{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:06:05Z","timestamp":1780445165312,"version":"3.54.1"},"reference-count":59,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T00:00:00Z","timestamp":1774656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Medicine and Pharmacy Timisoara"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Coronavirus disease 2019 (COVID-19) is characterized by excessive inflammatory responses, including the so-called cytokine storm, which contributes substantially to morbidity and mortality in hospitalized patients. The vagus nerve, through the cholinergic anti-inflammatory pathway, represents a theoretically attractive therapeutic target for modulating systemic inflammation. Vagus nerve stimulation (VNS) has emerged as a potential adjunctive treatment for COVID-19, with several randomized controlled trials (RCTs) investigating its efficacy on inflammatory biomarkers and clinical outcomes. The quality of this evidence base has not been rigorously evaluated. This systematic review critically appraises all available RCT evidence for VNS in hospitalized COVID-19 patients. Materials and Methods: We systematically searched PubMed, Scopus, Cochrane (CENTRAL), and Web of Science from database inception to January 2026, for RCTs evaluating any form of VNS (invasive, non-invasive, cervical, or auricular) in hospitalized patients with confirmed acute COVID-19. Two reviewers independently screened titles, abstracts, and full texts according to pre-specified eligibility criteria. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, with assessments initially performed using multiple artificial intelligence tools and subsequently validated by the authors in accordance with PRISMA 2020 guidelines. Given substantial heterogeneity and high risk of bias, narrative synthesis was performed rather than meta-analysis. Also, GRADE assessment was performed. Results: From 437 records identified, six RCTs comprising 221 patients met the inclusion criteria. Five trials (83%) were rated as high risk of bias, primarily due to inadequate blinding, substantial baseline imbalances, significant missing data and extensive multiple testing without statistical correction. The single double-blind trial with a credible sham control (Rangon et al.) found null results across all outcomes, including clinical progression, ICU transfer, and mortality, while the five \u201chigh\u201d risk-of-bias trials generally reported positive findings on various inflammatory markers and clinical outcomes. One trial (Corr\u00eaa et al.) measured heart rate variability as a direct indicator of vagal activation and found no change despite claiming anti-inflammatory effects, contradicting the proposed mechanism of action. Significant cognitive findings from an interim analysis (Uehara et al., n = 21) disappeared in the larger completed trial (Corr\u00eaa et al., n = 52), providing empirical demonstration of false positive findings in small, underpowered studies. Conclusions: Currently available evidence supporting the use of VNS for acute COVID-19 remains scarce; however, the physiological rationale remains sound, although the absence of reliable target engagement markers in the included studies limits confidence in this treatment method. Large-scale, double-blind, sham-controlled trials are required before VNS can be firmly recommended for COVID-19 management.<\/jats:p>","DOI":"10.3390\/medicina62040649","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:40:52Z","timestamp":1774878052000},"page":"649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy and Safety of Vagus Nerve Stimulation for Hospitalized COVID-19 Patients: A Systematic Review and Methodological Evaluation of Randomized Controlled Trials"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0519-5868","authenticated-orcid":false,"given":"Adrian","family":"Balan","sequence":"first","affiliation":[{"name":"Center for Research and Innovation in Precision Medicine of Respiratory Diseases, Department of Pulmonology, University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles","family":"Graham","sequence":"additional","affiliation":[{"name":"Europe to Europe, 78 Providence Park, Southampton SO16 7QW, UK"},{"name":"Royal Society of Medicine, 1 Wimpole Street, London W1G OAE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herban","family":"Sorin","sequence":"additional","affiliation":[{"name":"Department of Civil Engineering and Installations, Polytechnic University of Timisoara, 300006 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3394-385X","authenticated-orcid":false,"given":"Marius","family":"Marcu","sequence":"additional","affiliation":[{"name":"Department of Computer and Software Engineering, Polytechnic University of Timisoara, 300006 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nini","family":"Gheorghe","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Vasile Goldis Western University of Arad, 310414 Arad, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Gabriela","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Vasile Goldis Western University of Arad, 310414 Arad, Romania"},{"name":"Multidisciplinary Doctoral School, Vasile Goldis Western University of Arad, 310414 Arad, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea-Roxana","family":"Florescu","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Precision Medicine of Respiratory Diseases, Department of Pulmonology, University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania"},{"name":"Department of Doctoral Studies, University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"},{"name":"Institute of Pulmonology \u201cMarius Nasta\u201d Bucharest, 050159 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6026-8724","authenticated-orcid":false,"given":"Alina-Mirela","family":"Popa","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Precision Medicine of Respiratory Diseases, Department of Pulmonology, University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania"},{"name":"Department of Doctoral Studies, University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0600-1103","authenticated-orcid":false,"given":"Ana","family":"Lascu","sequence":"additional","affiliation":[{"name":"Department of Functional Sciences, Discipline of Pathophysiology, Centre for Translational Research and Systems Medicine, University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"},{"name":"Institute for Cardiovascular Diseases of Timisoara, Clinic for Cardiovascular Surgery, 300310 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian Ion","family":"Mot","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology Department, Municipal Emergency Hospital Timisoara, 300041 Timisoara, Romania"},{"name":"Department of Surgery, University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8897-8342","authenticated-orcid":false,"given":"Stefan","family":"Mihaicuta","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Precision Medicine of Respiratory Diseases, Department of Pulmonology, University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7469-6755","authenticated-orcid":false,"given":"Stefan Marian","family":"Frent","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Precision Medicine of Respiratory Diseases, Department of Pulmonology, University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","article-title":"Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention","volume":"323","author":"Wu","year":"2020","journal-title":"JAMA"},{"key":"ref_2","unstructured":"WHO (2025). 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