Letter-158A: How COVID-19 may work inside a human host

The RNA mechanics of, and response to, this coronavirus

Below is shared the deep domain expertise, Lucas Kogut, currently in his residency in the University of Lublin, Poland. Below that is a professional assessment by Dr Bill Bauer of Seattle, who specialises in internal medicine. These thoughts on how the coronavirus itself functions within infected hosts as well as the response through mid-April were shared in a separate thread on another social medium.

Both essays are well worth the thirty minutes to read through. I commend Dr Kogut for making complicated concepts accessible to lay readers uninitiated in the hard sciences (e.g., me).  While I obviously lack the expertise to endorse these analyses, I nevertheless trust it and pass it along to you. 

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Ned McDonnell QUESTION:
"One last question: ¿how solid is the argument that this virus will not mutate into a deadlier form as did the Spanish Flu?😳"

Lucas Kogut William ANSWER:
"Thank you Dr Bauer for that humbling introduction.. 😅

"But to answer your question on mutation and the 2nd wave, Ned McDonnell, the issue with this virus is not so much its mutational rate (which recently was the theory that it possessed a very high mutation rate leading to its own demise in sequential time) but rather, it's the ability of the virus to under-go very proficient and rapid recombination of its very large genome (~32 kb).

"The frequency of which this recombination of its massive nucleotide genomic sequence occurs is determined by selective pressure once trying to adapt to survive in a new host, or recently recovered host by a cousin strain of its lineage. And interestingly (and also quite problematic in terms of duration of this viral infection), they (coronaviruses as a whole) possess a proofreading enzyme/protein known as exonuclease (ExoN), which gives the virus a high fidelity rate once its recombination sequences have "fit just right" in being able to establish disease in its present host.

"Coronaviruses establish infection through their ability to actively inhibit and keep at bay, the host immune response (particularly the innate immune arm; aka; the "first line of defense" immune cells), thus giving the virus time (~4-5 days incubation) to replicate like mad and find its "winner-winner-chicken-dinner"- if you will, type viral strain. (Best sequence to maintain on-going viral activity and progeny).

"So to summarize and conclude; the second wave has potential to be very damaging as for reasons Dr Bauer just mentioned, and is indeed a very real and present threat with this very unique and evolutionarily well-tuned virus. However, to leave things on a positive note, our human innate systems (if not inhibited by age, comorbidities, or immunosuppression) are perfectly capable of overwhelming the coronavirus in due-time.

"Especially the younger the host. Antibody intervention and vaccination (modeled after antibody activation through natural infection*) will only go so far in prevention of this virus, and again that's due more to its massive recombination ability from its massive genome and not so much its mutational rate and ability."

Ned McDonnell QUESTIONs:
"Thank you, Sir, for a detailed response, accessible to a layman (i.e., me). Just three questions of differing types.

"> Can a vaccine be developped that permits anti-bodies to mirror re-combination by the virus?

"> May I post this in my Linked-In and F.B. feeds, of course with proper attribution?"

Lucas Kogut ANSWERs
"You are most welcome.

"As far as the vaccine trials currently underway; their aim is at development of a vaccine targeted against the mRNA genomic sequences made by the virus that codes for the "S-spike" protein domain. Which is its route of entry into our cells through the ACE2 receptor as I'm sure you are well aware of by now. This would be effective at preventing a large pool of the current virus from entering and establishing infection in our cells via ACE2, but as we've seen with other cousin strains, they may enter via other receptor routes (DPP4 receptor in MERS-CoV for example) and since they all share an "RNA-Quasispecies" interaction, they have capabilities to "call-up" and put in play other genomic sequences held within their 28-32 kb genome, via recombination, and hence allow for further infectivity.

"You most certainly may share and post away!

"The leading consensus is that this has not been a product of laboratory alteration and manipulation. The complexity and unique properties of this virus genus lies in its ability to affect a very wide range of hosts, from whales to bats. And bats, are the most heavily invested research target, ever since the 2002/2003 SARS outbreak, they are host to some staggering 400+ Coronavirus strains.. and have learned to live asymptomatically with the virus, almost in a symbiotic relationship. The more we can understand of that host-virion relationship, the better our understanding of what true immunity from this virus really looks like in humans. Though the cross-species adaptation models will require more intermediate host testing (ideally simian/primate hosts)

"If there are any further questions, please don't hesitate to ask, I will do my best to answer as honestly as I can. And since we still know only a handful of facts about this virus, I will do my best to answer any relevant information that I can. I have read numerous NIH/PUBmed, Lancet and JAMA articles in reference to the specific virology of these viruses and from the lump-sum of information I've gathered, there still seems to be a lot of guess-work involved thus far. But the information I've shared with you above is information that is reinforced by several relevant research articles, most notably from NIH."

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Assessment of Dr Bill Bauer of Seattle from 14th April 2020

"What I am working on. If you want to inject partisan politics or conspiracy theories in this thread I will delete your comment. I do, however, want serious input into this process, with references. especially if I am missing something! I will edit this document as your comments come in, in order to improve it and my always problematic grammar and typing.

"COVID First Wave After Action Report and Summary

"Executive summary

"The COVID 19 virus started in early December of 2019 in Wuhan China. From there it spread geometrically within Wuhan and eventually spread to China and the rest of the world. The crisis that ensued included large scale deaths associated with overwhelmed health systems. The mainstay of treatment was social isolation which when finally implemented a great economic cost seemed to stem the geometric growth of the disease.

"Viral diseases often come in waves. Currently most of the world in the first wave with China and Singapore possibly being in the beginning of a second wave. Generally, second waves of viral illnesses are deadlier than the first for a variety of reasons but usually thought mainly do to increased complacency as well as a loss of resources in the first wave, making resource depletion more problematic in the 2nd wave.

"There are many political and cultural issues at play throughout this crisis. It is not the purpose of this report to address these.

"Things that worked.

"1) Social Distancing. Large scale social distancing especially when practiced early seemed to have huge beneficial effects on outcomes. Without an effective vaccine, this will again be the mainstay of any mitigation efforts.

"2) Telemedicine and other work from home strategies. These should continue to be funded, in that they both mitigate disease spread and allowed valuable and scarce healthcare personnel to still treat and take care of their patients.

"3) Closing schools and preschools. This helped but at some cost to learning and inequity in learning as roughly 1/3 of students in public schools lacked adequate computers and internet connections to meaningfully participate.

"4) Distribution systems. For the most part Grocery and pharmacies remained stocked as did liquor stores. Similarly, gas stations remained brimming with gasoline as petroleum companies pushed inventory as far forward as possible.

"5) PPP and EIDL. These programs were huge lifesavers to all small businesses and their employees. They were given out to any and all small businesses without exception. This was a huge benefit after one week of getting it started the money was dispersed by banks and paychecks started flowing. The creativity and flexibility by the SBA and Federal reserve was crucial. Not limiting this money or putting restrictions on the recipients made it crucial to keep many employed in sectors that others find objectionable from abortion providers to parochial schools and churches to marijuana shops. Basically banks were told to disperse the money (which the fed loaned them) and the SBA would make them whole. This allowed money to go out within a week of this starting.
(Notably this experience had wide variations and is still indeterminate)

"6) Increased unemployment benefits. These helped stem the effects of the tide of layoffs and the effects of everyone's increased needs in preparing for the epidemic.

"7) Critical infrastructure plants housed their critical employees early on sight so as to have a non-infected isolated group of core employees to keep electricity and other services running.

"8) Critical infrastructure like water, sewage, NG, and electricity continued unabated despite their just in time practices practices prior to the crisis. Did they become aware and store necessary chemicals or were the chemicals domestically available?

"9) Safety issues – there was not the widespread looting or civil breakdown which we have seen in other crisis. This should be studied to figure out if this signals a change in culture or other factors with a high possibility that high rates of monitoring cameras by homes and neighborhoods, gun ownership. Isolation protocols, etc all served to deter this behavior.

"10) Bureaucratic rules. Early on several bureaucratic rules were suspended in this initial and second national crisis declaration, including state by state licensing, antitrust rules for hospitals to coordinate care and others. These helped hospitals coordinate resources and care.

"11) Use of teleconferencing technology to keep people together and reality checking their ideas.

"12) Takeout food and delivered food was negatively associated with disease progression

"13) Closing international travel seemed to help stem the early spread of the disease.

"14) Closing Churches seemed to help (Catholic, mainline protestant, LDS)

"15) Suspending airline "use it or lose it" rules at airports and landing spots.

"16) A ratio of 10 tests per positive test seemed correlated with bringing COVID under control in each state. With tests of 20 to 1 the disease did not seem to gain much of a foothold. This seemed to be the case repeatedly in fairly similar states with similar starting points.

"17) On a short term basis at least, massive quantitative easing stabilized the financial and bond markets.

Areas of breakdown

"1) Nursing home care. Nursing homes and other elder care facilities were centers of thousands of outbreaks within the united states. Enhanced isolation protocols including onsight living of crucial personnel during the outbreak and telehealth will need to be instituted in further outbreaks.

"2) Prisons. Prisons were sights of huge outbreaks and deaths in MI , LA, and with the BOP. Clearing and reducing prison sizes, length of incarceration, and clearing elderly prisoners seemed to stem the tide in other systems.

"3) School distance learning for early grade school years. 1/3 of grade school children did not have internet connections or computers with active camera/video conferencing capabilities. This must be addressed.

"4) Grocery store panic buying and crowding. We saw this increase disease in many locales where this occured. This must be limited in future outbreaks using assigned shopping times and online pickup and delivery systems.

"5) Not enough available online pickup and delivery capacity of groceries by the stores themselves and it is unclear if Instacart uses food stamps. This gap must be cleared quickly in a future outbreak given seniors limited resources.

"6) Inadequate spare petroleum storage. When the strategic petroleum reserve was first started it was to store oil in case of a shortage. It turned out to be crucial in emergently storing oil so as oil pumping and extraction was not stopped too quickly as to permanently damage oil fields and downstream operations. Large spare salt caverns should be developed to handle both crude and refined products in case of future emergencies. Natural gas already has developed an underground reserve systems and can also rely on making plastic pellets and nitogen fertilizer during low cost and reserve producing times.

"7) Limited industrial base – early on in the crisis shortages of PPE, ventilator, and testing reagents along with threatened shortages of generic drugs became evident. These shortages were critical because the US industrial base did not make and did not have the supplies and expertise needed to address many of these shortages. This critical industrial deficit has strategic and practical implications. These must be addressed through tariffs and limits to imports.

"8) Limited meatpacking facilities and providers – the concentration of meat packers allowed meat packers to close plants and increase both prices for products sold while decreasing prices for products bought. They were able to squeeze both sides of the market. This concentration was too much for efficient markets to prevail

"9) Loss of Insurance. The massive layoff that accompanied the social isolation orders caused huge dislocations in health insurance and care. People were left with having to spend their unemployment checks solely to obtain COBRA coverage, or accessing the ACA healthcare websites. This was made more perilous due to indefinite Medicaid recapture laws which in some states are thought to permanently bar passing inheritance if this insurance is accessed between the ages of 55-65.

"10) Loss of first responders due to quarantine and isolation. Many responders were employment was cut short due to isolation and quarantine protocols. After shortages of first responders appeared, they were called back to work. Upon finishing their shifts though they often lacked housing to go home to so as not infect their family. This needed to be addressed.

"11) Multiple essential industry workers faced going home to elderly parents and others after working in grocery stores, hospitals, firedepartments, and elsewhere where they were at high likely hood to be exposed to COVID. They also needed separate housing during this crisis. This was troubling because it was simultaneous to hotels and motels being empty.

"12) Lack of face covering for workers in high exposure industries and others early on. Further in many grocery stores employees were specifically disallowed to wear face coverings in their work place. All high risk businesses should maintain a one month supply of face coverings for those working and N95 and other PPE is in high risk areas. Employees should be allowed to face covering to help themselves or prevent/decrease risk of transmission of disease to customers.

"13) Adherence to pre-crisis drug testing protocols. During the crisis there was a large sociopolitical debate on the efficacy of quinine based and other antimicrobial drugs. This debate was informed by limited studies. It would seem a rapid randomization protocol could have been achieved and implemented in a national emergency to address this and other agents and protocols

"14) University professional lectures (Grand Rounds) were late in addressing this problem or failed to address it at all (University of Washington). Clearly emerging threats need early professional discussion and planning.

"15) CDC lacked critical infectious disease infrastructure, personnel, and response. It continuously underestimated the problem and most notably failed to come up with adequate testing for either the virus or its antibodies despite months of lead time.

"16) Lack of CDC communication with Taiwan. Taiwan was the first to alert and understand the nature of this crisis but its warnings were ignored due to political considerations. Taiwan’s public health infrastructure must be full recognized.

"17) Naval ships are close quarters operations. When the Nimitz prepared to re-deploy they decided to house the entire crew on ship for 2 weeks prior to departing. This caused hotbox phenomena and a spread of the epidemic within the ships crew. The navy should have isolated sailors in individual tents or other forced isolation for 3 weeks prior to leaving and weeded out all those who were symptomatic or tested positive.

"18) Large parades seemed to be correlated with large scale outbreaks in NYC and NOLA.

"19) Buffets were associated with outbreaks in the US and abroad. They should be closed early in epidemics.

"20) Keeping large scale gatherings, casinos, and ski resorts open once the first community spread occurred negatively impacted outcomes.

"21) Funerals were implicated in large scale outbreaks in several parts of the country, and Spain. Notably also with the Ebola crisis. This is probably because the deceased may have had COVID unknowingly from the deceased prior to them dying, and relatives picked it up and then spread it to fellow funeral goers who themselves are often and usually elderly.

"22) Not closing churches and orthodox synagogues in NY and GA seemed to increase spread.

"23) Not closing cruise ships which became hot boxes areas of disease spread both with COVID and enteroviruses. New cruise ship designs will need to consider design changes to limit spread of diseases (more copper on contact surfaces, negative pressure on interior rooms, limiting buffets).

Things that are indefinite

"1) Best method of coming out of a crisis
"2) Best way to pay for the crisis
"3) Effect of large-scale injection of monetary liquidity into the markets on a medium and long term basis.
"4) Effects of loss of rent payments.
"5) Use of second homes by those who had them – did they negatively impact the local healthcare environment or not?
"6) Was lock down necessary or better than isolation in place allowing for people to go outside and exercise at a distance.
"7) Racial and other SDOH measures on outcomes. In many states African Americans suffered disproportionately whereas others they suffered death at one half the ration of Caucasians and Asians (WA state). What factors came into play?
"8) Climate impact on the disease and disease progression.
"9) Does releasing prisoners increase or decrease crime and deaths.
"10) does widespread testing, if it were available, decrease spread and help in control of the disease?
"11) Should people have antibody testing prior to returning to work? Should we develop a health passport?
"12) If given adequate PPE and testing, could a more surgical approach to quarantine be effective as appeared to be the case in South Korea?
"13) Would surgical isolation work in a second wave disease where community spread was already present in the first wave.?
"14) How accurate where the statistical models used? what caused the high variation.
"15) long term effect of triaging on healthcare personnel.
"16 Outcomes in high trust verus low trust communities and states."