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What are the causes of Long COVID?

We list the top emerging theories and supporting evidence regarding the causes of Long COVID. Please note, this is an emerging field of science and new data is being evaluated continuously. 

IMPORTANT NOTE:

The following information is NOT to be construed as medical advice. This information is presented purely to encourage genuine discussion and information sharing amongst medical researchers, healthcare professionals and Long COVID patients alike. Please speak with your GP, doctor, Physician or other healthcare professional with regards to medical advice. 

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Content reviewed and updated: 

23 October 2021 (BST)

The research around Long COVID is evolving and being refined on a daily basis. If you have suggestions or amendments please let us know with the “Suggestions and Amendments” form at the bottom of the page. Thank you.

Long COVID - a new and complex disease

Approximately a million people are living with Long COVID in the UK, and the number is growing (according to the UK’s ONS - Office for National Statistics).

However, there is currently no widely agreed definition of this syndrome. The ONS defines Long Covid as “symptoms persisting for more than four weeks after the first suspected coronavirus (COVID-19) infection that were not explained by something else.” Many have symptoms extending beyond 6 months. 

In contrast, a recent Imperial College London study puts the figure closer to 2 million based on it’s REACT-2 study that defined Long COVID as COVID-19 symptoms lasting at least 12 weeks. 

Quick Overview of Long COVID causes

There are several themes emerging amongst researchers across the world and summarised below.

Endothelial / vascular damage and inflammation

It is now well known that the SARS-CoV-2 virus targets the ACE2 receptor (amongst others) and endothelial cells, which line each of the veins in our body, have large amounts of ACE2 receptors. It is hypothesized that this damage to the vascular system could lead to inflammation, micro-blood clots and multi-site organ damage.

(see sections 1a and 1b below)

Immune dysregulation 

- Initial dysregulation occurs during the initial SARS-CoV-2 virus infection and the subsequent ‘cytokine storm’ - it is hypothesized that this may continue after the initial infection recedes, with the immune system “stuck” in an activated state and autoantibodies could be involved (where the immune system attacks healthy cells by mistake).

- MCAS histamine issues could be involved (where histamine intolerance and allergenic symptoms emerge).

- NAD+ deficiency - here the theory is that COVID-19 causes NAD+ depletion, leading to MCAS issues, reactivation of dormant viruses and autoantibodies being generated. 

(see section 2a, 2b and 2c below)

Reactivating viruses or viral debris

This could be the initial SARS-CoV-2 virus reactivating or remnants of the virus still circulating in the body (viral debris) leading to inflammation (and microclots) and autoimmune reactions and/or the activation of other dormant viruses after the initial SARS-CoV-2 virus recedes. 

(see section 3a and 3b below)

Organ damage from the initial viral infection

This could be damage directly to organs, via direct damage to organs by the SARS-CoV-2 virus or indirectly via vascular inflammation, or indirectly via mitochondrial damage.

(see sections 4 and 5 below)

Multiple causes for Long COVID

There are several broad areas which have been developed in recent scientific discussions as the emerging causes of Long COVID. 

The content below would be correctly described as ‘medical hypothesis’.

Please note: numerical ranking below does not indicate our preference or weighting towards these theories. 

1a. Endothelial / vascular damage and inflammation (endotheliitis).

Research suggests that SARs-CoV-2 is more of an endothelial, rather than a lung disease as originally thought. Experience from prior coronaviruses has now fuelled hypotheses on the role of ‘endothelial dysfunction’ in the pathophysiology of SARS-CoV-2.  

For example, it is known that the SARS-CoV-2 virus targets the ACE2 receptor (amongst others) and endothelial cells, which line each of the veins in our body, have large amounts of ACE2 receptors. It is hypothesized that this damage to the vascular system could lead to inflammation, micro-blood clots and multi-site organ damage.

Scientists from Harvard Medical School and Imperial College London (Libby, P. and T. Luscher) envisage COVID-19 as a ‘disease of the endothelium’ which appears to align closely with its effects on multiple organ systems beyond the lungs, including the vasculature, heart, brain and kidneys.

1b. Endothelial inflammation leading to microvascular thrombi (micro-blood clots in smaller veins).

Blood clotting / thrombosis is clearly evidenced in the most acute COVID-19 cases, especially those requiring hospitalisation. These larger clots can be observed by attending physicians. However, this paragraph examines the idea of inflammation, damage and clotting in the smallest veins, and which are not readily visible during scans. This could explain why so many suffer from Long COVID but their “scans come back normal”. 

2a. Immune dysregulation - overactive immune response/ autoantibodies.

Mast cells are implicated in this overactive immune response, as they serve as a first line of defense against antigens entering the body due to their location in the skin and mucosa and mediate inflammatory responses such as hypersensitivity and allergic reactions.

Evidence indicates this increased inflammation in most Long COVID patients. It is not clear if the issue is autoantibodies mistakenly attacking healthy cells or if due to the lodging of viral debris which triggers a legitimate immune response involving mast cells.

2b. Immune dysregulation - MCAS & histamine intolerance.

The cytokine storm which is associated with the acute state of COVID-19 could lead to autoantibodies (that attack your own body) and increased inflammation, areas which then don’t revert back to a normalised state. 

Dr Kaiser, D. of the University of California’s Medical School stated, “there is also the possibility that, after the initial coronavirus infection resolves, the immune system may remain “stuck” in an activated state leading to ongoing flu-like symptoms.”

Mast cells are implicated in this overactive immune response, as they serve as a first line of defense against antigens entering the body due to their location in the skin and mucosa and mediate inflammatory responses such as hypersensitivity and allergic reactions.

Evidence indicates this increased inflammation in most Long COVID patients. It is not clear if the issue is autoantibodies mistakenly attacking healthy cells or if due to the lodging of viral debris which triggers a legitimate immune response involving mast cells.

2c. Immune dysregulation - NAD+ deficiency and the connection with Mast cells.

Here the theory is that COVID-19 causes NAD+ depletion, leading to MCAS issues, reactivation of dormant viruses and autoantibodies being generated.

Dr Wentzel's group (including Miller, R. and Richards, G in the journal Medical Hypotheses 2020 issue 144) articulated, ”we hypothesize that reduced Nicotinamide Adenine Dinucleotide(NAD+) levels with consequent deficient activity of the NAD+ dependent molecule SIRT1, which modulates cytokine production, may be the factor that predisposes the aged, obese, type 2 diabetics and other vulnerable groups to an increased mortality.”

3a. Reactivated SARS-CoV-2 virus and/ or SARS-CoV-2 viral debris.

This could be the initial SARS-CoV-2 virus reactivating or remnants of the virus still circulating in the body (viral debris) leading to inflammation (and microclots) and autoimmune reactions.

Professor of Immunology Charles Bangam, of Imperial College London, phrased it thus, “... the virus itself could be hiding in the body, much like we see with the Epstein Barr virus (EBV) that causes glandular fever, and herpes viruses that can hide in the body in a latent state before reactivating.”

Gaebler, C, from the Laboratory of Molecular Immunology at The Rockefeller University in New York found that 7 out of 14 individuals who were asymptomatic (i.e. not currently displaying any symptoms of having COVID-19) were found to be carrying SARS-CoV-2 virus components 4 months after being infected. 

[NEW] There is further emerging evidence that parts of the SARS-CoV-2 virus remain in the body after infection, in particular the spike protein. This ‘viral debris’ has been found inside monocytes and macrophages 15 months after Long COVID infection.

3b. Previously dormant viruses being reawakened.

A related theory to the above is that there is activation of other dormant viruses after the initial SARS-CoV-2 virus recedes.  

Here the theory is that dormant, normally harmless viruses contracted years earlier are reactivated post SARS-CoV-2 infection. The most common are the herpes family of viruses. Typically these viruses can be reactivated during times of stress or infection. 

Areas of damage 

4. Damaged mitochondria.

Saleh, J. et al. in their 2020 journal article for Mitochondrion, articulate their hypothesis as “[the] heightened inflammatory/oxidative state may lead to mitochondrial dysfunction leading to platelet damage and apoptosis”. 

5. Lasting organ damage caused by the virus. Tissue damage.

Dr Kaiser, D. of the University of California’s Medical School stated, “this acute inflammatory response [the result of COVID-19] can also cause significant collateral damage to uninfected cells, ultimately resulting in persistent end organ dysfunction.”

Marshall, M, in a news feature for ‘Nature’ wrote, “people with more severe infections might experience long-term damage not just in their lungs, but in their heart, immune system, brain and elsewhere. Evidence from previous coronavirus outbreaks, especially the severe acute respiratory syndrome (SARS) epidemic, suggests that these effects can last for years.”

Mallapaty, S. writing for ‘Nature News’, discusses the research investigating the damage done by COVID-19 in artificially grown human cell ‘organoids’ (lung, liver and kidney tissue grown in the lab). It was found the virus causes damage to organs directly, and not just via an overactive autoimmune issue. 

Scientific References

ONS - Office for National Statistics. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 1 July 2021.

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/1july2021

Whitaker, M. et al. Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people. Imperial College London. June 2021.

https://spiral.imperial.ac.uk/handle/10044/1/89844

Robin Gorna et al. Long COVID guidelines need to reflect lived experience.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755576/

NHS. Long-term effects of coronavirus (long COVID).

https://www.nhs.uk/conditions/coronavirus-covid-19/long-term-effects-of-coronavirus-long-covid/ 

National Institute for Health Research Centre for Engagement and Dissemination (NIHR). Living with Covid19 – Second review.

https://evidence.nihr.ac.uk/themedreview/living-with-covid19-second-review/

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https://royalsociety.org/blog/2021/02/what-do-we-know-about-long-covid/

Gavriilaki, E., et al., Endothelial Dysfunction in COVID-19: Lessons Learned from Coronaviruses. Curr Hypertens Rep, 2020. 

https://link.springer.com/article/10.1007/s11906-020-01078-6

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470753/

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488591/

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