HYPOXIA #7: WHAT MAKES COVID HYPOXIA UNIQUE?

From my initial post mortem of data I have gathered from my contacts on the front line in New Orleans this virus is hijacking hemoglobin's ability to carry oxygen to tissues.  It appears the spike protein of COVID is damaging the endothelium and RBCS to cause problems.  COVID is predominately a circulatory problem and a secondary lung issue.  The lung tissue then responds to this in a reactive way via imaging studies.   

HYPERLINK 

i don’t think this paper above is getting enough publicity right now in this pandemic. It helps explain why the COVID 19 hypoxia is unique in its presentation.  

The paper theorizes how and why coronavirus reduces blood O2 and causes "crushed glass" lung imagery. This happens because the virus attacks the beta chains of hemoglobin and this binding appears to kick out heme from RBCs rendering them unable to deliver oxygen to mitochondria. The risk factors of high A1C, blood sugar, high LDH and ferritin, and why certain treatments work. (Hydroxychlorquine)

One clinical pearl I have heard from all my MD friends on the front line in NOLA is “Very often, extreme fatigue hits first." PEEP and blood transfusions are not helpful. My bet is RBC transfusion won’t work well in patients who are actively shedding virus because the virus will immediately attack the new transfused RBC mimicking graft versus host disease response. COVID viral genes 1 and 8 have been predicted to interfere with heme synthesis. 

Heme synthesis first step occurs in the mitochondria. So if it is disrupted this virus compounds the situation. Heme is the red compound in blood and in cytochrome C oxidase, and catalase that carries oxygen and CO2.   When mitochondrial oxygen consumption slows more dissolved oxygen in the cell rises and this excess oxygen become substrate to make free radicals that further destroy the lipid membranes of mitochondria and RBCs to lead to the early fever, and cytokine storm seen in COVID19 via the NFLR3 inflammasome.

This destroys ATP formation by the ATPase and this causes extreme hypoxia that mimics suffocation or high altitude pulmonary exposure (HAPE). It appears once the virus attacks it acts by kicking out the iron and this gives a specific phenotype in the blood that mimics malaria. This explains why chloroquine seems effective as a treatment. Why would azithromycin help augment hydroxychloroquine? Azithromycin appears to be effective in the treatment of COPD through its suppression of inflammatory processes.  Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected. 

During a viral sepsis acid base balance is altered and most people become very acidotic. Azithromycin is an acid-stable antibiotic so its efficacy would not be altered in the face of metabolic or respiratory acidosis. This is why it has efficacy in COVID 19. It is one of the few antibiotics that can work in low pH environments. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility.

The damage to the beta chains of hemoglobin by COVID mimics malaria. Malaria also causes an inactivation of RBC to carry oxygen to mitochondria.  Malaria is an acute form of hemolytic anemia.  These types of anemia have symptoms that are similar to other forms of anemia (fatigue and shortness of breath), but in addition, the acute breakdown of red cells leads to jaundice and increases the risk of particular long-term complications, such as gallstones and pulmonary hypertension.

It appears COVID 19 happens so fast jaundice and gallstone do not have enough time to form but the pulmonary hypertension manifests as the key feature of the disease acutely.  The hemolysis can occur inside the vessels or outside the vessels.  I believe in COVID 19 it is an extravascular hemolysis that is operational.  Extravascular hemolysis refers to hemolysis taking place in the liver, spleen, bone marrow, and lymph nodes.  In this case very little hemoglobin escapes into blood plasma.

This is why no one is reporting jaundice in COVID 19 patients. 

Pulmonary hypertension is a condition of increased blood pressure within the arteries of the lungs.  Symptoms include shortness of breath, syncope, tiredness, chest pain, swelling of the legs, and a fast heartbeat.

All of these symptoms are found in COVID 19 patients. 

Extreme fatigue is a sign of HYPOXIA = HIF-alpha-1 = serious over use of thiamine which is a beacon of a loss of mitochondrial redox power no TCA use = lack of delta psi.  Without delta psi no new heme can be to replace hemoglobin or cytochrome C oxidase or catalase.  This explains why people present the way they do in the ER.  

Here is a report from a NOLA ER doc who graduated LSU in 1998.  

Clinical course is predictable. 

“2-11 days after exposure (day 5 on average) flu like symptoms start. Common are fever, headache, dry cough, myalgias(back pain), nausea without vomiting, abdominal discomfort with some diarrhea, loss of smell, anorexia, fatigue.

Day 5 of symptoms- increased SOB, and bilateral viral pneumonia from direct viral damage to lung parenchyma. 

Day 10- Cytokine storm leading to acute ARDS and multiorgan failure. You can literally watch it happen in a matter of hours. 

81% mild symptoms, 14% severe symptoms requiring hospitalization, 5% critical. 

Patient presentation is varied. Patients are coming in hypoxic (even 75%) without dyspnea. I have seen Covid patients present with encephalopathy, renal failure from dehydration, DKA. I have seen the bilateral interstitial pneumonia on the xray of the asymptomatic shoulder dislocation or on the CT's of the (respiratory) asymptomatic polytrauma patient. Essentially if they are in my ER, they have it. Seen three positive flu swabs in 2 weeks and all three had Covid 19 as well. Somehow this VIRUS has told all other disease processes to get out of town. This shows you how the virus is causing a loss of medical capacity inside the hospital.  

China reported 15% cardiac involvement. I have seen covid 19 patients present with myocarditis, pericarditis, new onset CHF and new onset atrial fibrillation. I still order a troponin, but no cardiologist will treat these heart attacks (STEMI) no matter what the number in a suspected Covid 19 patient. Even our non covid 19 STEMIs at all of our facilities are getting TPA in the ED and rescue PCI at 60 minutes only if TPA fails. 

Diagnostic 

CXR- bilateral interstitial pneumonia (anecdotally starts most often in the RLL so bilateral on CXR is not required). The hypoxia does not correlate with the CXR findings. Their lungs do not sound bad. Keep your stethoscope in your pocket and evaluate with your eyes and pulse ox. 

Labs- WBC low, Lymphocytes low, platelets lower then their normal, Procalcitonin normal in 95%

CRP and Ferritin elevated most often. CPK, D-Dimer, LDH, Alk Phos/AST/ALT commonly elevated. 

Notice D-Dimer- I would be very careful about CT PE these patients for their hypoxia. The patients receiving IV contrast are going into renal failure and on the vent sooner. 

Basically, if you have a bilateral pneumonia with normal to low WBC, lymphopenia, normal procalcitonin, elevated CRP and ferritin- you have covid-19 and do not need a nasal swab to tell you that. 

A ratio of absolute neutrophil count to absolute lymphocyte count greater than 3.5 may be the highest predictor of poor outcome. the UK is automatically intubating these patients for expected outcomes regardless of their clinical presentation. 

An elevated Interleukin-6 (IL6) is an indicator of their cytokine storm. If this is elevated watch these patients closely with both eyes. 

Other factors that appear to be predictive of poor outcomes are thrombocytopenia and LFTs 5x upper limit of normal. 

Disposition

I had never discharged multifocal pneumonia before. Now I personally do it 12-15 times a shift. 2 weeks ago we were admitting anyone who needed supplemental oxygen. Now we are discharging with oxygen if the patient is comfortable and oxygenating above 92% on nasal cannula. We have contracted with a company that sends a paramedic to their home twice daily to check on them and record a pulse ox. We know many of these patients will bounce back but if it saves a bed for a day we have accomplished something. Obviously we are fearful some won't make it back. 

We are a small community hospital. Our 22 bed ICU and now a 4 bed Endoscopy suite are all Covid 19. All of these patients are intubated except one. 75% of our floor beds have been cohorted into covid 19 wards and are full. We are averaging 4 rescue intubations a day on the floor. We now have 9 vented patients in our ER transferred down from the floor after intubation. 

Luckily we are part of a larger hospital group. Our main teaching hospital repurposed space to open 50 new Covid 19 ICU beds this past Sunday so these numbers are with significant decompression. Today those 50 beds are full. They are opening 30 more by Friday. But even with the "lockdown", our AI models are expecting a 200-400% increase in covid 19 patients by 4/4/2020. “

That is the clinical view from New Orleans now.  

If the patient isn't showing signs of respiratory difficulty but has extreme fatigue, one thing to question is whether the oxygen is getting from lungs to body tissues.

This would lead to organ and tissue death, roughly in the same way as if a patient were being suffocated.

Even when a patient can breath (fill lungs with air), the oxygen isn't getting to the colony of mitochondria in the cells in their body.

Similiarities between COVID 19 and High Altitude Pulmonary Edema

HAPE symptoms similar to covid: "HAPE was misdiagnosed for centuries, as evidenced by frequent reports of young, vigorous men suddenly dying of “pneumonia” within days of arriving at high altitude."

HAPE's mechanism results from low amounts of ambient atmospheric oxygen, so the subject's blood is unable to bring enough oxygen to the body.

Nothing is "attacking" the lungs, but the lungs show similar inflammatory symptoms to COVID, because O2 in blood is low. Remember UV light exposure increases venous O2.  

This would lead to organ and tissue death, roughly in the same way as if a patient were being suffocated.

Even when a patient can breath (fill lungs with air), the oxygen isn't getting to the cells in their body.

The inflammation in the lungs results from the lungs not being able to perform the oxygen/CO2 exchange, and would therefore appear to be a SECONDARY result of the hijacking of the blood. 

The lungs not working is a result of lack of O2 in blood, not the cause of it.  It might be a disease of heme.  

The reason why technology use exacerbates the disease because it also causes defects in RBC synthesis by blocking heme formation by causing mitochondrial damage. (pic below)

Several paper reviewed on drug models the behavior of chloroquine and faviparavir as well, which appear to bind to the non-structural viral proteins that hijack the heme groups, thus inhibiting them from knocking out the iron and wrecking the O2-carrying ability of the red blood cells.

This also explains the observation made by various ER docs that patients tend to have elevated ferritin: ferritin is used to store excess iron released from the RBC damage. If a lot of iron is knocked out of heme groups and floating around, the body produces more ferritin. 

In humans, it acts as a buffer against iron deficiency and iron overload. This overlaod happens hyperacutely in COVID19.   Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where it functions as an iron carrier. Plasma ferritin is also an indirect marker of the total amount of iron stored in the body; hence, serum ferritin is used as a diagnostic test for iron-deficiency anemia. This anemia can happen acutely or chronically. 

If this mechanism of damage is true, this implies we need to think a lot differently than we are now:

1. Starting drug treatment while symptoms are mild keeps virus from hijacking too much of the RBC and cytochrome C oxidase, or catalase, enabling a still-healthy body to mount an immune response. Plasma therapies should be done before RBC transfusions.

This explains why early drug treatment (first week of symptoms) is often successful. It stabilizes iron metabolism and stabilzes CO2/O2 delivery early on and maintains mitochondrial function via cytochrome C oxidase. This preserves ATP function. Red light therapy would augment this affect.  Nitric oxide mimicry might save cytochrome c oxidase.  This might be why UV light helps limit COVID 19 cases.  UV light increases the production of nitric oxide and this shuts down the use of cytochrome c oxidase.  

This would explain why all coronavirus seem to be inactive in summer months.  

2. Drug treatment and intubation once patient is critical these option will rarely work because tissues/organs are already damaged by viral destruction of the beta chain of hemoglobin; therefore, blood can't carry O2, and the body is too weak to produce new red blood cells able to carry iron (and thus oxygen/CO2) even if drugs inhibit more hijacking.

3. Thus: start severe patients on drug treatment upon hospital intake to suppress further hijacking of blood by the virus, then give them a blood transfusion of new red blood cells immediately that are unhijacked.

4. If heme/hemoglobin is involved, a higher hemoglobin count may be protective to the disease process.  This may explain why nicotine helps.  It maybe that's why smokers are so underrepresented in the data.  Their chronic hypoxia from smoking increases their hemoglobin counts.   This also would also predict less severe acute mitochondrial failure from COVID 19 disease in high altitude populations.  The Johns Hopkins map supports this.  Nairobi is untouched. 

5. Hypoxia explains the loss of taste and smell too.  We know that the human olfactory receptor becomes less sensitive under hypoxic hypoxia.  HYPERLINK 

CONCLUSIONS:

If all this is true, we would see rapid patient improvement with the use of plasma first. The reason for many cases of recrashing with COVID might be due to an inability to recovery the ability to make new heme because of the mitochondrial damage. People forget heme synthesis begins in the mitochondrial matrix. This implies we should consider RBC transfusion later in the disease during recovery.

These ideas should be very testable in the hospital environment now.  

Also, if it's true, we're gonna need a lot of blood donations after the acute phase of viral attack.

So far as I know, there are no studies where we've tried transfusing blood from a patient who HASN'T had or recovered from COVID-19.

We can verify/disprove this by comparing outcomes between plasma-only and full blood transfusion (and control), or just between blood transfusion vs control (both should be given hydroxychloroquine. It appears the hydroxychloroquin is a heme salvage operation before acute infection and beta chain destruction.  

So for ER/ICU/hospitalists MD’s handling incoming severe patients with multi-organ system failure that we consider early plasma therapies to protect all heme proteins and later blood transfusion with supportive care to deliver oxygen to mitochondria in tissues that are undergoing acute mitochondrial colony failure.  

CITES:

1. https://www.click2houston.com/news/local/2020/03/29/houston-methodist-first-in-nation-to-be-approved-by-fda-to-transfuse-donated-plasma-from-recovered-covid-19-patient/

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

3. https://jamanetwork.com/journals/jama/fullarticle/2763983

4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617508/