The biology of coronavirus COVID-19 - including research and treatments

Scientists Uncover Biological Signatures of the Worst Covid-19 Cases

https://www.nytimes.com/2020/08/04/health/coronavirus-immune-system.html

 

Some seemingly positive results for treatment with convalescent plasma - with caveats:

http://www.msn.com/en-gb/health/med...a-suggests/ar-BB17BDQX?li=AAnZ9Ug&ocid=ASUDHP

 

Suppose this is probably the best place:

BBC1 showed a programme last night called "Surviving the Virus: My Brother and Me". I came in part-way through it, but what I saw looked good and convincing, and emphasised the severity and variability of the illness. If you're in the UK, you can catch up with it on iPlayer. Partial review, courtesy of The Mirror:

http://www.msn.com/en-gb/entertainm...ronavirus-documentary/ar-BB17BYYe?ocid=ASUDHP

 

On this topic, several groups are developing monoclonal antibodies (often treatments combining several), which may be brought to market at around the same time as vaccines.

 

This isn't new, so may already have been posted before, but I couldn't find it.

Title : In Draft Results Accidentally Published by WHO, Gilead’s Remdesivir Shows No Benefit vs. COVID-19

Link : https://www.genengnews.com/news/in-...eads-remdesivir-shows-no-benefit-vs-covid-19/

Date Posted : 24 Apr 2020

 

@Jonathan Edwards what do you think about this?

https://twitter.com/user/status/1281181400809365505

 

https://www.theatlantic.com/health/...nity-is-the-pandemics-central-mystery/614956/

 

Another medical doctor who rarely if ever read epidemiological literature before COVID-19 the literature and believes the elite-group think that somehow far more people have been infected than measured.

The sensitivity of the serological tests is somewhere around 90%, meaning around 10% of cases are missed. But the specificity is not perfect either, even 99% specificity will over estimate cases by more than 10%, if a non-selected (general population) sample is used, and overall prevalence remains less than 10%.

 

Just stumbled across this:

https://twitter.com/user/status/1280211773623336961


A surprising claim. What do we make of it?

 

It turns out a percentage of asymptomatics are actually presymptomatic, something that shouldn't surprise anyone with experience with epidemics. What is scary here is that even people clinically considered to never show symptoms could have viral loads in the upper respiratory system as great as those classified as symptomatic. Here's the account in BGR, based on a paper in JAMA. The implications are that we are far from knowing how to control this, since nobody is isolating asymptomatic people for the period this study found necessary in some people. (This might fit in with Bill Gates comment that current tests are garbage.)

I'm going to weigh in on the side of infections being several times what tests show, even when you test everybody, for an unusual reason; I've used a multiplier to predict future cases loads with some success. We are only catching a fraction of cases, even when we are doing heavy testing.

There are many ways for false negatives to occur. Well-designed tests produce few false positives. A fundamental problem is that immune response is highly varied in type of immune activity as well as strength of response. There are a lot of possible immune activities to control a virus.

The word I would assign to one principle of immunology is "variety". Populations that present a monoculture of defenses are notoriously vulnerable, as animal breeders can tell you. Humans are far from being a monoculture. (This even concerns the way ordinary antibody responses develop in homozygous twins. The antibodies are not necessarily identical.)

We still don't know why everyone on various cruise ships was not infected. Those were like Petri dishes before anyone understood the seriousness of the problem.

Whatever protection those resistant had prior to exposure could not have depended on the unique spike proteins of SARS-CoV-2. It may have been connected with characteristic RNA sequences common to other coronaviruses, at least four of which cause "common colds". The study of immunity to RNA sequences is in its infancy, and I don't believe any RNA vaccines have been used on humans. Other proteins necessary for infection may not have been identified.

A second word I use to describe immune response is "specificity", which may seem like a mistake when you think about autoimmune diseases. Even these involve very precise targets on molecules which unfortunately are used for other purposes. The general conception of "strengthening the immune system", which any number of things are said to do, badly misjudges specificity.

Aside: I had an uncle who spent time sitting in uranium mines because this was shown to "stimulate immune response", as did springs with radioactive water. He died of cancer. Limited exposure to ionizing radiation does stimulate immune response, but that is not necessarily good.

Another word characterizing immune response might be "amplification", which is generally expressed in terms of "clonal expansion". Really tiny signals are amplified into powerful and specific responses when everything works as expected. The problem this introduces is that the original danger signal may be far too weak to identify, in an environment dominated by that response. I'm convinced that we generally don't find substantial quantities of antibodies until a great deal of damage has been done. In some cases, I'm convinced the damage is due to an early immune response we failed to detect, but I can't determine what that original action may have been.

The final words of importance I use are "time" and "rates". We are dealing with races between many exponential processes, if you aren't thinking in terms of rates, you are missing the point. That could take a book all by itself, so I will stop here.

 

The "40% of people have innate cellular immunity" is nonsense because it is nonspecific. (and specificity is the fundamental basis of the adaptive immune system!)

New York state's confirmed case rate is 2.5%. Claims that seven out of eight people infected have not been tested at all is not credible. If only 1/3-1/2 have been tested, then that puts the range 5%-7.5%.

Population based studies in Spain and Italy are finding around 2.5-5% have been infected.

But even if it was 20% in New York, that is still far from herd immunity, which still likely requires 80%+ with immunity, given the uncertainty about the R0.

True "asymptomatic" cases are rare to nonexistent. I daresay all examples of such are "presymptomatic" and the patient is simply ignoring the subtle signs suggesting they're coming down with an infection. (dismissing it as allergies, tiredness, etc)

It is important not to confuse a myriad of reporting biases with having no actual symptoms.

The study you cited was retrospective and did not measure symptoms in a systematic way that would eliminate the biases. (a flaw shared with many of the retrospective clinical-data based COVID studies). They also didn't explain why the patients were tested in the first place - given that back in March, people only got tested if they showed symptoms or were exposed to someone with the virus.

I'm reminded of several published anecdotes, such as the case study of a Chinese woman who went to the hospital complaining about shortness of breath, with the manuscript claiming this was an example of asymptomatic spreading (despite the fact that the woman turned up at the hospital with a symptom!). Or the cases of asymptomatic "glassy lungs" (which is a symptom by definition) - which suggests reporting biases by doctors as well as patients. Some people don't interpret their symptoms as being associated with a viral infection and thus don't report them, particularly if the patient doesn't have a fever. And then there are the patients who deliberately lie because they don't want to be stuck in hospital/forced to self isolate.

I don't buy that at all. I can accept the argument for undersampling of confirmed cases, with some people never getting tested, but invoking reasons just because the test data doesn't give the answer you want to see? Hmm. It is possible that samples might not being collected properly at particular sites due to improperly trained staff. But that is something that would show up in reviews of the lab data (though I guess some labs might want to hide this truth). Labs, if they know what they are doing do actually routinely test control samples (blindly) to make sure that nothing suspicious is going on.

Also, note that many of the estimates doing the rounds on social media claiming 10x undersampling were in the initial weeks when there were shortages of tests/test centres. That shortage no longer exists and social factors are also diminished, since pretty much everyone knows by now that the virus is serious. That leaves the people who choose not to see doctors, or lack ability/access to testing due to disability, lack of family support etc.

 

https://www.skynews.com.au/details/_6179108952001
Prof Tom Borody, Gastroenterologist... Ivermectin for prevention & treatment

 

In epidemiology it is standard to estimate how many cases you are identifying, versus the number implicitly in the community. We have had serious problems with political denial there is ANY community spread or ANY asymptomatic spreaders. As an example, we just had our governor authorize the return of people without symptoms to handle food in restaurants. (If you have trouble with that link, you might be able to read this one.)

For much of this pandemic I've been using a multiplier of 5, and assuming there was a great deal of community spread.

When this mess is over, and all kinds of things are known for certain, we will have a much better idea of various important numbers. What I'm telling you is that predictions made with a substantial multiplier have done better than many other models in making predictions. This is still true, even though the multiplier that works best has come down. Control of epidemics requires taking action based on incomplete data about transmission.

Waiting for the kind of reliable data you describe amounts to a default decision to let the pandemic burn itself out, at whatever cost that implies.

I'm not making detailed distinctions between asymptomatic, presymptomatic and oligosymptomatic, which your examples touch on. I'm talking about people who genuinely think they do not have any infection, and who exhibit no clinical symptoms their doctors recognize. That example of "glassy lung" would be a definite sign, not a symptom, but it would turn up on an X-ray. If the doctor and patient both fail to think anything is wrong there will not be such an X-ray.

After those initial chaotic months, the multiplier I used came down, but that was the same time when various authorities learned about manipulating numbers to fit some political narrative. The problem at present is that chaotic disorganization has been replaced with organized misinformation. Those responsible have not realized the problem with distorting data so that all the numbers fit together. Here in Florida we have local communities that are hard hit running their own community dashboards using data from local hospitals. We have the state firing those who created the original state dashboard. We have the White House intervening to cut the CDC out of the loop of collecting data for the entire nation, turning this over to political appointees at HHS. I could go on, but the result would simply be more distrust of the numbers. I'm having to act like an amateur intelligence analyst trying to figure out what is really going on in a hostile nation.

I've been in that situation before, but that is a different story.

(If you think Florida is unique, you should see the disparity between different counties in Texas. Some say they have had only a handful of cases, and don't expect more. Another county (Karnes) is currently running 306 cases per day per 100,000, many times what the state as a whole is doing. That infection rate is terrible. Here's an explanation of what it means. If I lived there, I would stay in my bunker until water ran out.)

My simple prediction is that we will find that Florida does not have the pandemic under control, nor does the nation. The bottom line will be a surge in deaths, weeks or months after infection. We are still running well over 100 deaths reported per day, (182 yesterday,) in this state alone. With 20% of this state's population counted as elderly, it will take a long time to exhaust the number of susceptible people at risk of dying.

For the nation, there are predictions of 300,000 dead by the end of this year. My private estimates look higher. I keep hoping something will change.

That study in Korea was done in a way that probably would not work in the U.S. When a rash of cases appeared in members of one church, the KCDC stepped in and isolated everyone who might have been exposed. They also chose a group to use for tests described in the paper. Nobody fought lawsuits all the way to their supreme court.

As for the phrase "since pretty much everyone knows by now that the virus is serious", (assuming you mean everyone sane,) you must not keep up with U.S. news and lack regular interactions with people who are still deep in denial, like some neighbors. When I went to get groceries last night I saw one person wearing both a face mask and a transparent shield. I also saw people who only put some kind of cloth over their face so they could get in the store, which now has someone outside to stop them if they don't.

We've just been through a bitter local dispute over reopening schools. There is no money allocated for personal protective equipment or extensive testing. Teachers are told to implement CDC guidelines, "if feasible". All you need to do is count class sizes and room sizes to see that recommended spacing is not feasible even if students should become compliant angels. My teacher friend has filed retirement paperwork. This makes sense to me, because while she indicated she preferred to teach via the Internet, she was given no guarantees. If she was ordered to teach face-to-face, and refused, she could be dismissed for cause.

I don't understand those, including teachers, who argued vociferously for face-to-face classes without adequate protection, support and testing.

Some aspects of our national debate sound to me a lot like Livia's pep talk to her gladiators in "I, Claudius", where she accuses them of using tricks that are ruining the games in an effort to stay alive. (Unfortunately, that clip misses her opening statement, "You're all scum, and you know it.")

 

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2769235

 

Here in my state of Oregon, the Oregon Health Authority reported at the end of July:

While the situation is better than it was in March, my understanding is that testing capacity remains a problem throughout much of the United States, especially in states mentioned by @anciendaze .

 

I just learned that a friend who is acting as city manager for a small Florida city needed to be tested to avoid spread among people providing essential services for city government. This is supposed to be a high priority to prevent a breakdown in government. It took 9 days for results to come back.

He also provided some insight on the subject of "asymptomatic" patients testing positive. One member of his staff tested positive some time ago, but showed no obvious symptoms. He then isolated for two weeks, and then was tested under the guidelines requiring two negative tests to return to official duties. He again tested positive twice. He has just gone through the third cycle of isolation, and again tested positive twice. This adds up to 6 weeks without symptoms anyone has found, while remaining positive by molecular tests.

Put these stories together and you can understand why current testing and tracing procedures are not working in this state. Even a small percentage of people with similar stories can infect a lot of people, if they are less scrupulous about isolation and testing.

 

and it still is. I wonder whether the virus could still be there?

 

Interesting research re role of misfolded proteins
https://phys.org/news/2020-08-protein-sars-cov-rapidly-cells.amp?__twitter_impression=true

 

The NY Times had a good feature on August 11 about immune response as a problem with COVID-19. Some articles on coronavirus are free access, but I have trouble telling because I have a subscription. They detect this even when I am not logged in. Forgive me if you hit a paywall.

Immunosuppression and immune modulation have been contentious subjects ever since steroids/glucocorticoids were discovered. I've had trouble finding published references to the first use in treating TB patients. Short version: it was a disaster. Patients felt better because of reduced inflammation, but the infection ran wild. By the 1950s there were regular reminders of previous experience.

Aside: at the time in the 1930s when steroids were first used it was not unusual to find about 1/3 of the patients in mental hospitals were infected with TB. Others had syphilis. In many cases symptomatic relief was about the best one could hope for. Deaths of mental patients were not considered entirely bad.

The problem is that many patients do not respond well to the stimulus-response paradigm used by far too many M.D.s
(Patient has R.A.=> prescribe analgesics and steroids.) Finding out which parts of a complex response are causing trouble, and limiting this requires considerable judgment. When used in infectious disease one needs to take great care to limit the intervention in immune response to the right paths and minimum strength and time. Most M.D.s have inadequate training in this field.

 

Biological systems are simplified down too much of the time. It would not matter if people understood it was a simplification but that gets lost and everything becomes black and white dogma.

I remember being shocked at the treatment protocol for ketosis in diabetes. It seems simple, give insulin to get rid of excess sugar in the blood then get rid of the ketones, but it is a very, very complex procedure with everything being reduced a little at a time and the patient's reaction continually monitored.

It annoys me that ME and FND are treated with trite soundbites that are remote from medical treatments for anything else.