Overactive immune cells might drive nerve pain in long COVID

Millions of people who recover from the initial stages of COVID-19 continue to suffer from lingering nerve pain, fatigue, and cognitive issues. A new academic review proposes that a specific type of overactive immune cell might be responsible for driving this persistent nerve damage. These findings were published in the Journal of Neuropathology & Experimental Neurology.

Long COVID, officially termed post-acute sequelae of SARS-CoV-2 infection, remains a widespread public health issue. Global estimates suggest the condition affects over 60 million individuals. One meta-analysis reviewing a massive sample of over two million confirmed COVID-19 cases estimated a global prevalence of nearly 36 percent. A different review of a massive sample of over 480,000 individuals found that over half of survivors experienced at least one lingering symptom for more than a year.

Despite these high numbers, the underlying biology of Long COVID is not fully understood. Patients report a wide array of symptoms across multiple organ systems. These frequently include extreme fatigue, brain fog, and shortness of breath.

A prominent feature of Long COVID is neuropathy, a general term for damage or dysfunction of the peripheral nervous system. Peripheral nerves connect the brain and spinal cord to the rest of the body. Data from several observational studies indicates that up to 59 percent of Long COVID patients show signs of small-fiber neuropathy.

Small-fiber neuropathy specifically affects the tiny, unmyelinated nerve endings in the skin and organs. These fibers transmit pain and temperature sensations. When damaged, they often cause burning pain, numbness, and tingling in the extremities.

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Conventional nerve conduction studies often fail to detect this specific type of damage. Standard medical tests primarily assess large, myelinated nerve fibers responsible for major muscle movements and gross sensation. Because standard diagnostic tools easily miss damage to small nerve fibers, the prevalence of Long COVID neuropathy likely went underreported in the early stages of the pandemic.

These small nerves also help control the autonomic nervous system, which manages involuntary body functions like heart rate and digestion. Autonomic dysfunction is frequently observed in Long COVID patients. Many develop postural orthostatic tachycardia syndrome, a condition where the heart races uncontrollably upon standing.

Zachary L. Morcos and Theoharis C. Theoharides, researchers affiliated with Nova Southeastern University and Tufts University, sought to explore potential cellular mechanisms connecting these varied symptoms. They noticed that many Long COVID complaints closely mirror an immune condition called mast cell activation syndrome. This prompted them to investigate whether mast cells might serve as the biological bridge between a past viral infection and ongoing nerve pain.

Mast cells are specialized immune cells that act as sentinels throughout the body. They are heavily concentrated in tissues that interface with the external environment, such as the skin, lungs, and gut. They also cluster heavily around blood vessels and nerve fibers.

Normally, mast cells help defend against pathogens and play a central role in allergic reactions. When triggered by a virus, an allergen, or physiological stress, they undergo a process called degranulation. During degranulation, the cells split open and dump an arsenal of chemical mediators into the surrounding tissue.

These inflammatory chemicals include histamine, tryptase, and various signaling proteins. While these mediators help orchestrate a defense against immediate threats, chronic release can damage surrounding tissues. Because mast cells are positioned directly next to nerve fibers, their chemical output can easily irritate pain receptors.

Mast cells are well known for their role in asthma and skin hives. However, researchers are increasingly recognizing their ability to modulate both neurovascular and neuroimmune responses. Because they sit at the biological crossroads of the blood supply and the nervous system, any prolonged mast cell hyperactivity can easily disrupt both systems simultaneously.

To evaluate this hypothesis, the researchers conducted a narrative literature review. They gathered and synthesized data from cell cultures, animal models, clinical case reports, and human observational studies. The goal was to build a comprehensive picture of how mast cells interact with the pandemic virus and the human nervous system.

The collected research suggests that the spike protein of the SARS-CoV-2 virus directly binds to specific receptors on the surface of mast cells. These docking points include the angiotensin-converting enzyme 2 and toll-like receptor 4 proteins. This cellular interaction triggers the mast cells to release their inflammatory payload without requiring a traditional allergic trigger. Once released, these harsh chemicals bathe nearby nerve endings, making them overly sensitive to pain.

The prolonged presence of these mediators initiates a localized chain reaction of inflammation. The chemicals degrade the structural integrity of small nerve fibers, leading to the numbness and burning characteristic of neuropathy. In the autonomic nervous system, this localized damage disrupts the normal transmission of signals required to regulate blood pressure and heart rate.

The researchers note that the collateral damage is not limited to peripheral limbs. Inflammatory mediators released by mast cells can travel through the bloodstream and compromise the blood-brain barrier. This barrier is a highly selective membrane designed to keep circulating toxins out of the central nervous system.

When the blood-brain barrier weakens, general immune cells and inflammatory molecules can slip into the brain. Once inside, they may aggravate microglia, the brain’s resident immune cell population. This localized brain inflammation is suspected to be a primary driver of the cognitive dysfunction and extreme fatigue often reported by patients.

Past clinical observations provide associative evidence that mast cells contribute to Long COVID. The review highlights a small study of 21 patients with severe COVID-19 where resting immune markers were abnormally elevated. Autopsy data from deceased patients has also revealed heavy accumulations of mast cells in the lungs and near blocked blood vessels.

In addition to causing direct nerve damage, overactive mast cells might intersect with other theorized Long COVID mechanisms. The chemicals they release can disrupt normal blood clotting, potentially contributing to the microscopic blood clots found in some patients. Their constant signaling might also skew the broader immune system, inducing the autoimmune responses seen long after the virus clears.

If hyperactive mast cells are causing neurological symptoms, targeting them directly might offer symptom relief. The review evaluated several potential therapeutic strategies reported in recent clinical literature. Standard antihistamines, which block the cellular receptors for one of the main chemicals released by mast cells, have provided mixed outcomes.

Some case reports describe patients achieving remission from autonomic nervous system issues after starting antihistamine therapy. However, human mast cells can release up to 390 different inflammatory mediators depending on the trigger. Blocking histamine alone might not be sufficient to completely halt the widespread nerve damage.

The researchers point to other chemical interventions, such as naturally occurring plant compounds called flavonoids. Specifically, natural molecules like luteolin and quercetin appear to stabilize the outer membrane of mast cells. Laboratory studies suggest these compounds prevent the cells from releasing their contents in the first place, rather than just blocking single mediators after they are loose in the tissue.

Another proposed treatment is alpha-lipoic acid, a natural antioxidant involved in cellular energy production. Previous research indicates this compound helps neutralize oxidative stress in biological tissues. It has also shown promise in promoting nerve regeneration and suppressing pain signals traveling along damaged nerve fibers.

While the biological mechanism appears plausible, the researchers outline several caveats to their conclusions. Narrative reviews synthesize existing evidence but do not act as standalone experiments to confirm a hypothesis. Much of the underlying data comes from isolated test tube studies, animal models, and individual patient case reports.

Additionally, blood tests designed to measure mast cell activation are not consistently elevated in all Long COVID patients. Because the results of these tests were not statistically significant across all cohorts, the authors suggest this might be because mast cell activity fluctuates. The inflammation might also be localized inside specific organ tissues rather than circulating through the whole body in high concentrations.

The wide variation in patient responses to immune-modulating treatments indicates that Long COVID is likely an umbrella term for several distinct biological problems. Mast cell dysfunction might be a primary driver for some individuals, while persistent viral fragments or blood clotting issues might dominate in others. These distinct but overlapping biological pathways make diagnosing and treating the condition exceptionally difficult.

The exact sequence of events leading from an initial respiratory infection to chronic nerve pain remains partially theoretical. Addressing this knowledge gap will require prospective clinical trials specifically designed to track mast cell activity over time. Until then, understanding this specific immune response offers a rational foundation for developing targeted therapies to help those suffering from chronic post-viral illness.

The study, “Long COVID neuropathy: The role of mast cells,” was authored by Zachary L. Morcos and Theoharis C. Theoharides.