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

Scientists are beginning to untangle one of the most complex biological mysteries of the coronavirus pandemic: Why do some people get severely sick, whereas others quickly recover?
When a more familiar respiratory infection, like a flu virus, tries to gain a foothold in the body, the immune response launches a defense in two orchestrated acts. First, a cavalry of fast-acting fighters flocks to the site of infection and tries to corral the invader, buying the rest of the immune system time to mount a more tailored attack.

Much of the early response depends on signaling molecules called cytokines that are produced in response to a virus. Like microscopic alarms, cytokines can mobilize reinforcements from elsewhere in the body, triggering a round of inflammation.
But this coordinated handoff seems to break down in people with severe Covid-19.

Rather than bowing out gracefully, the cytokines that drive the first surge never stop sounding the alarm, even after antibodies and T cells arrive on the scene. That means the wildfire response of inflammation may never get snuffed out, even when it’s no longer needed.
And the quality of these cytokines may matter as much as the quantity. In a paper published last week in Nature, Dr. Iwasaki and her colleagues showed that patients with severe Covid-19 appear to be churning out signals that are better suited to subduing pathogens that aren’t viruses.

Although the delineations aren’t always clear-cut, the immune system’s responses to pathogens can be roughly grouped into three categories: type 1, which is directed against viruses and certain bacteria that infiltrate our cells; type 2, which fights parasites like worms that don’t invade cells; and type 3, which goes after fungi and bacteria that can survive outside of cells. Each branch uses different cytokines to rouse different subsets of molecular fighters.
People with moderate cases of Covid-19 take what seems like the most sensible approach, concentrating on type 1 responses, Dr. Iwasaki’s team found. Patients struggling to recover, on the other hand, seem to be pouring an unusual number of resources into type 2 and type 3 responses, which is kind of “wacky,” Dr. Iwasaki said. “As far as we know, there is no parasite involved.”
This disorientation also seems to extend into the realm of B cells and T cells — two types of immune fighters that usually need to stay in conversation to coordinate their attacks. Certain types of T cells, for instance, are crucial for coaxing B cells into manufacturing disease-fighting antibodies.

Last month, Dr. Wherry and his colleagues published a paper in Science finding that, in many patients with severe Covid-19, the virus had somehow driven a wedge between these two close-knit cellular communities. It’s too soon to tell for sure, but perhaps something about the coronavirus is preventing B and T cells from “talking to each other,” he said.
Timing is also crucial. Dose a patient too early with a drug that tempers immune signaling, and they may not respond strongly enough; give it too late, and the worst of the damage may have already been done. The same goes for treatments intended to shore up the initial immune response against the coronavirus, like interferon-based therapies, Dr. Blish said. These could stamp out the pathogen if given shortly after infection — or run roughshod over the body if administered after too long of a delay.
 
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
 
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

Draft results accidentally published Thursday by the World Health Organization (WHO) on its website showed that Gilead Sciences’ closely watched COVID-19 candidate remdesivir failed to show clinical improvement in severely infected patients in a Chinese Phase III trial.

According to the draft, whose findings were disclosed by The Financial Times, remdesivir had not reduced the presence of SARS-CoV-2 in the bloodstream of 158 patients treated with the antiviral candidate in the 237-patient trial (NCT04257656). Eighteen patients were taken off the drug due to side effects.

Article continues at link given above...
 
Immunity, then, is usually a matter of degrees, not absolutes. And it lies at the heart of many of the COVID-19 pandemic’s biggest questions. Why do some people become extremely ill and others don’t? Can infected people ever be sickened by the same virus again? How will the pandemic play out over the next months and years? Will vaccination work?

To answer these questions, we must first understand how the immune system reacts to SARS-CoV-2 coronavirus. Which is unfortunate because, you see, the immune system is very complicated.
https://www.theatlantic.com/health/...nity-is-the-pandemics-central-mystery/614956/
 
Professor Karol Sikora said:
Antibody tests significantly underestimate the number of people infected

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%.
 
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.
 
Just stumbled across this:



A surprising claim. What do we make of it?


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.

It turns out a percentage of asymptomatics are actually presymptomatic, something that shouldn't surprise anyone with experience with epidemics.

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'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.

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.
 
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.")
 
August 6, 2020
Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea
Seungjae Lee, MD1; Tark Kim, MD2; Eunjung Lee, MD1; et al

Key Points

Question Are there viral load differences between asymptomatic and symptomatic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection?

Findings In this cohort study that included 303 patients with SARS-CoV-2 infection isolated in a community treatment center in the Republic of Korea, 110 (36.3%) were asymptomatic at the time of isolation and 21 of these (19.1%) developed symptoms during isolation. The cycle threshold values of reverse transcription–polymerase chain reaction for SARS-CoV-2 in asymptomatic patients were similar to those in symptomatic patients.

Meaning Many individuals with SARS-CoV-2 infection remained asymptomatic for a prolonged period, and viral load was similar to that in symptomatic patients; therefore, isolation of infected persons should be performed regardless of symptoms.

Abstract

Importance
There is limited information about the clinical course and viral load in asymptomatic patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Objective To quantitatively describe SARS-CoV-2 molecular viral shedding in asymptomatic and symptomatic patients.

Design, Setting, and Participants A retrospective evaluation was conducted for a cohort of 303 symptomatic and asymptomatic patients with SARS-CoV-2 infection between March 6 and March 26, 2020. Participants were isolated in a community treatment center in Cheonan, Republic of Korea.

Main Outcomes and Measures Epidemiologic, demographic, and laboratory data were collected and analyzed. Attending health care personnel carefully identified patients’ symptoms during isolation. The decision to release an individual from isolation was based on the results of reverse transcription–polymerase chain reaction (RT-PCR) assay from upper respiratory tract specimens (nasopharynx and oropharynx swab) and lower respiratory tract specimens (sputum) for SARS-CoV-2. This testing was performed on days 8, 9, 15, and 16 of isolation. On days 10, 17, 18, and 19, RT-PCR assays from the upper or lower respiratory tract were performed at physician discretion. Cycle threshold (Ct) values in RT-PCR for SARS-CoV-2 detection were determined in both asymptomatic and symptomatic patients.

Results Of the 303 patients with SARS-CoV-2 infection, the median (interquartile range) age was 25 (22-36) years, and 201 (66.3%) were women. Only 12 (3.9%) patients had comorbidities (10 had hypertension, 1 had cancer, and 1 had asthma). Among the 303 patients with SARS-CoV-2 infection, 193 (63.7%) were symptomatic at the time of isolation. Of the 110 (36.3%) asymptomatic patients, 21 (19.1%) developed symptoms during isolation. The median (interquartile range) interval of time from detection of SARS-CoV-2 to symptom onset in presymptomatic patients was 15 (13-20) days. The proportions of participants with a negative conversion at day 14 and day 21 from diagnosis were 33.7% and 75.2%, respectively, in asymptomatic patients and 29.6% and 69.9%, respectively, in symptomatic patients (including presymptomatic patients). The median (SE) time from diagnosis to the first negative conversion was 17 (1.07) days for asymptomatic patients and 19.5 (0.63) days for symptomatic (including presymptomatic) patients (P = .07). The Ct values for the envelope (env) gene from lower respiratory tract specimens showed that viral loads in asymptomatic patients from diagnosis to discharge tended to decrease more slowly in the time interaction trend than those in symptomatic (including presymptomatic) patients (β = −0.065 [SE, 0.023]; P = .005).

Conclusions and Relevance In this cohort study of symptomatic and asymptomatic patients with SARS-CoV-2 infection who were isolated in a community treatment center in Cheonan, Republic of Korea, the Ct values in asymptomatic patients were similar to those in symptomatic patients. Isolation of asymptomatic patients may be necessary to control the spread of SARS-CoV-2.

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

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

As of July 25, Oregon’s cumulative positive testing rate is 4.2% of tests performed. This is considerably lower than the national average of 10%. The number of tests performed each week has generally been holding steady, but supply chain issues continue to restrict Oregon’s testing capacity, as discussed below.

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 .
 
...
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.
 
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.
 
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The problem is that many patients to 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.
 
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