On The Line of Fire?

What went wrong with Padmashri, Padmabhushan Mr. S. P. Balasubramanyam, the legendary singer from India? He was recovering and suddenly he deteriorated and succumbed to the illness.

COVID can surprise you anytime, even in the recovery period. I got another note from social media, of a young doctor, a father of a six-month child – obviously a young family. He succumbed to complications of COVID. He was waiting to be discharged and go home.

Well, these unusual stories are gradually becoming common, and I thought of sharing it with you since doctors are seeing such scenarios very often. What is going wrong? Can we truly control it? Understanding these 10 points may possibly help prevent COVID-19. (Reading time 5 – 6 minutes; Scientific perspective).

(Note: We are planning to conduct a cross cutting expert global advisory session to clarify all relevant questions. We are planning to conduct this half day session before the start of the SECOND WAVE. Please share your questions to me in person or on this page as we are crowd sourcing questions from all).

Well, these unusual stories are gradually becoming common, and I thought of sharing it since doctors are seeing such scenarios very often (Please scroll to the bottom of the blog to see the detailed note). 

I had another gentleman who went to a Salon. He argued that he should support the local economy, a lame excuse. Well, even if he wants to support the local economy, he can donate bigger amounts and support the local economy, like many others who have supported their dependent workforce.  Time and again, I have been sharing rejoinders on awareness and precautions, and I am summarizing those below – 

1. A Constantly Mutating Virus:

The virus is constantly changing. It has a gene called RDRP (RNA-dependent RNA Polymerase) that encodes for an enzyme that makes a template for the RNA’s to produce in copies in billions. RDRP has a vulnerable to mutations and this results in the constantly changing nature of the virus. It is this enzyme that makes a (defective) template resulting in mutations. Every time, RDRP makes a template, it ends up producing an erroneous copy that results in mutant copies with every generation of the virus reproduction. 

2. Comorbidities and Unknown Risk:

Selective comorbidities and risk factors are known,however many are yet unknown. We all now know that diabetes, hypertension, smoking, cardiac problems, asthma, immune-compromised, and other respiratory illnesses predispose to COVID. However, we are seeing several youngsters without any of these comorbidities who are suffering and sometimes succumbing to COVID. 

3. Incomplete understanding of the Impact:

Also, we see that some have comorbidities and dies of COVID, whereas others with similar comorbidities survive despite having COVID. Knowing your comorbidities, science still cannot say if your disease will be asymptomatic, mild, moderate, or severe. 

4. Clean recovery or Long Haul Disease:

Despite the recovery, Science cannot predict if you will be ‘long hauler’, i.e. those have long term consequences. According to few reports, almost 10% to 1/3 recovered patients land up with Long Haul disease. The legendary singer, mentioned above, started showing signs of recovery, including light speech and physical activities. He deteriorated due to post COVID complication and eventually died of post recovery complications. 

5. Status of Vaccines:

Vaccines are in pipeline and serious efforts are being made to develop and durable vaccines but we don’t have one that we can rely upon. 

6. Repurposed drugs but No Specific Drugs:

We have supportive drugs but no specific drugs to remove the virus. We know it very well that HCQ was the mainstay at the beginning of the pandemic. Later, it fell into disrepute. Steroids were questioned and only after the ‘Recovery Trial’ substantiated the use of steroids with a randomized controlled trial, that changed the management of COVID. Tocilizumab similarly came in and had an ignominious walkout after the COVECTA trial. Just a few days back, the Japanese FDA approved Favipiravir. the later drug, with its RNA-dependent RNA polymerase activity, has anecdotal evidence of effectiveness since it’s a proofreading enzyme that renders the removal of nucleoside analog (drug molecule) and despite continue inducing mutations. Changes to the use of these guidelines may be anticipated as well. 

Different modalities of therapy for treating COVID-19.

7. Reinfections:

Several are indeed recovering but several reports of reinfections are emerging. It is a fact that several people are recovering from COVID, however, it is equally true that many lands up with severe disease, and those recovering are having long-term debility and need rehabilitation? 

8. Asymptomatic Spreader:

Are you sure, if you will just get the mild form of COVID or remain asymptomatic? Even if you remain asymptomatic, are you sure, you will not pass it on to your family members and if they get COVID, are you sure, like you, they too will be unscathed?   

9. Herd Immunity:

It is like playing with fire. Some insist that we should expose ourselves to build our innate resistance. Remember, this is not a natural virus, also, it evokes severe inflammatory and immune reactions within the body. It is structured or has been structured to keep changing. Our immune systems are built to remember, called immune memory. The changing nature of the virus renders the previously learned immune phenomenon useless. So even if we expose ourselves, our immunity will not last long. It is similar to Influenza. We see a different strain at least every year. With COVID, we see a different strain every few weeks. 

10. Convalescent Plasma and Antibodies:

Plasma from patients having recovered from COVID-19 has antibodies to SARS CoV2. Plasma, thus drawn from recovered patients helps treat and or contain COVID in infected patients. The earliest experiment was done by Edward Jenner in 1796 when he scratched the fluid from the blisters of a cow suffering from smallpox into the skin of a normal healthy man and induced protection. As we now know, Smal Pox is completely irradicated. Convalescent plasma (CP) uses the same principle, of tapping into existing antibodies for treating existing COVID-19 patients. 

However, there is a catch. CP is nonspecific, ie. it has other unrequired antibodies that may trigger untoward reactions. Also, if the virus itself is changing, those antibodies are ineffective. More so, the antibody levels drop after a certain period. Thus monoclonal antibodies become relevant. Placebo controlled randomized trials are being underway (as of this writing) that will offer solace to the treatment of COVID-19. Antibodies have to be targeting specific proteins called epitopes. In the presence of changing epitopes, it is fluid to understand the reliance on monoclonal antibodies. 

Myriad Complexity –

a) Cytokine and Bradykinin Storm: For the common men, the difference is nimble, it does, however, matter for the doctors though. Cytokine storms – processes in which the immune system overreacts to an infection. Ideally, cytokines disappear once the virus copies reach a threshold. COVID, however, puts the body into an overdrive mode and produces cytokines that ultimately result in damage to the organs. (drives the body to produce the immune system keeps producing them and the organs take the brunt from these excess cytokines). Cytokines are associated with myeloid differentiation and disease severity, concurrently the T cells are reduced as is evident from the reduced numbers of CD4+ and CD8+ T cells in patients with COVID-19. 

b) Kallikrein–kinin system: Irrespective of the pathognomic phenomenon (mechanism of the disease), COVID unleashes vast reaction from your own body to damage itself. Think, of this like a natural defense which is supposed to protect you, has turned up against you, causing a perfect storm to disrupt and incapacitate you.

Remember the fluid build up around the lungs, which is primarily caused by bradykinins. Bradykinins causes the blood vessels leaky and result in edema (swelling) around vital organs such as the lungs (short of breath), muscle (body aches), gastrointestinal tract (diarrhea), kidneys (congestion and rising serum creatinine), and a multitude other clinical features.    

c) Endothelial Nitric Oxide System: Endothelial nitric oxide synthase (eNOS) becomes a potential therapeutic target. Hypercholesterolemia, diabetes mellitus, arterial hypertension, and smoking are associated both to nitric oxide synthesis reduction or degradation increase. This nitric oxide bioavailability reduction is followed by endothelial dysfunction

A Picture is Worth 1000 Words:

A review of the work – A great deal of work has been done in the treatment and or containment of COVID-19 in the last 9 months. LitCOV provides an exclusive insight on the scientific literature within the filed of COVID-19. Based on the data from Milken Institute, few treatment modalities have been captured in a graphical format. A picture is worth 1000 words. Below pie chart shows the cumulative progress in the treatment of COVID.

Reflections On Human Urge to Move Freely

Our fundamental human urge to move and intermingle has been severely constrained, however, historical evidence shows that no calamities remain constant. If you recollect, no rains, volcanoes, earthquakes, or twisters (andhi) remains forever. One day it wanes and so will this virus, it is nature’s law and this virus too will follow this. 

Remember, humanity has a significant resilience built-in and as the history of human evolution shows, it has never been subdued nor will it ever let any event subdue its spirit and independence. However, events have always taken a huge toll and we never know if we are on the line of fire. 

Death of COVID Treating Doctor:

A 38 yrs old male doctor gen practitioner was admitted to our hosp with COVID on the 6th day of illness with 60% lung involvement, SpO2 borderline with mild dyspnoea. He became critical in the next 2 -3 days with a typical cytokine storm. We shifted him to ICU and on NIV. He was quite tachypneic, tocilizumab 2 doses were given and his NIV requirements decreased ..and eventually, after 5 days of ICU stay, he was weaned off from NIV and stable on nasal prongs 4-5 L o2. Later, he was shifted to the ward with oxygen. On the previous day of his discharge, he developed abdominal distension and severe abdominal pain, and constipation. A Ryles tube was passed and was kept NBM, X-ray abdomen showed dilated bowel loops but no air-fluid levels. GI doc advised enema, a CT abdomen was advised, radiologist suspected some bowel ischemia, so the patient was shifted to Ruby Hospital, Pune. After struggling with the consequences of ischemic bowel complications, the patient succumbed due to Sepsis and multi-organ failure.

It is now a routine, to see notes such as the one below, on social media. 

Do you want to be on the line of Fire?

COVID-19 cytokine storm: The anger of inflammation; Cytokine. 2020 Sep; 133: 155151. Published online 2020 May 30. doi: 10.1016/j.cyto.2020.155151 PMCID: PMC7260598; PMID: 32544563

https://www.bio.org/policy/human-health/vaccines-biodefense/coronavirus/pipeline-tracker

https://covid-19tracker.milkeninstitute.org/#vaccines_intro

Second Surge and COVID-19 prevention

The risk of infection is the same for everyone in that environment, but the consequences of infection are different depending on age, ethnicity, and comorbidities. Are there any formulae to calculate that? Possibly, emperical estimates can be made using known facts. However, remember, humanity is still in the discovery phase of COVID. We have identofied few risks factors, eg. Comobidities. However, a complete risk stratification is not yet available. Neither do we know who will have mild, moderate or severe disease. (On Behalf of COVIDRxExchange)

Now that aerosols are established as factors disseminating COVID, it is important to realize that COVID is persistent in the air. A few days back, I had a gentleman eating food in a restaurant or the patio of the restaurant. As usual, my relationship made me ask a few questions about his understanding of the disease. He said if we can eat outside food at home, why can’t we eat outside food in the restaurant.

Let us understand and analyze the situation. COVID is not foodborne, COVID is not water-borne, COVID is an airborne infection. The air around you will determine if you are likely to get COVID. In a setting such as a restaurant, this gentleman has a high probability of acquiring COVID. Factors that need to be considered while understanding your chances of getting COVID are the estimated prevalence of infection in that space, contact time and distance, and the degree of aerosolization.

The risk of infection is the same for everyone in that environment, but the consequences of infection are different depending on age, ethnicity, and comorbidities. I often cite an example – of inside and outside risk. Presume, it is snowing and the roads are all icy and slippery. Driving under such inclement conditions is fraught with severe risk. If during such times, you have an emergency at home, you still have to venture out and take care of that. However, if I say I just want to drive and see the fun, obviously it is stupidity.

Thus risk assessment becomes an important factor. Outside risk versus your own vulnerability. That also means that despite the outside risk is high, if you have a critical/essential function that needs immediate attention, you may want to consider doing that. However, if the vulnerability is high, ie. the impact is high, it also means that you want to seriously consider the probability of getting the disease. Thus likelihood and impact are important aspects that you want to consider.

Mitigation depends upon several aspects, face shields, masks (quality is important), and the time of exposure and the (presumably) pre & post-exposure mitigation you perform.

A simple approach to estimate your exposure can be shown in the below formula –

Exposure estimation = (Prevalence of the virus in the air) X (contact time) X (Distance of separation) X (inversely related to your protection mechanisms) X (your internal vulnerability).

The most significant aspect of COVID is that, as of now, SCIENCE DOES NOT HAVE A COMPLETE UNDERSTANDING OF AN INDIVIDUAL’S INTRINSIC RISK.

This is an opinion, not an advisory and you should consult your doctor to seek any advice. The author is not responsible or liable if you use this piece without consultation and advice from your doctor.

https://www.bmj.com/content/370/bmj.m3616

Let us not play God

It is not about China. It is about the human intrigue and opportunity to produce a new organism that unleashes vast implications for us as humanity. The day we start playing nature (God) that day, we should consider as doomsday, because we now know COVID very well and we are seeing how it erupted and further fractured our fault-lines and exposed us – logically, scientifically, politically, ideologically and just the very way we are organized and evolved as humanity.

Interesting repudiation. This is exactly what I was discussing in the first quarter of this year. The introduction is very intuitive and logically engaging. The policy makers across the world are turning a blind eye towards this synthetic source of the virus. However, it shows the power of how human can go wrong in trying to second guess the nature and remix and refactor its native form.

Again, it is not about China. It is about the human intrigue and opportunity to produce a new organism that unleashes vast implications for us as humanity. The day we start playing nature (God) that day, we should consider as doomsday, because we now know COVID very well and we are seeing how it erupted and further fractured our fault-lines and exposed us – logically, scientifically, politically, ideologically and just the very way we are organized and evolved as humanity.

  1. Has SARS-CoV-2 been subjected to in vitro manipulation?

1.1 Genomic sequence analysis reveals that ZC45, or a closely related bat coronavirus, should be the backbone used for the creation of SARS-CoV-2
1.2 The receptor-binding motif of SARS-CoV-2 Spike cannot be born from nature and should have been created through genetic engineering
1.3 An unusual furin-cleavage site is present in the Spike protein of SARS-CoV-2 and is associated with the augmented virulence of the virus

  1. Delineation of a synthetic route of SARS-CoV-2
    2.1 Possible scheme in designing the laboratory-creation of the novel coronavirus
    2.2 A postulated synthetic route for the creation of SARS-CoV-2

Step 1: Engineering the RBM of the Spike for hACE2-binding (1.5 months)
Step 2: Engineering a furin-cleavage site at the S1/S2 junction (0.5 month)
Step 3: Obtain an ORF1b gene that contains the sequence of the short RdRp segment from RaBtCoV/4991 (1 month, yet can be carried out concurrently with Steps 1 and 2)
Step 4: Produce the designed viral genome using reverse genetics and recover live viruses (0.5 month)
Step 5: Optimize the virus for fitness and improve its hACE2-binding affinity in vivo (2.5-3 months)

It is noteworthy that, based on the work done on SARS-CoV, the hACE2-mice, although suitable for SARS-CoV-2 adaptation, is not a good model to reflect the virus’ transmissibility and associated clinical symptoms in humans.

We also speculate that the extensive laboratory-adaptation, which is oriented toward enhanced transmissibility and lethality, may have driven the virus too far. As a result, SARS-CoV-2 might have lost the capacity to attenuate on both transmissibility and lethality during its current adaptation in the human population.

Serial passage is a quick and intensive process, where the adaptation of the virus is accelerated. Although intended to mimic natural evolution, serial passage is much more limited in both time and scale.

The following facts about SARS-CoV-2 are well-supported:

  1. If it was a laboratory product, the most critical element in its creation, the backbone/template virus (ZC45/ZXC21), is owned by military research laboratories in China.
  2. The genome sequence of SARS-CoV-2 has likely undergone genetic engineering, through which the virus has gained the ability to target humans with enhanced virulence and infectivity.
  3. The characteristics and pathogenic effects of SARS-CoV-2 are unprecedented. The virus is highly transmissible, onset-hidden, multi-organ targeting, sequelae-unclear, lethal, and associated with various symptoms and complications.
  4. SARS-CoV-2 caused a world-wide pandemic, taking hundreds of thousands of lives and shutting down the global economy. It has a destructive power like no other.

On point 2 above, I would like to add that, it is possible the military labs never realized the virulence of the new virus since most of the experiments were done on cell lines and animal models, such as laboratory rats and monkeys.