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 amount of scientific literature exclusively within the field of COVID-19. Based on the data from Milken Institute, select treatment modalities have been captured in the pie chart below (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 those laws. 

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

Am I Culpable for Spreading Virus?

This is a classic example of invincibility and complacency – that nothing will happen to me even while the entire world is suffering from COVID.

Passengers went on a cruise while COVID was raging, presuming that COVID won’t infect their isolation on the ship (in deep water!) never realizing that asymptomatics are the core carrier rather than those who are actively infected.

Exactly this is what happens around us. Yesterday, I was talking with a friend and I realized, he was not using a mask despite the incidence being very high in their state.

That’s pathetic, I understand coronavirus is not seen and leave behind a trail of fragrance but understand, every time an asymptomatic exhales or sneezes, they blow approximately 54 million copies of the virus in the air. It is now known that these copies stay for at least 3-6 hours in the air. That air may drift in your direction and not having a mask while exposed to the potentially infectious airborne virus is culpable negligence, especially knowing that it may make you another asymptomatic carrier.

This pandemic is replete with examples where the asymptomatic have infected the gullible and innocent unexposed. It is the later who has taken the brunt from SARS CoV2.

Shashank Heda, MD
Dallas, Texas, US

Coronavirus: Dozens test positive for Covid-19 on Norwegian cruise ship
https://www.bbc.co.uk/news/world-europe-53636854

The ‘Good and Not So Good’ of COVID-19

While COVID-19 is taking a huge toll across the globe, humanity is displaying a polar reaction – a not so invincible risk taking attitude and a scared, vulnerability. The answer lies in between these two polar extremes. A balanced approach will help to prevent COVID at the individual and family level, which will eventually also be reflected as a social index for measuring our progress while preventing SARS CoV2 and treating COVID-19 patients.

I discussed the ‘good and not so good’ aspects associated with the prevention of COVID-19 and our own vulnerabilities. The initial battle with COVID is in our mind, where we either think we are vulnerable or invincible.

Let us visit the “Not So Good” part early. 

The spike of COVID-19 is huge across the sunbelt of the US. Several southern states are massively infected due to the COVID-19. The virus is seeing a massive resurgence in the UK, EU, and Australia. It is still in its ascendancy in India, Pakistan, Sri Lanka, and several southeast Asian countries. The Middle East is just catching the fever. Brazil and Latin America (currently in their winter) are seeing a heavy toll. 

While COVID-19 is still raging across the globe, humanity is displaying a polar reaction. On one side, we feel strong and ready to take risk, on the other side we are scared and vulnerable. Can we balance our approach and fight this virus? The answer is a definite yes. How do we do that?
The Good and Not so Good of COVID-19

Intrinsic Vulnerabilities are in our mind

You may be thinking, our body is vulnerable and weak and so we catch the infection. While, most amongst us are following precautions., precautions are not enough. We see at least two major vulnerabilities despite following precautions – 

  1. Strictly following precautions and giving up occasionally
  2. Not understanding the innate immunity and how that helps

Let us talk about the occasional vulnerability that we create and expose. 

Restless Inside Home

Several amongst you are restless inside the confines of your home. You are frustrated, bored and some are just angry enough to throw those precautions to disdain. You want to step outside, you are thinking the risk is not what it sounds like, you may be thinking you are young and have a very low probability of acquiring the viral infection. You may be thinking some socialization is ok, more is not good, so let us go for a walk, maybe pub, may have a blast with a limited circle of friends, maybe shopping, etc. etc. 

Are you Alone? 

Think like this – 

1. If the risk is low, why do we see the resurgence or ascendancy of COVID across the globe? 

2. If you are young, have no risk factors, why are young people succumbing to illness?

3. If you say, your ethnicity provides protection? Can you check the mortality data for those exposed within your ethnicity? 

You may be thinking little social interactions are good (walks, pubs, dinners, outings, little shopping, little business, etc.). It is exactly these vulnerabilities that are perpetuating the spread of viruses. 

Do you know?

For every symptomatic patient, we have anywhere from 5 to 10 asymptomatic patients. Are you sure you are interacting with someone asymptomatic (carrier) and have no virus? I have seen several cases where the person stepping out got the asymptomatic carrier, infected those innocent parents/kids/spouse/family members and the later died. Consider these scenarios

  1. I don’t think you can live with the guilt of being responsible for the death of near or dear one. 
  2. Presuming you will survive, what is the guarantee that your organs will not be compromised for a long time? 
  3. Let us presume, you die from illness, have you thought of the implications of your loss on those surviving? Please read surviving with COVID stories and make your choice. 

How do you protect yourself?

CDC has given guidelines for protecting yourself. Every Government has made the best attempts in guiding their citizen from COVID-19. Following those is the utmost while undertaking any activities for your local area. 

Activate your Internal Resilience 

First and foremost, please decrease your exposure and risk. However, boosting your immune system with Yoga, Physical Activities, Sleep, Balanced Diet (and avoid refined diet), and meditation are great ways of doing so. I also saw some interesting read on Mayo Clinics. However, several educational institutions are providing a wealth of knowledge on those. However, reaching out to your doctor at the first instance of suspicion is best. 

The Good News

In its July 7, 2020 issue, Nature Immunology carried an interesting article on why the disease burden varies differently across regions. Simultaneously, the same paper has speculated that previous infection from Common Cold Coronaviruses (CCC) exposure also provides protection, against SARS CoV2. Excerpts from the article below

‘Pre-existing T cell immunity is related to CCC exposure, it will become important to better understand the patterns of CCC exposure in space and time. It is well established that the four main CCCs are cyclical in their prevalence, following multiyear cycles, which can differ across geographical locations. This leads to the speculative hypothesis that differences in CCC geo-distribution might correlate with the burden of COVID-19 disease severity. Furthermore, highly speculative hypotheses related to pre-existing memory T cells can be proposed regarding COVID-19 and age. Children are less susceptible to COVID-19 clinical symptoms. Older people are much more susceptible to fatal COVID-19. The reasons for both are unclear’. 

If these speculations are proven, it can rightly be said that T Cells have a lasting memory towards previous CCC that may be reactivated during a SARS CoV2 infection and offer protection. 

https://www.nature.com/articles/s41577-020-0389-z

Shashank Heda,

Dallas, Texas

(On behalf of CovidRxExchange) 

a nonprofit initiative to help global doctors fight Covid-19

Visit – https://www.covid-19rxexchange.org/)

COVID & Spanish Flu – Comparison and Contrast

102 Not out – Approximately 102 years back, the world was ravaged by Spanish Flu (a misnomer) and today, we are reeling under COVID-19. Both pandemics caused significant pandemonium, and share a common pattern. While it is understandable to see an intermittent new ‘human – microbe’ interaction, going awry, the current pandemic has exposed our fault lines and our preparedness after 102 years. It is not about microbes and our immunity, it is a testimony of our (un)evolved human journey or rather stagnation of evolution in the last 102 years.

102 Not Out, provides a succinct comparison and contrast between the Spanish Flu and COVID-19 and a poignant story of our collective failure.

Background

1918-19 – That period must be the one coinciding with your grandparents or great parent’s birth. So, memories are only through archival records. The global toll was almost 50-100 million, whereas the US lost some 685000 people (a very high percentage for the population at that time). India had 5% mortality with over 12 million succumbing to Spanish Flu.

Spanish Flu – What is that?

Is it truly Spanish flu? It started in France and England. However, they both were at war and wanted to keep this covered. However, Spain being neutral, and news being public, it was reported transparently. It is a misnomer to call it Spanish flu. That is derisive, as Spain was neutral during WW I. It was World War I and soldiers were living in overcrowded barracks. It started in Etaples, France in 1916. It will similarly be wrong to construe that it was an element of French warfare because a similar disease was also observed in 1917 at Aldershot, England. Then too, it was commonly thought to have jumped the animal-human borders as pigs and poultry were a mainstay at these hospitals.

It never occurred to them that they would take the Influenza bug along with them while traveling back home. A disease that once was restricted to specific geography quickly became ubiquitous and spread out indiscriminately. As John Barry said, in New York Times, “None alone provides great protection, but the hope was that if most people followed most of the advice most of the time, the interventions could significantly reduce the spread of the disease, or “flatten the curve,” a phrase now all too familiar. This may sound simple, but it is not. As with a diet, people know what to eat but often stray; here straying can kill”.

3D_Influenza_transparent_key_pieslice_med

(Picture Credit – CDC illustration on influenza virus. Influenza A viruses are classified by subtypes based on the properties of their hemagglutinin (H) and neuraminidase (N) surface proteins. There are 18 different HA subtypes and 11 different NA subtypes. Subtypes are named by combining the H and N numbers – e.g., A(H1N1), A(H3N2). Click on the image to enlarge the picture).

It almost engulfed an entire then connected globe. However, the definition of connectedness, which was ignored then and which is ignored now too, is common to both the Spanish Flu and COVID-19. An estimated 500 million people worldwide were affected. It was a rudimentary period in the evolution of medicine and of course, there were no vaccines or medicines to treat the patients. The findings were, as usual, generally, healthy young adults succumbed to the illness, contrary to most diseases that took the life of the young and old. Today, we call this onslaught of infection against those with a mature immune system as Cytokine Storm. Then, we only knew it killed the young. Then too, people used hand washing, isolation, masks, avoiding public places, and quarantining those ill/suspected ill. It ravaged the economy and disrupted public life, basic civic services like garbage clean up, and postal delivery government services etc. were compromised. There was no one to cremate dead bodies; garbage was flying astray across the streets, no one to light neither lamp posts nor sufficient people to deliver the mail. City offices started digging mass graves, closed schools, public places including theaters. The truth was not transparent, trust in authorities deprecated. Then too, there was a lurking fear that ““civilization could easily disappear from the face of the earth.” Reopening then was marked by a rebound in cases.

Rebound after Reopening

Spanish Flu Rebound

In its intense and acute form, the malady lasted for almost 15 months, from the spring of 1918 to the summer of 1919. It is said that this pandemic Flu almost killed 50-100 million people. Today, we call that Influenza A or H1N1 flu. H1N1 kept lingering, again due to mutations, for 38 years until it was controlled with specific therapies.

Antigenic Shift versus Antigenic Drift

Influenza A and B, each has 8 genes and a variation keeps happening to make a combination each year. As investigations reveal, the 1918 pandemic started with an H1N1 strain, that kept mutating. At this moment, it is wise to understand the meaning of H and N, H stands for those proteins which are required to latch on the cell (inside) and release themselves (N proteins) when mature to infect other cells. This protein structure keeps changing slightly, called antigenic drift. Sometimes, the virus mutates significantly with major changes in the structure of the H and N proteins, called an Antigenic shift.

fcimb-08-00343-g0001

Fast Forward 2019-20 – Comparison and Contrast

It is commonly accepted believe that SARS CoV2 jumped the animal-human barrier. It too spread out from densely populated places. Like COVID-19, it took the world by surprise. No one anticipated that the global burden of death would be over 250, 000 in just 4 months. Then, there was no medicine and here again, we have no specific remedy. The mechanism of death was the same, cytokine storm prevailed then and it is reigning now. It took away the young healthy adults then, however, it is incapacitating for those young adults now, though the mortality is very high in the elderly. Then too, we used masks, isolation, and barrier protection, which we see as the mainstay of stopping the virus within the communities. We call it social distancing, back then, they called it crowding control.

What have we learned?

We see a commonality in the pattern. The biological behavior of the bugs is not changeable. The human response was almost the same. We respond exactly the same way how we responded then. We distanced from each other, we realized, it was spreading through our breath and mouth, so we used masks in 1918 and again, we are using masks. Is there anything wrong with this?

Quotable quotes from Christopher Nichols, Associate Professor of History at Oregon State University –

“The questions they asked then are the questions being asked now,”

“And while it’s very rare that history provides a simple straightforward lesson for the present, this is one of those instances. The Spanish flu tells us that social distancing works. And it works best if we act early, act fast and stick together — and base our decisions not on social or economic concerns, but on science and data and facts.”

References:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1997248/
https://www.nytimes.com/2020/03/17/opinion/coronavirus-1918-spanish-flu.html
https://www.webmd.com/lung/news/20200420/four-lessons-from-the-1918-spanish-flu-pandemic#4
https://www.cdc.gov/flu/about/viruses/types.htm
https://www.cdc.gov/flu/about/viruses/change.htm

 

https://interactives.nejm.org/iv/playlist/index.html?media_id=siCcYW3U&pcs=sidebar

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1997248/https://www.nytimes.com/2020/03/17/opinion/coronavirus-1918-spanish-flu.htmlhttps://www.webmd.com/lung/news/20200420/four-lessons-from-the-1918-spanish-flu-pandemic#4https://www.cdc.gov/flu/about/viruses/types.htm

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1997248/https://www.nytimes.com/2020/03/17/opinion/coronavirus-1918-spanish-flu.htmlhttps://www.webmd.com/lung/news/20200420/four-lessons-from-the-1918-spanish-flu-pandemic#4https://www.cdc.gov/flu/about/viruses/types.htm

COVID Rx Exchange

We created this group for doctors managing COVID patients. While those on the ground are managing clinical challenges, practice guidelines are being developed, enriched, and enhanced daily. This group is focused on sharing realtime expertise across boundaries during these crises. It is nonprofit & non-commercial.

We are very optimistic about a professional discussion. Please invite your colleagues managing Covid patients. For a complete description please visit https://wp.me/p7XEWW-1hj

Welcome to all those who joined recently using the group’s invite.

We started this collaborative initiative to cross-pollinate experiences and expertise with COVID-19 across the borders. As is obvious, the EU and the US have a maximum toll from COVID-19 and obviously, the body of experience is significant. We wish to transfer the insight gained from these experiences to those where COVID is now on the rise, especially in India, South East Asia, and the Middle East.

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A key need is to have a realtime dialog with those on the ground on either side of the COVID Wave, both the receding and the rising. The intent is to share actionable and supporting ancillary information. SARS CoV2 is a new virus to humanity, is constantly mutating while humanity is unraveling the multitudes of mechanisms involved in the pathophysiology of COVID. This pandemic has driven several intelligent folks across the globe to research and refine the management guidelines regularly.

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Convalescent Serum and COVID-19

The convalescent serum has been used for several diseases since 1890 by Behring initial experiment with Diphtheria. Eventually, the convalescent serum has been used bacterial infections, pertussis, measles, Argentine hemorrhagic fever, influenza, chickenpox, infections by cytomegalovirus, parvovirus B19 and, more recently, Middle East respiratory syndrome coronavirus (MERS-CoV), H1N1 and H5N1 avian flu, and severe acute respiratory infections (SARI) viruses. Suffice it to say, it is as older as vaccination.

Compiled by

Shashank Heda, MD., Dallas, Texas.

Question: The serum could actually be a virus as there have been cases (documented of course) were even recovered patients were spreading the virus.

Answer: You raised a very interesting question. I appreciate your raising this. However, kindly get the references.

The convalescent serum has been used for several diseases since 1890 by Behring initial experiment with Diphtheria. Eventually, the convalescent serum has been used bacterial infections, pertussis, measles, Argentine hemorrhagic fever, influenza, chickenpox, infections by cytomegalovirus, parvovirus B19 and, more recently, Middle East respiratory syndrome coronavirus (MERS-CoV), H1N1 and H5N1 avian flu, and severe acute respiratory infections (SARI) viruses. Suffice it to say, it is as older as vaccination.

Keeping with the intent of dispelling myth and provide confidence to the community, I am making every attempt to provide transparency based on the existing scientific research. Below, I am attaching two excerpts along with their references.

Convalescent blood products (CBP), obtained by collecting whole blood or plasma from a patient who has survived a previous infection and developed humoral immunity against the pathogen responsible for the disease in question, are a possible source of specific antibodies of human origin. The transfusion of CBP is able to neutralize the pathogen and eventually leads to its eradication from the blood circulation. Different CBP has been used to achieve artificially acquired passive immunity:  (i) convalescent whole blood (CWB), convalescent plasma (CP) or convalescent serum (CS); (ii) pooled human immunoglobulin (Ig) for intravenous or intramuscular administration; (iii) high-titer human Ig; and (iv) polyclonal or monoclonal antibodies.

==           ==

Convalescent Plasma:

In the absence of specific antiviral agents and vaccines for COVID-19, clinical trials have been conducted aimed at investigating the efficacy of convalescent plasma in treating COVID-19. A very recently published study by Chinese researchers confirmed the efficacy of convalescent plasma in controlling SARS-CoV-2 (Table 1) (Roback and Guarner, 2020). The report suggested that COVID-19 patients showed signs of improvement approximately 1 week after convalescent plasma transfusion. Another clinical study involved 10 critically ill patients infected with COVID-19 from 3 different hospitals in Wuhan suggested high-titer convalescent plasma transfusion can effectively neutralize SARS-CoV-2, leading to impeded inflammatory responses and improved symptom conditions without severe adverse events. All 10 patients receiving convalescent plasma transfusion showed improvement of clinical outcomes or were cured and discharged from the hospital (Duan et al., 2020). Given the clinical effectiveness of convalescent plasma, the FDA has granted clinical permission for applying convalescent plasma to the treatment of critically ill COVID-19 patients (FDA, 2020).

Convalescent plasma collected from donors who have survived an infectious disease by producing protective antibodies is considered to provide a great degree of protection for recipients affected by the emerging virus (Dodd, 2012). Convalescent plasma has been successfully employed to treat numerous infectious diseases, including the 2003 SARS-CoV-1 epidemic, 2009-2010 H1N1 influenza virus pandemic, and 2012 MERS-CoV epidemic (Dodd, 2012, Hung et al., 2011, Mair-Jenkins et al., 2015), for which modern medicine has no specific effective treatment.

Mayo Clinic named national site for Convalescent Plasma Expanded Access Program

https://www.sciencedirect.com/science/article/pii/S0889159120305894?via%3Dihub.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175848/

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

Mayo Clinic named national site for Convalescent Plasma Expanded Access Program

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

 

Civic Liberty and Public Health

The US is the most affected country bearing 32% of global (COVID-19) disease burden. A prominent influencing factor is the fundamental percept of individual freedom, as enshrined in the constitution and supported with the first amendment. Across the US, people are protesting about the compromise of personal freedom with the Stay at Home orders. Coronavirus has challenged all frontiers of humanity, its evolution and exposed our fault lines, irrespective of the countries, economies, ethnicities, ideologies, and our model of governance.

Civic liberty or public health – How do we achieve the right balance? Finally, balance also has a context and background. While there is a tendency on part of the state to erode individual freedom, the situation with Coronavirus is obvious. The inability to impose restrictions will definitely compromise the health of the society and ultimately the individual. In fact, not doing so will abrogate the state’s duties of providing safety for the individual. The scientific principle that underlines the “flatten the Curve” is provided along with a link to the international tracker of individual freedom across the globe. Also, expert opinion from Human Rights Experts and Legal Expert from Brooking, Harvard, University of Chicago, and Columbia University is cited in my blog. Realtime R(not) factor can be tracked for your county from the link provided herein.

What is compromised? What is indispensable?

COVID has opened a dialectical discussion on individual freedom and individual freedom that can harm the wider community. Freedom of movement is enshrined in the first amendment. To a few, these are considered at odds with each other. However, it’s a matter of perception. In the case of COVID-19, the common good outweigh individual freedoms.

When can we consider individual freedom compromised?

Ideally, we can consider that individual freedom is compromised if it results in (1) enhanced surveillance powers that compromise privacy (as in China, drones, cameras, and Bluetooth trackers) (2) suspension of rights, (3) control over information; and (4) delayed elections.

None of these are used here in the US. So, it is wrong to construe that freedom is compromised. More so, the federal government has declared an emergency. Nancy Gertner, a senior lecturer on law and a retired federal judge, says that the types of surveillance measures lately used in South Korea might even be feasible here, if somewhat less likely. “The issue is whether the measures are proportionate with the purpose. Since this is a public health emergency, we’re not dealing with the usual rules and regulations.”

Testing and stepwise removal of the restriction to movement

Therefore, restrictions could ease once widespread testing for the virus becomes available. Once the Govt. ramps up the testing, then you can dovetail the precautions according to who’s vulnerable. If you’ve got no idea, you quarantine everybody. But if you can test widely you can also titrate the response. However, it worth noting that, RNA testing and not testing the antibodies, is important. Thus sensitivity and specificity of a test become important. Sensitivity is used for screening, whereas, specificity is used for diagnosis. in case of Corona, we can’t wait for the antibodies to develop since those take time to develop after the infection and before the antibodies become evident, the person is infective (even if asymptomatic) and can potentially shed the viruses. Thus, personally, I am averse to antibody testing for screening, though the opposite is currently practiced.

Lesser restrictions in favor of more fundamental freedoms is more a policy concern rather than a matter of law. Temporarily accepting lesser freedoms for the good of the country and the wider population, in general, is acceptable in order to regain fundamental freedoms of movement more quickly and permanently our, to earn a living, and to attend events and gatherings. Protests such as these are uncalled for since we don’t need proof to weigh the cost versus benefits.

How best to mitigate the concern?

Freedom of movement, due to Lockdown secondary to COVID-19, should be tied to the growing, declining curve of the infection and or testing. It cannot be blanket freedom for the entire nations. States, Counties, and Cities are displaying a distinct pattern. Those which are on the rising side of the curve, also called hotspots, should definitely have “Stay at Home” Order. Those on the declining part of the curve should be tallied with the R(not) factor (explained later). and if the R(not) is declining below one, then we should consider the removal of restrictions.

While the outcry for compromise of individual freedom is healthy, a governance and policy framework to monitor and remove the temporary restrictions on individual freedom should be tracked, monitored, and reported to provide transparency.

Citations

https://jamanetwork.com/journals/jama/fullarticle/2761556?widget=personalizedcontent&previousarticle=2764283

New restrictions on civil liberties during coronavirus

Freedom and privacy in the time of coronavirus

COVID-19 Civic Freedom Tracker: https://www.icnl.org/covid19tracker/

https://news.uchicago.edu/story/fight-against-covid-19-how-much-freedom-are-you-willing-give

https://www.cjr.org/analysis/coronavirus-press-freedom-crackdown.php

Tracking Realtime R(not) factor https://rt.live/

Facts will unravel the truth

Facts alone pave the way for unraveling the truth

The US alone contributes to 29% of the global burden of COVID-19 positive cases. As against, the US, India has a paltry 0.5%. I liked PM Modi’s lockdown, despite the criticism. Any crisis moment is likely to have its collateral damage. However, a leader has to weigh the big picture and make the right decisions at the right moment. I am not a great fan of PM Modi but let us not be partisan at such critical times. Figures talk, and they talk a lot. You cannot hide those in a country like India. If the lockdown persists for another 3 weeks, India would have controlled the giant virus adorably!

Various schools of thought are rife with speculation. Some think Indians have a healthy immunity, while data from the UK points towards a specific predilection for the Asian Indian population. From the get-go, I (Shashank Heda) have been holding a grouse against China (not the Chinese ethnicity) that they have tried a more diminutive and (an unknowingly an attenuated strain) against India. Given India’s porous borders and the uncontrolled travel and social interaction, it is possible that India was already infected with a milder version sometimes back, and now Indians have an immune response to some of those Spike proteins or possibly the hemagglutinins. Time alone will reveal the telltale genetic fingerprinting and the genesis of this virus.

In the interim, it is definitely not the time to drop the guards. Let us educate our folks for –

  • Social distancing (no social/community/outdoor activities)
  • Isolation and shelter at home
  • Masks and decontamination precautions

Most important, they need to remember to

  • destress themselves,
  • implement a balanced life,
  • keep active and connected and
  • sleep well.

They need to be reminded that, they are not alone, 40% of the global population is going through the same routine.

Excerpts from BBC below –

“Our [infection] growth rate is highly contained although we are actively chasing the fire,” she told me. “Almost all of our testing has been driven by protocol, starting with people with travel history, contact tracing of people in touch with them and so on. The probability of getting more positive cases [from this cohort] would have been much higher.” Many are also pointing to the lack of reports about any surge in hospital admissions with influenza like illness and Covid-19 patients, which would hint at a rapid community transmission.

https://www.bbc.com/news/world-asia-india-52265061

Herd Immunity

Anthony Fauci, the well-known face of CDC, says that it is unlikely the coronavirus will ever be eradicated, though nations can bring the level of infection down to “low levels.”

According to Dr. Fauci, a combination of three-pronged strategy will provide a cautiously optimistic to control the COVID-19 menace. The three-pronged collective strategy should consist of

1. Good public health measures,
2. Degree of global herd immunity and
3. Good vaccine

What are the failures? Well, those are intrinsic inabilities. It is the collective callousness that is resulting in a raging fire of COVID-19. Faultlines differ, however, our ineptitude and complacency are primarily the cause. We are thoroughly bored in the confines of our homes, or for some, it is personal freedom, and for others, the virus is a hoax and far less believe, they are invincible, not realizing that they are the source of transmission (Carrier) of infection to unsuspecting innocents who face the morbid consequences or mortal end.

A raging debate is ongoing on Herd Immunity versus isolation. While herd immunity has been a de-facto nature’s standard for protecting the masses or herd, (not necessarily human alone), Coronavirus (SARS CoV2) has thrown this natural principle into question for several reasons –

1) It is new and has high mortality and morbidity due to its properties
2) we have no innate defense against it
3) Even the most highly industrialized nations have no capacity to accommodate sick patients.

Let us review the factors why we should not YET resort to Herd Immunity. Before getting started, let us see a live example of herd immunity being practiced to counter Covid-19. Let’s visit Sweden (Updated May 4, 2020).

“Herd immunity,” in which a critical mass of infection occurs in lower-risk populations that ultimately thwarts transmission. “relies more on calibrated precautions and isolating only the most vulnerable than on imposing a full lockdown.”

Excerpts from CNBC August 2020 –

“According to epidemiologists, herd immunity is necessary to contain a virus and is reached when enough of the population is either vaccinated or survive infection and build antibodies to ward of new infections. The virus then doesn’t have enough hosts to infect.

Most scientists think 60% to 80% of the population needs to be vaccinated or have natural antibodies to achieve herd immunity, Dr. Mike Ryan, executive director of the World Health Organization’s health emergencies program, said last month. ” from CNBC August 11, 2020. 

I am strongly convinced for Herd Immunity because that’s the only mechanism for mass protection at the lowest cost (understanding the collateral damage). Herd Immunity, should not be construed with the development of commensals, or symbiosis between the bugs and the host. Of note, let us understand the process of herd immunity and commensal development from an evolutionary basis. For these bugs (those existing in GI tract) the external environment is harsh and toxic. They cannot exist outside and so have taken refuge inside the host. Eventually, the host and the bugs take a symbiotic relationship or often, at least don’t harm the host unless in rare circumstances. Summarize to say that there is no evolutionary angle to this novel coronavirus. It is de-novo, not an adaptive organism.

Herd Immunity and Vaccination

Second, from the perspective of spreading immunity – understand that the collateral damage it may cause is irrespective of the value of the individual. At a theosophical and spiritual level, who are we to decide a 78-year-old should die or survive? We only have to create a judicious system to protect if we know the risk is higher in this population.

 

Biologically and from the perspective of Epidemiology, Herd Immunity, especially as it plays from a vaccine perspective, offers lesser chance unless a vaccine is introduced. It provides better protection when a vaccine is introduced in the population. They both have a synergistic effect. In fact, the lesser a population is vaccinated, the lesser the herd immunity phenomenon.

Despite, not knowing this Coronavirus ever existed, I strongly feel that Herd Immunity is best for general mass protection if the morbidity, as well as the mortality, are low and this is considering the varying Rho factors for various bugs.

UK and Sweden tried Herd Immunity and failed. In a partial sense, the US unknowingly imposed the principle of herd immunity (by not imposing the lockdown) and paid the cost. Today, the UK, the US, and Scandinavian countries all are reversing their stand on herd immunity. This is because of the grim reality of 20000 plus deaths in the US and several thousand deaths in the UK. Those sticking to Herd Immunity have taken a heavy toll because –

  • This is a new virus (as against the others which evolve) whose least quantity infects (S protein configuration, antiviral suppression, and cytokine storm)
  • There mortality and morbidity significantly high for the state to prepare and manage this huge tide.

Excerpts from Kevin Kavanaugh from the link cited below –

“Mitigation strategies can decrease a contagion’s R0. To decrease the total number of individuals with active infections, the R0 will have to be less than one. So, on average, each infected person spreads the virus to less than one person. When this happens, the epidemic will eventually burn out.

Herd immunity strategies rely on a significant portion of the population to become immune to stop the spread of the virus. The higher the R0, the larger the percentage of the population who must become immune before the total number of those with active infections decreases and the epidemic burns out. An R0 of 5 to 7 will require 80% to 85% of the population to become immune before the number of infected will start to decrease. Thus, it can be argued that without mitigation, the R0 will be far too high to be able to stop this epidemic with herd immunity. Almost all of the population would have to contract the infection before the epidemic would stop, which probably will not happen. The availability of a vaccine to prevent infections with pathogens having a high R0 is of utmost importance.

Other concerns are that immunity to coronaviruses which cause the common cold only lasts between 1 to 2 years and there is mounting evidence that cats and dogs may become infected, giving concerns of an animal host.

Thus, without a vaccine, this virus will be with us for some time. Herd immunity may slow the expanse of the epidemic, but it is not likely to meaningfully stop it without mitigation strategies. And there is significant concern that those who currently recover could be re-infected in the near future. Strategies of social distancing, not gathering in large crowds, wearing masks and protecting those at increased risk are required to manage this epidemic.Returning to life as usual with the dependence on herd immunity in a non-vaccinated population to control spread is almost certainly a false narrative”.

Thus, I feel, our ultimate recourse is our own defense – innate and adaptive complimented by herd immunity. The only reason, we are not resorting to herd immunity exclusively is because of the morbidity and mortality associated with this virus.

Citations:

https://www.nationalreview.com/2020/05/coronavirus-crisis-sweden-refused-lockdown-other-countries-following/ (Updated May 4, 2020)

https://www.infectioncontroltoday.com/covid-19/viewpoint-have-you-heard-about-herd-its-covid-19-fallacy (Kevin Kavanagh)

https://www.historyofvaccines.org/content/herd-immunity-0 (Animation)

https://www.aap.org/en-us/aap-voices/Pages/It-Takes-a-Herd.aspx (A simple scientific version)

https://www.technologyreview.com/2020/03/17/905244/what-is-herd-immunity-and-can-it-stop-the-coronavirus/

https://watermark.silverchair.com/cir007.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAlIwggJOBgkqhkiG9w0BBwagggI_MIICOwIBADCCAjQGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQM2OVG8xg2pfYzNM-QAgEQgIICBSi7ifrpZhiYGndgs3xVawidKzRobUyILH54jTeTTCVvKXxKjfGTstEXY_TVc27do_oKohDgo0nlz3sEmDDDyXdf08bkvBxpUii7mooK0y4Cuonz8aMhK7uIcSVRndSJMKxsIbyrpXVSlgjnaCC387cZvR4qtxWfBcQqadTp1SmLZjw2qFgFm-w6W5Z6lzhNeAo9T4z-I9fVbPBPIlHS5ja0OrR19tlb7-bqbhxSlHujS0BnE5vGEjkB3yukP_2fTAR-2tir3Kje3j0Ae8jjDw2jV2AcCxjCxI6d-AdHTOKaB0JDka3AtdPccwhK-aHmteNLQCqnf9LAPbKHp075g79itw-qyLDc2ymz3IQg5lAWgKu1KO_vMkbCwkdr0Mx196-Rta8ssMWA7BxYySK2_hzcXcNicgsyy63sjXK6VHTy5UZNgSOw_F80rslfOgrCeP_yU-lFkMXB0Ll_2PRTXV5npNHbi0CwP0C-2oaGBpAUKeLycCOIDphV7F7bKQSlaKW4kgRf-XH3bqtsjnezQWGk2NllH4l_ErIujEUBev0hTMAaTPTIEMXc6OO429S6zwpF8JHpzdsmPLDXypaadLjseQk3Goikt2WmOKQB50WdqkYMYSWlcO2SUxMDA7_HZi_SkZhRPIigFE9Ocgo23y5UxAjHk3C6k5HRTbN0mQSmmKEA4Ag

Click to access f26ca43be04880eaf4ad046a1f9408cb2e11.pdf

https://www.sciencedirect.com/science/article/pii/S1074761320301709