Thursday, May 07, 2020

Fancy some serology?

Just a one liner-ish type post.

I had the privilege of listening-in to one of the weekly Royal College of Pathologist webinars on the SARS-CoV-2 virus, this one on serology testing. These webinars are really fantastic, they are given as a 15 minute presentation by a scientist at the top of their field, in the complete absence of political interference or the sort of financial pressures applied to produce a 100% specific, 98% sensitive serology test to make billions of dollars for a commercial company. They have spent their careers as coronavirus "enthusiasts". The presentations are by pathologists, for pathologists. They are technical and utterly honest (as far as I can tell).

So. There are three types of people in the world. If you have had SARS-CoV-2, confirmed by PCR, have been seriously unwell, hospitalised, needed supplementary oxygen and been considered for a respirator/ITU admission then the chances are good that you will be solidly seropositive for SARS-CoV-2 on a blood sample in recovery. I would suggest that your medical history might be quite a big hint in this direction, which might render the use of the serology test under these circumstances somewhat superfluous.

The second type of person has also had SARS-CoV-2, confirmed by PCR test, been clearly unwell but not so unwell as to need any hospital admission for management. With the best possible testing using multiple different antibodies and different test techniques these people are very, very difficult to detect on a serology basis. Many will be negative on serology within the limits of what we have available now and what will be developed commercially. That is worth thinking about.

The third type of person has never been ill, has never been PCR tested, has no idea whether they have been exposed to SARS-CoV-2 or not. These are the apparently healthy population, the sort of people John Ioannidis sampled in Santa Clara County.

Of the 3300 people Ioannidis tested, 2.5-4.2% turned out to be sero-positive. Listening to the RCPath webinar on the problems of serology testing in mildly unwell people (let alone those apparently never unwell) this implies that the values from Ioannidis might well be the absolute, rock bottom, tip of the iceberg minimum. Exposure has probably been much, much higher in this still healthy population.

I find that rather hopeful.

It is difficult to describe how badly I feel that the COVID-19 pandemic has been managed here in the UK. I don't make political posts on the blog (or anywhere else) but the level of utter incompetence of our current government is breathtaking. I suppose a different administration could have done worse, but that's hard to imagine.

Peter

46 comments:

Bob said...

Great post and information. Makes sense, too, even to me.

I'm of two minds on political leaders. They're not subject-matter experts, and they have to rely on credentials to decide whom to hire and listen to. In the US, this means Anthony Fauci et al (in another age it meant Ancel Keys et al). While Donald Trump is given to stream-of-consciousness rambling, I think a different president would have had nearly-identical policies. The problem is the threat of deaths threatens a leader's power. Govern accordingly.

In the US, I think the real power, however incoherent, resides in the enormous Federal bureaucracy and the laws and politics which create and nurture it. The bureaucracy precedes the inauguration of a new president and remains after he is gone. Can't speak for the UK (but a crack about Neil Ferguson might fit here).

And then there's the Madness of Crowds, which has whipped COVID-19 into the 20th century Black Plague. Cooler heads will tut tut when they write the story in the history books of the future.

ctviggen said...

"While Donald Trump is given to stream-of-consciousness rambling, I think a different president would have had nearly-identical policies." I highly doubt this.

It's up to the states to open. Only I can say when we can open. It's up to the states to open. If you don't like what your state is doing, protest!

It's up to all 50 states to get their own PPE, get their own tests, make their own rules (unless I don't like your state or governor, then I'll interfere), etc. And the Federal Gov't is in direct competition with the states for all of these. I mean, who doesn't think this is a good idea?

WWII: Sorry about that bombing of Pearl Harbor, Hawaii. Maybe you should start building some planes and ships? No, you can't have ours, as those are for us.

I could go on for testing, how many cases we will have, etc.

We can argue until we're blue in the face about whether lock down is good, bad, both, suicidal, etc., but Trump's response has been incoherent. And remains so.

Kevin FST said...

It is strange; my view from France, while closely following what's going on in the UK, is that the UK's handling has been dreadful, while France's (far from perfect) has been fairly good and quite transparent. Yet I see recent opinion polls showing 60%+ approval of UK Gov and 61% here giving the thumbs down to the French Gov!

Bob said...

Peter,

Is that RCPath video available on YouTube? The Ioannidis study was highly criticized, especially for not being sufficiently "random", and I'm curious if any of that criticism was discussed in the video.

A report about the criticisms is here.

Ioannidis also published a similar study in Los Angeles County (with similar results), and there were plans to do a study of US Major League Baseball teams to get a national perspective.

https://www.hoover.org/research/fight-against-covid-19-update-dr-jay-bhattacharya-1

Peter said...

Bob, It will be there in about a week I believe. A couple are up already, go to Youtube and search for Royal College of Pathologists.

Kevin, yes, I understand Boris is doing well in opinion poles. I find this disturbing. I have to live in this country. My wife, who is nothing like as cynical/sceptical as myself considers that people are stupid. I rest my case.

Peter

altavista said...

The year was 1957. 1.1 mil deaths. It's how we got here, bags of viruses.

https://www.aier.org/article/elvis-was-king-ike-was-president-and-116000-americans-died-in-a-pandemic/

Stuart said...

Any reports on the latest tests like this one.
https://www.eurekalert.org/pub_releases/2020-04/acs-nct041520.php

Authorities are claiming that they are making adjustments for 95% accuracy when a large number of tests are being done.

Bob said...

altavista,

Interesting article. Here's a UK paper about the '57 flu. Seems as though it hit younger folks the hardest. Lots of school and factory closures. Even the word "recession" was used. The UK response seems eerily similar to the initial UK response to COVID-19.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714797/

I was two years old during most of 1957. I didn't even know there had been a flu epidemic until recently. My then 39-year-old mother gave birth to my younger brother just before I turned 3.

My parents, who had known the Great Depression, never said anything about the '57 outbreak. We lived in semi-rural Virginia at the time.

Very different era then. The national press had nothing like the speed and reach of modern social media. And I'd bet people had more faith in their doctors and less expectation of miracle cures.

Peter said...

Hi Stuart,

It's a modified PCR looking for viral RNA. It's not looking to pick up previously exposed but never unwell people. These can only be picked up on serology and that's difficult.

Bob, yes, times change, attitudes change. And undoubtedly the total cockups we make today are certainly different to those we made 50 years ago...

Peter

Justin said...

As always, good stuff Peter and thank you. Looking forward to watching this video when it's available.

Stuart said...

Here is other tests that claims to be more sensitive.

https://www.eurekalert.org/pub_releases/2020-04/acs-snt042920.php

https://www.eurekalert.org/pub_releases/2020-04/du-dan042720.php

I have no idea if these are any better that the previous ones but it seems to address part of the problems of older types of tests but I have no idea if it has promise or not having no background in the field.

I know here in Canada everything has to pass a cost/benefit analysis before approval so were are always behind in the latest technology.

I think these lock downs has been reactionary and not based on scientific observations and are being applied so poorly that losses in old age homes is obscuring the true statistics.

Thanks Peter for clearing the air on this subject.

Peter said...

Hi Stuart,

We would need to see their data rather than the their press release. That's what's nice about the FRCPath chats.

Peter

Eric said...

I'm looking forward to the webinar being released.

If detecting antibodies in those that have been mildly ill or asymptomatic is that hard, the question is if they are immune at all. Last I looked (and that was in the second half of April), antibody tests were roughly compatible with random PCR test, i.e. test where they randomly selected people, such as the Austrian study. That means that of course, the number of people with antibodies should have been a little higher at the end of March than the active infections. By now, that might be different.

This is from middle of April. Christian Drosten didn't give the impression that picking up antibodies is the issue. He was more concerned with false positives, which is why he thought additional testing is needed with more elaborate tests to confirm positives:

https://www.ndr.de/nachrichten/info/31-Eine-Wiederinfektion-bleibt-unwahrscheinlich,podcastcoronavirus186.html#Antikoerpertests

Frunobulax said...

@Eric
Drosten had a podcast (in German) last thursday about testing. He says three things:

(a) Most antibody tests have about 1% false positives. They will report someone as positive even though they aren't. This number can increase to 2-3% during flu season, a test can be false positive if the subject had another corona infection (the one that cause a cold or a flu, not COVID-19) during the past ~6 weeks.

(b) Immunity does not rest on antibodies. He believes that people are immune even if their antibodies don't register with a test. There is a learning component there, our immune system learns how to detect the virus and produce antibodies if needed.

(c) There are several commercial antibody tests out there, using different methods. Apparently not all tests detect all antibodies. If someone had corona (diagnosed by PCR), and the antibody test comes up negative, they should ask the laboratory to use a different test (or send the serum to another laboratory that uses a different test).

Gyan said...

If 80% of the people show no symptoms to the novel corona-virus infection then why it is generally said that humans have no immunity to this novel coronavirus?

Re: the false positive rate, if the true positive rate itself is low say 1% then even the 1% false positive rate seriously misleads.

Peter said...

Hi Frunobulax and Gyan,

If the pandemic has told us anything it is how little people understand about immunity. My wife's PhD was on certain aspects of the innate immune system in cattle, particularly NK cells. It is impossible to stress how important the innate immune system is. The adaptive immune system has always seemed like an add-on to me. You had a virus. Your innate immune system saved your life and probably stopped you getting ill at all (if you were lucky about which virus it was). Couple of weeks later the adaptive immune system produces some antibodies. Bully for it. Happily you survived long enough for it to get a chance.

Taking antibodies out of someone who survived and giving them to someone who is clearly not going to survive (think serum therapy for Ebola) is buying survival in the face of a dysfunctional innate immune system (as in SARS-CoV-2). I might suggest avoiding hyperglycaemia might preserve your innate immune system.

Try not to be elderly. Try not to be diabetic. Probably only the second statement matters.

Peter

Eric said...

@ Fruno:
I didn't get to finish listening to that podcast. He said something else he said before a few weeks ago: if you have a positive, you still have to do a neutralisation test. Overall, he did not seem concerned about false negatives.

@ Peter:
What is your take on Vitamin D? Malcolm did a blog about it that generated 700+ replies.

There was also a paper: https://www.medrxiv.org/content/10.1101/2020.05.01.20087965v1.full.pdf

Overall, the trend seems convincing, but there is too much lazy armchair epidemiology for my taste. For example, Japan, South Korea, Germany and Canada were seen as outliers in the Norther hemisphere, and there was some vague handwaiving about fish consumption and/or supplementation. I can see more fish being eaten in Japan as beneficial, but for Germany I can vouch that less fish is eaten than in England, France, the Netherlands, etc. and there are no supplementation programs.

Also, they didn't bother with differences between the Nordic countries or look at Greece vs. Spain or Italy. They didn't even mention Brazil. It ain't all latitude!

Frunobulax said...

@Peter There is a fascinating correlation, IMO. The death rates for COVID-19 by age look pretty much like the average CAC scores by age. Almost zero below 50, but then rising exponentially. Just a coincidence?

I really wonder what the role of the immune system is here. Obviously it decides on whether the virus starts to replicate, but it doesn't seem to make a lot of difference once you're infected. Small children are usually considered to have a weak immune system, yet they don't die from COVID-19. Also children and symptomless carriers are nearly as infectice as people with symptoms. I usually don't speculate a lot about corona, because this is not my area of expertise, but it seems to me that the virus concentrations must be very similar for people with and without symptoms. Many symptoms (like fever) are caused by our immune system fighting the intruder. Corona is different somehow.

I'm still waiting for someone to correlate insulin markers (fasting insulin or HbA1c) to COVID-19 symptoms. Diabetes, CVD and hypertension correlate to disease severity, so it would be straightforward to look for prediabetes too. Is it really that hard to connect the dots? :( But I'm preaching to the choir here of course :)

Bob said...

"If the pandemic has told us anything it is how little people understand about immunity...It is impossible to stress how important the innate immune system is."

I just love this idea. When I started reading recently about innate immunity (as a beginner, mind you), I was struck by how complex and, well, "complete" it is. PAMPs, DAMPs, pattern-recognition receptors, dendritic cells, etc, etc. Quite an elaborate and impressive toolkit! And I'm sure I'd win a bet that we have no clue what else is involved. And all for "free", because we seem to be born with it.

My first thought was that it was just kind of a first-line holding defense to keep us going until adaptive immunity set in. Now my Wild A$$ Guess is that an antibody is mostly a memory of an encounter, so with the inevitable rematch we start with an edge.

I'm painfully aware my knowledge is so very superficial, but, still it's quite cool to see you express your view that way.

cavenewt said...

Ran across this today. "Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019". By which they mean *high* levels of LDL appear to be protective, although the discussion section points out some possible alternatives. "LDL levels inversely correlated to disease severities, which could be a predictor for disease progress and poor prognosis."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166305/

Gyan said...

@Frunobulax,
WHO has stated that true asymptotic infectiousness is unproven. People that develop symptoms may be infectious before displaying symptoms but people that never develop symptoms are not shown to be infectious.

The whole notion of cytokine storms being an effect of "strong" immune system I find very dubious. The immune system has not evolved to kill us.
The reason children are not affected by covid might be that children are not been damaged by metabolic syndrome Their immune system is strong, in fact, and not weak. What would be the evolutionary point in having weak immunity in children?

Frunobulax said...

@Gyan, we had a very recent study about the infectiousness of children: https://zoonosen.charite.de/fileadmin/user_upload/microsites/m_cc05/virologie-ccm/dateien_upload/Weitere_Dateien/analysis-of-SARS-CoV-2-viral-load-by-patient-age.pdf
"Children may be as infectious as adults."

Young children do not have a strong immune system. If you consider diseases like influenza, young children are a high risk group. If you ever had a child, you know they come down with something every other week in kindergarden age. Historically, more than half of the children would die from diseases. This is because their immune system needs to learn to detect all those enemies. They do get COVID-19 allright and have a high viral load, they just don't show any symptoms.

Assuming that metabolic damage is to blame would be simple application of occams razor, IMO.

Gyan said...

Were these children asymptotic?

In an evolutionary sense, the immune system of children is as strong as it should be. Unless we poison it by engaging in things that evolution had not equipped us for. As children have lesser exposure to these things than adults, the children are less poisoned than the adults.

I have a naive question. Given that a person suffers from common cold repeatedly, what does it say about that person's innate immune system? Not very good, I guess.

Unknown said...

The Royal College of Pathologist's Serology talk is now available: https://www.youtube.com/watch?v=LCKnfpsTBFk

Found this interesting too. An interview with Consultant Dr Rich Breeze: https://anchor.fm/wdgll/episodes/23-COVID-19-ICU-care--long-term-effects-and-immunity-with-Dr-Richard-Breeze-edaopg/a-a21t9ab

He has led Lewisham Hospital ICU during the pandemic. Interesting views on Serology too.

Frunobulax said...

@Gyan yes, viral loads were equivalent in symptomatic and asymptomatic patients.

Disagree with the immune system. Evolutionary, half of the children die because of evolution, survival of the fittest. Having half of them die ensures a reasonable selection process in early age. Today we have less children, but keep them alive with medication. Which is a good thing of course. Still, without modern medicine we'd see a lot of children die. But not from COVID-19.

cavenewt said...

Gyan said..."I have a naive question. Given that a person suffers from common cold repeatedly, what does it say about that person's innate immune system? Not very good, I guess."

Which is related to what Peter said above about the innate immune system being damaged by anti-evolutionary eating ("avoid being diabetic"). In support of this, there is the well-known anecdotal evidence of low-carb eaters experiencing very few if any colds and other infectious ailments. And I appreciate Peter pointing out the difference between the innate and adaptive immune systems.

As a tangential aside, and as someone who has a rare mystery neuropathy that is commonly considered to be autoimmune, I think it's kind of dumb to refer to someone's immune system as being too "strong" or "overactive". I prefer to think of the immune system in these cases as, instead, *misdirected*. And because of my situation I have been reading for 10 years about the immune system and autoimmunity and have concluded that it's such a complex system, modern medicine knows next to nothing about it, but is too arrogant to admit it.

Bob said...

Unknown,

Thanks for the links. Fascinating presentations.

Passthecream said...

Gyan, Cavenewt - need to describe what exactly is a cold??? Is it the immune system functioning properly perhaps?

If you hang around in densely populated areas you are probably going to be exposed to more pathogens and most of the symptoms of colds are signs that your immune system is cranking into action. Just how far it has to go to fight of a new pathogen is going to be based on a series of consequences depending on the power and novelty of the pathogen versus the different defensive and barrier functions ie the complexities of innate defenses and adaptive defenses and whatever else can be thrown at it.

Antibiotics and vaccines wouldn't be necessary if healthy people didn't die of infection! There are plenty of horror stories of native peoples around the world dying by their thousands when first exposed to western diseases such as measles and other common viruses. I'm sure you can have a lifestyle which doesn't only not lower your odds of fighting off pathogens but also increases those odds, but there is a deadly ongoing struggle between evolving pathogens and evolving humans.


Btw, cholera, enh. SNAFU 130 yrs ago:
https://www.npr.org/2020/05/06/849996451/what-hamburgs-missteps-in-1892-cholera-outbreak-can-teach-us-about-covid-19-resp

cavenewt said...

@Passthecream—my comment was meant simply to point out that low-carbers anecdotally don't get various infections as much as people eating the SAD, therefore presumably have more robust immune systems in general. I know in my 10 years of eating this way I no longer get colds or other viruses, nor do I sunburn.

Most of the underlying pre-existing conditions that predispose people to bad outcomes of COVID-19 are what we tend to think of as being caused by the SAD, with handicapped metabolisms.

Passthecream said...

Only speculation on my part. I also no longer get sunburnt very easily and I spend a lot of time exposing myself to it, even more as our local uv index heads below 3 for the winter. I work with primary age children R-7 so lots of chances for new colds every year. I sometimes feel one starting up and it quickly goes away but at other times I go through the defensive stages one by one, occasionally ending more seriously. It isn't pleasant but I'd rather it happened than not because I'm guessing that this is a matter of different layers of innate immunity.

Malcolm Kendrick discussed this paper recently:

https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-5-29

There are many interesting questions in there. This is a good conundrum:

" influenza mortality and hospitalization rates for older Americans significantly increased in the 80's and 90's, during the same time that influenza vaccination rates for elderly Americans dramatically increased [7, 8]. Even when aging of the population is accounted for, death rates of the most immunized age group did not decline [9]. Rizzo et al studying Italian elderly, concluded, "We found no evidence of reduction in influenza-related mortality in the last 15 years, despite the concomitant increase of influenza vaccination coverage from ~10% to ~60%" "

That strongly suggests to me that innate immunity is key, and it is probably weak in the aged. All the Hyperlipid logic about metabolic health is relevant to this concept! If your innate immunity is not strong enough you are probably f$$#%t, plus an unhealthy lifestyle may also reduce your adaptive immune capacity. Perhaps you don't get to mount a good adaptive response unless the innate reaction is strong enough?

Peter said...

Unknown,

Just got chance to listen to the ITU chap talking about his experience of COVID-19. Very cool. I like the guy.

Thanks for the heads up.

Peter

Passthecream said...

A useful primer on various immune system components:

https://www.ncbi.nlm.nih.gov/books/NBK27090/

"The innate immune response makes a crucial contribution to the activation of adaptive immunity. The inflammatory response increases the flow of lymph containing antigen and antigen-bearing cells into lymphoid tissue, while complement fragments on microbial surfaces and induced changes in cells that have taken up microorganisms provide signals that synergize in activating lymphocytes whose receptors bind to specific microbial antigens. Macrophages that have phagocytosed bacteria and become activated can also activate T lymphocytes. However, the cells that specialize in presenting antigen to T lymphocytes and initiating adaptive immunity are the dendritic cells.

Go to:
1-6. Activation of specialized antigen-presenting cells is a necessary first step for induction of adaptive immunity
The induction of an adaptive immune response begins when a pathogen is ingested by an immature dendritic cell in the infected tissue. These specialized phagocytic cells are resident in most tissues and are relatively long-lived, turning over at a slow rate. They derive from the same bone marrow precursor as macrophages, and migrate from the bone marrow to their peripheral stations, where their role is to survey the local environment for pathogens. Eventually, all tissue-resident dendritic cells migrate through the lymph to the regional lymph nodes where they interact with recirculating naive lymphocytes. If the dendritic cells fail to be activated, they induce tolerance to the antigens of self that they bear."

Justin said...

Passthecream, thanks a lot for the link! I wonder if there are any good YouTube presentations that would complement this? If I find one I will be sure to post it up.

Justin said...

Makes you think twice about taking anti-inflammatories during an infection as this inflamation facilitates the speady migration of neutrophils and monocytes to the site of infection.

Passthecream said...

Justin, yup. A lesson I have learned over the years is that most of the symptom relieving nostrums you could take usually end up prolonging the misery. I don't think the immune system is absolutely perfect, I'm sure it can over-react in various circumstances, but it is pretty damn good.

Passthecream said...

At that link there is this diagram

https://www.ncbi.nlm.nih.gov/books/NBK27090/figure/A55/?report=objectonly

"Macrophages encountering bacteria in the tissues are triggered to release cytokines that increase the permeability of blood vessels, allowing fluid and proteins to pass into the tissues. They also produce chemokines that direct the migration of neutrophils to the site of infection. The stickiness of the endothelial cells of the blood vessels is also changed, so that cells adhere to the blood vessel wall and are able to crawl through it; first neutrophils and then monocytes are shown entering the tissue from a blood vessel. The accumulation of fluid and cells at the site of infection causes the redness, swelling, heat, and pain, known collectively as inflammation. Neutrophils and macrophages are the principal inflammatory cells. Later in an immune response,
activated lymphocytes may also contribute to inflammation."


ie cytokine mediated vascular 'loosening', porosity and infiltration of blood borne components into tissue. I wonder how this relates to arterial plaque, cholesterol, life, the universe and everything?

Unknown said...

Thanks Peter - glad you enjoyed the podcast. Dr Rich Breeze was a breath of fresh air (no apologies for the pun).

For those trying to get a hold of the complexities of Immunology, the book by Daniel Davis, 'The Beautiful Cure', is a good start.

cavenewt said...

Passthecream said..."ie cytokine mediated vascular 'loosening', porosity and infiltration of blood borne components into tissue. I wonder how this relates to arterial plaque, cholesterol, life, the universe and everything?"

The answer will involve 42 of something.

Passthecream said...

A regular array of 7 by 5.

Passthecream said...

Innate immunity is also adaptive.

https://pubmed.ncbi.nlm.nih.gov/24997561/

Wouldn't expect any less would you?

Peter said...

Unknown, he reminds me of many of the speakers who addressed us over the years at meetings of the Association of Veterinary Anaesthetists. The meetings were often joint with the medics. I loved that he found he was seropositive with IGG and worked the whole pandemic without PPE. Educated, sensible, pragmatic. A man after my own heart.

Peter

Peter said...

cave and Pass,

I'm missing the significance of the 7 x 5 array. Obviously 42 is involved somewhere...

Peter

Passthecream said...

Misremembered. It's 6 by 9.

"What do you get if you multiply six by nine?"

"Six by nine. Forty two."

"That's it. That's all there is."

"I always thought something was fundamentally wrong with the universe."

Passthecream said...

Peter I notice you managed to have the 42nd comment there!

Peter said...

LOL and LOL

Peter

cavenewt said...

June 2, 2020

"Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes"

Highlights
• A cohort of 7,337 COVID-19 patients with or without diabetes was retrospectively studied
• Diabetes status increased the need for medical interventions during COVID-19
• Diabetes status increased the mortality risk of patients with COVID-19
• Well-controlled blood glucose correlated with improved outcomes in infected patients

https://www.sciencedirect.com/science/article/pii/S1550413120302382