Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance

Abstract

Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection. The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation. Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting the vagus nuclei, and higher centers in the brain of ME-patients and induce a sustainable, ~30% reduction in overall symptom scores after eight weeks of treatment. By performing longitudinal, systemslevel monitoring of the blood immune system in these patients, we uncover chronic immune activation in ME, as well as immunological correlates of improvement that center around the IL-17 axis, gut-homing immune cells and reduced inflammation. The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We wish for these results to bring some hope to patients suffering from ME and inspire researchers to help test our new hypothesis that ME is a condition caused by a failure of inducing disease tolerance upon infection and persistent immune activation.

Antibody Response to SARS-CoV-2 is Associated with Long-term Clinical Outcome in Patients with COVID-19: a Longitudinal Study

“…Interestingly, patients with mid-term lasting symptoms showed persistent residual inflammation. Elevated markers of inflammation and autoimmunity have been reported in post-infectious syndromes linked with Chikungunya or Epstein-Barr viruses, or in myalgic encephalomyelitis [25][26][27].…”

Long-term clinical, virological and immunological outcomes in patients hospitalized for COVID-19: antibody response predicts long COVID

“…Interestingly, patients with mid-term lasting symptoms showed persistent residual inflammation. Elevated markers of inflammation and autoimmunity have been reported in post-infectious syndromes linked with Chikungunya or Epstein-Barr viruses, or in myalgic encephalomyelitis [24-27].…”

Immune determinants of COVID-19 disease presentation and severity

“…The condition involves a range of symptoms such as persistent fatigue, myalgia, autonomic dysregulation manifested as postural orthostatic tachycardia syndrome, abnormal thermoregulation, intestinal disturbances and skin manifestations 17 . This post-COVID syndrome bears resemblance to postinfectious syndromes that followed outbreaks of chikungunya 18 and Ebola 19 , for example, and selected symptoms overlap with myalgic encephalomyelitis, a disease that is also often triggered by infection and immune activation 20 and manifests as a dysregulated autonomic nervous system and perturbed immune parameters 21 . More research is needed to understand the pathogenesis of all of these postinfectious conditions, and long COVID offers a unique opportunity to perform such studies in larger numbers of individuals, all infected by the same virus during a limited time frame.…”