In Search of a Haplotype

The new variant of the virus has already spread out to over 45 countries. While scientists are understanding the impact of the mutant variants, what should we do as individuals and societies to counter the potential threat from the virus?

In this article, I have provided an insight on personal and administrative/social preparation that needs attention.

(Word Count 942, reading time 4 -5 minutes).

By now, we all know the virus is mutating, and mutating every few weeks. For those who are not aware of what a mutation is, it is a change in the genetic program embedded within the virus. However, only a few mutations have possible implications on the infectivity, ability to induce severity, response to the drug, and the response to vaccines. All of these are critical for individuals, families, and society in general. Of course, everything is intertwined and ultimately has an impact on the socioeconomic structure. We have seen the devastation of several families. When the virus went on the rampage, we saw how the economies faltered and GDP’s collapse.

Variants and their implications

We all know that the UK, EU, and the US are badly reeling under the virus. Hospital beds and ICU bed availability in many regions are critically stretched, and so are the human resources like HCW. London Mayor Sadik has already implemented a lockdown with punitive citations for overriding the lockdown. Rightly so, despite our freedom mongering and yearning for personal freedom, we ultimately land up with the hospitals.

At least three variants are known with possible implications on the infectivity, severity of the disease, resistance to drugs, and efficacy of the vaccines. N501, B1.1.1.7, D614G and A222 are mainly prevalent in the UK, South Africa, and the EU. All these variants are known to be more contagious than the wild type, that is universally prevalent. Also, a collaborative study between Duke University, Los Alamos National Laboratory and Sheffield University has revealed that D614G variant is associated with higher viral loads in the upper respiratory tract. As of now, we are not yet sure if there is a variant that exists in LA and other parts of the US that are reeling under the virus. At least 45 countries have so far reported the presence of these new variants as of Jan 10, 2021. The National Laboratories from individual countries are searching for the virus’s existence within their societies and implications if any.

Japanese National Institute of Infectious Disease has similarly identified a new strain after the Japanese Government realized passengers’ arrival with the variant viruses. Naturally, the imposition of a ban on incoming flights from infected countries is the first knee jerk response. Many countries have reimposed the ban on travel from those countries with the presence of this virus. While the respective Governments are working to identify the new virus variants, individuals and the administration should gear up to deal with the increased threat level.

Credits: News Medical Lifesciences, Dr. Liji Thomas, MD. D614G mutation now the dominant variant in the global COVID-19 pandemic
  1. Individually, we all should follow the precautions stringently. Masks, social distancing, and containment strategies such as quarantine are basic. However, never presume that asymptomatic individuals are non-infectious. Research has proven without a doubt that asymptomatics are the ones who are spreading the virus. It goes beyond saying that kids harbor more viruses and remain asymptomatic. Kindergarten and schools can be the potential source of spread. While many schools have opted to go into virtual schooling, it is challenging for the daycare centers to do so. It is best to huddle into your bubble and only interact when it is essential or critical, understanding that those interactions should follow the strictest precautions mentioned above.

Vaccines
Vaccines are derived based on a certain genotype of the virus. If the virus changes its structure, the vaccines may have a potential dent in its efficacy. Second, vaccines, even if they are efficacious, may protect only the ones who are vaccinated. Vaccinated individuals may still harbor the virus. Thus, protection has to continue despite vaccines.

  1. City and Corporation Planning – Many cities, especially in South East Asia, are basking and boasting their success with COVID-19. COVID-19, as well all know, can strike back anytime. Complacency is not alone a defunct but also a counterproductive strategy. Europe and other countries undergoing a severe COVID-19 pandemic spike have realized how the spike overstretches the HCW. Doctors are overburdened, and so are the supporting staff.

Realistic modeling of the unfolding second spike is critical. R Naught, which was widely used at the pandemic initiation, has been revealed to have several flaws. It only threw our economy into shambles and society into unrequired chaos. Newer modeling that is closer to realism is the need of the time.

Second, the infrastructure that was propped up during the pandemic’s initial phase helped but was not necessarily sufficient. We need to identify a more long term viable solution to our healthcare services to deal with the virus. Using the same knee jerk response is unlikely to provide an adequate safeguard. Mere lockdowns are too insufficient and, at best knee jerk; we need more than a rational response, now that we know the pandemic better from our recent experience.

  1. Society – Herd Immunity
    Sweden, the UK, and the US are great examples that serve as potent examples that herd immunity is not enough. It does not offer protection without collateral. The collateral is the death and devastation of an individual with a permanent compromise with residual sequelae on health. Those who survived COVID-19 are physically either compromised in functioning or occasionally rendered dependent on supplemental oxygen.

The only and ultimate panacea would be a natural selection of a haplotype (a genotype) that would be less infective, cause inconsequential disease, and still respond to drugs and vaccines. The emergence of such strains is a natural selection process. The virus will possibly realize that if it has to cohabitate like several other bugs, in a symbiotic relationship with human beings.

Shashank Heda, MD.
Dallas, Texas
(For COVIDRxExchange, a global nonprofit initiative for disseminating insight and expertise in the care of COVID)

https://www.lanl.gov/discover/news-release-archive/2020/July/0702-newer-variant-covid-dominates-infections.php

https://www.news-medical.net/news/20200925/D614G-mutation-now-the-dominant-variant-in-the-global-COVID-19-pandemic.aspx

School Closure and Kids Infectivity?

Excerpts:

Are my kids susceptible?

Now that COVID has started raging once again across the US, it is very possible that the schools in your area may decide to close or remain open. Select states may choose to keep the schools open, whereas others may decide to close. Is there any data to support the spread of disease with the schools opting to remain open?

It is important to understand if the Kids are infectious? Are they likely to be an asymptomatic carrier? Are they more susceptible? Do they have enough antibody response? A map of the US with states mandated school closure is provided in this blog. (Word count 795, reading time 3-4 minutes).

Are kids “Briefly Infectious”?

Now that some states have mandated the schools to reopen, and though the kids have the option to physically attend or participate remotely, it is important to understand the implications for the family.

3% or 9% Threshold? What’s Right?

NY Mayor Bill D Blasio imposed a 3% moratorium on the case positivity rate to keep the school system open. You may see your state or local officials changing their decision to keep the schools closed if they see a rising number. The debate of 3% or 5% is seemingly not important. These numbers are related to the incidence of test positivity on a daily basis. Presume, you have 100 people visiting for testing, and 9 are positive (9%). Now presume, you have 500 people visiting for testing, and 3 per 100 are positive (3% but a total of 15 cases). Obviously, the absolute number matters most. However, New York Governor Andrew Cuomo or Iowa, Gov. Kim Reynolds has set the state’s closure threshold at 9 percent and 15 percent respectively. Why is the difference?

Hospital Beds influence the policy decision

The absolute numbers posted above make it clear that the more the number of the population infected, the more the number of beds required to treat the population. In fact, if the severity of the cases rises, another parameter that frequently influences the decision is the total number of ICU beds. If the system is inundated, these beds become significantly crunched and so lockdowns are enforced.  

These exact sentiments were communicated by Dr. Celine Gounder, Adviser to President Elect Joe Biden, when she said, “there may come a tipping point where you do need to go back to virtual schooling. But I think the priority is to try to keep schools open as much as possible, and to provide the resources for that to happen”.

Impact of Lockdown

Lockdowns have a significant impact on the daily lives and economic health of a nation or state. It has been observed that Lockdown has rendered a significant portion of working women to discontinue work and focus on the kids. This almost significantly reduces household income and increases stress and unhappiness due to an inability to meet family needs. Across the globe, educational planners are concerned about the pandemic inflicting an indelible harm to the academic development to the kids.

Are kids more susceptible? 

Recent research points to the Type 1 IFN that offers protection with the innate and adaptive immune response. As we age, the functioning is likely to get compromised and make us vulnerable. That is the reason, kids are less affected, whereas the elderly are more likely affected due to COVID. Second, children, have powerful innate immunity that mounts a severe and rapid response to the viruses, thus not allowing the viruses to gain a foothold, thus sparing them from severe disease. 

Do Children have a less protective response? 

Research from Karolinska Institute in Stockholm has demonstrated that the antibodies produced by kids are IgG type whereas, those produced by adults are of several types. The IgG antibodies bind to the S protein, whereas the diverse range of antibodies produced by adults bind to various proteins and help better neutralization of the virus.

The range of antibodies that children produced differed from those of adults. Children primarily made one type of antibody, called IgG, that binds to the spike protein on the surface of the virus. Adults, by contrast, made several types of antibodies that bind to the spike protein and other viral proteins, and these antibodies were more powerful than IgG at neutralizing the virus. Adult COVID-19 cohorts had anti-spike (S) IgG, IgM, and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibodies, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. 

Are Schools the Superspreaders? 

According to a report from Ney York Times, very little transmission happened in schools. The latest data shows that random testing since October has produced a positivity rate of just 0.17 percent.  Please visit an article cited below from the Journal of Pediatrics, an official journal of the American Academy of Pediatrics.

Take-Home Message:

  1. Kids may have better immunity burst to deal with SARS CoV2 but they may not have a complete armamentarium of antibodies to deal with every aspect of the virus.
  2. Kids may be less susceptible to the virus, but that does not rule out a possibility of MIS-C.
  3. Elderly parents at home are susceptible to infections from the kids, even if you presume, the kids are likely to have less probability of the disease. Grandparents and other senior elderly family members should be segregated from the kids to provide adequate protection. 

https://www.edweek.org/ew/section/multimedia/map-coronavirus-and-school-closures.html

https://www.nature.com/articles/s41590-020-00826-9

Compiled on behalf of COVIDRxExchange, a Nonprofit initiative 

Note: This is not a medical advice or recommendations. Please consult your doctor or local policy planner while making a decision. This is author’s personal Opinion and readers are strictly advised to consult medical professionals. Follow your local official advice and guidelines while trying to prevent the spread of coronavirus.

Visit Vaccine and Drones (https://mymilieu.org/2020/11/16/vaccines-and-drones/) to learn more about the effectiveness of the vaccines.

https://pediatrics.aappublications.org/content/pediatrics/early/2020/10/16/peds.2020-031971.full.pdf.

https://www.edweek.org/ew/articles/2020/03/20/when-americas-schools-shut-down-we-all.html

Can I Get Severe COVID?

Are you vulnerable to develop a severe COVID-19? How to predict if you are likely to get a mild disease or a severe disease? Since the onset of COVID-19, we know that 80% of those affected are likely to have mild disease, 15% a moderate disease and 5% have severe disease. We never knew why only 5% had a severe disease. Also, we knew that elderly patients had more mortality and male gender was more affected because of the disease.

This fact kept the medical community guessing the cause, until we found out that certain genes have mutations or certain antibodies develop in this high risk patients that counter the protection offered by our innate immune mechanism. At least for now, a piece of puzzle is solved.

This article talks in detail revealed by latest research that help us understand those changes that makes these vulnerable population for a severe disease. You may want to know if you have those intrinsic vulnerability?

Silence of the Genes or their products

Why Some Patients Have Severe COVID? Why More Males dies of COVID and Why the disease is more mortal in elderlies? The genetics underlying severe COVID-19There is a crucial role of type I IFNs that offers protective immunity against SARS-CoV-2. After the initial infection, small amounts of IFNs are induced by the virus that become crucial in offering a protection against severe disease. However, few patients have developed neutralizing auto-Abs against type I IFNs, like inborn errors of type I IFN production. This sways the balance in favor of the virus and results in devastating disease due to absence of innate and adaptive immune responses.

Two pathways in which these genes can be perturbed are –

1) Genetic mutations resulting in deletion or functional compromise of the type I IFNs.
2) Development of antibobodies to type I IFNs. The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs).

Individuals who lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Adaptive autoimmunity impairs innate and intrinsic antiviral immunity.

A crucial role of type I IFNs in protective immunity against SARS-CoV-2. These auto-Abs against type I IFNs were clinically silent until the patients were infected with SARS-CoV-2—a poor inducer of type I IFNs which suggests that the small amounts of IFNs induced by the virus are important for protection against severe disease. At least 10% of patients with life-threatening COVID-19 pneumonia have neutralizing auto-Abs against type I IFNs. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system. Genetics may determine the clinical course of the infection. High titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified.

A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least

a) 2.6% of women and
b) 12.5% of men.

Provide an explanation for the excess of men among patients with life-threatening COVID-19 and the increase in risk with age. They also provide a means of identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, including plasmapheresis, plasmablast depletion, and recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-β).2) At least 10% of patients with life-threatening COVID-19 pneumonia have neutralizing auto-Abs against type I IFNs. With our accompanying description of patients with inborn errors of type I IFNs and life-threatening COVID-19, this study highlights the crucial role of type I IFNs in protective immunity against SARS-CoV-2.These auto-Abs against type I IFNs were clinically silent until the patients were infected with SARS-CoV-2—a poor inducer of type I IFNs which suggests that the small amounts of IFNs induced by the virus are important for protection against severe disease. The neutralizing auto-Abs against type I IFNs, like inborn errors of type I IFN production, tip the balance in favor of the virus, which results in devastating disease with insufficient, and even perhaps deleterious, innate and adaptive immune responses.

At least for now, a piece of puzzle is solved. We now know that if Type 1 IFN develop auto-antibodies, or have mutations in the genes, or any (gene) silencing ensues, then it is possible, you may have individual vulnerability. The last aspect, silencing of the genes through methylation, though not yet proven may be potentially possible. Let us wait for science to unravel more.

Translational Medicine

What is typically called as translational medicine, it takes time to transfer the technological advances from laboratories to bed side. However, with COVID-19, we have seen a significantly reduced latency from lab to bed side (bed side here means for common use in practice).

Science  23 Oct 2020: Vol. 370, Issue 6515, eabd4585; DOI: 10.1126/science.abd4585

https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html

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.

Website Picture

Scope of this initiative:

To provide realtime information on –

1) Share actionable information to make decision making
2) Share ancillary medical information
3) Dispel myths and untrue (rumors) wandering on WhatsUp University

Activities:

  • Open and transparent real-time interaction between the members
  • Live Webinars conducted under the aegis of this podium
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  • Sharing of credible Webinars and Information

Accessing the archival information:

A website is being developed for uploading all this information. You will be asked to access via Facebook, Google, or LinkedIn. A link will be updated.

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.

This is a non-profit, pro-bono initiative where several professionals are investing their time for humanity. We insist on using this podium to use this as an academic and non-commercial, non-promotional intent. Further, with the intent of serving humanity, this initiative is open to all ethnicities, religion, faith, or political boundaries. We ALL are committed to ethics and the highest value of service towards humanity. Last, we request you to share information that is based on scientific evidence and EBM. Professional interaction is an underpinning framework between our interactions. I am confident, you all are equally committed as I in upholding these standards.

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Invite to COVID Rx Exchange (below):

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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