New Evidence of the Role of Brain Immune Mechanisms in Long COVID

brain immune mechanisms

A recent case study sheds new light on the role of brain immune mechanisms in long COVID [1]. The study, the first of its kind, documents rapid and sustained clinical improvement following a single dose of perispinal etanercept (PSE) in an individual with severe long COVID.

Etanercept is an immune modulator that rapidly neutralizes elevated circulating levels of a proinflammatory cytokine, tumor necrosis factor (TNF); perispinal administration is designed to facilitate delivery of etanercept to the central nervous system, including the brain [2].  Etanercept has been widely used as a chronic treatment for immune-mediated disease, such as rheumatoid arthritis and psoriasis, for more than 20 years.

Standardized instruments were utilized to measure and quantitate the response to PSE, including Grip Strength, Beck Depression Inventory-II; Fatigue Assessment Scale; Trail Making Test, Parts A and B; Controlled Oral Word Association Test; Montreal Cognitive Assessment; Mini-Mental State Examination; Timed Finger-to-Nose Test; 20-meter Self-Paced Walk Test; and the 5 Times Sit-to-Stand Test. Following PSE there was rapid improvement in all clinical measures. The case report contains a detailed description of the clinical history, the response to treatment, and a thorough scientific discussion [1].

Brain dysfunction caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may extend for months after infection has resolved [3,4]. Intractable cognitive dysfunction, depression, and fatigue are cardinal features of long COVID, a post-viral syndrome also named, variously, post-COVID syndrome, post-acute sequelae of SARS-CoV-2 infection, or post-Covid-19 condition [3,4]. In contrast to acute infection, there is no specific pharmacological or non-pharmacological intervention that is universally recognized as being effective for long COVID [4]. A central role of neuroinflammation in the pathogenesis of long COVID was suggested by increasing clinical evidence and is the subject of intense current interest [3-19].

The potential of etanercept to ameliorate the damaging cytokine storm induced by SARS coronavirus infection was first proposed in 2004 [20]. Increasing evidence documents neuroinflammation following SARS-CoV-2 infection [10,15,18,19,21-28]. Neuroinflammation is increasingly recognized as a cause of chronic brain dysfunction; for example, accumulating evidence documents the existence of chronic neuroinflammation after stroke, with widespread microglial activation [29,30].

Activated microglia secrete TNF, and TNF results in microglial activation, resulting in a feed-forward autocrine loop that may perpetuate deleterious neuroinflammation [31-34]. Perispinal etanercept has previously been reported to produce rapid and sustained improvement in cognition, fatigue, sensation, central post-stroke pain, taste, smell, vision, and hearing in individuals with chronic stroke [2,35-38]. Etanercept, by rapidly neutralizing excess TNF, which functions as a neuromodulator, is thought to improve synaptic, circuit, and network function in the brain [2,36,37,39]. The similarities of the rapid neurological effects of perispinal etanercept in long COVID and chronic stroke are striking and suggest brain neuroinflammation, with microglial activation and elevation of TNF, is a shared pathophysiologic mechanism that is of central importance in both conditions.

Clinical trials will be necessary to further define the response to treatment and to establish optimal dose levels, dosing intervals, duration of response to treatment and safety in larger populations. Nevertheless, the clinical response documented in the case study, quantitated using standard and widely used measures, suggests that long COVID involves perturbed brain immune mechanisms that are at least partially reversible. Furthermore, the clinical response documented in the case study suggests that these perturbed brain immune mechanisms are a viable target for therapeutic intervention and merit further investigation.

The complete case study is available here: Tobinick, R. N. Spengler, T. A. Ignatowski, et al., Rapid improvement in severe long COVID following perispinal etanercept. Curr Med Res Opin, 2022. 38(12): p. 2013-2020.

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Author Affiliations

Edward Tobinick MD, Director, Institute of Neurological Recovery; Boca Raton, FL, USA; Contact information: Telephone: 561.353.9707; Fax: 561.372.7874

Robert N. Spengler, PhD, Executive Director, Brain-Body Research Institute, Lancaster, NY, USA. Contact information: Telephone: 716.683.4939.

Tracey A. Ignatowski, PhD, Assistant Professor, University at Buffalo-SUNY, Jacobs School of Medicine and Biomedical Sciences, Department of Pathology and Anatomical Sciences, 955 Main Street, Buffalo, NY, USA. Contact information: Telephone: 716.829.3102; Fax: 716.829.2725


Dr. Tobinick is the inventor of multiple issued U.S. and international patented treatment methods involving the use of etanercept, including methods of perispinal administration and related devices, for treatment of neurological disorders, and utilizes perispinal etanercept in his medical practice, the Institute of Neurological Recovery, in Boca Raton, Florida.