Immune System Glitches. What Causes Long COVID? Part 1.

Top 23 Potential Causes of Long COVID (LC)

This disease is not your imagination or your fault!

People with Long COVID experience health problems long after supposedly recovering from COVID-19. If you think you have not completely recovered from COVID-19 you are likely right.

People with Long COVID experience health problems long after supposedly recovering from COVID-19. If you think you have not completely recovered from COVID-19 you are likely right. Click for a list of some of Long COVID symptoms.

Check out what causes exercise intolerance in Long COVID or other fatigue disorders.

Mateo E. (20 year old man): "I was finishing up my junior year of university when I got Long COVID. Truth was I was a bit sluggish but I planned to start cycling. But before I could even start exercising, I caught covid. It's now been 19 months. I'm still enjoying the benefits (ha) of LC like the brain fog, the weird drunk feeling, and fatigue...tired all the freaking time. My 67 year old abuela has more energy than me! I feel like I'm the retiree not her.

I can't work at all right now and get dizzy just standing up. I just want all the chronic illness to go away and to be in better shape. I never wanted to be chronically ill; I wish I could start my life over from scratch and not get COVID. This seems so unfair."

Carl Krenek Sleeping Beauty c1905 tempera.

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Part 1 includes six way your immune system may be sabotaging you after COVID:

1) Unwanted squatter. The virus is still in the house.

2) Your immune cells have zoned out.

3) Rise of the dead! Virus infection summons zombie viruses hiding in your body.

4) Rambo immunity style; your immune system went full on kick butt after COVID infection and started packing heat.

5) Self sabotage. Your autoantibodies attack yourself.

6) Too sensitive; the immune system is dialed up too high.

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1) Like an unwanted house guest, the virus is still present and causing problems:

The COVID-19 virus, SARS-CoV-2, lingers in the body even after the person is no longer infectious. These viral reservoirs may contribute to LC since your body is still battling them. Think of the viruses as an entrenched terrorist group fighting a gorilla style war with your bodies's immune cells. They hide in fat cells and organs, put on masks to deceive immune cells, and strike when your immune system is engaged elsewhere. Sneaky viruses have been detected lurking in many organs in the body (discussion in Turner et al. 2023). These dangerous viruses may also be hanging out in your gut causing microbiota dysfunction.

Virus pathogens are associated with other chronic disorders such as myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Human herpes viruses, B19V, enteroviruses and other viruses can remain latent in the body only to reactivate later and trigger ME and CFS. This is because viral infections can cause changes to host cells which contribute to ME and CFS development. These include chronic inflammation, autoimmunity, immune cell alterations, and mitochondrial modulation (Rasa et al. 2018).

Places that COVID-19 likes to hang out:

Right now it looks like COVID-19 can hide everywhere in the body including the gut (Natarajan et al. 2022), kidney, and spleen (Gupta et al. 2022). Stein et al. 2022 found evidence of the COVID-19 virus in almost all areas of the body including lungs, heart, brain, gut and eyes. Evidence of the virus was found up to 7 months after infection in autopsies of 44 patients with Long Covid.

COVID-19 loves fat cells. SARS-CoV-2, the virus commonly known as COVID-19, can infect and hide out in human fat cells (Martnez-Coln et al. 2022). This may be why obesity is an independent risk factor for Long COVID. People who are overweight have a 20% increased risk of Long COVID while people who are obese have a 36% increased odds of developing Long COVID. The risk of Long COVID was 20% higher for each 5kg/m2 increase in BMI.

2) Your immune cells are quietly quitting:

Your immune cells are exhausted and communication in the immune system has broken down. It is one big toxic workplace with zoned out employees gossiping and panicking about the big COVID takeover. Long COVID is defined by out of touch immune cells including dysfunctional T cells; CD4+ T cells with increased inflammation; dysregulated immune cells overall; and a lack of crosstalk or coordination between your B and T cells (Yin et al. 2023). It makes The Office look functional.

T cells in Long COVID are really tired of the daily grind. These infection fighting lymphocytes (white blood cells) are still fighting after the ill person is supposedly better. They might be battling a hidden reservoir of SARS-CoV-2 (the COVID-19 virus) or wrestling with a reactivated pathogen like Epstein-Barr virus (EBV), herpes simplex virus, or Hepatitis C (Klein et al. 2022, Davis et al. 2023, discussion in Turner et al. 2023). Yin et al. 2023 found that the cells specifically fighting COVID-19 (SARS-CoV-2-specific CD8+ T cells) are exhausted from fighting.

Whatever enemy they are fighting, these T cells are tired of the battle. Unfortunately, often these weary warriors will just lay down their guns and stop fighting. That is not good for you or your health.

In addition to troops giving up, armies of CD4+ T immune cells start traveling to already inflamed tissues where they cause more inflammation. Yes, instead of helping out like they should, these inflamed and immature acting immune cells go rogue like sailors on shore leave and cause more trouble by releasing inflammatory cytokines near your healthy cells. The chemicals cause more inflammation which attracts more immune cells to perpetuate a giant self reinforcing loop.

When compared to CD4+ T cells in healthy people, CD4+ T cells from people with Long COVID were in a higher inflammatory state (Yin et al. 2023). A small study also found that women with LC have higher amounts of a subgroup activated by cytotoxic T cells. These T cells are associated with gastrointestinal LC symptoms (Su et al. 2022, Yin et al. 2023).

3) COVID-19 infection summons zombie viruses already laying latent in your body.

Yes, dormant (zombie) viruses may basically raise from the dead due to COVID-19 infection (Klein et al. 2022, Davis et al. 2023, discussion in Turner et al. 2023). NEW FEAR UNLOCKED! When your immune response is weakened or challenged dormant viruses may become reactivated and rise up to wreak havoc on your gene expression, protein production, and immune regulation (Proal et al. 2021). By the way, this is not limited to COVID-19; other viruses can also activate chronic symptoms using this one trick.

Reanimation of other latent viruses may occur during the initial COVID-19 infection. Su et al. 2022 conducted a long term study of COVID-19 patients from initial infection to recovery. They reported that 14% of tested patients had reactivation of Epstein-Barr virus (EBV) that causes mononucleosis (mono), and 25% of people had positive SARS-CoV-2 RNAemia (an pneumonia known as acute respiratory syndrome coronavirus 2). These viruses can make people feel sick for months and may contribute to Long COVID.

An Italian family crochets bags while the father is sick in bed c1912.

4) Instead of quitting; your immune system went full on crazy after COVID infection:

So maybe your immune cells aren't quitters. Maybe they are going all out Rambo style and rooting out every single COVID virus with extreme bloodthirsty violence. What's the problem with such energetic enthusiasm, you may ask?

Unfortunately, once the immune system is activated and destabilized by the COVID-19 virus it may be hard for it to reset to normal. Hypersensitive immune cells attack parts of the body and start to attack your own body in autoimmune reactions. Hyper alertness causes the immune system to go off on normal things that shouldn't be perceived as threats; like your own cells, foods, or pollens.

Indeed, Phetsouphanh et al. 2022, found that people with Long COVID had immune systems that were in a constant state of high alert when compared to people who recovered fully from LC. In Long COVID the white blood cells were highly activated and most of the T cells and B cells had been recruited to fight. In addition to a hyper alert immune systems, people with LC had chronic inflammation.

This is not normal. Healthy people have a large pool of inactive T and B cells just lounging around drinking mock cocktails and chilling. They aren't down to fight all the time; they are just waiting in reserve.

Long COVID also causes dysregulation of the complement system, which is an automatic part of the immune system that contributes to immunity and homeostasis. The complement system is made of a number of distinctly shaped plasma proteins that react and connect with each other to make pathogens easier to kill and induce a series of inflammatory responses that help to fight infection. Think of them as Lego® bricks that can be combined to make all sorts of machinery.

The complement system is part of the innate immune system that targets pathogens and damaged cells (for an amazing video on the complement system see: Tiny Bombs in your Blood - The Complement System by Kurzgesagt in a Nutshell). Watch this video to see these ultra versatile proteins assemble into drilling machines that bore holes in viruses and other pathogens! This kills the virus.

For one year, scientists compared the blood of 113 people with confirmed COVID-19 (SARS-CoV-2) infection with that of 39 people who didn't get COVID. They found that people with Long COVID had changes in blood serum proteins related to the complement immune system. These changes included activation of the immune system's complement cascade, altered coagulation (blood clotting), and tissue injury such as hemolysis (blood cells bursting), platelets activated and monocyte-platelet clumping (Cervia-Hasler et al. 2024). We are not sure how long it takes for the complement system to recover after COVID.

5) You start making autoantibodies (ANAs) that attack your own body:

As we discussed above, COVID makes your immune system go nuts! After COVID-19 infection, your body can make autoantibodies that attack your own organs and tissues. Viral infections can trigger immune cells' inner Hulk and they start threatening your own cells. New evidence suggest that an autoimmune response plays a role in LC. People with Long COVID have antibodies in their blood that can attack their own tissues. These are called antinuclear/extractable-nuclear antibodies (ANAs).

Compared to healthy people of the same age and gender, people who previously had COVID-19 had high amounts of ANAs in their blood. The ANAs were present in the blood for at least 6-12 months after recovery from COVID (Peker et al. 2021, Lui et al. 2021, Son et al. 2023).

There is a direct connection between high levels of ANAs and inflammation. People with the highest amounts of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP) had higher ANAs at 1 year after COVID. Likewise, people with the highest levels of TNFa, D-dimer (a product of blood clot breakdown), and interleukin-1β (IL-1β) had worse LC symptoms after 1 year. High concentrations of D-dimer are associated with disease and inflammation. It may also be associated with gut inflammation (Feng et al. 2022).

ANAs are produced when a person's own immune system mistakenly targets and assaults the body's tissues and organs. They are found in people who have chronic inflammation; injury to joints, skin, nervous system, and other tissues; or diseases like lupus or rheumatoid arthritis. Autoimmune responses like ANAs occur due to exposure to other viruses as well.

The ANAs detected in people with Long COVID even predicted their specific Long COVID syndromes such as fatigue, shortness of breath, and coughing (Son et al. 2023). Men were more susceptible to developing ANAs after COVID-19 infection than women.

6) Your immune system is dialed up too high (the interferon pathway):

Cells release interferon when they sense an infection or invader. Like a warning siren, interferon lets cells know it is time to fight the invading virus. Cells use receptors, such as interferon receptor 2 (IFNA R2), to detect interferon. When infereron signaling is too low or too high it causes the immune system to under or overreact. When your immune system is dialed up too high, you are more likely to get severe or Long COVID.

There are two versions of IFNAR2; a working version and a shorter nonfunctional version. Short IFNAR2 can sense interferon but cannot transmit a signal to cells. It acts as a decoy and interfere with signaling from the normal length IFNAR2. This blunts the cell's immune response to viruses. The ratio of normal to short IFNAR2 may work as a tuning dial to help control the strength of your immune response. People with a abnormally high amount of the short variant of IFNAR2 could be more prone to severe infections; while people with low levels of short IFNAR2 could develop more autoimmune problems like Long COVID (discussion in Pasquesi et al. 2024).

There is hope for your immune system: In most people after COVID, the immune system resets to normal over 1-2 years

A study looking at 31 women and men with Long COVID (age 40-60) compared to 31 age and sex matched controls found the immune system recovered over time. The abnormally active humoral and cellular immune responses seems to calm down and return to normal after 24 months in most people (Photosphere et al. 2024).

This was a small study but fairly robust. We don't know what happens with the complement system yet.

Want to read about more causes of Long COVID? Click here for part 2: What Causes Long COVID: Beyond the Immune System.

Definitions:

Brain gut axis is based on how the brain and the gut communication with each other. This complex network involves crosstalk between the vagus nerve; the central nervous system; and gut microbiota; using neural, endocrine, immune, and humoral links. It regulates gastrointestinal homeostasis and it connects the emotional and cognitive areas of the brain with gut functions.

Cytokine storms are life-threatening systemic inflammatory syndromes which involve dangerously high levels of circulating inflammatory chemicals, cytokines, along with hyperactivation of the immune system.

Post-exertional malaise (PEM) which is also called post-exertional symptom exacerbation (PESE) or post-exertional neuroimmune exhaustion(PENE): a medical condition that causes symptoms to get worse after even minor physical or mental exertion. It is common in Long COVID, fibromyalgia, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

* Names and some other small details have been changed to protect people's privacy.

This information is for informational purposes only and does not constitute medical advice, diagnosis, or treatment.

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