sharon sanders
Editor-in-Chief & President
Neuroimmune pathophysiology of long COVID
Janna K. Moen PhD, Christopher A. Baker PhD, Akiko Iwasaki PhD
First published: 19 June 2025
https://doi.org/10.1111/pcn.13855
Abstract
Although COVID-19 was originally considered a respiratory illness, it is now well established that SARS-CoV-2 infection can have far-reaching impacts on the nervous system. Neurological symptoms such as chemosensory dysfunction are frequently observed during acute infection and approximately 10% of COVID-19 cases will go on to develop new or persistent long-term symptoms, a condition known in the literature as post-acute symptoms of COVID-19 (PASC) or by the patient-coined term Long COVID.
Common neurological symptoms in Long COVID include new onset cognitive difficulties, dysautonomia, fatigue, and peripheral neuropathy. The emergence of Long COVID has prompted renewed interest in the study of post-acute infection syndromes (PAIS), particularly in the area of neuroimmune interactions. In this review we provide a comprehensive overview of the current body of literature on neurological manifestations of SARS-CoV-2 infection and Long COVID, with an emphasis on neuroimmune mechanisms drawn largely from autopsy studies and animal models. A more complete understanding of neuroimmune crosstalk in Long COVID will not only guide the development of therapies for this highly disabling condition but will also contribute to our general understanding of neuroimmune interactions in health and disease.
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Summary and Concluding Remarks
Despite the perception that COVID-19 is now a mild disease, there is overwhelming evidence indicating that SARS-CoV-2 infection is capable of producing widespread post-acute sequelae in a significant percentage of infections. This includes a substantial impact on the nervous system resulting from a combination of direct infection, systemic inflammation, immune dysfunction, vascular complications, and tissue hypoxia. These factors range from changes in neurotransmitter metabolism to blood–brain barrier dysfunction. Both innate and adaptive immune responses appear to play a role in the pathophysiology of Long COVID by giving rise to pronounced neuroinflammation, synaptic remodeling, infiltration of CNS parenchyma, and autoimmunity. Understanding the pathophysiology of Long COVID will require a focus on neuroimmune interactions and continued investment in mechanistic research. Unfortunately, there are no treatments or therapies that have proven effective for Long COVID, and the highly heterogeneous nature of the condition means a personalized treatment approach will likely be necessary. Overall, these data highlight the need for better approaches to both treat and prevent Long COVID.
https://onlinelibrary.wiley.com/doi/10.1111/pcn.13855
Janna K. Moen PhD, Christopher A. Baker PhD, Akiko Iwasaki PhD
First published: 19 June 2025
https://doi.org/10.1111/pcn.13855
Abstract
Although COVID-19 was originally considered a respiratory illness, it is now well established that SARS-CoV-2 infection can have far-reaching impacts on the nervous system. Neurological symptoms such as chemosensory dysfunction are frequently observed during acute infection and approximately 10% of COVID-19 cases will go on to develop new or persistent long-term symptoms, a condition known in the literature as post-acute symptoms of COVID-19 (PASC) or by the patient-coined term Long COVID.
Common neurological symptoms in Long COVID include new onset cognitive difficulties, dysautonomia, fatigue, and peripheral neuropathy. The emergence of Long COVID has prompted renewed interest in the study of post-acute infection syndromes (PAIS), particularly in the area of neuroimmune interactions. In this review we provide a comprehensive overview of the current body of literature on neurological manifestations of SARS-CoV-2 infection and Long COVID, with an emphasis on neuroimmune mechanisms drawn largely from autopsy studies and animal models. A more complete understanding of neuroimmune crosstalk in Long COVID will not only guide the development of therapies for this highly disabling condition but will also contribute to our general understanding of neuroimmune interactions in health and disease.
snip
Summary and Concluding Remarks
Despite the perception that COVID-19 is now a mild disease, there is overwhelming evidence indicating that SARS-CoV-2 infection is capable of producing widespread post-acute sequelae in a significant percentage of infections. This includes a substantial impact on the nervous system resulting from a combination of direct infection, systemic inflammation, immune dysfunction, vascular complications, and tissue hypoxia. These factors range from changes in neurotransmitter metabolism to blood–brain barrier dysfunction. Both innate and adaptive immune responses appear to play a role in the pathophysiology of Long COVID by giving rise to pronounced neuroinflammation, synaptic remodeling, infiltration of CNS parenchyma, and autoimmunity. Understanding the pathophysiology of Long COVID will require a focus on neuroimmune interactions and continued investment in mechanistic research. Unfortunately, there are no treatments or therapies that have proven effective for Long COVID, and the highly heterogeneous nature of the condition means a personalized treatment approach will likely be necessary. Overall, these data highlight the need for better approaches to both treat and prevent Long COVID.
https://onlinelibrary.wiley.com/doi/10.1111/pcn.13855