Auricular Neuromodulation for Mass Vagus Nerve Stimulation: Insights From SOS COVID-19 a Multicentric, Randomized, Controlled, Double-Blind French Pilot Study

Abstract

Importance: An exacerbated inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is believed to be one of the major causes of the morbidity and mortality of the coronavirus disease 2019 (COVID-19). Neuromodulation therapy, based on vagus nerve stimulation, was recently hypothesized to control both the SARS-CoV-2 replication and the ensuing inflammation likely through the inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway and could improve the clinical outcomes as an adjunct treatment. We proposed to test it by the stimulation of the auricular branch of the vagus nerve, i.e., auricular neuromodulation (AN), a non-invasive procedure through the insertion of semipermanent needles on the ears.Objective: The aim of this study was to assess the effect of AN on the clinical outcomes in patients affected by COVID-19.Design, Setting, and Participants: A multicenter, randomized, placebo-controlled, double-blind clinical trial included 31 patients with respiratory failure due to COVID-19 requiring hospitalization. Within 72 h after admission, patients received either AN (n = 14) or sham neuromodulation (SN, n = 15) in addition to the conventional treatments.Main Outcome and Measures: The primary endpoint of the study was the rate of a clinical benefit conferred by AN at Day 14 (D14) as assessed by a 7-point Clinical Progression Scale. The secondary endpoint of the study was the impact of AN on the rate of transfer to the intensive care unit (ICU) and on the survival rate at D14.Results: The AN procedure was well-tolerated without any reported side effects but with no significant improvement for the measures of both primary (p > 0.3) and secondary (p > 0.05) endpoints at the interim analysis. None of the AN-treated patients died but one in the SN group did (81 years). Two AN-treated patients (73 and 79 years, respectively) and one SN-treated patient (59 years) were transferred to ICU. Remarkably, AN-treated patients were older with more representation by males than in the SN arm (i.e., the median age of 75 vs. 65 years, 79% male vs. 47%).Conclusion: The AN procedure, which was used within 72 h after the admission of patients with COVID-19, was safe and could be successfully implemented during the first two waves of COVID-19 in France. Nevertheless, AN did not significantly improve the outcome of the patients in our small preliminary study. It is pertinent to explore further to validate AN as the non-invasive mass vagal stimulation solution for the forthcoming pandemics.Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [NCT04341415].

Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics

“…Three different articles [ 80 , 81 , 82 ], using three different non-invasive VNS techniques, started randomized controlled trials in 2020 in France (SOS-COVID-19) and Spain (SAVIOR I), and in 2021 in Austria, respectively, enrolling stage 3 hospitalized COVID-19 patients requiring oxygen supply. Rangon et al [ 80 ] treated the patients with four semi-permanent needles on the conchae of both outer ears (without concurrent electrical stimulation) to stimulate the auricular branch of the vagus nerve, once within the first 3 days after admission. Tornero el al.…”

“…The device delivered intermittent electrical stimulation (3 h on/3 h off) with a 1 Hz frequency, 0.5–0.9 mA peak current (1.5 mA maximum), 1 ms pulse width, and 3.8 V fixed amplitude. No study at all was able to show a significant improvement in the clinical outcomes of the COVID-19-positive inpatients (clinical status assessed either too early (14 [ 80 ] and 5 days [ 81 ] after the first VNS session), or not at all [ 82 ]), but a good tolerance of the neuromodulation treatments was confirmed. Interestingly, two studies reported a significant improvement in the biological inflammation status of the patients (regarding C-reactive protein and procalcitonin levels [ 81 ]; or C-reactive protein, TNF alpha, DDIMER, and IL-10 levels [ 82 ]).…”

Neuromodulation Strategies to Reduce Inflammation and Improve Lung Complications in COVID-19 Patients

“…A French study is assessing auricular nerve stimulation via four percutaneously placed leads on each tragus and is being compared to sham (no needle placement; NCT04341415). Enrollment has been halted due to a low case load ( 142 ).…”

Neurostimulation as a Method of Treatment and a Preventive Measure in Canine Drug-Resistant Epilepsy: Current State and Future Prospects

“…VNS application extends beyond neurological diseases: a growing body of clinical evidence from human patients indicates its suitability for treatment of chronic heart failure ( 90 , 91 ) or inflammatory diseases such as Crohn's disease ( 92 , 93 ) or rheumatoid arthritis ( 94 , 95 ). Recently, nVNS has been proposed and applied to patients with respiratory symptoms of COVID-19 to modulate their inflammatory response ( 96 – 98 ). VNS improved cardiovascular parameters and decreased plasma and heart tissue biomarkers associated with heart failure in a canine model of heart failure ( 99 ) and lead to weight loss in dogs ( 100 ) and minipigs ( 101 ).…”