COVID-19 update and summary as of 5/22/2020

As we've moving to gradually opening up the community in phases with the new normal of wearing masks and practicing physical distancing (I am not sure if the term social distancing is appropriate since I feel like my social connection to people and patients, especially through phone and various social media applications has increased due to the pandemic!) I have continued to attend daily calls and online seminars regarding COVID19. I have every intention to stay away from political and biased information and focus on the scientific data that is available through reliable scientists and physicians and try to think of practical ways we can strengthen our body and battle this invisible invader.

As we have learned more about SARS CoV 2 causing COVID-19, we have learned that the effects of the virus on the body is more than just on the lungs but rather on the endothelium, the lining of all of our vessels. Hence we have to think of the battle with this virus as more like marathon training, a long process and to really work to improve our physical and mental health to its optimal level should we become in contact with SARS CoV 2 virus. Like the common cold and the influenza virus, majority of us are most likely going to be eventually exposed to it and knowing what we know now about the pathophysiology of the disease, we know how impactful proper nutrition, supplements and habits such as meditation can reduce the overall inflammation of our body and strengthen our immune systems and improve our chances of winning the battle should we contract COVID-19. Majority of the information below is gathered by attending calls, reading recent blogs, papers and podcasts from people who are at the frontline.

Some of the information might be redundant (thankfully) from the prior blogs and some new as we get more insight into the pathophysiology of this disease which we now know puts the body at a hypercoagulable state and has been associated with strokes, blood clots and amputations in some younger patients. Please excuse the presentation of this blog as it is almost notes that I've taken while attending these calls and listening to experts in the field. I would like to thank Dr. Roger Seheult, an intensivist in Riverside County who I first had the pleasure of meeting in my third year of medical school when he was an internal medicine resident for providing daily on the ground knowledge about this virus and sharing it with all of us through his informative lectures and calls. I would also like to thank one of my mentors, Dr. David Perlmutter, functional medicine neurologist for vast, unbiased knowledge as well as his daily updates regarding COVID-19.
We know now that only 30% of adults presenting to the hospital present with fever, higher proportion of the pediatric population develop fever when exposed to SARS CoV 2 or other viruses and this is partly contributed to children's better innate immune system. Therefore solely relying on one's temperature as a screening method will potentially only catch 30% of the people who might have contracted COVID-19, hence higher contagiousness of this virus compared to SARS-1 and MERS.
As we know from prior blogs, SARS CoV2 virus attacks the ACE 2 receptor in the lungs which is the entry point of the virus into the body. From there, it also gets into the body and attacks the ACE 2 receptor on the endothelial cells (Cell walls of blood vessels) which also contain this receptor. Underneath the cell wall, after the attack this causes release of certain coagulation chemicals, specifically Von Willebrand Factor (vWF) and Factor VIII. vWF is a blood glycoprotein involved in hemostasis. Again,  vWF is sub endothelial and is procoagulant (clot forming). On some studies, on day 21 serum vWF was at 520% and Factor VIII 369%. D-dimer levels have also been noted to go up significantly in COVID 19 patients and come down with injection of low molecular weight heparin (Lovenox). Anticardiolipin Ab and beta 2 glycoprotein levels also go up. Generally blood clots have been mediated by high levels of vWF and factor VIII mediated by endothelial inflammation. Thrombosis or clotting also causes hypoxia and opacification in the lungs and eventually oxidative stress. 
Therefore it is thought that people who at baseline are at higher risk of oxidative stress such as people with obesity, diabetes, heart disease, and metabolic syndrome who have a higher level of inflammation overall (higher levels of C-reactive protein) have the highest rate of dying from COVID-19. This hypercoagulable state is also a possible explanation for "Happy Hypoxics" who have oxygen levels below 90% but do not seem to be in any respiratory distress but end up having cardiovascular collapse and blood clots and when put on ventilators, get minimum relief. 
 Type O blood has better mortality, Type O blood has the Lowest level of circulating VWF which is now thought to be the cause of better outcome with this blood type compared to other blood types.
Recommendation regarding Aspirin:  we don't know the interaction between ASA and COVID19. it is not recommended for people that need to be on aspirin to get off of it unless specifically noted by their prescribing physician.
NSAIDs (e.g. ibuprofen, naproxen): initially thought to be contraindicated due to decreased platelet adhesion and increased bleeding which can be deleterious in case of COVID-19. Also NSAIDs can negate body's febrile response which is a part of the innate response and can potentially mean worse outcomes and are best reserved as last resort if acetaminophen or paracetamol are ineffective at therapeutic doses.
As mentioned, ACE 2 is the target of COVID 19. SARS CoV 2 virus binds to the ACE 2 receptor and makes it completely inactive. This is how it affects the Renin-Angiotensin system. Active ACE 2 receptor converts Angiotensin 2, a vasoconstrictor (a chemical that causes constriction or tightening of blood vessels) to Angiotensin 1,7 a vasodilator and reduces inflammation. When the SARS CoV2 binds to the ACE2 receptor and blocks this conversion, it increases blood pressure, vascular permeability (leakage of fluids outside of vessels), pulmonary edema (swelling in the lung) and ARDS (Adult Respiratory Distress Syndrome) 
SARS CoV 2 also attacks the CD 147 receptors on lymphocytes resulting in very low lymphocyte counts which is one of the initial findings. It also causes increased neutrophils (similar to SARS and MERS). Neutrophils give a lot of oxidative burst which can make oxidative stress worse and is correlated with an increased chance of death. 
Innate Immune system (NK Cells and monocytes) is also the target of SARS and MERS 
SARS CoV2 also suppresses the adaptive immune response (hence why Ivermectin, an anti-parasitic drug which suppresses this suppression has shown to have some promise in certain COVID19 patients) Innate immune response is a critical factor in disease outcome.  
BCG vaccine, a vaccine used in the past to immunize against tuberculosis also stimulates the adaptive immune response and there is a spill over to the innate immune system which is also activated. In people who have had the BCG vaccine (Middle East, Asia and Africa), they've seen an improved innate immune response. (US, Canada, Italy have not received the BCG vaccine) Magnitude of difference is 10 fold in disease and mortality between countries who've received the BCG vaccine and countries without the BCG vaccination program. (still don't know if this is an association or causation?)  There are some clinical trials about use of BCG vaccine for prevention of COVID19 along with other vaccines.
Hospitalization: (JAMA, admission in NYC) 60% male 40% female. only 31% fever, 14% ICU admission, ICU median age 68, 66% being male, 12% needed mechanical ventilation. 21% of patients admitted to the hospital died, 88% of people needing mechanical ventilation died. >65% on a ventilator mortality was 97%!
USC study: 863 tests. estimated 4.1% infected based on antibodies, 22-55 X higher than what thought. 
80% of symptomatic patients do not need hospitalization: innate immune system plays a big role here (Natural Killer cells and monocytes) 
Here are the tests that show poor prognosis and possible progression to Respiratory failure:
CRP> 100 mg/L
Ferritin> 500 mcg/L
D-Dimer > 1000 ng/mL, If D-dimer is 1 mcg/L elevated there is an 18 fold increase in odds of dying, hence thrombosis is a big issue in dying. 
LDH > 255 U/L
Lymphocytes <800/microM
Antibiotic Use: No routine antibiotics are recommended unless superinfection is present. However, superinfection is NOT common in COVID 19
Some other common recommendations that have come up during meetings: 
Avoid nebulizers (can spread the germs)
Steroids: WHO recommends against using it for "Just COVID 9" and has been associated with increased mortality in influenza and decreased viral clearance in MERS-CoV. However, if there are other indications such as asthma exacerbation, joint inflammation, etc, OK to use.
ACE/ARBs: no firm knowledge about lower or increased risk of COVID19, do not start for COVID19
Did not work in Ebola
Stops transcription of virus
available through compassionate use for pregnant and pediatric cases
also available through clinical trials
Not available through emergency use by the FDA yet
RCT in Lancet (study in China) did not show benefits but study could not reach full study due to shorter epidemic in China
it showed no difference in time to recovery or mortality
RCT in US (enrolled over 1000 patients) time to recovery 11d vs 15 d (P,0.001)
Mortality 8% vs 11.6% (p=0.059) NNT 28
study had to be stopped early because endpoints were reached.
It did not show that Remdesivir was a cure but shortened the recovery and improved outcome, reduced mortality.
Ivermectin: this is an anti-parasitic medication which as mentioned above, prevents transport of viral proteins into the nucleus of the host cell. It prevents the virus from suppressing the immune system. It is dosed about once/week and has little side-effects and has shown some promise but not approved for use yet due to lack of adequate data. Physicians are not prescribing it yet due to insufficient data.
Convalescent plasma: 
Available only through clinical trials with expanded access programs through FDA
emergency individual use, some case series which were promising but no RCT published yet.
Toclimizumab (IL-6 receptor inhibitor): a drug used for rheumatic diseases and it suppresses cytokine storm. So far the case reports good outcomes but no randomized clinical trials available yet.
WHO currently has active trials for the use of:
Who should be hospitalized:
hypoxemia<93% on Room Air and/or P/F<300 mmhm,
Respiratory Rate>30
more than 50% of the lung involved on Chest X-ray 
Severe labs CRP>100  ferritin >500, D dimer >1000 ng/mL, LDH >245
These COVID19 patients do not need hospitalization: fever, malaise, cough, URI, absence of shortness of breath.
Some Additional information regarding supplements, habits, diet:
Vitamin D: "A role for vitamin D in the response to COVID-19 infection could be twofold". First, vitamin D supports production of antimicrobial peptides in the lining of the lung, thus making infection with the virus and development of COVID-19 symptoms less likely. Second, vitamin D might help to reduce the inflammatory response to infection with SARS-CoV-2. Deregulation of this response, especially of the renin–angiotensin system, is characteristic of COVID-19 and degree of overactivation is associated with poorer prognosis. Vitamin D is known to interact with a protein in this pathway—angiotensin-converting enzyme 2 (ACE2)—which is also exploited by SARS-CoV-2 as an entry receptor. While SARS-CoV-2 downregulates expression of ACE2, vitamin D promotes expression of this gene. (
Vitamin C, another anti-oxidant has shown mainly to reduce ARDS and sepsis 
Quercetin (found to be beneficial Ebola) is mainly a zinc ionophore similar to mechanism of action of hydroxychloroquine, helping zinc get into the cells and maybe beneficial in treatment of COVID19
Zinc: inhibits coronavirus replicase in vitro Quercetin and hydroxychloroquine have shown to be zinc ionophores, facilitating entrance of zinc into cells which in turn inhibits coronavirus replication.
Progesterone therapy is currently being studied in men
N-acetylcysteine: an antioxidant for glutathione peroxidase system, reducing oxidative stress. Oral and IV forms (oral NAC and IV glutathione) have shown great promise in preventing and treating respiratory symptoms associated with COVID-19 and investigations are currently underway. NAC is available as an over the counter supplement.
Hyperthermal therapy used in 1918 H1N1 Pandemic as well as treatment of neurosyphilis and also used in Finland to improve innate immune system.
Placental mesenchymal cells high in NK cells and are being studied to see the impact in improving the innate immune response.
Sleep (7+ hours) has a great impact in improving the Natural Killer cells and improving the innate immune system. 1-2 hours of sleep loss nightly has shown to have a great impact raising the risk of heart disease, stroke, obesity, poor blood sugar control as well as increased risk of upper respiratory tract infections (as noted in college students during finals)
Proper nutrition to reduce oxidative stress (a healthy, Mediterranean diet, low in refined carbohydrates, glucose, fructose, especially from corn syrup, dried fruits, and candy rather than whole fruits and saturated fats from farmed animal protein). Again, If one wants to reduce their chances of serious outcomes associated with COVID-19, this is a great time to focus on improving one's diet, exercise, meditation and losing weight. 
In one study, out of the 5700 cases studied in NYC surprisingly this was the breakdown:  
Hypertension:  57%
Heart disease: 11%
Congestive Heart Failure: 7%
BMI>30 42% (vs 28% in general population)
Asthma 9%
Obstructive sleep apnea 3%
Hence, diseases associated with more inflammation such as hypertension, diabetes, obesity and heart disease are at higher risk of complications if they contract COVID-19 than asthma and COPD which are primarily pulmonary diseases.
Again, I advise my patients to look at the current situation as preparing for a marathon. No matter how this virus got here, as time goes by, the majority of the population will get exposed to it. Rather than focusing on fear and solitude, we need to turn our focus to ways we can strengthen our body to be able to improve our innate and adaptive immune system and put our body at the optimum level of health to be able to battle this disease.
As mentioned above, proper diet, sunlight (Vitamin D), sleep, meditation and lastly exercise are critical things that will strengthen our mind and body.  In the future blogs, I will have more information about some supplements such as selenium, zinc, NAC, Vitamin C and D.
To Health and a passionate life
Pouya Shafipour, MD



Dr. Pouya Shapifour, MD Dr. Pouya Shafipour, MD Pouya Shafipour, MD, in Santa Monica, California, is a board-certified family medicine specialist with subspecialty training in a field of medicine known as bariatric or obesity medicine. He uses safe and effective medications in conjunction with dietary, nutritional, behavioral, and exercise counseling to manage obesity and medical conditions related to excessive weight gain or loss.

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