Hypothesis: 2 long-haul COVIDs: had mild symptoms and had needed ICU - April 2022

Two Long Covid Groups - April 24, 2022

In Research Gate
I (Patrick W Chambers) decided to expand my Long Covid, Short Magnesium - Chambers April 2022 (preprint article) to include the below.
Discussion has been limited to Long Covid in the non-hospitalized. But there appear to be two kinds of Long Covid, both vitamin D/magnesium deficient - white middle aged women who contracted Covid-19 but were never hospitalized and those with comorbidities who were.
Those that developed Long Covid more than 12 weeks after discharge from the ICU (severe not mild Covid-19) appear to be a different group. In addition to low IFN gamma, TGF beta (transforming growth factor) is elevated[1]. TGF beta inhibits IFN gamma[2] and is elevated in diabetics, especially those with nephropathy[3] and in hypertensives[4].
TGF beta is also elevated in POTS, which shares some dysautonomic features with Long Covid[5] and is treated with Losartan[6]. Vitamin D deficiency has also been implicated in autonomic dysfunction[7]. Elevated TGF beta also connects CFS/ME with Long Covid[8,9]. High levels of TGFB1 are associated with hard to treat asthma attacks, fibrosis in organs such as the liver/kidney/lungs[10] and autoimmunity.
The elevated TGF beta in CIRS (Chronic Inflammatory Response Syndrome), which overlaps with Long Covid, can be lowered with losartan[11].
Ang II induces TGF-ß expression via AT1Rs[12] and is treatable by angiotensin receptor blockers[13,14] (in addition to vitamin D and magnesium). Chronic vitamin D deficiency induces lung fibrosis through activation of the RAS[15].

References

1. Oronsky, B., Larson, C., Hammond, T.C. et al. (2021) “A Review of Persistent Post-COVID Syndrome (PPCS)” Clinic Rev Allerg Immunol (2021). https://doi.org/10.1007/s12016-021-08848-3
2. Barros-Martins, J., Förster, R. & Bošnjak, B. (2022) “NK cell dysfunction in severe COVID-19: TGF-ß-induced downregulation of integrin beta-2 restricts NK cell cytotoxicity” Sig Transduct Target Ther v7, article 32 https://dx.doi.org/10.1038%2Fs41392-022-00892-5
3. Qiao, Yong-Chao, Chen, Yin-Ling, Pan, Yan-Hong, Ling, Wei, Tian, Fang, et al (2017) “Changes of transforming growth factor beta 1 in patients with type 2 diabetes and diabetic nephropathy” Medicine 96(15):e6583 https://doi.org/10.1097/md.0000000000006583
4. Laviades, C, Varo, N, Díez, J. (2000) “Transforming Growth Factor ß in Hypertensives With Cardiorenal Damage” Hypertension. 2000;36:517–522 https://doi.org/10.1161/01.HYP.36.4.517
5. Johansson, M, Ståhlberg, M, Runold, M, Nygren-Bonnier, M, Nilsson, J, et al. (2021) “Long-Haul Post–COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience” JACC: Case Reports, 3(4):573-580 https://doi.org/10.1016/j.jaccas.2021.01.009
6. Stewart, JM, Taneja, I, Glover, J, Medow, MS (2008) “Angiotensin II type 1 receptor blockade corrects cutaneous nitric oxide deficit in postural tachycardia syndrome” Am J Physiol Heart Circ Physiol. 2008 294(1):H466–H473. https://doi.org/10.1152/ajpheart.01139.2007
7. Wadhwania R. (2017) “Is Vitamin D deficiency implicated in autonomic dysfunction?” J Pediatr Neurosci 12:119-23 https://doi.org/10.4103/jpn.JPN_1_17
8. McCarthy, MJ (2022) “Circadian rhythm disruption in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for the post-acute sequelae of COVID-19” Brain, Behavior, & Immunity - Health 20:2022,100412 https://doi.org/10.1016/j.bbih.2022.100412
9. Zhang, HY, Liu, ZD, Hu, CJ, Wang, DX, Zhang, YB, Li, YZ (2011) “Up-regulation of TGF-ß1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome” Journal of the Formosan Medical Association 110(11):701-704 http://dx.doi.org/10.1016/j.jfma.2011.09.006
10. Meng, Xm., Nikolic-Paterson, D. & Lan, H. (2016) “TGF-ß: the master regulator of fibrosis” Nat Rev Nephrol 12:325–338 https://doi.org/10.1038/nrneph.2016.48
11. Hoffman Centre for Integrative and Functional Medicine March 9, 2021 by Dr. Bruce Hoffman https://hoffmancentre.com/chronic-inflammatory-response-syndrome-cirs-evaluation-and-treatment
12. Mahmudpour, M, Roozbeh, J, Keshavarz, M, Farrokhi, S, Nabipour, I. (2020) “COVID-19 cytokine storm: The anger of inflammation” Cytokine v133, 2020,155151 https://doi.org/10.1016/j.cyto.2020.155151
13. Ehanire, T., Ren, L., Bond, J. et al. (2015) “Angiotensin II stimulates canonical TGF-ß signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction” J Mol Med 93:289–302. https://doi.org/10.1007/s00109-014-1211-9
14. Lanz, TV, Ding, Z, Ho, PP, Luo, J, Agrawal, AN, Srinagesh, H, et al. (2010) “Angiotensin II sustains brain inflammation in mice via TGF-ß” J. Clin. Investig., 120 (8) (2010), pp. 2782-2794 https://doi.org/10.1172/JCI41709
15. Shi, Y., Liu, T., Yao, L. et al. (2017) “Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system” Sci Rep 7:3312. https://doi.org/10.1038/s41598-017-03474-6

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