According to the World Health Organisation, ‘long COVID’ can be defined in the following way: “Post Covid-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of Covid-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis.”
It is estimated that 1.2 million people in the UK were reporting long Covid symptoms in the four weeks up to 2nd October 2021 by the Office of National Statistics (ONS), about 1.9% of the population
Imperial College London have reported data about the symptoms of long COVID in their COVID Symptom Study, identifying two main groups of symptoms.
Some reports have described symptoms with similarities to Myalgic encephalomyelitis (ME), also known as, chronic fatigue syndrome or ME/CFS.
There are many multifactorial and complicated mechanisms involved in the pathogenesis of COVID 19 and other neuropathology symptoms have been described, such as, pain, dizziness, headache, dysgeusia, or anosmia and flacid paraparesis to more serious symptoms including stroke, Guillain-Barré syndrome (GBS), acute haemorrhagic necrotising encephalopathy, meningoencephalitis, and cerebral venous thrombosis.
Many patients experiencing long COVID symptoms are ‘flying under the radar’, without much medical intervention, but may have significant deficiencies affecting their ability to perform at their usual state of health.
If mild to severe versions of Guillain Barre were a factor in the long COVID symptoms, should they undergo investigations for Guillain Barre and this be a new approach in their treatments? Are long COVID patients being assessed with GBS or other neuropathology variants in mind?
Further, what can we learn from the MERS outbreak about neuropathy and cerebrovascular disease?
Should we be performing nerve conductivity tests on long COVID patients and investigating autoimmune mechanisms to improve appropriate treatment strategies?
Journal of Molecular Neuroscience (2021) 71:2192–2209 https://doi.org/10.1007/s12031-020-01767-6
Yes, nerve conduction study will be helpful and fMRI can also be done
Grateful to hear any further thoughts on this.
Understanding more of the neuroinvasive potential of SARSCoV-2, in some viraemic patients, may give clues to a para-infectious course of the disease. It is known that activated mast cells can mediate bronchoconstriction associated with some viral infections and are a source of inflammatory cytokines that contribute to an autoimmune pathology, as the specific dynamics of the cytokine environment can then activate autoimmune T cell responses (Kritas SK et al J Biol Regul Homeost Agents. 2020).
There is some evidence that post COVID-19 infected patients experience a perivascular inflammation where tissue has a specific immune attack on the myelin sheath. Both central and peripheral nervous systems have low levels of resident mast cells. Degranulation of these cells are catastrophic to the tissue and can contribute to demyelination of the nerves. This is similar to the pathogenesis of Guillain Barre. Other components of the immune system can also contribute to this process, such as, T cells, B cells, macrophages and complement. Molecular mimicry of SASRCoV-2 to proteins of the myelin sheath to motor nerve cells that activate B cell and antibody attack should also be considered in long COVID patients (Johnson, D; Krenger, W. Neurochem Res 1992; Seeldrayers, P A; Levin, L A; Johnson, D. J Neuroimmunol, 1992).
Symptoms of flacid parathesis have been described in some long COVID patients that may be explained by this.
Although T cell responses are essential to the immune response to a virus, they may also contribute to the pathology of some autoimmune responses and one cytokine associated with this is IL-17 that mobilises the activation and degranulisation of neutrophils and mast cells
(Kolls JK, Lindén A. Immunity 2004). Interleukin-17A (IL-17A) expression is up regulated by Th17 cells at sites of inflammation in several autoimmune diseases.
A high number of CCR6+ Th17 cells were observed in the cytokine storm in a severely affected COVID-19 patient supporting the hypothesis that Th17 cells are important factors of the cytokine storm in the disease (Wu D, Yang XO. J Microbiol Immunol Infect. 2020).
(Houldsworth A. J Emerg Dis Virol 2021).
Schwann cells are known to be deleteriously affected by some proinflammatory cytokines, such as, IL-17, which can injure the peripheral nervous system. Indeed, cells that secrete IL-17 have been detected near to Schwann cells in the endoneurium (Stettner, M., Lohmann, B., Wolffram, K. et al. J Neuroinflammation. 2014).
Further to using neuro-conductivity, in diagnosing long COVID patients, could some cytokine and T cells patterns of expression and activation be important diagnostic markers for neuropathology in post viral SARSCoV-2 infection, especially Guillaine-Barre type demyelinating conditions.
References:
- Johnson, D; Krenger, W (1992) Interactions of mast cells with the nervous system--recent advances. Neurochem Res 17:939-51
- Seeldrayers, P A; Levin, L A; Johnson, D (1992) Astrocytes support mast cell viability in vitro. J Neuroimmunol 36:239-43
- Kritas SK, Ronconi G, Caraffa A, Gallenga CE, Ross R, Conti P. Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy. J Biol Regul Homeost Agents. 2020 January-February,;34(1):9-14. doi: 10.23812/20-Editorial-Kritas. PMID: 32013309.
- Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity. 2004 Oct;21(4):467-76. doi: 10.1016/j.immuni.2004.08.018. PMID: 15485625.
- Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. J Microbiol Immunol Infect. 2020 Jun;53(3):368-370. doi: 10.1016/j.jmii.2020.03.005. Epub 2020 Mar 11. PMID: 32205092; PMCID: PMC7156211.
- Houldsworth A The Perfect Storm: Review: Immune Dysregulation in Severe COVID-19 and the Possible Role of Mast Cell-Vitamin D Interactions. J Emerg Dis Virol 2021 6(1): dx.doi.org/10.16966/2473-1846.161
- Stettner, M., Lohmann, B., Wolffram, K. et al. Interleukin-17 impedes Schwann cell-mediated myelination. J Neuroinflammation 11, 63 (2014). https://doi.org/10.1186/1742-2094-11-63
Please, has the given histopathological spectrum anything to it that might be said to set long COVID specifically apart?
Thank you, Franz, for this very important point.
Post-mortems of patients with COVID 19, who displayed neurological symptoms, had brain lesions. Some brain tissue from autopsy showed signs of oedema, neural degeneration and signs of acute hypoxic ischaemia. Other patients showed signs of haemorrhage. The presence of viral RNA was evident in the cerebrospinal fluid and brain tissue in autopsies, following the demise of patients with neurological symptoms.
Clearly, COVID 19 mainly effects the respiratory systems of patients infected with SARSCoV-2, with similar histological findings to that of SARSCoV-1 and MERS infections and described in much detail, however, many other body systems are not spared in some patients who are severely affected, such as, nervous system, integumentary system, cardiovascular, urinary, gastrointestinal tract, and reproductive systems. Thus, the organ tissue affected are lungs, heart, kidneys, skin, intestines, brain, nerves, testes and ovaries.
SARSCOV-2 was found to spread, in early pathological findings, in the epithelial linings of the respiratory tract, digestive tract, distal convoluted tubules of the kidney, the sweat glands of the skin and testicular epithelium including spermatogonia and sertoli cells. There was macroscopic evidence of congestion and haemorrhagic necrosis.
In mice models of disease following olfactory inoculation of SARCoV-1 and MERS, viral entry through the olfactory route was shown to cross the blood brain barrier and enter the central nervous system (CNS).
The symptom of anosmia and ageusia is thought to imply that the virus effects olfactory nerves and may enter the CNS through this route. Neurotropism of SARCoV-2 is indicated in a similar way the alveolar tropism with hyer inflammatory immune responses attaching the myelin sheath of peripheral nerves via astrocyte and microglial activities.
Long OCVID 19 patients have not been investigated to the level that severely effected and fatal OCVID-19 patients so we await further developments in this area.
Refs
- Deshmukh V, Motwani R, Kumar A, et al Histopathological observations in COVID-19: a systematic review, Journal of Clinical Pathology 2021;74:76-83
- Tremblay Marie-Eve, Madore Charlotte, Bordeleau Maude, Tian Li, Verkhratsky Alexei, Neuropathobiology of COVID-19: The Role for Glia, Frontiers in Cellular Neuroscience
In due appreciation of all this, respected Annwyne:
Don't your data show we are limited to dealing with circumstantial pieces of evidence?
Is Sars-CoV-2 RNA detected in some brain or CSF samples of some patients indicating the commonly found ischemic brain lesions are of a viral origin?
Does a positive pharyngeal Covid PCR test prove the related vascular brain lesions are virus-induced?
Quite right, Franz! This is why I started the discussion to encourage someone to develop the questions and collect further data, thanks Franz
Thanks a lot for sharing these concerns, and even more so for being that open-minded, our quite exceptional Annwyne!
Over 2 years since the start of pandemic and as a pediatricean am not facing any child with long term consequences post covid 19
Over 2 years since the start of pandemic and as a pediatricean am not facing any child with long term consequences post covid 19
Dear Dr Annwyne Houldsworth . See the following useful RG link: Article Neuropathologic findings of patients with COVID-19: a system...
Kindly see also the following RG link: Article Long Covid-19: Proposed Primary Care Clinical Guidelines for...
Also check please the following useful RG link: Article Neurological Sequelae in Patients with COVID-19: A Histopath...
The following RG link is also very useful: Article A Contemporary Review of Neurological Sequelae of COVID-19
Please, Dr. Aref Wazwaz, could you be so kind as to indicate how to make the best use of the given papers?
Are there any data showing that COVID-19 affects the nervous system in some peculiar, or even specific, way?
Are the neuropathological findings you refer to diagnostically more reliable than what is seen on MRIs?