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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.

背景：多达80%的新型冠状病毒肺炎（Coronavirus Disease 2019, COVID-19）感染者后续会出现长新冠（long covid）/新冠后综合征（post-covid syndrome）。世界卫生组织（World Health Organization, WHO）估算，全球已有超过7.7亿人感染COVID-19。即便仅10%的感染者会罹患长新冠，也将有超过7500万患者长期受此困扰。在新冠后综合征的诸多症状中，疲劳最为常见，受累患者比例可达60%。正如其他病毒感染中所见，炎症细胞因子水平升高可能在此过程中发挥作用。经皮耳迷走神经刺激（Transcutaneous Auricular Vagal Nerve Stimulation, taVNS）是一种通过中枢神经系统调节免疫系统的非侵入性手段，在自身免疫性疾病治疗及疲劳症状改善中已展现出良好应用前景。本先导性研究旨在探讨每日实施taVNS用于新冠感染后疲劳患者的可行性，并分析taVNS对疲劳症状及生活质量的影响。

方法：本研究计划纳入45名成年新冠感染后疲劳综合征患者，在告知受试者将感知到刺激后，将其随机分配至阈值上刺激组、阈值下刺激组或假刺激组。阈值上刺激组将接受为期4周的左侧耳甲艇taVNS刺激，参数设置为25 Hz频率、250 μs脉宽，采用28秒刺激/32秒间歇的循环模式，每日刺激时长为4小时。阈值下刺激组将接受低于感知阈值的刺激，而假刺激组则会被放置非功能性电极，但不给予实际刺激。每日的刺激方案将通过手动记录或配套应用程序进行记录。本研究将在刺激前及刺激4周后，让受试者完成3份成熟量表：多维疲劳量表20项版（Multidimensional-Fatigue-Inventory-20, MFI-20）、简明健康调查问卷36项版（Short-Form-36, SF-36）、贝克抑郁量表（Beck-Depression-Inventory, BDI），以及新开发的新冠后综合征评分（Post-Covid-Syndrome-Score, PCS-S）。

讨论：本研究的主要终点设定为4周后受试者的每日平均刺激时长，次要终点则包括taVNS对疲劳症状及生活质量（Quality of Life, QoL）的改善效果。作为一种非侵入性治疗手段，taVNS有望成为新冠感染后疲劳患者的潜在治疗选择。

试验注册：本研究已获得当地伦理委员会批准（批准号：23/7798），并已完成注册（注册号：DRKS00031974，详见支持信息文件）。

伦理与传播：既往研究已证实taVNS的安全性，为本研究的伦理合理性提供了支持。受试者将由全科医生招募，并签署书面知情同意书。所有数据将采用去标识化方式进行收集与存储。本研究结果将发表于同行评议期刊，旨在为taVNS用于长新冠管理的潜在价值提供循证依据。本研究将严格遵循《赫尔辛基宣言》的相关原则开展。