Long Covid: Research Studies; Possible Causes and Solutions

Long Covid is the persistence of symptoms after having COVID-19. It seems to affect both severe COVID-19 patients as well as people who had mild cases. Fatigue, brain fog, heart rate problems, and breathing issues are the most common symptoms, but the list of associated problems is varied and long.

This article digs into current research on long Covid. I’ll explain the theories on the underlying causes and then review some treatments being researched. Finally, I’ll include some genetic variants that tie into possible root causes of long Covid.

Before we begin, I want to explain that I’m going to use the term long Covid to keep it simple. Other names for this syndrome include long-haul COVID-19, chronic Covid, and Post-acute sequelae of COVID (PASC).

SARS-CoV-2: Lingering Effects of a Viral Infection

While this article will cover the current research on long Covid, I wanted to back up and explain the viral infection process as well as the body’s response to the virus. The immune response to the virus may be a key to why some people have lingering effects. Stick with me here for some background…

The SARS-CoV-2 virus causes the symptoms known as COVID-19.

Viruses are non-living strands of RNA or DNA that can only replicate inside a host cell. Essentially, they have to be taken into a cell, and then the host cell replicates the viral genetic material. The viral genes are then translated into their proteins and packaged up by the host cell. The replicated virus then gets released (usually) into the host so that it can infect other cells. Rinse and repeat.

I will briefly explain how the SARS-CoV-2 virus infects and replicates, and then go into the immune system response.

SARS-CoV-2 is a member of the coronavirus family. It is an airborne virus. Other coronaviruses cause the common cold in people, or respiratory diseases, such as kennel cough, in animals.

This virus is an enveloped, single-stranded RNA virus. “Enveloped” means that the RNA that makes up the virus is packaged within a lipid outer membrane. The outside layer of the virus contains spike proteins that bind to a couple of receptors located on the membranes of host cells. The main receptor that the spike protein binds to is the ACE2 receptor. Additionally, the spike protein can likely bind to the CD147 receptor as well.[ref]

The ACE2 receptor is found on the membranes of cells in the lungs, stomach, nose, brain, prostate, testis, placenta, kidney, intestines, and liver. This receptor binds with the spike protein subunits (S1 and S2). Once bound, another host protein, TMPRSS2, cleaves the spike protein off, allowing the release of the viral RNA into the cell.[ref][ref][ref]

The CD147 receptor (basigin) is a transmembrane glycoprotein of the immunoglobulin superfamily.[ref] Platelets and precursor cells to platelets express the CD147 receptor, and it has been shown that SARS-CoV-2 can enter platelets through this receptor.[ref]

As the SARS-CoV-2 virus enters the host cell, it releases its viral RNA into the cell. The host cell then replicates and transcribes the viral RNA into the viral proteins. The viral proteins are taken into the host cell’s endoplasmic reticulum (ER) membrane, where the virus is assembled. It is then translocated to the cell surface to be released via exocytosis to infect other cells.[ref]

Immune response to viruses:

Innate Response: The innate immune system mounts an immediate response to foreign pathogens, such as viruses. It is a kind of generic response not specific to which virus has invaded. Interferons are one of the first responders in fighting a virus.

For the SARS-CoV-2 virus, the host’s cells recognize patterns associated with viral particles (pattern recognition receptors). This recognition is a general response to any virus with particles that can be recognized. In SARS-CoV-2, parts of the RNA genome are recognized by Toll-like receptors (TLRs) 3, 7, and 8, as well as MDA5 and RIG-I. Activation of these immune system receptors triggers an antiviral response leading to the induction of a couple of types of interferon as well as proinflammatory cytokines.

When this initial innate immune response is enough to control the infection, it results in the SARS-CoV-2 virus causing mild, cold-like symptoms. A lot of research points to this initial, innate immune response being the key to not having the severe Covid-19 symptoms seen in many older individuals.[ref]

Genetics also plays a role here in whether the innate immune response will kick the virus to the curb. People with mutations in specific toll-like receptors or interferon-related genes end up with severe Covid-19, even if young and healthy. (Read more about TLR7 variants.)

Adaptive Immune Response: The adaptive immune response takes a bit longer (days), but it is specific to the virus. This additional time is important for the body to produce specific antibodies to bind to the virus and make it non-infective. IgM antibodies are produced in large amounts for a few weeks, and IgG antibodies can last for a while.

There is a second type of adaptive immune response called cell-mediated immunity. This type of immunity refers to T cells, which are a type of white blood cell that present antigens on their surface. Several different subtypes of T cells are involved in the immune response to SARS-CoV-2, including CD4⁺  and CD8⁺ T cells.

In SARS-CoV-2 infections, neutralizing antibodies are produced that bind to the S1 unit of the spike protein and block it from entering cells. In looking at the immune response of people with asymptomatic, mild, or severe Covid, the researchers found that they all had a similar antibody response. Asymptomatic people, in this study, had a better natural killer cell response.[ref]

Research studies on long Covid:

The studies on long Covid are all over the place…

• Like this one in the Wall Street Journal, some articles claim that it is all in the patients’ heads.[ref]
• Some researchers writing published journal articles about long Covid aren’t convinced that it is a real condition. One study put it: “Critically, we should not dismiss their complaints as being all in their head. This may not be true and, even if correct, is not helpful. It is appropriate to acknowledge their distress, get those with fatigue or dyspnea in a structured exercise program, and work with all on symptomatic relief.”[ref]  (This echoes a lot of research journal articles  about ME/CFS —  slyly inferring the fatigue was psychosomatic and the patients just needed some exercise, which has now been thoroughly debunked.)
• Many “studies” on long Covid are just surveys of symptoms or reviews of health record data to draw conclusions. These are surface-level or epidemiological studies that don’t tell us what is actually going on.

Importantly, though, researchers who are diving deeper and testing for physiological parameters are finding significant differences in patients with long Covid. I’ll cover these physiological and cellular differences in the next section.

Defining Long Covid:

Older people who had severe COVID-19 and ended up in the ICU often had long-term decreased functional capacity. This result is true for many other illnesses that include ICU stays — termed post-intensive care unit syndrome. For example, lung problems persist for many months for COVID-19 patients after the ICU stay. It makes sense when looking at the damage and cell death in the lungs.[ref]

Long covid (or long-haul covid) is a term usually applied to young or middle-aged adults who have lingering symptoms for a month or more after clearing the initial COVID-19 infection symptoms.[ref][ref][ref]

Long Covid symptoms commonly include:

• fatigue
• cognitive impairment (brain fog, problems thinking clearly)
• dyspnea (not breathing as well as normal)
• heart palpitations
• loss of taste or smell
• problems sleeping
• hair loss
• headache
• gynecological problems
• hyperhidrosis (sweating a lot)

These symptoms aren’t really new or unexpected: 
It’s important to point out that long-term effects from viral infections have long been known and well-researched. Here are a few examples of lingering viral effects:[ref][ref][ref][ref][ref]

• Some SARS and MERS patients had long-lasting significant impairments for years after their infections.
• Post-viral syndrome, which usually involves significant fatigue, muscle pain, brain fog, etc., occurs with Coxsackie virus, brucellosis, poliovirus, viral meningitis, Ross River virus, and Epstein-Barr virus.
• Hearing loss is a serious complication after having mumps.
• Poliovirus causes long-term disability.
• Zika virus and cytomegalovirus can have significant long-term effects on children if exposed as an infant.
• Herpes simplex 1 (the cause of cold sores) is linked to neurodegenerative disorders in aging.

Importantly, though, lingering viral symptoms are not well studied nor easily treated. Just because the post-Covid lingering effects are not unexpected, doesn’t mean that they shouldn’t be researched in depth.

Getting specific on the root cause of long Covid:

There are a number of theories on what is going on with long Covid, and the research here is not yet settled.

Theories include:[ref]

• The virus lingers in hidden reservoirs, or the virus is still active somewhere in the body.
• Tissue damage from the virus is driving chronic or acute inflammation that hasn’t been resolved.  
• Alterations to the gut or oral microbiome cause lingering symptoms.
• Autoimmune disease has been triggered.

With the wide range of symptoms, it could be that several of the theories are true at the same time.

Let’s dig into some of the research findings:

Lingering spike protein: Research shows that the spike protein alone (without the virus) causes an immune response, including abnormal clotting.[ref][ref]

• A recent study found that CD16+ monocytes had persistent spike (S1) proteins in patients with PASC (Post-acute sequelae of COVID) long after the infection should have cleared. CD16+ monocytes interact with the endothelium and with platelets.[ref]
• Another study found similar results with the spike protein found in a long Covid patient’s monocytes 15-months post-infection. Note: this was just the spike protein fragments found in the long Covid patients, not the full SARS-CoV-2 virus.[ref]
• Note that the spike protein is also given in the mRNA viruses. These studies on PASC/long Covid patients don’t include information on whether the patients were also vaccinated. A recent study published in Cell shows that the spike protein mRNA is present in some lymph nodes eight weeks after vaccination.[ref]

Reactivation of Epstein-Barr Virus: A study of patients with long Covid showed that 67% had positive Epstein-Barr titers showing a reactivation of the virus. (Only 10% of the control group had active Epstein-Barr virus titers.) The study concludes: “These findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation.”[ref]

Persistent clotting problems and inflammation: A study looked at plasma samples from long Covid /PASC patients and found large anomalous deposits (microclots). The clots were resistant to fibrinolysis. Additionally, the researchers noted various inflammatory cytokines that were elevated in long Covid patients, including “α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA)”.[ref] Serum amyloid A is an acute-phase protein indicating active inflammation.

Post-COVID-19 Tachycardia Syndrome: Researchers have identified that a subset of patients end up with heart palpitations or tachycardia that persists for 3+ months after Covid. This abnormality can also include POTS (postural tachycardia syndrome) patients. Interestingly, the researchers did not find Holter ECG monitoring matched with reported symptoms. The researchers think that direct and indirect damage to the heart from the viral infection may lead to post-covid-19 tachycardia syndrome. Additional causes are theorized to include persistent lung injury, persistent fevers, pain, anxiety, or depression.[ref]

Altered microbiome: Changes to the gut microbiome or oral microbiome due to SARS-CoV-2 could lead to immune dysregulation and chronic inflammation.

• A study of COVID-19 patients looked at changes to the gut microbiome in the participants who still had lingering symptoms at 6-months (mainly fatigue, brain fog, and hair loss). The gut microbiome of long Covid patients showed persistent differences. “Butyrate-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii showed the largest inverse correlations with PACS at 6 months.”[ref]
• A study of the oral microbiome in patients with COVID-19 showed that those who developed long Covid had significant differences in the oral microbiome. The long-covid patients had “significantly higher abundances of microbiota that induced inflammation, such as members of the genera Prevotella and Veillonella, which, of note, are species that produce LPS. The oral microbiome of patients with long COVID was similar to that of patients with chronic fatigue syndrome.”[ref]

Persistent Immune System Changes: A study of upregulated genes in people with long Covid showed that platelet-related pathways were downregulated and genes involved in transcription, translation, and the cell cycle were upregulated. The downregulation of platelet-related genes (e.g. platelet factor 4, coagulation factor XIIII) may correlate to thrombocytopenia (low platelet count) seen in COVID-19 patients – and be a source of fatigue. Interestingly, the researchers also identified interferon-related genes as being downregulated.[ref]

Systemic inflammation: Elevated inflammatory cytokines are found in people with long Covid.

• A PET/CT study of people with long Covid showed that systemic inflammation might be the underlying cause. The imaging study found hypometabolism in the brain, which is typical of whole-body inflammatory changes. It means that regions of the brain are literally not getting enough energy, and the cause is likely inflammation in the body.[ref] What the study doesn’t show is whether the systemic inflammation is due to lack of resolution of inflammation, persistence of viral infection, or sterile inflammation due to cell death from the inflammatory response to the virus.
• TNF-alpha and interferon-gamma: Another preprint describes the differences between people who fully recovered from Covid and people with long Covid. “participants with respiratory PASC had up to 34-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood and elevated levels of plasma CRP and IL-6.”[ref]

Spike protein in the brain: One researcher theorizes that the spike protein causes neurological issues in long Covid. This researcher points to indirect evidence of the spike protein being released and possibly crossing the blood-brain barrier. A number of research papers have shown direct pathological effects of the spike protein alone, mainly in damaging the endothelium. Animal studies show that the spike protein alone can cross the blood-brain barrier.[ref]

Autoimmune antibodies: A study of patients with severe COVID-19 found that 34% of them were positive for antinuclear antibodies, another 34% were positive for anti-β2GPI antibodies, and several other antibodies were also determined. Importantly, none of the patients in the study had previously been diagnosed with a rheumatic disease (which would be a source of these specific autoimmune-related antibodies).[ref] The question, though, is how long the autoimmune antibodies last after an illness. It is thought that the low-level autoimmune antibodies will likely fade away fairly quickly after the illness.[ref] But what if these autoantibodies linger for some people? The autoimmune pathology theory is backed by other studies of severe Covid patients, also showing higher levels of autoantigens.[ref]

Persistence of virus: Many viruses can stick around in the body, in some form, for a long time. Take chickenpox, for example. The varicella-zoster virus that causes chickenpox lies dormant in the nervous system and can reactivate as shingles in adulthood. The question is whether long Covid symptoms are caused by the SARS-CoV-2 virus still lingering, at low levels, somewhere in the body.

• A preprint of a study on viral persistence shows that people with long Covid have higher cytokine levels such as TNF-alpha and IL-6. The researchers thought that this might indicate persistent infection.[ref]
• Lung tissue biopsy showed the persistence of SARS-CoV-2 RNA in the lungs more than 100 days after a mild infection.[ref]
• Intestinal biopsies of asymptomatic individuals also showed SARS-CoV-2 RNA in half the patients at four months post-infection.[ref]
• A trial using sweat samples and dogs that can sniff Covid found that about half the long Covid patients tested (sniffed) positive for viral infection.[ref]

Let me reiterate:  It is entirely possible that all of the above theories about the cause of long Covid are correct. Long Covid symptoms won’t necessarily have the same underlying cause for everyone. One theme that threads through several of the above theories is the chronic elevation of inflammatory cytokines (for various reasons).

Clinical trials on treatments:

I was surprised at the lack of true clinical trial data for long covid. Here’s what I found:

Researchers conducted a clinical trial with 18 ‘long haul’ Covid patients. The treatment used was a combination of 300 mg/ twice a day of maraviroc and 10mg/day of pravastatin. Maraviroc is a prescription medication used for HIV infections. It is a CCR5 antagonist. Pravastatin is a statin (traditionally used as a cholesterol-lowering medication). After 6 to 12 weeks of treatment, symptoms improved enough to stop the medications in the long Covid patients.[ref]

A clinical trial in Italy used oxygen-ozone autohemotherapy for patients with PASC. The results showed that 67% of patients completely recovered.[ref]

A clinical trial using histamine receptor antagonists (aka antihistamines) found that 72% of the patients had improvement. The patients used both H1 and H2 medications:

• H1: loratadine 10 mg two times per day or fexofenadine 180 mg two times per day
• H2: famotidine 40 mg once daily or nizatidine (Rx) 300 mg once daily[ref]

Clinical trials in the works:

• Axcella Health has 40 patients involved in a clinical trial using a mixture of amino acids that increase fatty acid oxidation and ATP production.[ref]
• A clinical trial using boswellia, curcumin, and vitamin C is expected to begin soon.[ref]
• AgelessRX has a clinical trial underway using low-dose naltrexone and nicotinamide riboside.[ref]

There are a bunch of other trials still recruiting patients, and several studies that show that they were completed but didn’t publish any results.

Other interesting studies:

Lipids and Orlistat: A new preprint is available for a study on how the SARS-CoV-2 virus requires the host cells to produce certain lipids during the replication of the virus. Think about it — cranking out all the new viruses uses up a lot of cellular resources, including the lipids used in the viral envelope.

The researchers found that the lipids needed were specific to the virus. The cells are biosynthesizing the specific lipids necessary for the viral envelope. The study found that 409 different lipids (phospholipids, glycerolipids, etc.) were altered in cells infected with SARS-Cov-2.

Using different molecules that block the biosynthesis of lipids, the researchers could completely stop the replication of the virus. One of the molecules that stops replication of the virus is orlistat — aka Alli, the over-the-counter weight loss medication that blocks fat absorption.[ref]

Other studies have also determined that interrupting lipid biosynthesis (with orlistat or other drugs) is a viable method of inhibiting replication of SARS-CoV-2.[ref][ref]

HSP90: Another recent study (March 2022) found that heat shock protein 90 is involved in the cellular damage from the spike protein (Covid or vaccine). The animal study showed that inhibiting HSP90 prevented and repaired the damage from the spike protein.[ref] While not specific to long covid, this research is something to keep an eye on.

Lifehacks:

If you are looking for a doctor that specializes in long Covid, check out these websites:

• Covid Long Haulers – https://covidlonghaulers.com/
• FLCCC I-Recover protocol – https://covid19criticalcare.com/covid-19-protocols/i-recover-protocol/

The rest of these ‘lifehacks’ target the theoretical causes of long Covid covered above.

Targeting the gut microbiome:
Low levels of butyrate-producing bacteria are linked to long Covid.[ref][ref] Additionally, low microbial diversity in the gut is also connected to long Covid.[ref]

• Butyrate-producing bacteria are enriched in the gut microbiome by eating fiber-containing vegetables and legumes.[ref] Take a good look at your diet. If you’re eating a lot of processed foods, it has likely impacted your gut microbiome negatively. Try adding a big salad at dinner, and incorporate whole-grain and legume recipes for lunch. Cleaning up your diet is a no-brainer – no downside, and it may help with long Covid.
• A clinical trial of probiotics (Simovixx800) after COVID-19 showed that it prevented long Covid in a statistically significant number of patients. The probiotic formulation used included Streptococcus thermophilus, Bifidobacterium lactis, Bifidobacterium lactis, Lactobacillus acidophilus, Lactobacillus helveticus, Lactobacillus paracasei, Lactobacillus plantarum, and Lactobacillus brevis.[ref]
• Related article: FUT2 variants (non-secretors) and Gut Microbiome

Focus on oral health: Research shows that long Covid sufferers have different oral microbiomes than healthy controls.[ref]

If you have long-term gum inflammation (gingivitis or periodontal disease), focusing on your oral microbiome may help. There are oral probiotics available, and you may want to brush and floss more frequently. Read about genetic variants related to gum disease (mainly inflammatory genes).

☑ Specialized pro-resolving mediators:
If long Covid symptoms are caused by chronically elevated inflammatory cytokines, targeting the inflammation through pro-resolving mediators may be something to investigate.[ref] Pro-resolving mediators initiate the active process of resolving inflammation. Without this active resolution, chronic elevation of inflammatory cytokines can persist. DHA and EPA, found in fish or krill oil, are the precursors for creating specialized pro-resolving mediators. The clinical trial showing efficacy using a statin intersects here. Statins increase the half-life of pro-resolving lipid mediators (similar to the effect from low-dose aspirin).

• Read all about specialized pro-resolving mediators and chronic inflammation. Seriously. It’s a long article, but SPMs may hold the key to resolving inflammation that causes long Covid symptoms.

Autoimmune diet:
If you think your long Covid symptoms relate to an autoimmune root cause, you may want to look into an autoimmune diet like the AIP diet.

POTS: postural orthostatic tachycardia syndrome

A lot of long Covid patients are reporting issues with tachycardia and the autonomic nervous system. You can read more about POTS and see the genes related to POTS here.

Member’s Blueprint (Genetics, Supplement Research):

The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article, which includes supplement research and possible genetic connections.

Related Articles and Topics:

TLR7: Susceptibility to COVID-19
A genetic variant related to Covid severity.

Genetic susceptibility to viruses
Your genetic variants shape your immune system and give you superpowers against some pathogens – and perhaps more susceptible to others.

Vitamin D, Genes, and Your Immune System
Vitamin D is more than just a ‘vitamin’. It is actually a hormone that is essential to so many processes in your body – including your immune system.

Acute Respiratory Distress Syndrome Genes 
This is article explains what happens to the body in ARDS, and it goes into the genetic variants that increase or decrease the risk of ARDS (due to all causes – not just COVID-19). ARDS is a ‘syndrome’, and thus a collection of symptoms rather than a disease.