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Discussion thread VI - COVID-19 (new coronavirus)

Emily as the article points out this is one competing hypothesis. It goes on to show a correlation between high viral loads and disease outcome but this is not high initial viral load but peak viral titers which will have much more to do with how well the immune system is handling the infection. In this disease, for most patients, they have little or no replicating virus when they are most ill, they are dealing with the immune dis-regulation and damage caused by it. PCR readings for patients who are infectious are of the order of 1million RNA matches, to the probe, per ml of swab. I have difficulty seeing how the tiny quantity of initial innoculum can have any bearing on this unless everybody's immune response is identical. Fortunately we are all different.
COVID parties are definitely a bad idea, and will lead to more illness, but I do not think it will make any difference to the illness severity spectrum which will match the age and comorbidity profile of the partygoers. If you have seen any data showing otherwise I would be keen to have a look if you have links.
The use of the term Variolation in this article is misleading as it is to do with introducing the virus into a part of the body that does not have many cells the virus can attach to and infect but does allow immune cells to interact with it and prime the immune system against reinfection. https://en.wikipedia.org/wiki/Variolation
 
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JJackson, the reference from the article will help you understand the use of 'variolation' better than Wikipedia. https://www.nejm.org/doi/full/10.1056/NEJMp2026913

Also, I did not say initial viral dose was the only factor in outcomes. If you read my other posts you can see that I'm very aware of environment and host factors, so no need for links to support a statement I never made.

As for references on viral load, they are right in the article:
"In The Lancet Respiratory Medicine, a group led by Carlos Cordon-Cardo, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, reported that the viral loads of patients who died from COVID-19 illness were significantly higher than those of patients who survived (mean log10 6.4 copies per mL vs 5.2 copies per mL, respectively). In addition, for each additional unit of viral RNA detected, researchers observed a 7% increased risk of mortality.
An earlier study published in The Lancet Infectious Diseases also found that the mean viral load in severe coronavirus cases was more than 60 times that of mild cases, according to Yang Liu, MD, of Nanchang University in China, and colleagues."

Maybe there is conflicting research that shows lower viral loads in some deaths. I'd be happy to look at links if you have any. Either way:
"Ravina Kullar, PharmD, MPH, an infectious disease expert and epidemiologist speaking on behalf of the Infectious Disease Society of America, said that the question of how providers should treat patients with a high viral load is a critical one.
Patients with a higher viral load "should potentially be put on the steroid dexamethasone from the get go, rather than an antiviral, to help prevent that cytokine storm that might lead to worse outcomes," Kullar said."
 
sharon sanders said:
snip

“I think there’s good enough data to say that aerosol transmission does occur,” Dr. Fauci, the country’s leading infectious disease expert, said in a live Facebook discussion with Gov. Philip D. Murphy of New Jersey. “Aerosol means the droplets don’t drop immediately. They hang around for a period of time.”

Dr. Fauci’s assessment comes at a time when state and local authorities are trying to find reliable guidance for what mitigation efforts are needed indoors and how indoor spaces should be ventilated.


https://www.nytimes.com/2020/09/24/w...#link-6d900248
Click to expand...




...
Dr. Jay Butler, CDC’s deputy director for infectious disease, told The Associated Press that the agency continues to believe larger and heavier droplets that come from coughing or sneezing are the primary means of transmission.

Last month Butler told a scientific meeting that current research suggests aerosol spreading of the coronavirus is possible but it doesn’t seem to be the main way that people get infected.
...
There could be another way for tiny particles to spread. They may not necessarily come directly from somebody’s mouth or nose, says William Ristenpart of the University of California, Davis. His research found that if paper tissues are seeded with influenza virus and then crumpled, they give off particles that bear the virus. So people emptying a wastebasket with tissues discarded by somebody with COVID-19 should be sure to wear a mask, he said.

Scientists who warn about aerosols say current recommendations still make sense.

Wearing a mask is still important, and make sure it fits snugly. Keep washing those hands diligently. And again, staying farther apart is better than being closer together. Avoid crowds, especially indoors.
...
Best of all: Just do as much as you can outdoors, where dilution and the sun’s ultraviolet light work in your favor.
...
It might seem strange that for all the scientific frenzy to study the new coronavirus, the details of how it spreads can still be in doubt nine months later. But history suggests patience.

“We’ve been studying influenza for 102 years,” says Milton, referring to the 1918 flu epidemic. “We still don’t know how it’s transmitted and what the role of aerosols is.”

https://apnews.com/article/virus-outbreak-43fe5ca3fba1d4ebc05949a11643e03b
 
I know flu researchers who say they are still learning. I think common sense has to prevail here. COVID-19 is spread among people who are in close proximity. We know this from the church choir members who infected their fellow members. So avoid closed rooms with groups of people - especially if they are yelling, singing, etc.

There are documented instances in China of people becoming infected whose indoor restaurant table was close to a test positive person. So avoid sitting inside a restaurant at a table that is close to other tables.

It appears cruise ships were a petri dish for COVID-19 in the pre-mask, temperature taking protocol.

There is one study that shows an unmasked person infected 16 others on an airplane.

Ok - so the real life body of evidence is that this spreads to some extent in the air and also via virus on surfaces. Household transmission is the most infectious situation. This makes sense because air and surfaces are shared.

So how to we move forward? Well...this won't be popular....but these massive shut downs are going to generate as many "sick" as the virus itself. We had an economic melt down in the spring. Millions lost their jobs and they can become "sick": emotionally ill and physically ill as a result of losing their jobs.

A tiny fraction of the studies that show the effect of job loss on health:

Am J Public Health . 2014: Recessions, job loss, and mortality among older US adults

Am J Epidemiol . 2015 : Who suffers during recessions? Economic downturns, job loss, and cardiovascular disease in older Americans

Int J Epidemiol . 2014: Job loss, wealth and depression during the Great Recession in the USA and Europe


We have lost the battle. We can not stop COVID-19. It is like "trying to stop the wind". No amount of widespread lockdowns will stop it. China pretends they have stopped it with their lockdowns and contact tracing. More likely they are not testing. No tests = no cases. So don't use China as an example of how draconian measures stop this virus.

Nothing stops this virus.

What we need - and still do not have - are freely available personal protective equipment. We should ALL be able to receive FREE N95 masks. Not the crappy KN95. The real NIOSH approved N95. All of us. We should have been making a bazillion of these since February. Where are they? This is stopping society.

WIth abundent PPE and cleaning solutions we could live our lives as near normal. But no. We are stuck. Shame, shame, shame on all world leaders for not providing these products.

We are at a tragic turning point. Open up societies so our healthy workers can produce & deliver essentials like food and medicine OR continue to try to stop the unstoppable.

While we have lost the battle, let's not add insult to injury by losing the war.

UN World Food Program Executive Director David Beasley:

"He underscored the critical importance of balancing sensible measures to contain COVID-19, with others to keep borders open and trade flows moving. It is vital to guard against unintended consequences that can hit the poorest the hardest." link
 
put some infected animals in cages into a room. Remove them including cages and put other
animals in new cages into the room.. See how many get infected.
Fouchier must have done this ?!
 
also that study from the German meat-factory, discussed in a podcast, was it mentioned here ?
I can search an URL. They found exactly at what distance on the assembly line people got infected
 
ok, I'm starting to understand ... (took a while, and the press, WHo,RKI,twitter-experts didn't say it yet0
-------------------------
the 2nd wave is just slower than the first wave in western Europe. redoubles every 14 days instead of every 4 days..
This is probably because of the measures, masks and closures.
But we have no drastic measures, lockdowns - so it is probably not declining as in wave1 but will take longer.

In total we will probably get more people infected than in wave1 ... (by seroprevalence)
and the total mortality may be 30%-50% of wave1's in Italy,Spain,France,UK

who also gives predictions ? (except IHME,, covid-projections)
https://ncovinfo.createaforum.com/ncov-discussion/apr07-model-uofwa/msg207/#msg207


who so bad in Israel,Argentina,Kosovo,in wave 2
 
NEWS RELEASE 23-SEP-2020

US study shows decline in viral load of patients with COVID-19 as pandemic progressed


EUROPEAN SOCIETY OF CLINICAL MICROBIOLOGY AND INFECTIOUS DISEASES

Research News

A US study from the city of Detroit, presented at this week's ESCMID Conference on Coronavirus Disease (ECCMID, online 23-25 September) shows that the initial SARS-CoV-2 viral load in nasopharyngeal samples has been decreasing as the pandemic progressed. The authors also observed that the decline in viral load was associated with a decrease in death rate. The study is by Dr Said El Zein, Wayne State University/ Detroit Medical Center, Detroit, MI, USA, and colleagues.

The dynamics of the SARS-CoV-2 viral load (VL) on a population level remain poorly characterised. In this study, the authors present data describing the downward trend in the initial SARS-CoV-2 VL in nasopharyngeal swab samples of hospitalised patients in Detroit, Michigan during the period of April 4- June 5, 2020.

They conducted a retrospective study that included all hospitalised patients who had initial nasopharyngeal swab samples analysed at the Detroit Medical Center, that returned positive for SARS-CoV-2 by PCR testing between April 4 and June 5, 2020. To estimate the viral load, the authors used the so-called cycle threshold (Ct) value provided by the test for each sample - a higher Ct indicates a lower viral load. Based on their studies, the authors designated high, intermediate, and low VL samples to have a Ct value of 25 or under, 26-36, and 37 or over, respectively.

During the first week of the study (week of April 4, 2020), 49% of the initial VL samples were in the intermediate group, compared to 25.5% each in the low and high VL categories respectively. Thereafter, there was a progressive decline in the percentage of samples in the high and intermediate VL categories with a concomitant rise in the percentage of samples in the low VL category.

By week five of the study, 70% of the positive samples had an initial low VL. This trend in initial VL coincided with a decrease in the percent of deaths (see figure 1 in abstract). Almost half of the patients in the high VL group died (45%) compared to 32% and 14 % of the intermediate and low VL categories respectively (Figure 2).

The authors concldue: : "During the April-June 2020 period of the COVID-19 pandemic, the initial SARS-CoV-2 load steadily declined among hospitalised patients with a corresponding decrease in the percent of deaths over time.Though confounding variables have not been evaluated, this suggests an association between initial viral load and mortality."

Dr El Zein adds: "Exact reasons for a decrease in initial viral load over time are unclear. A downward trend in the initial VL may reflect a reduction in the severity of the pandemic and trends in the viral load values over time may represent a marker to assess the progress of the pandemic. Rapid implementation of social distancing measures, lockdown and widespread use of facemasks may have contributed to a decrease in the exposure to the virus."

###

https://www.eurekalert.org/pub_releases/2020-09/esoc-uss092320.php
 
I am not sure their conclusion re initial viral load makes a lot of sense. If I was looking for evidence of masks, or physical distancing, reducing initial viral load I would be looking at the time between infection and symptom onset. The course of illness has four phases Incubation, the viral phase, the immune pathology phase and the clotting phase. The <25Ct scores would relate to the viral phase and indicate that the patient was shedding virus, for most people this would last about a week from a day or two prior to symptom onset, in severe cases shedding can go on for much longer. Ct scores >25 would be expected in patients with very low viral loads who are now hospitalised to deal with immune pathology.
Of these phases the least predictable, in terms of how long it takes, is going to be the first which is normally given as from 2 to 14 days. This covers the slow multiplication of a minuscule initial viral load to the point it could be detected by PCR and then a very rapid increase up to the point the patient notices they have a problem. Most of this variability will be due to the host immune response, which may clear the virus without the patient ever developing symptoms, but in part it will be due to how many infectious virions in the initial droplet actually got into a cell and started replicating - less initial viral load needing more replication cycles needed to catch up to the point that a higher viral load started at. If our changes in behaviour reduced the average initial viral load then the time these initial additional replication require should show up as a lengthening of the time taken to reach peak viral titers. This will also provide the immune system a little more time to get its act together. How much each of these contributes will be difficult to unpick without a lot more well documented initial infection time points and detailed longitudinal examination of the Ct values over the infectious phase. In post #273 (https://flutrackers.com/forum/forum...covid-19-new-coronavirus?p=891772#post891772) of this thread I posted a graph showing the typical viral attack and decay curve.
 
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just speaking about what I remember from influenza :
when a virus enters a cell , it creates 10000-100000 progeny in 6-10h and the cell eventually
dies because of too many viruses. So it won't matter how many initially go in ?!
OK, the start of the replication process going into nucleus, could depend on
luck so only a fraction succeeds, increasing the probabbility with higher initial loads.
But once the first cell emits progeny, this should overwhelm the initial load.
Flu symptoms start suddenly within minutes becuse the process goes 8h..8h..8h
per virus-generation. SARS2 could be lurking, entering cells with delay
 
Interesting timing. We don't know if there is any truth in this.

I would not be surprised if they will be "cured" completely. By hydroxychloroquine?
 
gs
As you point out once infection starts producing new virions the numbers grow exponentially to the point the initial load is insignificant. By the time you have a Ct score of 25 you have about a million copies of RNA per ml in your swab sample and trillions of virions in your body. In practice initially the first step is transcription/translation of proteins which are none structural (most of the CoV genome) as these are involved in the suppression of the intracellular immune response (principally INF alpha). This is all in the cytoplasm and controlled by expression and suppression markers attached to the RNA which tell the polymerase complex which proteins need producing first and in what quantities. At this point some viral peptides are transported to trans-membrane MHC class 1 proteins and made 'visible' to the extracellular immune system ready to prime the adaptive immune response. Once the NSPs have dampened the cells immune response the structural proteins can begin production ready for new virion formation and the viral RNA needs to get into the Nucleus to start whole gene replication to make new copies which are exported back into the cytoplasm where they are coated in NP and packaged inside the new structural protein capsid prior to budding. At least that is my understanding of the process.
Corona viruses are a lot more complex than flu as they have over a dozen NSPs and accessory proteins where flu has just one. Flu's NS is heavily involved in interferon suppression which is the cell's primary defense, I think NSP3, in CoVs, plays a similar role but I do not know what all the others do so there may be others involved. I do not know if anybody knows what they all do but I suspect as we learn we will find they account for much of SARS-CoV-2's complex pathogenicity profile.
 
jjackson, thanks for the overview. You have a much more detailed understanding than I.
So initially it's a complicated "fight" with intracellular defense.
And only if the viruses survive , one or more of them can later produce full virions.
It could be an advatage for the initial load to get as many as possible of them into the same cell
immediately (droplets), rather than getting lost in multiple different cells (airborne). (?)
 
I tend to believe it. If you look at his actions and the amount of people he is around at the White House, rallies, fund raisers, etc. it is actually probable in my opinion. COVID-19 is highly transmissible. His campaign is off track now. The nomination of Judge Barrett is pending...a lot of things he wants to do. I do not think he would see it as in his interest to stay in the family quarters of the White House for 2 of the 4 weeks before the election.
 
gs
In answer to your droplet vs aerosol question the short answer is I do not know.
The long answer goes back to your 'complicated fight' which has far more moving parts to it than my simplified comment. In the evolutionary arms race between host and pathogen many measures and countermeasures and counter-countermeasures have been evolved. For example flu has a -ssRNA genome and negative sense RNA is not produced by the host so there is a mechanism to detect -RNA in cytoplasm and destroy it. CoVs have +RNA which there is plenty of in the cell as it is produced as mRNA in transcription. mRNA is short, compared with vRNA (nearly 30,000 bases for CoVs), so that host cells have developed two trans-membrane proteins such that if the RNA is long enough to stretch between them it turns on a pathway that leads to the translation of a protein to chop it up. There are lots of other defense mechanisms and it will also need to produce a protein to let it breach the nuclear membrane as the vRNA is too big to use the nuclear pores. From the cells point of view it will immediately start ramping up interferon production and releasing it (INF is normally retained in the producing cell) so neighboring cells can detect it and start shifting transcription to defensive proteins. The cell also starts making MHC class 2 proteins and inserting them in the cell wall (normally cells, apart from some immune cells, do not have class 2) which display peptides that can be detected by T cells and mark the cell for destruction by CD8 cells. From all of this if a cell gets a low viral load it may be longer before it is detected and the cell's response will be dose related i.e the more copies detected the faster and more aggressive the response. A rapid response at a point source may be less of a problem to deal with than lots of dispersed low level warnings any one of which that got control of the cell could rapidly produced lots of infectious virions. There are some interesting advances in microfluidics that allow the placing of one cell in each of many wells which can then all be infected and there are vast differences in the rate at which disease progression occurs between the wells. Normally in a plaque assay you can not observe this as you only see the net effect.
Nothing to do with this but I learnt something new recently I thought might interest you, the H17 & H18 bat flus do not use sialic acid residues for cell entry but they do have H & N so I have no idea what the N does - if anything.

Edit. On re reading this I note that I did not explain the relevance of the microfluidics. The cell placed in each well are the same (Vero cells or similar) and they all get a similar initial viral load. New virus produced by any of the wells stay in that well and can not infect others in the well grid. When looked at under the microscope most of the single cell wells develop disease but at wildly different rates. In vivo, if you get the same behaviour, the same amount of virus infecting lots of separated cells will elicit some that handle the infection well and some that get immediately overrun. With our current technology finding out exactly how each of these battles played out is still out of reach.
Edit2
I checked and H17/18 uses MHC class2 which rather limits what it can infect as these are nothing like as ubiquitous as glycans.
 
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