Covid-19 Viraemia Iron Displacement Theory 

A proposed pathophysiological explanation

https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173/1

The basis of my theory of the pathophysiology of SARS-CoV-2 is based on and an extension of the above paper by Liu wenzhong and Li hualan who used conserved domain analysis, homology modeling, and molecular docking to postulate that in an infection, the ORF8 and surface glycoprotein of the SARS-CoV-2 virus bind to the porphyrin of the heme of our hemoglobin while its orf1ab, ORF10 and ORF3a proteins act to unbind iron from the heme and release it into the plasma as ferrous or ferric ions.

So my theory goes like this:

(1) 80% of the infected are mild and they recover because their immune system is strong enough to clear the virus from the mucous membranes of the nasopharynx, bronchial tree and perhaps the superficial parts of the lung parenchyma where it replicates. If this superficial infection is not cleared in good time, it will enter the bloodstream causing a sudden deterioration after about 1 week of infection.

(2) Unlike classic SARS and the MERS viruses, SARS-CoV-2 has the tendency to enter bloodstream through perhaps the alveoli in hosts with weak immune system or whose immune system is weakened by prolonged infection. Significant viraemia occurs in about 20% of hosts.

(3) Once in the bloodstream, in the mechanisms as described by Liu wenzhong and Li hualan above, the virus binds to hemoglobin, thereby unbinding iron from heme, releasing ferrous or ferric ions into the plasma which is carried in the bloodstream as non-transferrin bound iron (NTBI) to all parts of the body. 

(4) Iron in this form is highly toxic because it is a catalyst for the formation of reactive oxygen species which causes oxidative damage and inflammation in many organs contributing to organ damage including the lungs itself producing the typical uniform ground-glass appearance on chest CT scan. This ground-glass appearance may not be a sign of pneumonia as asymptomatic patients also show this radiological sign (a sign of undetected viraemia).

(5) Meanwhile, the displacement of Fe from the hemoglobin causes prolonged and profound hypoxemia that may not be correctable by O2 and/or ventilation.

(6) The combination of oxidative and/or hypoxic damage of multiple organs leads to their failure and eventually to death.

If this theory is correct, there are several implications:

(1) Early signs like high fever and chills, severe headache, body aches and joint pains, fatigue, diarrhoea, skin rashes and neurological symptoms are signs of early viraemia and should be recognised/treated as such.

(2) Once infected, the key to preventing severe illness and and death is early supportive care and early administration of anti-viral treatment (if available) to all patients to prevent viraemia.

(3) If no such reliable or safe anti-viral is available, high dose anti-oxidants may be administered prophylactically and maintained throughout the illness.

(4) This may explain why Chloroquine/Hydroxychloroquine seems to have some therapeutic benefit because it may inhibit the binding of ORF8 and surface glycoproteins to the porphyrins and prevent the action of orf1ab, ORF3a and ORF10 proteins in unbinding Fe from the heme. Big efforts should be expended to ensure its safety if used.

(5) Since the problem in severe/ critical cases is not lack of oxygenation or ventilation, but an inability of pre-existing haemoglobin to carry oxygen and an abundance of toxic iron in the plasma, a blood transfusion/exchange transfusion may the appropriate treatment once viraemia is significant.

6) Patients with Type A blood type have more severe symptoms than those of Type O maybe because the binding of iron to their heme is probably genetically weaker, and therefore iron is more easily displaced from it.

I may be horribly wrong, but this theory explains many of the peculiar things about Covid-19. I welcome all criticisms.