Vagus Nerve Dysfunction in Post-COVID-19 Condition: Unraveling the Pathogenesis and Implications for Clinical Management


The post-COVID-19 condition (PCC) or “Long-COVID” has emerged as a significant global public health and medical challenge, affecting a considerable percentage of individuals who survive acute SARS-CoV-2 infection.

Approximately 5-10% of COVID-19 survivors experience persistent symptoms that extend beyond the acute phase, posing a substantial burden on healthcare systems worldwide.

Clinical management of PCC is hindered by the lack of effective treatments and objective diagnostic biomarkers, necessitating a deeper understanding of its pathogenesis to develop accurate diagnostics and improved therapeutic strategies.

Exploring Vagus Nerve Dysfunction

Recent studies have shed light on the potential involvement of the vagus nerve, also known as the Xth cranial nerve, in the pathogenesis of PCC.

The vagus nerve plays a crucial role in innervating various organs, including the larynx, pharynx, lungs, heart, and gastrointestinal tract, which are known to be primarily affected by PCC symptoms. However, the comprehensive objective evidence of vagus nerve dysfunction in individuals with PCC is currently lacking.

Research Methodology and Findings

To address this gap, a PubMed search was conducted up to March 9th, 2023, using the search terms “Long COVID OR Post Covid Condition OR Post-Acute COVID-19 Syndrome) AND (vagus nerve OR dysautonomia).” This search yielded 16,716 results, which were further filtered using English language criteria and refined search terms “(Long COVID) OR (Post Covid Condition) AND (vagus nerve).” Manual literature screening resulted in the identification of 14 relevant studies.

The initial studies, published between May 2020 and June 2021, explored possible pathways of SARS-CoV-2 entry into the brain, including transmission through the vagus nerve. These studies suggested that infection of the vagus nerve could be a potential cause of dysfunctional brainstem/vagus nerve signaling and chronic symptoms associated with PCC.

In 2022, a study proposed that autonomic dysfunction, including vagus nerve involvement, may contribute to PCC symptoms. The study observed vagus atrophy and prolonged sympathetic skin response latencies.

In September 2022, another study suggested that vagal underactivation could be the underlying cause of dysautonomia and fatigue in PCC. Non-invasive vagus nerve stimulation (nVNS) was proposed as a potential therapy for fatigue.

Subsequently, in March 2023, a study identified vagus nerve neuropathy as a potential cause of persistent chronic cough or other long-term effects of COVID-19. Furthermore, in May 2023, four clinical trials investigating the efficacy of nVNS in the management of Long-COVID were registered.

Significance of the Study

The study discussed in this article provides valuable insights into the structural and functional alterations in various organs and body territories innervated by the vagus nerve in individuals with PCC. The researchers employed a wide range of objective measurements and consistently observed abnormalities in the respiratory and digestive apparatus, as well as in the autonomous innervation of the heart.

These findings align well with the commonly reported dysphonia, exertional dyspnea, and digestive symptoms experienced by individuals with PCC.

Key observations from the study included altered dysphonia scales, reductions in maximum inspiratory pressure, diaphragm flattening, reduced esophageal-gastric-intestinal peristalsis, and altered swallowing efficiency and safety.

Of particular significance was the frequent involvement of respiratory muscles, with over 60% of PCC subjects exhibiting reductions in maximum inspiratory pressure, diaphragmatic flattening, and decreased diaphragmatic thickness and mobility. These findings suggest respiratory muscle weakness, which could explain dyspnea despite normal lung imaging.

Implications of the Evidence

The findings of this study strongly support the central role of vagus nerve dysfunction in the pathophysiology of PCC. They provide valuable information to standardize clinical evaluations of PCC and inform larger cohort studies focused on this syndrome. Additionally, the study opens the door to potential interventions that could ameliorate some of the most debilitating PCC symptoms, such as dysphagia, dyspnea, and dysautonomia.

Further research and clinical trials, including non-invasive vagus nerve stimulation, hold promise for identifying novel therapeutic approaches to address the vagus nerve dysfunction in PCC. By unraveling the intricate mechanisms underlying the post-COVID-19 condition, we can pave the way for more targeted treatments and improved outcomes for individuals affected by this chronic syndrome.

In conclusion, the growing body of evidence points towards the involvement of vagus nerve dysfunction in the pathogenesis of PCC. Understanding the complex interplay between SARS-CoV-2 infection, the vagus nerve, and the subsequent manifestations of PCC is crucial for developing effective interventions and improving the quality of life for those experiencing long-term COVID-19 symptoms.

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