Anti-influenza Immune Plasma for the Treatment of Patients With Severe Influenza A: A Randomised, Double-Blind, Phase 3 Trial

John H Beigel, Evgenia Aga, Marie-Carmelle Elie-Turenne, et al

Lancet Respir Med 2019; 7: 941-950

Background 背景

Infection with influenza virus causes substantial morbidity and mortality globally, although antiviral treatments are available. Previous studies have suggested that anti-influenza immune plasma could be beneficial as treatment, but they were not designed as randomised, blinded, placebo-controlled trials. Therefore, we aimed to prospectively evaluate the clinical efficacy of high-titre immune plasma compared with standard low-titre plasma to improve outcomes in patients with severe influenza A infection.

尽管进行了抗病毒治疗，流感病毒感染的全球罹患率与病死率仍然很高。既往研究提示，抗病毒免疫血浆治疗可能有益，但是尚缺乏随机设盲安慰剂对照试验。因此，我们前瞻性比较高滴度免疫血浆与标准低滴度血浆对严重甲型流感病毒感染患者临床预后的影响。

Methods 方法

We did this randomised, double-blind, phase 3 trial at 41 US medical centres to assess the efficacy of high-titre anti-influenza plasma (haemagglutination inhibition antibody titre ≥1:80) compared with low-titre plasma (≤1:10). Children and adults with PCR-confirmed influenza A infection, a National Early Warning score of 3 or greater, and onset of illness within 6 days before randomisation were eligible. Patients were randomly assigned (2:1) using an interactive web response system to receive either two units (or paediatric equivalent) of high-titre plasma (high-titre group) or low-titre plasma (low-titre group), and were followed up for 28 days from randomisation. High-titre and low-titre plasma had the same appearance. Randomisation was stratified by severity (in intensive care unit, not in intensive care but requiring supplemental oxygen, or not in intensive care and not requiring supplemental oxygen) and age (<18 years and ≥18 years). All participants, site staff, and the study team were masked to treatment allocation until after the final database lock. The primary endpoint was clinical status assessed by a six-point ordinal scale on day 7 (death, in intensive care, hospitalised but requiring supplemental oxygen, hospitalised not requiring supplemental oxygen, discharged but unable to resume normal activities, and discharged with full resumption of normal activities) analysed in a proportional odds model (an odds ratio [OR] >1 indicates improvement in clinical status across all categories for the high-titre vs the low-titre group). The primary analysis was done in the intention-to-treat population, excluding two participants who did not receive plasma. This trial is registered with ClinicalTrials.gov, NCT02572817.

我们在美国41个医学中心进行了一项随机双盲3期临床试验，以评价高滴度抗流感病毒血浆(血凝素抑制抗体滴度≥1:80)与低滴度血浆(≤1:10)的临床疗效。PCR确诊的甲型流感病毒感染儿童及成人，国家早期预警评分3分或更高，且随机分组前发生不足6天的患者入选研究。患者按照2:1的比例根据互动网络响应系统接受随机分组，分别输注2个单位(或儿童相应剂量)高滴度血浆(高滴度组)或低滴度血浆(低滴度组)，随访至随机分组后28天。高滴度与低滴度血浆外表相同。根据疾病严重程度(在ICU住院，未在ICU住院但需要氧疗，或未在ICU住院且无需氧疗)及年龄(<18 岁及 ≥18 岁)进行分层随机。治疗分组对所有入选患者、中心人员和研究团队隐藏，直至最终数据库锁定。主要预后终点为第7天的临床状态，通过6分顺序变量(死亡，收入ICU，住院且需要氧疗，住院但无需氧疗，出院但不能进行正常活动，出院且能进行正常活动)采用比例优势模型进行评估(OR >1 提示与低滴度组相比，高滴度组所有类别的临床状态改善)。主要分析采用意向治疗人群，排除了2名没有接受血浆输注的患者。试验在 ClinicalTrials.gov注册，注册号 NCT02572817。

Findings 结果

Participants were recruited between Jan 26, 2016, and April 19, 2018. Of 200 participants enrolled (177 adults and 23 children), 140 met the criteria for randomisation and were assigned to the high-titre group (n=92) or to the control low-titre group (n=48). One participant from each group did not receive plasma. At baseline, 60 (43%) of 138 participants were in intensive care and 55 (71%) of 78 participants who were not in intensive care required oxygen. 93% of planned plasma infusions were completed. The study was terminated in July, 2018, when independent efficacy analysis showed low conditional power to detect an effect of high-titre plasma even if full accrual (150 participants) was achieved. The proportional OR for improved clinical status on day 7 was 1·22 (95% CI 0·65–2·29, p=0·54). 47 (34%) of 138 participants experienced 88 serious adverse events: 32 (35%) with 60 events in the high-titre group and 15 (32%) with 28 events in the low-titre group. The most common serious adverse events were acute respiratory distress syndrome (ARDS; four [4%] vs two [4%]), allergic transfusion reactions (two [2%] vs two [4%]), and respiratory distress (three [3%] vs none). 65 (47%) participants experienced 183 adverse events: 42 (46%) with 126 events in the high-titre group and 23 (49%) with 57 events in the low-titre group. The most common adverse events were anaemia (four [3%] vs two [4%]) and ARDS (four [3%] vs three [5%]). Ten patients died during the study (six [7%] in the high-titre group vs four [9%] in the low-titre group, p=0·73). The most common cause of death was worsening of acute respiratory distress syndrome (two [2%] vstwo [4%] patients).

2016年1月25日至2018年4月19日期间入选患者。共有 200 名患者入选 (177名成人，23名儿童)，其中140名符合随机分组标准，分别分至高滴度组 (n=92) 或低滴度对照组 (n=48)。两组各有1名患者未输注血浆。在基线时，138名患者中60名 (43%)在ICU住院，未收入ICU的78名患者中 55 名 (71%) 接受氧疗。93%的患者按计划完成了血浆输注。试验在2018年7月终止，因为独立的疗效分析显示，即使按计划入选全部150名患者，仅有极小可能检验高滴度血浆的效果。第7天临床状态改善的比例OR为1·22 (95% CI 0·65–2·29, p=0·54)。138名患者中47名 (34%) 发生88次严重不良事件：其中，高滴度组32名 (35%) 患者发生 60 次，低滴度组15名 (32%) 患者发生28次严重不良事件。最常见的严重不良事件包括ARDS (4 [4%] vs two [4%])，输液过敏反应 (2 [2%] vs 2 [4%]) 及呼吸窘迫 (3 [3%] vs 0)。65名 (47%) 患者发生 183 次不良事件：高滴度组42名 (46%) 患者发生 126 次，低滴度组 23 名 (49%) 患者发生57次。最常见的不良事件为贫血 (4 [3%] vs 2 [4%]) 和 ARDS (4 [3%] vs 3 [5%])。研究期间10名患者死亡 (高滴度组6名 [7%] vs 低滴度组4名 [9%], p=0·73)。最常见死因为ARDS病情恶化 (2 [2%] vs 2 [4%] 名患者)。

Interpretation 结论

High-titre anti-influenza plasma conferred no significant benefit over non-immune plasma. Although our study did not have the precision to rule out a small, clinically relevant effect, the benefit is insufficient to justify the use of immune plasma for treating patients with severe influenza A.

高滴度抗病毒血浆与非免疫血浆相比并无显著优势。尽管我们的研究并不能排除较小但有临床意义的疗效，但不足以支持在严重甲型流感感染患者使用免疫血浆进行治疗。

Funding 资助

National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, MD, USA).