Millions of people who have recovered from the early stages of COVID-19 continue to suffer from lingering nerve pain, fatigue and cognitive problems. A new academic review proposes that certain types of overactive immune cells may be responsible for this persistent nerve damage. These findings were published in the Journal of Neuropathology & Experimental Neurology.
Long-lasting coronavirus, officially referred to as the acute sequela of SARS-CoV-2 infection, remains a widespread public health problem. Global estimates suggest that more than 60 million people are affected by this condition. A meta-analysis that looked at a huge sample of more than 2 million people infected with COVID-19 estimated the global infection rate to be nearly 36 percent. Another study of a large sample of more than 480,000 people found that more than half of survivors had at least one symptom that lasted for more than a year.
Despite these high numbers, the underlying biology of Long COVID is not fully understood. Patients report a wide range of symptoms spanning multiple organ systems. These often include extreme fatigue, brain fog, and shortness of breath.
A hallmark of Long COVID is neuropathy, which is a general term for damage or malfunction of the peripheral nervous system. Peripheral nerves connect the brain and spinal cord to other parts of the body. Data from several observational studies show that up to 59% of Long COVID patients show signs of small fiber neuropathy.
Small fiber neuropathy specifically affects small unmyelinated nerve endings in the skin and organs. These fibers transmit sensations of pain and temperature. Injuries often cause burning pain, numbness, and tingling in the extremities.
Traditional nerve conduction studies often fail to detect this particular type of injury. Standard medical tests primarily evaluate the large myelinated nerve fibers that are responsible for major muscle movement and overall sensation. The prevalence of Long COVID-19 neuropathy was likely underreported during the early stages of the pandemic, as standard diagnostic tools tend to miss damage to small nerve fibers.
These tiny nerves also help control the autonomic nervous system, which manages involuntary bodily functions such as heart rate and digestion. Autonomic dysfunction is frequently observed in patients with long corona. Many people develop postural orthostatic tachycardia syndrome. This is a condition in which your heart beats uncontrollably when you stand up.
Researchers Zachary L. Molkos and Theoharis C. Theoharides, from Nova Southeastern University and Tufts University, sought to explore the underlying cellular mechanisms linking these different conditions. They found that many of the long-term symptoms of coronavirus closely reflect an immune condition called mast cell activation syndrome. This prompted us to investigate whether mast cells act as a biological bridge between past viral infections and ongoing neural pain.
Mast cells are specialized immune cells that act as sentinels throughout the body. These are concentrated in tissues that are in contact with the external environment, such as the skin, lungs, and intestines. They are also densely packed around blood vessels and nerve fibers.
Normally, mast cells help defend against pathogens and play a central role in allergic reactions. When triggered by viruses, allergens, or physiological stress, a process called degranulation occurs. During degranulation, cells crack open and release large amounts of chemical mediators into the surrounding tissue.
These inflammatory chemicals include histamine, tryptase, and various signaling proteins. These mediators help coordinate defenses against immediate threats, but when chronically released, they can damage surrounding tissues. Because mast cells are located right next to nerve fibers, their release of chemicals can easily stimulate pain receptors.
Mast cells are well known for their role in asthma and skin urticaria. However, researchers are increasingly recognizing its ability to modulate both neurovascular and neuroimmune responses. Because mast cells are located at the biological crossroads of the blood supply and the nervous system, prolonged periods of mast cell hyperactivity can easily disrupt both systems simultaneously.
To evaluate this hypothesis, the researchers conducted a narrative literature review. They collected 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 pandemic viruses and the human nervous system.
The collected research suggests that the spike protein of the SARS-CoV-2 virus binds directly to specific receptors on the surface of mast cells. These docking points include angiotensin-converting enzyme 2 and toll-like receptor 4 proteins. This cellular interaction allows mast cells to release inflammatory payloads without the need for traditional allergens. When these harsh chemicals are released, they penetrate nearby nerve endings, making them overly sensitive to pain.
The long-term presence of these mediators initiates a local chain reaction of inflammation. The chemicals reduce the structural integrity of small nerve fibers, causing the numbness and burning sensation that is characteristic of neuropathy. In the autonomic nervous system, this localized damage disrupts the normal transmission of signals needed to regulate blood pressure and heart rate.
Researchers note that collateral damage is not limited to the peripheral limbs. Inflammatory mediators released by mast cells can travel through the bloodstream and damage the blood-brain barrier. This barrier is a highly selective membrane designed to prevent circulating toxins from entering the central nervous system.
A weakened blood-brain barrier allows common immune cells and inflammatory molecules to enter the brain. Once they enter the body, they can aggravate microglia, a population of immune cells that reside in the brain. This localized brain inflammation is thought to be a major cause of the cognitive dysfunction and extreme fatigue often reported by patients.
Past clinical observations have provided relevant evidence that mast cells contribute to long coronaviruses. This review focuses on a small study of 21 patients with severe COVID-19 infection who had abnormally elevated resting immune markers. Autopsy data from deceased patients also revealed large accumulations of mast cells in the lungs and near blocked blood vessels.
In addition to causing direct neurological damage, excess mast cells may intersect with other theoretical Long COVID mechanisms. The chemicals they release can interfere with normal blood clotting and may be responsible for the microscopic blood clots seen in some patients. Their constant signaling can also skew the broader immune system and trigger autoimmune responses that are seen long after the virus has been cleared.
If hyperactive mast cells are causing neurological symptoms, targeting them directly may alleviate symptoms. In this review, we evaluated several potential treatment strategies reported in recent clinical literature. Standard antihistamines block cellular receptors for one of the main chemicals released by mast cells, but results are mixed.
Several case reports report that patients achieved remission from autonomic nervous system problems after starting antihistamine therapy. However, human mast cells can release up to 390 different inflammatory mediators depending on the trigger. Blocking histamine alone may not be enough to completely stop widespread nerve damage.
Researchers point to other chemical interventions, such as natural plant compounds called flavonoids. Specifically, natural molecules such as luteolin and quercetin appear to stabilize the outer membrane of mast cells. Laboratory studies suggest that these compounds not only block single mediators after they are released in tissues, but also prevent cells from releasing their contents in the first place.
Another proposed treatment is alpha lipoic acid, a natural antioxidant involved in cellular energy production. Previous studies have shown that this compound helps neutralize oxidative stress in living tissues. It is also expected to promote nerve regeneration and suppress pain signals that travel along damaged nerve fibers.
Although the biological mechanism seems plausible, the researchers outline several caveats before reaching their conclusion. Narrative reviews synthesize existing evidence but do not serve as independent experiments to confirm hypotheses. Much of the underlying data comes from individual 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. Since the results of these tests were not statistically significant across all cohorts, the authors suggest that this may be due to fluctuations in mast cell activity. Inflammation may also be localized within specific organ tissues rather than circulating in high concentrations throughout the body.
The wide variability in patient response to immunomodulatory treatments indicates that Long COVID is likely an umbrella term for several different biological problems. For some people, mast cell dysfunction is the main cause, while for others, persistent viral fragments or blood clotting problems are the main cause. These distinct but overlapping biological pathways make the diagnosis and treatment of this condition extremely difficult.
The exact sequence of events from initial respiratory infection to chronic neuralgia remains partially theoretical. Prospective clinical trials specifically designed to track mast cell activity over time are needed to address this knowledge gap. Until then, understanding this specific immune response provides a rational basis for developing targeted therapies to help people suffering from chronic diseases following viral infections.
The study, “Long-term COVID-19 neurological impairment: The role of mast cells,” was authored by Zachary L. Morcos and Theoharis C. Theoharides.
