发作的潜在机制。
方法：BenRex是一项多中心前瞻性队列研究，招募符合国家关于贝那利珠单抗用于哮喘的许可标准的参与者。研究在英国15家重度哮喘中心开展。收集基线数据后，给予开放标签贝那利珠单抗治疗12-18个月。发生急性发作时，参与者在开始治疗前到研究中心接受医疗评估，并检测呼出气一氧化氮分数（FeNO）、进行肺功能检查和哮喘控制问卷评估，同时采集血液和痰液标本。
结果：2019年9月30日至2024年4月23日期间，在156名参与者中评估了121次急性发作事件。90名参与者（58%）为女性，66名（42%）为男性；147名（94%）参与者自我认定为白人。急性发作时血嗜酸性粒细胞计数中位数为0个/μL（IQR 0-0）。在有痰液标本的急性发作中，55%存在气道中性粒细胞增多（27/49）。C反应蛋白（CRP）中位数由基线时的3.00 mg/L（1.00-6.00）升至急性发作时的9.00 mg/L（3.00-17.00；p=0.0067）。39份痰液标本中，8份（20.5%）检出具有临床意义的病毒病原体，而病毒总检出率为22/39（56.4%）。最常见的病毒病原体为甲型流感病毒、人偏肺病毒和鼻病毒，三者均在39份标本中的2份（5.1%）检出。新获得的细菌包括卡他莫拉菌〔3/22（13.6%）〕、流感嗜血杆菌〔4/22（18.2%）〕和肺炎链球菌〔2/22（9.1%）〕。从基线到急性发作期，DNA-中性粒细胞弹性蛋白酶复合物（p=0.0080）和天青杀素-1（p=0.012）浓度升高。在111次接受评估的急性发作中，56次（50.5%）的FeNO≥50 ppb，并与细菌检出可能性降低相关。FeNO与CRP或痰液中性粒细胞均无相关性。
结论：研究结果提示，患者接受贝那利珠单抗治疗期间发生的急性发作并不涉及嗜酸性粒细胞性炎症。气道中性粒细胞增多、病毒病原体及痰微生物组改变均提示感染是急性发作最主要的原因。这一观察结果有望改善贝那利珠单抗治疗下仍发生哮喘急性发作的精准管理。
（中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校）
（Lancet Respir Med. 2026 Aug;14(8):683-693. DOI: https://doi.org/10.1016/S2213-2600(26)00096-2）
（Lancet Respir Med. 2026 Aug;14(8):683-693. DOI: https://doi.org/10.1016/S2213-2600(26)00096-2）
Asthma exacerbation profile of benralizumab for severe eosinophilic asthma (the BenRex study): a multicentre, prospective cohort study
Jennifer Logan, Kirsty Martin, Lynsey Gillespie, Alex McConnachie, Wai-Ting Nicola Lee, Hassan Burhan, Thomas Brown, Shoaib Faruqi, David J Jackson, Ramesh Kurukulaaratchy, Adel H Mansur, Dinesh Saralaya, Stephen J Fowler, Pujan Patel, James Brown, James Lordan, Salman Siddiqui, Steven James Smith, Peer Ameen Shah, Koirobi Haldar, Spyridon Megremis, Sophie A Harrison, Rhys Brown, Charlotte Nelson, Vijay Mistry, Vanessa Brown, James D Chalmers, Ratko Djukanovic, Ian D Pavord, Liam G Heaney, Christopher E Brightling, Rekha Chaudhuri
Abstract
BACKGROUND:
Benralizumab, an interleukin-5 receptor α antagonist, depletes blood eosinophils, reducing exacerbations of severe asthma by approximately 50% versus placebo. In this study, we aimed to characterise mechanisms underlying exacerbations occurring on benralizumab.
METHODS:
BenRex, a multicentre, prospective cohort study, recruited participants meeting national licensing criteria for benralizumab for asthma. The study was conducted in 15 UK severe asthma centres. After collecting baseline data, open-label benralizumab was administered for 12–18 months. At exacerbation, participants attended for medical review before initiating treatment, fractional exhaled nitric oxide (FeNO), spirometry, asthma control questionnaire, and blood and sputum sampling.
RESULTS:
Between Sept 30, 2019, and April 23, 2024, 121 exacerbation events were assessed in 156 individuals. 90 participants (58%) were female and 66 (42%) were male; 147 (94%) of participants identified as White. Median blood eosinophil counts at exacerbation were 0 (IQR 0–0) cells per μL. Airway neutrophilia was present in 55% of exacerbations where sputum was available (27/49). Median C-reactive protein (CRP) increased from 3.00 mg/L (1.00–6.00) at baseline to 9.00 mg/L (3.00–17.00) at exacerbation (p=0.0067). Clinically relevant viral pathogens were seen in eight (20.5%) of 39 sputum samples; although viruses were detected in 22 (56.4%) of 39 samples. Influenza A, metapneumovirus, and rhinovirus were the most common viral pathogens (each found in 2 [5.1%] of 39 samples). New acquisitions of Moraxella catarrhalis (3 [13·6%] of 22), Haemophilus influenzae (4 [18·2%] of 22), and Streptococcus pneumoniae (2 [9·1%] of 22) occurred. DNA-neutrophil elastase complexes (p=0.0080) and azurocidin-1 (p=0.012) concentrations rose from baseline to exacerbation. FeNO was ≥50 parts per billion in 56 (50.5%) of 111 assessed exacerbations and was associated with reduced odds of bacterial detection. FeNO did not correlate with CRP or sputum neutrophils.
CONCLUSION:
Our findings suggested that eosinophilic inflammation is not involved in exacerbations when a patient is being treated with benralizumab. Airway neutrophilia, viral pathogens, and alteration of the sputum microbiome point to infection as the most prominent causes of exacerbations. This observation should improve precision management of asthma exacerbations occurring despite treatment with benralizumab.
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