However, based on common clinical manifestations and emerging research, clinicians have identified several contributors to long COVID symptoms.
Spike Protein Appears to Be the Leading Contributor
The spike protein sits on the surface of the COVID-19 virus and is the key to breaking into cells and causing the virus to spread in organs and tissue.
Autopsy reports on people who died from COVID-19 have found spike protein in the brain, heart, pancreas, liver, kidney, thyroid, reproductive organs, adrenal glands, lungs, nasal and oral cavities, blood, fat, bone, muscle, skin, and even the eyes.
However, the symptoms and laboratory test results vary depending on the patient. Clinicians have therefore developed various hypotheses on the reasons behind these symptoms.
1. Inflamed Immune Cells and Blood Vessels
Inflammation is not harmful if controlled and short-term; it is essential to a person’s immune defense. But in the case of long COVID, inflammation is chronic, and this causes cells to become stressed and damaged.
A significant contributor to long COVID may be inflammation within and of the blood vessels.
When interviewed by The Epoch Times, Dr. Bruce Patterson, a viral pathologist and the CEO and founder of IncellDx, a diagnostic company, and internal medicine physician Dr. Jessica Peatross each pointed out the relationship between inflammation and long COVID.
Peatross voluntarily surrendered her medical license in November 2022 to the Medical Board of California due to facing disciplinary actions for approving two vaccine exemptions—one for a child with severe eczema and asthma, and one for a child who had previously experienced side effects to vaccines, according to Peatross’s own statement.
She pointed to studies on acute COVID as a systemic disease driven by inflammation of the lining of the blood vessel walls.
Patterson found spike protein in long COVID patients’ non-classical monocytes. Non-classical monocytes are immune cells. They can attach to blood vessel walls and cause inflammation.
Patterson’s other studies have found high levels of cytokines in long COVID patients’ blood, indicative of inflammation.
Inflammation of blood vessels can reduce blood flow to tissues and organs, causing pain and impaired organ function. Low blood flow also means fewer nutrients are supplied to the cells, causing fatigue and weakness.
Unsurprisingly, significant symptoms of inflammation in blood vessels are fatigue, and joint and muscle pain, which overlap with long COVID symptoms.
Symptoms vary depending on where the inflammation occurs.
Vascular inflammation in the superficial layers of the skin may cause clusters of red dots, bruises, or hives.
Inflammation in blood vessels that supply the eyes may cause the eyes to become sensitive to light or even cause vision impairment.
2. Mitochondrial Dysfunction
California physician Dr. Jeffrey Nordella told The Epoch Times that mitochondrial dysfunction is another major contributor to long COVID symptoms.
It should be noted that all of the symptoms, from inflammation to mitochondrial dysfunction, can overlap. Mitochondria can become stressed from low oxygen due to blood vessel inflammation or nearby inflammation.
Mitochondria are present in practically all cells in the body. Mitochondria make energy for the cell by concurrently burning fuel—carbohydrates, proteins, and fats—and consuming oxygen. However, this process can also produce toxic oxygen species that are highly reactive and damaging to mitochondria.
These oxidants must be immediately neutralized, but in the case of many long COVID patients, this is often not resolved quickly enough.
Common long COVID symptoms, like fatigue and dyspnea, then appear. In laboratory studies, cells exposed to spike protein led the mitochondria to become dysfunctional and stressed (1, 2). This would impact mitochondrial energy output.
A recent study on long COVID patients suggested that mitochondrial dysfunction may cause fats to be poorly metabolized for energy needs. The authors found that many of the study’s participants had fatigue, brain fog, and dyspnea; all had high lipid levels, suggesting poor lipid breakdown and utilization.
Interestingly, these patients had both low protein and carbohydrate-related substances in their blood. This pattern is also seen in type 2 diabetes. At the same time, weight gain and an increased risk of developing metabolic diseases have been documented in post-COVID patients.
3. Inflammatory Allergic Response
Mast cells, which are involved in allergies, may contribute to long COVID symptoms.
Mast cells are highly reactive, like many immune cells. They carry ACE2 receptors, which allow entrance to the virus or spike protein. Once activated, mast cells can send vast amounts of histamine and inflammatory cytokines into circulation.
A 2021 study that surveyed 136 long COVID patients about their laboratory test results showed that over 30 percent had high biomarkers that may be indicative of mast cell problems. These patients had high histamine and prostaglandin levels, which are often elevated in people with mast cell problems.
Histamine can cause an increase of cytokines, which can contribute to the cytokine storm and endothelial inflammation present in acute COVID.
Histamine also causes many allergic symptoms, leading to swelling, redness, pain, and fever in the regions of its release.
High histamine levels can bring about itching, abdominal cramps, and even brain fog. If concentrated in the heart muscles, histamine may also contribute to rapid heart contractions, causing arrhythmias and tachycardia.
Many of these symptoms overlap with long COVID symptoms.
Mast cell disorders have also been associated with postural orthostatic tachycardia syndrome, commonly known as POTS. Research shows that 2 to 14 percent of long COVID patients report POTS symptoms of lightheadedness, fainting, and rapid heartbeat upon standing up.
Psychiatrist Dr. Adonis Sfera, who has led several studies on COVID-19, said that there might be shared pathways between long COVID and mast cell disorders.
Some studies have shown that COVID-19 patients on drugs that block mast cell activation did better than patients who were not on such drugs.
An example Sfera gave is the antihypertensive drug losartan. The drug works by blocking ACE2 receptors and lowering histamine activation. COVID patients who took this drug had a lower risk of death from COVID-19 early in the disease than patients who did not.
4. Gut Dysbiosis
Gastroenterologist and CEO of Progenabiome Dr. Sabine Hazan runs a research lab and conducts fecal tests for long COVID patients.
She found that these patients carried COVID-19 genetic material in their guts months after the initial infection. Their gut microflora would be in a state of imbalance called dysbiosis.
Dysbiotic guts can lead to gastrointestinal symptoms such as diarrhea, constipation, bloating, abdominal pain, and indigestion.
Gut dysbiosis is also associated with chronic diseases such as poor mental health, obesity, diabetes, cancer, and cardiovascular disease.
The gut plays a critical role in physical well-being. A consequence of gut dysbiosis is the breakdown of the gut barrier (a condition called “leaky gut”). Bacteria can leave the gut and enter the bloodstream, leading to an immune response.
Sfera said that many bacteria in the gut are similar in structure to the body’s own cells. So when the immune system attacks bacteria, it may also mistake healthy tissues for bacteria, triggering an “autoimmune inflammation, in which the body attacks itself.”
Autoimmune diseases associated with gut dysbiosis include Lupus, rheumatoid arthritis, ankylosing spondylitis (arthritis of the joints and ligaments of the spine), and inflammatory bowel disease, all of which have been reported after a COVID infection.
Some Reported Symptoms May Not Be From Long COVID
Patterson’s studies on cytokines suggest that many people who report “long COVID” symptoms may not be experiencing long COVID but rather a reactivation of latent viruses.
When the body’s immune system becomes dysregulated, viruses and infections—such as herpes and Lyme disease—that had been under control may suddenly develop as opportunistic infections.
A patient, Mary Lee, had been experiencing long COVID symptoms since December 2021.
Her cytokine test revealed elevated cytokine levels with results indicating long COVID. However, a subsequent blood test showed that she was also positive for Lyme disease.
Elevated cytokines have been observed with both long COVID and Lyme disease. The diseases have similar symptoms, including headache, fatigue, joint pain, and brain fog, amongst others.
Lee has been suffering from migraines and fatigue for many years. She suspects that her untreated Lyme disease contributed to developing long COVID.
The cause of long COVID is far from settled, and a great deal of the evidence clinicians use to support their hypotheses is anecdotal. Given its complicated clinical symptoms, research will likely continue for many years.