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COVIVA:经皮耳迷走神经刺激对新冠后综合征患者疲劳综合征的影响——一项安慰剂对照的前瞻性研究方案

COVIVA: Effect of transcutaneous auricular vagal nerve stimulation on fatigue-syndrome in patients with Long Covid - A placebo-controlled pilot study protocol.

作者信息

Gierthmuehlen Mortimer, Gierthmuehlen Petra Christine

机构信息

Department of Neurosurgery, University Medical Center Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany.

Department of Prosthodontics, University Medical Center Duesseldorf, Duesseldorf, Germany.

出版信息

PLoS One. 2025 May 9;20(5):e0315606. doi: 10.1371/journal.pone.0315606. eCollection 2025.


DOI:10.1371/journal.pone.0315606
PMID:40343901
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12063903/
Abstract

BACKGROUND: Up to 80% of patients who develop coronavirus disease-2019 (Covid-19) infection subsequently experience long covid/post-covid syndrome. The World Health Organization (WHO) has estimated that >770 million patients have been infected with Covid-19 globally. Even if only 10% of these patients develop long covid, > 75 million patients will suffer for a long period. Among the various symptoms of post-covid syndrome, fatigue is common, affecting up to 60% of the patients. As observed in other viral infections, elevated levels of inflammatory cytokines may play a role. Transcutaneous auricular vagal nerve stimulation (taVNS) is a noninvasive method that modulates the immune system via the central nervous system and has shown promising effects in autoimmune diseases and improving fatigue. In this pilot study, we investigated the feasibility of daily taVNS in patients with long covid-related fatigue. Additionally, the effects of taVNS on fatigue and quality of life will be analyzed. METHODS: A total of 45 adult patients with long covid associated fatigue syndrome will be enrolled in this study, and will be randomized to the above-threshold-stimulation, below-threshold-stimulation, or sham-stimulation arms, after being informed that they will feel the stimulation. The above-threshold-group will receive a 4-week-long left-sided cymba conchae taVNS with 25 Hz, 250 µs pulse width 28s/32s on/off paradigm for 4 h throughout the day. The below-threshold group will receive stimulation below the sensational threshold, whereas the sham group will receive no stimulation following application of a non-functional electrode. The daily stimulation protocol will be recorded either manually or using the provided app. Three well-established questionnaires, the Multidimensional-Fatigue-Inventory-20, Short-Form-36, and Beck-Depression-Inventory, and the newly established Post-Covid-Syndrome-Score will be completed both before and after 4 weeks of stimulation. DISCUSSION: The primary endpoint has been set as the patients' average daily stimulation time after 4 weeks, while secondary endpoints include the effects of taVNS on fatigue and Quality of Live (QoL). As a non-invasive treatment option, taVNS may be a notable alternative for patients with post-covid related fatigue. TRIAL REGISTRATION: This study was approved by the local ethics committee (23/7798) and registered (DRKS00031974) (see supporting information files). ETHICS & DISSEMINATION: The ethical justifiability of this study was supported by prior research demonstrating the safety of taVNS. Patients will be recruited by general practitioners, and written informed consent will be obtained. All data will be pseudonymized for collection and storage. The study results will be published in peer-reviewed journals with the aim of providing evidence of the potential of taVNS in long covid management. The study will be conducted in accordance with the principles of the Declaration of Helsinki.

摘要

背景:感染新型冠状病毒肺炎(Covid-19)的患者中,高达80%随后会经历新冠后综合征/长期新冠综合征。世界卫生组织(WHO)估计,全球已有超过7.7亿人感染了Covid-19。即便这些患者中只有10%发展为长期新冠,也将有超过7500万患者长期受苦。在新冠后综合征的各种症状中,疲劳很常见,影响多达60%的患者。正如在其他病毒感染中所观察到的,炎症细胞因子水平升高可能起了作用。经皮耳迷走神经刺激(taVNS)是一种通过中枢神经系统调节免疫系统的非侵入性方法,在自身免疫性疾病和改善疲劳方面已显示出有前景的效果。在这项初步研究中,我们调查了每日进行taVNS治疗长期新冠相关疲劳患者的可行性。此外,还将分析taVNS对疲劳和生活质量的影响。 方法:本研究将招募45名患有长期新冠相关疲劳综合征的成年患者,在告知他们会感觉到刺激后,将其随机分为阈上刺激组、阈下刺激组或假刺激组。阈上刺激组将接受为期4周的左侧耳甲腔taVNS治疗,频率为25Hz,脉冲宽度250µs,采用28秒开/32秒关的模式,每天刺激4小时。阈下刺激组将接受低于感觉阈值的刺激,而假刺激组在使用无功能电极后将不接受刺激。每日刺激方案将手动记录或使用提供的应用程序记录。在刺激4周前后,将完成三份成熟的问卷,即多维疲劳量表-20、简明健康状况量表-36和贝克抑郁量表,以及新制定的新冠后综合征评分量表。 讨论:主要终点设定为4周后患者的平均每日刺激时间,次要终点包括taVNS对疲劳和生活质量(QoL)的影响。作为一种非侵入性治疗选择,taVNS可能是新冠后相关疲劳患者的一个显著替代方案。 试验注册:本研究已获得当地伦理委员会批准(23/7798)并进行了注册(DRKS00031974)(见支持信息文件)。 伦理与传播:先前的研究证明了taVNS的安全性,为本研究的伦理合理性提供了支持。患者将由全科医生招募,并获得书面知情同意。所有数据将进行匿名化处理以进行收集和存储。研究结果将发表在同行评审期刊上,目的是为taVNS在长期新冠管理中的潜力提供证据。本研究将按照《赫尔辛基宣言》的原则进行。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe83/12063903/82a942655350/pone.0315606.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe83/12063903/82a942655350/pone.0315606.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe83/12063903/82a942655350/pone.0315606.g001.jpg

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引用本文的文献

[1]
Transcutaneous Auricular Vagal Nerve Stimulation for the Treatment of the Fatigue Syndrome in Patients with Primary CNS Lymphoma - A Protocol for a Randomized and Controlled Single Center Clinical Trial.

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本文引用的文献

[1]
A pooled analysis of the side effects of non-invasive Transcutaneous Auricular Vagus Nerve Stimulation (taVNS).

Front Hum Neurosci. 2025-2-5

[2]
Insula-Medial Prefrontal Cortex Functional Connectivity Modulated by Transcutaneous Auricular Vagus Nerve Stimulation: An fMRI Study.

IEEE J Biomed Health Inform. 2024-10

[3]
A predictive study of the efficacy of transcutaneous auricular vagus nerve stimulation in the treatment of major depressive disorder: An fMRI-based machine learning analysis.

Asian J Psychiatr. 2024-8

[4]
Transcutaneous vagus nerve stimulation improves Long COVID symptoms in a female cohort: a pilot study.

Front Neurol. 2024-5-2

[5]
Does vibrotactile stimulation of the auricular vagus nerve enhance working memory? A behavioral and physiological investigation.

Brain Stimul. 2024

[6]
Effect of transcutaneous auricular vagal nerve stimulation on the fatigue syndrome in patients with gastrointestinal cancers - FATIVA: a randomized, placebo-controlled pilot study protocol.

Pilot Feasibility Stud. 2023-4-22

[7]
The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants With Primary Sjögren's Syndrome.

Neuromodulation. 2023-4

[8]
The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue.

Front Immunol. 2022

[9]
Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis.

Sci Rep. 2022-12-21

[10]
A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms.

Bioelectron Med. 2022-8-25

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