Morcos & Theoharides (2026)
- Authors: Zachary L. Morcos, Theoharis C. Theoharides
- Institutes: Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States, Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Publisher: Journal of Neuropathology & Experimental Neurology
- Link: DOI
Summary
This review identifies mast cell activation as a central driver of the neuropathic and autonomic symptoms seen in Long COVID. By explaining how the virus triggers these cells to damage nearby nerves, the study provides a clear biological target for future treatments. This research offers a unifying explanation for symptoms shared across Long COVID, small-fiber neuropathy, and ME/CFS.
What was researched?
The research investigated whether mast cell activation serves as a primary mechanism for neuropathic pain and autonomic dysfunction in patients with Long COVID. It explored the interactions between the SARS-CoV-2 spike protein and immune cells located near the nervous system.
Why was it researched?
Despite millions of people suffering from persistent neuropathic symptoms after COVID-19, the underlying cause remains largely unknown. The researchers hypothesized that mast cells, which are strategically located near nerves, could be the missing link in explaining this chronic inflammation.
How was it researched?
This narrative review synthesized evidence from preclinical models and clinical case reports. The authors analyzed the pathways through which the spike protein binds to receptors like ACE2 and TLR4 on mast cells to trigger the release of pro-inflammatory mediators.
What has been found?
The study found that spike-protein-activated mast cells release neurotoxic mediators such as tryptase and interleukin-6, which sensitize peripheral nerves and disrupt the blood-brain barrier. This process mirrors the pathology found in small-fiber neuropathy and ME/CFS, and the authors suggest that flavonoids 💊 and antihistamines 💊 may help manage these symptoms.
Discussion
The review highlights that mast cell proximity to nerves and blood vessels makes them uniquely capable of causing multi-organ dysfunction. While therapeutic responses to mast cell stabilizers vary, the identified mechanisms support the use of targeted immune-modulating therapies.
Conclusion & Future Work
Chronic mast cell activation appears to be a plausible cause for the persistence of neuropathic symptoms in Long COVID. Future clinical studies should focus on validating mast-cell-directed treatments to improve patient outcomes.