Coronavirus

[renim]

Yawn.

Yes, there are 6 other Coronaviruses out there which we have all be exposed to (common cold viruses).

Just because you have a T-cell response or an anitbody DOES NOT mean that response is an "effective immune response" and indicates immunity.

They are called "Cross Reactive" T-Cell and antibodies. There is a small chance they will help, but it's like . . . trying to fill a lake with a garden hose.

i used "some level of immune response " which (to me anyway) is not quite the same as "effective immune response", but rather was meant to imply a range from from near zero to perhaps a meaningful amount. In particular, I would expect historic exposure to other Coronavirus to have different levels of +ve benefit vs covid19, just as different co-morbidities have different levels of -ve detriment.

My first thought was, what a pity this data is not also within the comornidity data, (by then its too late to collect)

 

[bkp_duke]

Understood. On a scale of 0 to 1, with 0 being useless immune response, and 1 being protective, I would estimate this hovers between the 0.05 and 0.1 range.

The S-protein on SARS-CoV-2 is different from other coronaviruses, and that is what determines it's virulence. It's evolved so that it bypasses most existing immune responses.

 

[AlanSubie4Life]

i used "some level of immune response " which (to me anyway) is not quite the same as "effective immune response", but rather was meant to imply a range from from near zero to perhaps a meaningful amount. In particular, I would expect historic exposure to other Coronavirus to have different levels of +ve benefit vs covid19, just as different co-morbidities have different levels of -ve detriment.

My first thought was, what a pity this data is not also within the comornidity data, (by then its too late to collect)

And, from everything I've read (and the abundant evidence from multiple institutions/locations showing nearly everyone can be infected and become infectious!), it's simply baked into the IFR, and most likely does not affect the herd immunity threshold (really the most important possible additional benefit of T-cells!).

So (perhaps) a way to think about this is that without cross-reactive T-cells, the IFR would be even higher than it already is.

So...baked in; perhaps very helpful in reducing mortality (no idea!) - but regardless of whether it does or does not, we already have realized that improvement.

More of an academic exercise to determine WHY some people do better after infection. But most likely it's not very predictable how effective the cross-reactive T-cells will be in any given person, so it's not like you could do a pre-screen and tell people "yeah, you have cross-reactive T-cells, you're good to go." Also potentially helpful for developing therapies I guess, but I know nothing about that.

I knew we were going to end up talking about freaking T-cells again. Again the key thing is: no apparent impact on herd immunity threshold, unfortunately.

 

[dfwatt]

Drs. Maureen E. Czick, an anesthesiologist, Christine L. Shapter, MD, a psychiatrist; and Robert K. Shapter, MD, a family medicine doc offered this summary in MedPage as an Editorial about the biology of COVID19. I think it’s really worth reading. I could add that all of these nasty effects emerging from the disruptions of a key branch of the RAS of course are over and above and in addition to the standard disruptions caused by innate immune system activation as it encounters a novel pathogen, and has to attack and destroy cells that have become viral factories. And over and above the suffering imposed on us by our own cytokines in that process, perhaps esp. interferons (most critical players in relationship to viruses), which are notoriously unpleasant signaling molecules. I have posted the whole thing below to save you time, and it includes some analysis of the now famous and promising bradykinin disinhibition theory. Apologies if this is a bit too technical for some, but hopefully with repetition, some of these ideas can begin to make real sense. By way of simple explanations, the renin-angiotensin system, is the critical system for the regulation of blood pressure, blood volume and fluid balance homeostasis, but has other collateral functions as well (on INFLAM and cell fate decisions), and the RAS has an inhibitory feedback control loop via the ACE2 receptor. That inhibitory branch of the system is basically devastated in Covid 19.

“Occam's Razor posits that "the simplest explanation is usually correct." With COVID-19 the simplest explanation is that the coronavirus strikes one cellular target but does so in essentially every organ and tissue within the human body, such that a single mechanism underpins all coronavirus effects. To accomplish this, the target must be a cellular pathway that impacts nearly every bodily system.

COVID-19 defied public expectations of a flu-like respiratory illness, and instead presented something unpredictably menacing. A maelstrom of unexpected coronavirus complications perplexed the medical community, from renal failure to silent hypoxia, from hyperglycemia to loss of olfactory sensation, from a Kawasaki-like myocarditis syndrome in children to blood clots and strokes in young adults.

Simultaneously dysregulating blood clotting and gastrointestinal function, damaging kidneys and lungs, perturbing neuronal processes and immunological function, the coronavirus appeared to be disrupting myriad cellular pathways simultaneously. But that would indicate that a tiny RNA virus, incapable of even replicating itself independently, can perform a staggering array of disruptive cellular actions.

RAS, the renin-angiotensin system, is well known as a circulating corrective mechanism, restoring blood pressure and blood volume in the event of hemorrhage or dehydration. But RAS is also a pervasive regulator of myriad tissue-level functions, ranging across the spectrum of bodily systems: glucose metabolism, cardiovascular functions, hypoxia sensing, neural crosstalk, inflammatory response, coagulation, and more.

During stress response to severe injury, the priority is re-establishing physiologic homeostasis compatible with survival and that requires integrated responses by almost all organ systems. Evolution made RAS the master regulator coordinating these processes.

The classical depiction of RAS is a linear cascade of enzymatic activations, beginning with angiotensinogen conversion to angiotensin I (AI) by renin, followed by AI conversion to angiotensin II (AII) by ACE. This sequential pathway is called "the ACE axis." AII binds the AT1 receptor, initiating its multiple effects, including renal sodium conservation, coagulation, inflammation, fibrotic repair, and cell death.

RAS contains additional components that counterbalance the ACE axis. The AT2 receptor offers an alternative for AII binding, yielding anti-coagulation, anti-inflammation, and anti-fibrosis effects. And ACE2, a "younger brother enzyme" to ACE, metabolizes AII, so that it is unavailable to bind AT1.

ACE2 converts AII into an anti-inflammatory counterpart called A1-7. ACE2 also diverts AI out of the ACE axis, converting AI to an anti-inflammatory precursor, A1-9, thereby preventing creation of AII. Thus, "the ACE2 axis" decreases activation of AT1 by AII, and acts as a counterweight to the ACE axis. RAS is not linear after all, but rather a web of interlinked enzymatic processes.

SARS-CoV-2 enters cells by binding cell-surface ACE2, traveling as an uninvited guest when a cell recalls ACE2 to its interior. Once inside, coronavirus shuts down cellular production of ACE2, leaving the ACE axis running amok.

AII (angiotensin 2) overproduction by unbalanced ACE triggers unnecessary coagulation leading to blood clots and strokes; it provokes inflammation and fibrosis that damage renal tissue and promote arrhythmias. And it disables glucose-regulating functions of the insulin receptor, leading to hyperglycemia and diabetes. AII also disrupts cellular volume regulation and triggers inappropriate cell death, both of which may explain carotid body failure to register hypoxemia, leading to silent hypoxia, as well as loss of olfactory neurons, which disables sense of smell.

COVID-19 is deadly because it targets the RAS master-regulator, and there is no backup quarterback. Multiple organ functions spiral into disarray, as SARS-CoV-2 turns a guardian of our evolutionary survival against us.

Importantly, many population subsets demonstrating worse COVID-19 outcomes express a pre-existing RAS imbalance, with elevated ACE activity and diminished ACE2 counterweight, before ever encountering SARS-CoV-2. These include people with diabetes, people with hypertension, people who smoke nicotine products, people with obesity, certain cancer patients, males, and older adults.

In addition, there is evidence that some African Americans and Hispanics may carry genetic predisposition to RAS imbalance, due to ancient evolutionary pressures from water and sodium scarcity in tropical climates.

In essence, coronavirus pushes organ function toward a cliff by downregulating ACE2; but high-risk individuals who have baseline ACE overactivity and low ACE2, begin closer to that cliff, and thus are more likely to be pushed over it by the virus.

This does not indicate that RAS imbalance is the only factor responsible for COVID-19 severity. People with diabetes, cancer patients, older adults, and people with obesity have demonstrable nutritional deficiencies and immune impairment. Males have recognized differences in immune function compared to females, and males typically have higher rates of smoking. Socioeconomic disadvantages have been rightly emphasized when assessing mortality disparities breaking along ethnic lines.

Yet the fingerprints of RAS imbalance are clearly found across the widespread organ damage and demographic outcomes in COVID-19, suggesting that RAS is in fact the common denominator.

ACE inactivates the vasodilatory mediator bradykinin, so RAS imbalance would trigger bradykinin depletion (EDIT THIS IS A LIKELY TYPO!!- collapse of ACE2 signal triggers BK disinhibition), the root of the COVID-19 bradykinin hypothesis. And although a recent study did not find increased levels of circulating inflammatory mediators in COVID-19 patients, evidence from the hypertension realm suggests that tissue RAS is more important than circulating RAS for organ system damage and tissue levels of RAS and cytokines are not as easily quantified in humans.

Hence, the evidence suggests that ameliorating RAS imbalance, via ACE inhibitors or angiotensin receptor blockers, should be the urgent focus of more widespread clinical trials.

There are multiple ongoing or planned ACE inhibitor and angiotensin receptor blocker trials, but many are looking at the same agents, rather than exploring many other available drugs in those classes. All of these have distinct pharmacologic properties that may influence potential effectiveness -- including some that cross the blood brain barrier and thus may impact COVID-19 neurological dysfunction.

In addition, recombinant ACE2, entered in one European COVID-19 trial, and an AT2 agonist C21, trialed in pulmonary fibrosis, could be more widely studied. The vitamin D receptor inhibits RAS at the tissue level, and African Americans and older adults more frequently exhibit vitamin D insufficiency, so targeted vitamin D trials in higher-risk COVID-19 populations may yield benefit.

As COVID-19 continues raging through many parts of the world, and new outbreaks emerge in areas once deemed under control, finding the means to blunt the mechanism of COVID-19's destructiveness grows only more urgent. Evidence suggests RAS imbalance is that mechanism.

We already possess pharmacological tools to squash ACE axis overactivity; we should use them all." (Medpage Sept 29 2020)

In a separate piece, here is a graphic that summarizes some of this and makes it (minimally?) easier to see the imbalance in the system caused by the crashing of the ACE2 branch, although its still a busy slide and it leaves out BK promotion. But the green blocking arrows are protective effects, the red pointy arrows are destructive ones associated with COVID19.

 

[renim]

Domestic flight Australia

Flight-Associated Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Corroborated by Whole-Genome Sequencing
Flight-Associated Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Corroborated by Whole-Genome Sequencing.

 

[AlanSubie4Life]

Domestic flight Australia

Flight-Associated Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Corroborated by Whole-Genome Sequencing
Flight-Associated Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Corroborated by Whole-Genome Sequencing.

I sure hope that 1) masks help 2) they are keeping airplane bathrooms clean 3) they've taken steps to review their ventilation settings to maximize air cleanliness.

i used "some level of immune response " which (to me anyway) is not quite the same as "effective immune response", but rather was meant to imply a range from from near zero to perhaps a meaningful amount. In particular, I would expect historic exposure to other Coronavirus to have different levels of +ve benefit vs covid19, just as different co-morbidities have different levels of -ve detriment.

My first thought was, what a pity this data is not also within the comornidity data, (by then its too late to collect)

Just wanted to follow up on this with a relevant thread from a researcher on cross-reactive T-cells (I think I've posted it before though) - offers a good primer & explanation of why cross-reactive T-cells are of interest:

Thread by @profshanecrotty: 1/ There are various tweets misinterpreting COVID-19 “pre-existing immunity” and making dangerous claims about herd immunity. Since many of…

 

[madodel]

Drs. Maureen E. Czick, an anesthesiologist, Christine L. Shapter, MD, a psychiatrist; and Robert K. Shapter, MD, a family medicine doc offered this summary in MedPage as an Editorial about the biology of COVID19.

Thanks for posting this. This is the best explanation I have read so far of how this virus is so damaging to the body.

 

[SMAlset]

Just read on Bloomberg that Hope Hicks who traveled with the president for the debate on Tuesday and then to a Wednesday rally has come down with covid. No masks worn at those events. Says reportedly experiencing symptoms and that no indication the president has contracted it. Isn’t it likely too early to show signs of infection though? Kind of a long article and it’s sort of paywall with limited articles per month but that’s the gist of the article if you can’t see it. Sure more press coverage will be out soon on this due to being WH staff.

Trump Aide Hope Hicks Tests Positive for Coronavirus Infection

 

[NikolaACDC]

Coronavirus vaccine trial participants report day-long exhaustion, fever and headaches — but say it's worth it

"After getting the first shot on Aug. 18, he said he felt a little under the weather for several days with a low-grade fever. He got his second shot at a clinic on Sept. 15. Eight hours later, he said he was bed bound with a fever of over 101, shakes, chills, a pounding headache and shortness of breath. He said the pain in his arm, where he received the shot, felt like a “goose egg on my shoulder.” He hardly slept that night, recording that his temperature was higher than 100 degrees for five hours.
After 12 hours, Hutchison said he felt back to normal and his energy levels returned.
...
A Maryland participant in his late 20s said he experienced nausea after the first shot, but it wasn’t until the second that he “really felt things.”
He said he woke up at 1 a.m. with chills and a 104 fever. He said the fever went down after he took Advil and Tylenol but it lasted until around 8 p.m.
...
Another participant in Pfizer’s trial said he was up all night after the first shot from the pain of the injection. The booster injection he received caused more of that same pain in his arm, followed by intense flu-like symptoms that hit him around 1a.m. He couldn’t sleep that night without an electric blanket, and shook so hard that it became uncontrollable and he cracked part of his tooth from chattering them."
--------------
Seems we might have to expect some discomfort after getting a vaccine.
Unless they all had a bad reaction to saline solution.

Still, beats death. In more than one way.

 

[AlanSubie4Life]

Just read on Bloomberg that Hope Hicks who traveled with the president for the debate on Tuesday and then to a Wednesday rally has come down with covid. No masks worn at those events. Says reportedly experiencing symptoms and that no indication the president has contracted it. Isn’t it likely too early to show signs of infection though? Kind of a long article and it’s sort of paywall with limited articles per month but that’s the gist of the article if you can’t see it. Sure more press coverage will be out soon on this due to being WH staff.

Trump Aide Hope Hicks Tests Positive for Coronavirus Infection

Please refer to the chart I posted: Coronavirus

It's likely too early for Trump to show symptoms or get a positive test result. Transmission is not a given due to over-dispersion (a small percentage of cases are responsible for a large percentage of transmissions - it's not clear whether this is entirely due to the specific environment (inside, enclosed, etc.), or something specific to certain carriers).

I don't trust the WH testing protocols. It's not even clear that they test every day.

Even with a test every day, with low viral loads, it's possible to get negative tests even when you have the disease.

What we can say it that it's basically certain that she is truly positive, given she is symptomatic and she has a positive (likely PCR) result.

Given that she was symptomatic on Wednesday, if she happened to be a superspreader, she would have likely had the disease and been potentially infectious for several days prior (and this was missed by the testing - which is not all that surprising to me, both due to likely lax protocols and the poor sensitivity of the test the WH is likely using). The disease timeline is obviously quite variable from person to person so it is hard to say.

Given that she's apparently not big on mask wearing, it's entirely possible that she ended up with a virus inhaled deeper into her lungs, and that could have led to viral reproduction without necessarily having much reproduction in the nose (harder to pick up with PCR). Another possibility with no mask wearing: it's possible the initial dose could also have been larger, which would potentially mean higher exhaled viral loads prior to a positive test result (because larger amounts of viral reproduction could occur over a 24-hour period due to the initial starting point being much higher).

In any case, we'll see how it goes. If Trump contracts it, I hope he survives. See above for the statistics (looks like 2-7% IFR at 74, but the impact of comorbidities is complex, and he has the best medical care in the world).

 

[dfwatt]

Coronavirus vaccine trial participants report day-long exhaustion, fever and headaches — but say it's worth it

"After getting the first shot on Aug. 18, he said he felt a little under the weather for several days with a low-grade fever. He got his second shot at a clinic on Sept. 15. Eight hours later, he said he was bed bound with a fever of over 101, shakes, chills, a pounding headache and shortness of breath. He said the pain in his arm, where he received the shot, felt like a “goose egg on my shoulder.” He hardly slept that night, recording that his temperature was higher than 100 degrees for five hours.
After 12 hours, Hutchison said he felt back to normal and his energy levels returned.
...
A Maryland participant in his late 20s said he experienced nausea after the first shot, but it wasn’t until the second that he “really felt things.”
He said he woke up at 1 a.m. with chills and a 104 fever. He said the fever went down after he took Advil and Tylenol but it lasted until around 8 p.m.
...
Another participant in Pfizer’s trial said he was up all night after the first shot from the pain of the injection. The booster injection he received caused more of that same pain in his arm, followed by intense flu-like symptoms that hit him around 1a.m. He couldn’t sleep that night without an electric blanket, and shook so hard that it became uncontrollable and he cracked part of his tooth from chattering them."
--------------
Seems we might have to expect some discomfort after getting a vaccine.
Unless they all had a bad reaction to saline solution.

Still, beats death. In more than one way.

A well-done vaccine should not make you this sick. Obviously they've got more work to do. I pity the well-intentioned volunteers who may sacrifice their health at least for some period of time in order to get the vaccine up and running

 

[Norbert]

Trump and FLOTUS tested positive.

 

[SMAlset]

CNBC news just reporting it: President Donald Trump says he has tested positive for coronavirus

 

[SMAlset]

His age, weight, unhealthy eating, stress don't necessarily bode well for him. Always being around people not wearing masks, and favoring large crowds, and the fact that testing doesn't always accurately pick up the virus doesn't help either.

 

[AlanSubie4Life]

Trump and FLOTUS tested positive.

His age, weight, unhealthy eating, stress don't necessarily bode well for him. Always being around people not wearing masks, and favoring large crowds, and the fact that testing doesn't always accurately pick up the virus doesn't help either.

It is what it is.

 

[ZeApelido]

Trump and FLOTUS tested positive.

FAKE NEWS! This is just another attempt by the liberal media to - oh wait.

 

[ZeApelido]

Have no fear, hydrochloroquine is here.

 

[Daniel in SD]

His age, weight, unhealthy eating, stress don't necessarily bode well for him. Always being around people not wearing masks, and favoring large crowds, and the fact that testing doesn't always accurately pick up the virus doesn't help either.

His doctor said he's the healthiest president ever. We all know Trump is the asymptomatic super spreader. It is what it is.

 

[Tiger]

Have no fear, hydrochloroquine is here.

Faith loves irony. Could someone remind us what was the Trumps' go-to shortlist of covid cures? Bleach?

Knock on wood.

 

[TespaceX]

Among my many thoughts on this development, I think one possibility is that Trump would really downplay this virus further to his base if he happens to be an asymptomatic or very mildly symptomatic case.