Safety and efficacy of adjunct dexamethasone in adults with herpes simplex virus encephalitis in the UK (DexEnceph): a multicentre, observer-blind, randomised, phase 3, controlled trial.

HSV encephalitis is treated with the antiviral aciclovir but still has substantial mortality and morbidity.

HSV脑炎使用抗病毒药物阿昔洛韦进行治疗，但仍然有相当高的死亡率和发病率。

Adjunct corticosteroids are sometimes used, but whether they improve the outcome is unclear.

有时会使用辅助性皮质类固醇，但它们是否能改善结果尚不明确。

We aimed to establish the safety and efficacy of adjunct corticosteroids in HSV encephalitis.

我们的目标是确定辅助性皮质类固醇在单纯疱疹病毒性脑炎中的安全性和有效性。

Methods

In this multicentre, observer-blind, randomised, phase 3 trial, adults with HSV encephalitis admitted to 53 hospitals in the UK were randomly assigned to receive intravenous dexamethasone (10 mg/kg, four times daily for 4 days) plus intravenous aciclovir (10 mg/kg three times daily for at least 14 days; dexamethasone group), or intravenous aciclovir alone (control group).

在这项多中心、观察者盲法、随机、第三阶段试验中，被送往英国53家医院的成人单纯疱疹病毒性脑炎患者被随机分配接受静脉注射地塞米松（每天四次，每次10 mg/kg，连续4天）加上静脉注射阿昔洛韦（每天三次，每次10 mg/kg，至少14天；地塞米松组），或者仅接受静脉注射阿昔洛韦（对照组）。

Eligible patients aged 16 years or older had suspected encephalitis (a febrile illness with new onset seizure, new focal neurological signs or alteration in consciousness, cognition, personality, or behaviour), with positive HSV type 1 or type 2 PCR test in CSF.

符合条件的16岁或以上的患者怀疑患有脑炎（一种伴有发热的疾病，伴有新发癫痫发作、新的局灶性神经症状或意识、认知、个性或行为改变），且脑脊液中单纯疱疹病毒1型或2型PCR检测呈阳性。

Participants were randomly assigned by the trial team at the recruiting site, using a secure web-based randomisation programme.

参与者由招募点的试验团队通过一个安全的基于网络的随机化程序随机分配。

The primary outcome was verbal memory score at 26 weeks, measured by the Wechsler Memory Scale (WMS)-IV auditory memory index.

主要结果是26周时通过韦氏记忆量表（WMS）-IV听觉记忆指数测量的言语记忆评分。

Analyses of primary and secondary outcomes were performed according to the modified intention-to-treatprinciple, and safety analyses were based on whether participants received at least one dose of the study drug.

主要和次要结果的分析是根据修改后的意向治疗原则进行的，安全性分析基于参与者是否至少接受了一次研究药物的剂量。

Trial neuropsychologists assessing the primary outcome, and statisticians involved in the study's primary outcome, were masked to treatment group allocation.

评估主要结果的试验神经心理学家，以及参与研究主要结果的统计学家，对治疗组的分配情况是不知情的。

The trial is registered with the International Standard Randomised Controlled TrialNumber Registry, ISRCTN11774734, and EudraCT, EudraCT2016-004835-19, and is completed.

该试验已在国际标准随机对照试验编号注册处注册，注册号为ISRCTN11774734，以及在EudraCT注册，注册号为EudraCT2016-004835-19，并已完成。

Results

Between Sept 22, 2016, and Feb 2, 2022, 94 patients with HSV encephalitis were recruited, 47 (20 [43%] female and 27 [57%] male) to the dexamethasone group, and 47 (24 [51%] female and 23 [49%] male) to the control group.

2016年9月22日至2022年2月2日期间，共有94名单纯疱疹病毒性脑炎患者被招募，其中47名（女性20名[43%]，男性27名[57%]）被分配到地塞米松组，另外47名（女性24名[51%]，男性23名[49%]）被分配到对照组。

Dexamethasone was initiated a median 7 (IQR 4-8) days after hospital admission.

地塞米松在入院后中位数7（四分位数间距4-8）天开始使用。

Seven patients withdrew consent, and six were lost to follow-up.

七名患者撤回了同意，六名患者失访。

Thus, 81 were included in the modified intention-to-treatanalysis (39 in the treatment group and 42 in the control group).

因此，共有81名患者被纳入改良意向治疗分析（治疗组39人，对照组42人）。

The primary outcome, verbal memory score at 26 weeks, did not differ significantly between the groups (71 [SD 26] in the dexamethasone group, and 69 [SD 25] in the control group; adjusted difference 1·77 [95% CI -9·57 to 13·12; p=0·76).

主要结果，26周时的言语记忆评分，在两组之间没有显著差异（地塞米松组为71 [标准差26]，对照组为69 [标准差25]；调整后差异为1.77 [95% 置信区间-9.57至13.12；p=0.76]）。

There were 27 adverse events involving 18 (38%) participants in the control group, and 25 adverse events involving 18 (40%) participants in the dexamethasone group.

对照组中有18名（38%）参与者出现了27起不良事件，而地塞米松组中有18名（40%）参与者出现了25起不良事件。

The most common serious adverse events were seizures requiring readmission to hospital (affecting one [2%] patient in the dexamethasone group and one [2%] patient in the control group) and thrombotic events, including deep vein thrombosis (affecting one [2%] patient in the dexamethasone group) and pulmonary embolism (affecting one [2%]patient in the dexamethasone group).

最常见的严重不良事件是需要重新住院的癫痫发作（地塞米松组和对照组各有1名[2%]患者受影响）以及血栓事件，包括深静脉血栓形成（地塞米松组有1名[2%]患者受影响）和肺栓塞（地塞米松组有1名[2%]患者受影响）。

There were no treatment-related deaths.

治疗相关死亡率为零。

interpretation

In adults with HSV encephalitis, dexamethasone plus aciclovir had a satisfactory safety profile but did not improve verbal memory score compared with aciclovir alone.

在成人单纯疱疹病毒性脑炎患者中，地塞米松联合阿昔洛韦的安全性良好，但与单独使用阿昔洛韦相比，并未改善言语记忆评分。

Given the established role of corticosteroids in other inflammatory encephalitides, our findings suggest that their early use in suspected encephalitis is unlikely to be harmful.

鉴于皮质类固醇在其他炎症性脑炎中的已确立作用，我们的发现表明，在疑似脑炎中早期使用它们不太可能有害。

Future studies should assess more targeted immunomodulatory approaches in HSV encephalitis.

未来的研究应该评估在单纯疱疹病毒脑炎中更针对性的免疫调节方法。

funding

National Institute for Health and Care Research.

国家健康与护理研究机构