Beyond the Immune System. What Causes Long COVID? Part 2.

Top 23 Potential Causes of Long COVID (LC)

These reasons likely apply to other post viral infections such as chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or similar disorders.

Viral infections can gut your body in ways that don't include the immune system. This includes attacks on your nervous system, gut bacteria, oxygen supply, blood and more.

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Read below for nine scary ways COVID-19 can wreck your heath:

7) COVID causes abnormal blood clotting.

8) COVID viral infection changes how RNA is built in host cells.

9) Long COVID drains your energy due to metabolomic and immune disturbances.

10) COVID-19 cuts off your oxygen supply.

11) Don't freak out about this though; stress makes getting Long COVID worse.

12) COVID decreases cortisol causing weakness and depression.

13) The COVID virus causes nervous system dysfunction.

14) COVID hammers your gut bacteria.

15) Your hypothalamus-pituitary-adrenal axis (HPA axis) is disrupted by COVID.

16) Endothelial dysfunction drives oxidative stress and inflammation in Long COVID.

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Lee Russell 1937 Exhausted flood refugee resting, Sikeston, Missouri.

7) You have abnormal blood clotting full of strange microscopic structures:

Long COVID is associated with microclots; small weird blood clotting proteins. Long COVID sufferers had significantly more and larger microclots (Thierry et al. 2025).

Microclots clump together due to sticky immune webs called neutrophil extracellular traps, or NETs. These NETs may stabilize the microclots and prevent them from being dissolved.

The innate immune response known as NETosis, normally produces NETs. Like Spiderman, neutrophils eject their DNA to form thread-like webs (filamentous). The webs are embedded with cytotoxic enzymes to quickly trap and neutralize pathogens and other dangers to the body. This can go horribly wrong though.

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Why are microclots so bad:

Abnormal microclots form dense matted clots that are fibrinolytic‐resistant. This means they are hard for your body to dissolve. These tangled microclots entrap different inflammatory molecules (which include compounds that prevent clot breakdown). All of these proteins combine in one big messy clump.

The mere presence of SARS‐CoV‐2 S1 spike protein causes fibrinolytic ‐resistant microclots to form (discussion in Thierry et al. 2025). Lung biopsies from people who died of COVID-19 showed excess NETs formation with neutrophilic infiltration (Collete et al. 2025).

Excess NETs formation may contribute inflammatory and blood clotting diseases, including autoimmune disorders, pulmonary embolism, deep vein thrombosis, severe infections, cancer, diabetes, and arthritis (discussion in Thierry et al. 2025).

8) COVID-19 infection changes how RNA is built.

Infection by SARS-CoV-2 causes changes in gene expression and transcript usage.

Gene expression is the process by which information copied from DNA is used to make a functional product; usually a protein or RNA. Transcription is when an RNA copy is made of a DNA gene segment. The RNA copy is used to carry the gene's instructions to ribosomes. Ribosomes make proteins using these instructions.

When COVID-19 strikes it can change gene expression influencing blood coagulation, neutrophil activation, and cytokine production. The COVID-19 virus changes the original splicing patterns of numerous cellular transcripts. More severe cases of COVID-19 had greater transcript dysregulation.

The virus often targets the cellular spliceosome. The cellular spliceosome is an extremely large and complex multi-megadalton (megadalton has a mass equal to one million daltons) ribonucleoprotein (RNP) complex (Wang et al. 2022).

9) Long COVID drains your energy due to metabolomic and immune disturbances:

Just like the COVID pandemic did in real life, Long COVID disrupts the pathways and supply chains in your body that make energy and build infrastructure. We can see this disruption by studying the chemicals created by these metabolic pathways; this is called metabolomics.

Metabolomics are the study of small molecules, called metabolites, that are within tissues, cells and fluids of organisms. Metabolites are created when the body runs chemical reactions during metabolizing. They are used for energy, as building blocks, to create structure, as fuel, for cell signalling, as cofactors or catalysts for enzymes, for defence, in epigenetics, during interactions with other organisms and for other purposes. The human metabolic database had 217,920 compounds (metabolites) in 2022 (Wishart et al 2022).

Filippo Palizzi - Pastore addormentato con il suo cane (1850-1855).

People with COVID-19, people with Long COVID, people who recovered from COVID-19 and appeared healthy, and healthy people all show different metabolome profiles. In addition, many metabolic pathways are altered due to catching COVID-19, recovering from the virus or living with LC (Saito et al. 2024).

Saito et al. 2024 main findings:

People with Long COVID (LC) had less plasma ATP (energy).

★ People who currently are ill with an acute COVID-19 infection had 29 metabolic pathways that were significantly altered compared to healthy people.

★ People with LC had 18 metabolic pathways that were significantly different from healthy people AND people who had recovered from LC (15 of these pathways were the same):

∇ The changes in the metabolic pathways meant the levels of aspartate (amino acid- AA), uracil, serine (AA), sarcosine (AA), arginine (AA), dehydroalanine, thymine, and porphobilinogen were lower in LC patients than healthy people. To understand the impact of this: Thymine is one of the bases used in building DNA while uracil is used to make RNA. Porphobilinogen helps build hemoglobin in red blood cells. Amino acids build proteins. This means that people with LC have less of the building blocks needed to make DNA, RNA, proteins and red blood cells.

∇ The levels of other metabolites; such as 5-Aminolevulinate, cysteate, putrescine, 4-Aminobutyraldehyde, kynurenine, serotonin, Formyl-5-hydroxykynurenamine, 5-Hydroxykynurenine, 2-Aminomuconate, xanthine, and 5-Aminolevulinate; were higher in people with LC compared to healthy people.

★ People who had seemly recovered from COVID had alterations in 15 metabolomics pathways when compared to healthy people. Of these, 13 pathways were similar to those found in LC. The other two were vitamin B6 and glutathione metabolisms.

★ Amino acid and nitrogen metabolism was disturbed in many cases.

★ People with LC had a significant reduction in two amino acids; sarcosine, found in muscles, and serine, used to make proteins, nucleic acids, antibiotics, and folate. Sarcosine and serine amounts were inversely correlated with depression, anxiety, and cognitive dysfunction scores. In other words, decreased levels of sarcosine and serine were associated with increased anxiety, depression and cognitive dysfunction.

★ People with Long COVID had elevated proinflammatory cytokines such as  IL-1α, IL-6, TNF-α, Flt-1, and sCD14 when compared to people who were healthy or who had recovered from COVID. This means those with LC had a higher level of inflammation.

Check out the cool charts in Saito et al. 2024 for all the details!

10) COVID cuts off your oxygen:

COVID-19 patients hyperventilate when exercising. Hyperventilation is breathing deeper and faster than normal. It increases the amount of carbon dioxide in the body and can cause light-headedness, muscle spasms, rapid heartbeat, shortness of breath, numbness and chest pain.

Hyperventilation in Long COVID may be due to irregularities in the physiological mechanisms involved in the control of breathing (called ventilatory control) (Mutagenic et al. 2021).

Problems with breathing may contribute to low oxygen uptake. Genevans et al. 2023 found that 1/3 of 264 people with Long COVID had dysfunctional breathing. People in this group (48 total patients) reported that they had had hyperventilation (21%), periodic deep sighs/erratic breathing (47%), and mixed types of dysfunctional breathing (33%) (Genevans et al. 2023). Almost all of them also had fatigue, difficulty focusing, muscle aches and pains (myalgia), forgetfulness and trouble sleeping.

Several small studies suggested that during intense exercise people with Long COVID may have impaired tissue oxygen consumption and oxygen extraction when compared to age matched healthy people (Singh et al. 2022, Heerdt et al. 2022). They found that people who had recovered from COVID infection had reduced peak exercise aerobic capacity (oxygen consumption [VO2]) when compared with control participants. VO2, measures the amount of oxygen a person's body uses during intense exercise. It is usually measured in milliliters of oxygen consumed per minute per kilogram of body weight (mL/kg/min).

This reduction in peak VO2 was connected with impaired systemic oxygen extraction. The muscle cells of people with Long COVID cannot take in oxygen. LC patients with exercise intolerance, may have a skeletal muscle myopathic process (muscle disease) that causes hypoxia (Sing et al. 2022, Norweg et al. 2023). Hypoxia is when your tissues and muscles do not take up oxygen. Basically, blood delivers the oxygen but the tissues can not take it up.

Basically, people who had COVID previously are using less oxygen during exercise and their tissues are having a harder time removing oxygen from the blood. Some symptoms of Long COVID; such as fatigue, post-exertional malaise, and dyspnea; may be due to dysfunctional oxygen uptake, delivery, and ventilation.

How the gauze-cotton mask should be worn c1910s authors K. Chimin Wong (王吉民) and Wu Lien-Teh (伍連德).

Do you have exercise intolerance? More on how to recover from exercise intolerance here.

11) You have experienced a stressful event or you are in psychological distress:

If you experience the death of a loved one, financial troubles, food insecurity, or a new developed disability you are twice as likely to have symptoms of Long COVID a year after recovery from COVID-19 (Frontera et al. 2022). Likewise, being in psychological distress such as depression, anxiety, worry, perceived stress, and/or loneliness, before catching COVID-19 was associated with up to a 45% increase in your chances of developing Long COVID (Wang et al. 2022).

Well, that stinks...

If you have depression or anxiety see if you can get some help. Since not everyone has access to professional mental health care or the money to buy it we include some information on how to reduce stress right away, unplug for your sanity, fight depression, use nature to heal, PTSD, use music to heal, heal from religious trauma, help prevent suicide, and regenerate your brain.

You are important and worthy of self care. You matter enough that we have created this website to help YOU (it certainly wasn't for financial gain ha, ha). Take care of yourself.

12) Low cortisol causes weakness and depression:

People with LC often have low concentrations of cortisol (Klein et al. 2022, Giunta et al. 2024). Cortisol is a stress hormone that effects almost every system in your body. It helps regulate inflammation; fine tunes the use of fats, proteins and glucose in the body; controls your wake/sleep cycles; controls motivation, mood and fear; and regulates blood pressure.

We all hear that high cortisol concentrations are bad but low cortisol is also harmful. Too little cortisol can cause muscle weakness, low blood glucose, loss of appetite, nausea, low blood pressure, extreme fatigue, muscle and joint pain, depression, irritability and hair loss.

Low cortisol may be due to hormone inbalances. See 15) Your hypothalamus-pituitary-adrenal axis (HPA axis) is disrupted.

13) You have an Autonomic Nervous System (ANS) dysfunction:

The autonomic nervous system (ANS) regulates body processes; like blood pressure, blood clotting, digestion, and breathing; that work automatically (autonomously), without you having to think about it. It helps regulate inflammation, cognition, immune function, blood clotting (coagulation) pathways, fatigue, cognition, exercise intolerance, and other factors that may contribute to Long COVID.

Researchers used the composite autonomic symptom scale 31 (COMPASS 31) questionnaire to help determine the health of the autonomic nervous system in 2,314 women and men (87% were women between 31-65 years old). They looked at 53 different symptoms.

COMPASS 31 is a self-rating questionnaire that helps evaluate six areas of autonomic function: orthostatic intolerance (your ability to remain upright), vasomotor (body temperature dysfunction like hot flashes), secretomotor (ability of glands, like sweat glands, to secrete a substance), gastrointestinal (digestion), bladder (integration between the autonomic and somatic nervous systems), and pupillomotor (controls changes in the eye pupil). COMPASS-31 scores are added over the six autonomic systems to a total score of 1-100; a higher score is more severe (Shouman et al. 2021).

A COMPASS-31 score of above 20 was found in 67% of people with Long COVID. This score shows that the autonomic dysfunction is moderate to severe (Larsen et al. 2022). Most people with Long COVID have a autonomic system that is not working properly.

The severity of COVID-19 did not match with the severity of the autonomic dysfunction; even very mild SARS-CoV-2 infections can cause major autonomic dysfunction (Larsen et al. 2022).

14) Your gut and respiratory microbiota are altered:

The gut and respiratory microbiota are significantly altered in patients with active COVID-19 and Long COVID (Xu et al. 2021, Wang et al. 2022). Microbiota, the community of micro-organisms that live in your gut, are powerful immunomodulatory factors in different human diseases, including cancer, type 2 diabetes, obesity, ulcerative colitis, Crohn’s disease, and some viral infections.

Changes in gut bacteria, called gut dysbiosis, is associated with Long COVID. Six months after recovery from COVID-19, the gut microbiota of patients without Long COVID were similar to healthy people. People with Long COVID, however, had substantially different gut micro-organism communities from those of the healthy people. Notably, people with Long COVID had reduced bacteria diversity and richness when compared to the healthy individuals (Lui et al 2022, Wang et al. 2023). The bacteria population contained more conditional pathogens and opportunistic microorganisms.

This can have an effect on the immune system. For a more complete list of depleted and enriched microbe species due to COVID-19 see Table 1 and 2 in Wang et al. 2023. There is some evidence that full recovery from COVID may restore gut microbiota (discussion in Wang et al. 2023).

15) Your hypothalamus-pituitary-adrenal axis (HPA axis) is disrupted.

Your adrenal glands go crazy and either produce too much or too little cortisol; aldosterone; adrenaline (epinephrine); DHEA and androgenic steroids; and noradrenaline (norepinephrine)!

Adrenal glands produce the fight, flight/flee, friend hormones epinephrine (adrenaline) and norepinephrine (noradrenaline) in response to stress. These hormones increase your heart rate, relax muscles, increase blood flow, regulate nutrients, and help maintain blood pressure. In addition to these hormones, the adrenal glands also produce cortisol.

Cortisol is a steroid hormone that regulates glucose metabolism, the immune system, sleep, blood pressure and the stress response.

COVID disrupts the hypothalamus-pituitary-adrenal axis (HPA axis) (Banu et al. 2023, Koch 2024). Some of the symptoms of Long COVID are similar to chronic adrenal insufficiency. These include chronic fatigue, brain fog, nausea, joint pains, and headaches.

Some researchers believe that COVID could trigger a reversible adrenal gland dysfunction known as critical illness-related corticosteroid insufficiency (CIRCI). Factors contributing to CIRCI include hypothalamic–pituitary–adrenal axis dysfunction, impaired cortisol metabolism and/or glucocorticoid receptor alpha tissue resistance (discussion in Kanczkowski et al. 2022, Durcan et al. 2023). Other illnesses; such as stroke, trauma, encephalitis, meningitis, and sepsis; can cause CIRCI as well.

Why does COVID attack the adrenal glands? The COVID-19 virus, SARS-CoV-2, need cells with the proper co-receptors for a host. Two potential receptors, transmembrane protease serine 2 and furins, are present in human adrenocortical cells. Other possibilities are blood vessel damage and inflammation (discussion in Kanczkowski et al. 2022).

The adrenocortical response was compromised in people hospitalized with COVID. The adrenal glands were not producing enough hormones (adrenal insufficiency). Interestingly, both mildly and severely sick patients were effected more than moderately sick people. In the severely sick were 27.3% had adrenal insufficiency, followed by the mildly sick (25.9%) and least in the moderately sick (3.8%) (Banu et al. 2023).

The adrenal cortex plays an important role in the endocrine response to major stress. HPA axis impairment during critical illnesses is connected with HPA axis dysfunction, tissue corticosteroid resistance, and disrupted cortisol metabolism (discussion Durcan et al. 2023).

Roxbury-de Gray1120: adrenal glands in yellow.

16) Endothelial dysfunction drives oxidative stress and inflammation.

Both endothelial dysfunction and oxidative stress play an important part in the pathophysiology of Long COVID. Your blood vessels and lungs are lined with endothelial cells. Endothelial dysfunction can alter cell permeability and cause fluid build up (Izzo et al. 2022).

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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