Despite ongoing research, few effective treatments have emerged
Although the COVID-19 pandemic was declared officially over on May 11, 2023, the original SARS-CoV-2 virus and new variants, such as EG.5 or “Eris,” continue to circulate and cause thousands of infections. At the same time, an estimated 16 to 34 million Americans continue to experience symptoms of long COVID, broadly defined by the Centers for Disease Control and Prevention (CDC) as signs, symptoms and conditions that continue or develop after acute COVID-19 infection. The World Health Organization (WHO) uses a broader definition, saying long COVID usually occurs three months from the onset of COVID-19 with symptoms that last for at least two months and can’t be explained by an alternative diagnosis. The symptoms may have persisted since the initial illness, gone away and reappeared, or be new.
The CDC reports the prevalence of long COVID has declined somewhat, from 7.5% among all U.S. adults in June 2022 to 6% in June 2023, or roughly one in 10 of all adults who have been infected with the virus. One in four people with long COVID continues to experience significant limitations in their activity.1
The number of Americans experiencing long COVID may be even higher. To be officially diagnosed as having long COVID, a patient needs to have a positive COVID test — but that excludes the millions of people exposed to COVID early in the pandemic, when there was no testing to confirm the diagnosis. A recent study of a small group of people infected early in the pandemic revealed that 41% had symptoms of long COVID. Based on this data, the researchers believe an additional 4 million people have long COVID.2
Long COVID symptoms
More than 80 different symptoms have been identified as characteristic of long COVID. However, in more than 80% of long COVID patients, the same group of symptoms appears together:3
- Fatigue and post-exertional malaise
- Brain fog
- Loss of or change in smell and taste
- Dizziness, gut issues and palpitations
The underlying causes of long COVID are still not fully understood. However, research has begun to elucidate the root of one of the most common, long-lasting and devastating symptoms: severe fatigue with post-exertional malaise.
Fatigue in long COVID
Severe, long-lasting fatigue, often combined with post-exertional malaise, is one of the most distressing and frustrating long COVID symptoms. An international study in 2021 showed fatigue affects 80% of long COVID patients, while post-exertional malaise affects 73%.4 Fatigue is also one of the most common long-term symptoms preventing a return to work and normal activities.5 It is the most common symptom in people claiming COVID-related disability benefits.
The role of mitochondria
The debilitating fatigue of long COVID may be related to virus-triggered damage to the mitochondria, the tiny power plants within every cell. Recent research has shown the SARs-CoV-2 virus can change the mitochondria and hamper energy generation by damaging the mitochondria’s delicate internal structures and the mitochondrial membrane. The damage leads to increased production of reactive oxygen species (ROS) free radicals, which can overwhelm antioxidant levels, leading to additional damage from oxidative stress and triggering inflammation.
The virus also inhibits the mitochondrial genes that produce proteins critical for making energy. In this process, viral proteins bind to host mitochondrial proteins and disrupt glycolysis, the complex process in which glucose is broken down by oxidative phosphorylation to generate adenosine triphosphate (ATP) — the energy that runs all the body’s cells. Lowered ATP levels lead to fatigue, hypersensitivity and chronic, widespread pain. By turning down energy production in the mitochondria, SARs-CoV-2 forces the surrounding cell to use alternative approaches — which are then hijacked by the virus for its own reproduction. The host cells attempt to compensate for the viral damage by activating innate immune system defenses and suppressing mitochondrial gene expression. The cells of the innate immune system, such as macrophages, produce inflammation as part of their defense system, but don’t produce antibodies to fight the virus. When the immune defense isn’t sufficient, it leads to chronically impaired mitochondrial function, ultimately leading to severe fatigue. In severe cases, impaired mitochondrial function can lead to fatal organ failure.6
The tipping point
In less severe cases, ongoing inflammation and impaired energy production from dysfunctional mitochondria create a self-perpetuating loop of continuing damage preventing a return to homeostasis. These patients are stuck — they can’t get better on their own. But why are the mitochondria of some people so severely affected they cannot restore homeostasis? It’s possible they were already experiencing mitochondrial stress before they became ill. A recent study of more than 800,000 people found those with long COVID were more likely to be older, female and with more chronic conditions than those in a comparison group who had been sick with COVID but didn’t develop long COVID symptoms. The study found the leading risk factors for long COVID included high blood pressure, chronic lung disease, obesity, diabetes and depression.7 In other words, the people most likely to get long COVID are people who, before they got sick, had at least one chronic disease related to a poor lifestyle (particularly obesity and diabetes) causing suboptimal mitochondrial function throughout the body, including in the immune system. Their older age and poor lifestyle, along with chronic disease, means they were already more susceptible to viral illness and less equipped to fight it off.
A poor lifestyle leading to suboptimal mitochondrial function also leads to chronic low-level inflammation, which causes further mitochondrial dysfunction, a downward spiral of ongoing inflammation and more mitochondrial dysfunction. When an older person with a chronic disease and mitochondrial dysfunction becomes ill with COVID-19, they are more likely to have a severe case. The virus creates even more inflammation and forces them past a tipping point of prolonged recovery.8
In addition to direct damage to the mitochondria from the COVID virus, the mitochondria also go into the cell danger response (CDR), defined as “the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical or biological threats that exceed the cellular capacity for homeostasis. ”9 In other words, during the CDR, mitochondrial activity switches from energy production to cell defense to support the immune system — the mitochondria downregulate as a protective mechanism.
The switch button in cellular energy production favoring immune defense leaves little energy for other functions, leading to persistent fatigue. The danger response in the mitochondria can’t be turned off until the cell receives signals from the adaptive immune system telling it the danger is past. Until then, in an attempt to eradicate the perceived danger, the CDR remains in a repeating loop that blocks further healing. Persistent activation of the cell danger response inhibits healing and is a factor in chronic illness.10
Other sources of damage
In long COVID, the mitochondrial switch may be delayed because the cells are effectively in a state of siege from persistent viral infection. These patients may be experiencing ongoing low-level infection that keeps the mitochondria in the cell danger response. Persistent SARS-CoV-2 virus fragments, particularly from the spike protein antigen, may linger in one or more bodily organs after the infection has cleared. These “viral ghosts,” capable of stimulating the immune system, cause symptoms of a chronic viral infection.
The virus may persist in the brain, lungs, heart or gut.11 A gut viral reservoir could release the virus and virus particles into the circulation through increased intestinal permeability. About 13% of COVID-19 patients continue to shed the virus in their stool after four months, and almost 4% continue to shed it after seven months. These patients also often have gastrointestinal symptoms several months after infection, suggesting a gut reservoir.12 The immune response triggered by the fragments may keep the mitochondria from switching off the cell danger response.
Some patients with long COVID show evidence of reactivation of other latent viruses. The SARS-CoV-2 infection may reawaken these dormant viruses and stimulate an immune response. High levels of antibodies to the Epstein-Barr virus (EBV), a herpesvirus well-known for causing fatigue, have been found in many long COVID patients.
Restoring mitochondrial function
A healthy lifestyle means healthy mitochondria can create an effective immune response when the cells are under viral attack. They have enough reserve to continue generating energy effectively and enough effective antioxidant capacity to resolve inflammation efficiently.
For those who need support for improving their mitochondrial function and managing the cell danger response, the following supplement protocol is suggested:
- B vitamins: 60 mg/day
- CoQ10: 300 mg/day
- Acetyl-L-carnitine: 1,000 mg/day
- NMN (nicotinamide mononucleotide), a precursor to NAD+: 200 mg/day
- Alpha-lipoic acid (ALA): 600 mg/day
- NAC/liposomal glutathione: 500 mg/day
- Magnesium: 200 mg/day
- Zinc: 40 mg/day
- Selenium: 200 mcg/day
- Vitamin C: 2,000 mg/day
The immune activation supplements protocol should also include a mixed medicinal mushroom blend:
- Lion’s mane
Sleep and exercise
In addition to the supplement protocol, good sleep is essential for managing fatigue. Carefully graded physical activity may also restore good mitochondrial function for some people with long COVID. However, this must be weighed against the risk of post-exertional malaise.
A plant-forward Mediterranean-style diet rich in natural antioxidants, vitamins and minerals is recommended for people with long COVID. Processed foods, sugar, high-carbohydrate foods and unhealthy fats should be avoided. Adding omega-3 fatty acids and arachidonic acid, an anti-inflammatory omega-6 fatty acid, helps reduce inflammation. Good sources include fish, eggs, vegetable oil, nuts and seeds.
The ketogenic diet stimulates mitochondrial function and can help with fatigue from long COVID.13 Intermittent fasting stimulates autophagy, removes damaged or senescent cells and stimulates mitochondrial renewal. This, too, may help with long COVID fatigue by removing dysfunctional mitochondria and stimulating the growth of healthy new mitochondria.14
Low-level laser therapy (LLLT)
Within the mitochondria, ATP is produced in the inner mitochondrial membrane through the electron transport chain (ETC). In this complex process, high-energy electrons are passed along a chain of protein carriers from one carrier protein to the next. In mitochondrial dysfunction, the ETC is disrupted. Low-level laser therapy (also known as non-thermal laser) can help restore the mitochondria to function better. The energy from a non-thermal laser (NTL) can improve the function and stability of the mitochondria by delivering highly energetic photons of energy into the cell. When photons of visible light energy from a non-thermal laser strike certain atoms in the inner membrane, the energy may push an electron from that atom to a higher energy level, where an electron acceptor in the ETC can pick it up. Photons in the visible laser light spectrum are believed to affect complexes I, II, III and IV of the ETC. Complexes I and II are stimulated by laser light in the 400 to 450-nm range; complex III is stimulated by laser light in the 500 to 560-nm range; complex IV is stimulated by laser light in the 600 to 670-nm range. By improving the activity of the ETC complexes, the rate-limiting mechanism for ATP is restored, and ATP production within the mitochondria is increased.
Look toward the future
So far, four years after the pandemic’s start, few people with long COVID are fully recovered. The future for them is uncertain. One study found that 85% of patients with long COVID symptoms two months after their initial infection still had symptoms a year later.15 A recent Veterans Affairs study showed that two years after COVID infection, people were still at elevated risk for many long COVID conditions across all organ systems, including fatigue, diabetes, lung problems, blood clots and digestive disorders.16
Despite much ongoing research, few effective treatments for long COVID have emerged in the traditional medical model. However, a growing body of evidence shows that focusing treatment on supporting patients through lifestyle changes, targeted supplementation and non-thermal laser therapy can be effective for helping long COVID recovery.
ROBERT G. SILVERMAN, DC, DACBN, DCBCN, MS, CCN, CNS, CSCS, CIISN, CKTP, CES, HKC, FAKTR, is a chiropractic doctor, clinical nutritionist, national/international speaker, author of Amazon’s #1 bestseller “Inside-Out Health,” and founder and CEO of Westchester Integrative Health Center. He graduated magna cum laude from the University of Bridgeport College of Chiropractic and has a Master of Science degree in human nutrition. The ACA Sports Council named him Sports Chiropractor of the Year in 2015. He is on the advisory board for Functional Medicine University and is a seasoned health and wellness expert on both the speaking circuits and in the media. He is a thought leader in his field and practice, and a frequently-published author in peer-reviewed journals and other mainstream publications.
- Ford ND, et. al. Long COVID and Significant Activity Limitation Among Adults, by Age — United States, June 1–13, 2022 to June 7–19, 2023. MMWR Morb Mortal Wkly Rep. 2023;72:866–870. CDC website. Long COVID and Significant Activity Limitation Among Adults, by Age — United States, June 1–13, 2022, to June 7–19, 2023 | MMWR (cdc.gov). Accessed Sept. 15, 2023.
- Orban ZS, et. al. SARS-CoV-2-specific immune responses in patients with postviral syndrome after suspected COVID-19. Neurol Neuroimmunol Neuroinflamm. 2023;10(6). PubMed website. SARS-CoV-2-Specific Immune Responses in Patients With Postviral Syndrome After Suspected COVID-19 – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Thaweethai T, et. al. Development of a definition of postacute sequelae of SARS-CoV-2 infection. JAMA. 2023;329(22):1934-1946. PubMed website. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Davis HE, et. al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. PubMed website. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Aiyegbusi OL, et. al. Symptoms, complications and management of long COVID: A review. J R Soc Med. 2021;114:428–442. PubMed website. Symptoms, complications and management of long COVID: a review – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Guarnieri JW, et. al. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. Sci Transl Med. 2023;15(708). Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts | Science Translational Medicine. Accessed Sept. 15, 2023.
- Song Z, Giuriato M. Demographic and clinical factors associated with long COVID. Health Aff (Millwood). 2023;42(3):433-442. Demographic And Clinical Factors Associated With Long COVID | Health Affairs. Accessed Sept. 15, 2023.
- Nunn AVW, et. al. Understanding long COVID; Mitochondrial health and adaptation-old pathways, new problems. Biomedicines. 2022;10(12):3113. MDPI website. Biomedicines | Free Full-Text | Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems (mdpi.com). Accessed Sept. 15, 2023.
- Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014;16:7-17. PubMed website. Metabolic features of the cell danger response – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Naviaux RK. [Perspective] Cell danger response biology: The new science that connects environmental health with mitochondria and the rising tide of chronic illness. Mitochondrion. 2020;51:40-45. Perspective: Cell danger response Biology-The new science that connects environmental health with mitochondria and the rising tide of chronic illness – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Swank Z, et. al. Persistent circulating severe acute respiratory syndrome Coronavirus 2 spike is associated with post-acute Coronavirus disease 2019 Sequelae. Clin Infect Dis. 2023;76(3). PubMed website. Persistent Circulating Severe Acute Respiratory Syndrome Coronavirus 2 Spike Is Associated With Post-acute Coronavirus Disease 2019 Sequelae – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Natarajan A, et. al. Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. Med. 2022;3(6):371-387. Europe PMC website. Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. – Abstract – Europe PMC. Accessed Sept. 15, 2023.
- Paoli A, et. al. The dark side of the spoon—Glucose, ketones, and COVID-19: A possible role for ketogenic diet? J. Transl. Med. 2020;18:441. PubMed website. The dark side of the spoon – glucose, ketones and COVID-19: a possible role for ketogenic diet? – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Hannan MA, et. al. Intermittent fasting, a possible priming tool for host defense against SARS-CoV-2 infection: Crosstalk among calorie restriction, autophagy and immune response. Immunol. Lett. 2020;226:38–45. PubMed website. Intermittent fasting, a possible priming tool for host defense against SARS-CoV-2 infection: Crosstalk among calorie restriction, autophagy and immune response – PubMed (nih.gov). Accessed Sept. 15, 2023.
- Tran VT, et al. Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort. Nat. Commun. 2022;13:1812. PubMed website. Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort – PubMed (nih.gov). Sept. 15, 2023.
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