Monday, 30 March 2020

Corona Virus Update: tests, tests, tests and how they work (part 21)

The Corona Virus Update Podcast of Wednesday the 25th of March was mostly an interesting lecture about tests. With pain in my heart I cut out the part on the different types of antibodies and the different parts of the immune system. So if you know some German, do read the German transcript. It was a really interesting interview.

The interview with Prof. Dr. Christian Drosten, who studies emerging viruses, was performed by science journalist Korinna Henning. I presume colleagues now call her Corona Henning. Or maybe German public radio is more professional than a university.

The podcast is my main source of Corona science. It is great to listen to someone who knows what he is talking about and is honest about the current limits of our knowledge.

The podcast is about tests for the virus itself, which is what we currently mainly do, and about various antibody tests to detected whether people had the disease, that is had an immune response producing antibodies against the virus.

Polymerase Chain Reaction tests

The main work horse to determine whether people have COVID-19 is a Polymerase Chain Reaction test. This test detects the presence of virus DNA by multiplying it, if present.

Korinna Hennig:
We've already talked a couple of times in this podcast about antibody testing, which has high hopes because it can provide education about the many potentially very mild infections that go undetected. And about how much immunity is already in the population. But we have also repeatedly spoken about the need for large-scale testing for the virus itself. Perhaps we can clear up the large field a bit: The current test for the virus is a PCR test, which means Polymerase Chain Reaction. This is where the genetic information of the virus is multiplied and a colour reaction generated. In simple terms: what exactly is happening actually?
Christian Drosten:
This is a reaction in which the genetic material of the virus is copied and thereby multiplied. This is an invention from the late 1980s that has since then gained an increasing foothold in microbiological and virological diagnostics and in principle has increasingly replaced cultural methods - i.e. the cultivation [breeding] of such a bacterium or virus - in virology in particular; a lot is still being cultivated in microbiology.

This is due to the fact that PCR is both very sensitive and very fast, in terms of the method used, and also has a high specificity. This means that what you find there is really what you are looking for. That is because you have to add small DNA sections, really molecules, physical molecules, to this reaction in order to multiply what exactly matches these molecules.

This means that if, for example, I want to detect this new coronavirus in the polymerase chain reaction, then I have to produce small pieces of this new coronavirus in the laboratory, in the form of RNA, i.e. small snippets of RNA, which are only about 20 bases long, and they will then attach themselves to the genome. And they can only do this if they are really almost or completely identical, i.e. in the sequence of bases, with the genome of the virus you are looking for. And if there is another virus in there that is even a little bit similar, but is actually a different, we won't be able to detect it.
Korinna Hennig:
This means that other corona viruses are not incorrectly identified here?
Christian Drosten:
Right. So, the four cold viruses, human corona viruses, we can't detect them with that. That's not what we want. We only want the test to be positive if this new virus is actually present.

Where and when does the PCR test work?

The test by itself is highly reliable, but it is important that the sample of the patient is taken correctly.

Korinna Hennig:
But the test shows that presence of the virus, you just explained, not the immune response of the patient. In other words, if I do it too late, if I perhaps have symptoms, but the disease is already subsiding, then it is going nowhere, so to speak?
Christian Drosten:
With this disease, it is the case that in the first week of symptoms, the samples from the throat, i.e. the smears, are actually very reliably positive in the PCR. And then, in the second week, they are no longer reliably positive. Then the patient still has symptoms, but in the throat the test might not be able to detect this. This is not because the test is not good, but simply because the virus is no longer present in the throat, but it is present in the lungs.

We now know that even in patients who have very mild symptoms, i.e. who notice almost nothing of their illness, there is still quite a lot of virus in the lungs. And this remains there for about two weeks, or even three weeks, in the uncomplicated cases. That's how long we are able to detect the virus in the lungs with this polymerase chain reaction. However, many patients cannot simply cough up such a sample from the lungs, so throat swabs are actually the most common sample. What can be done, which is not yet well established systematically, is to take a stool sample. The virus is detectable there as well, and for quite a long time actually, as long, or almost as long, as in the lungs.
Korinna Hennig:
But no longer infectious, that was a realization that we also addressed at some point in the podcast: That this contact infection - as is the case with noro-viruses, for example - is not a transmission route for the coronavirus.
Christian Drosten:
Yeah, right. So in our tests, the virus is highly detectable in the stool. So that means it can be used as diagnostic information. But it doesn't look like an infectious virus. We can say this because we simply place the same sample in parallel on cell culture and then see whether a virus grows there and is alive. And it's not.

Random ELISA antibody tests

Sampling patients and people they may have infected makes it hard to interpret the data in terms of how the population is doing. This would require tests of random people. Such information would be very important for public policy.

Germany at the moment has about 50 thousand infections. With a population of about 80 million people, this means that in the order of one in a thousand are infected. Such random tests would thus need to be large to get reliable numbers. Germany already made about half a million tests. So such random tests would be possible, but would reduce capacity for potential patients. The current way of thinking is to wait doing random sampling until we have large scale antibody tests, which does not interfere with patient care.

Korinna Hennig:
You said before that we'll have to take a look around Easter, and then politicians will have to decide whether to take action. Then of course it would be good to know even more. Is it conceivable, as I just mentioned, that random tests could be carried out to detect even more really undetected infected persons?
Christian Drosten:
But what there will be in the very near future, and which is actually much more important and informative, are such random tests for antibodies. This is a completely different test procedure. If we get infected, it takes about ten days for us to produce antibodies in this disease. We have already looked at that; other studies agree. And those antibodies will then become even more apparent and even better in the next few days. So, at first, it's such a low level. And then, two or three weeks after infection, you have a very clear antibody in your blood.

And you can use a blood sample with a technically different kind of test - these are [[ELISA]] tests, enzyme-linked immunosorbent assay - to measure whether a patient has antibodies in his blood, regardless of whether he had a severe infection or a mild infection or a completely unnoticed infection. And that is what we are actually speculating on. If we knew that all infections were symptomatic, then you could actually say: well, we actually record quite precisely what we have in terms of PCR results, and now we do the calculations on that basis.

But what we do not know at the moment, and what unfortunately does not come out well from studies in other countries either - there are unfortunately no convincing data from China on this either - is the rate of those who are really completely unnoticed and infected in the population. So what is the incidental immune activity of this virus? How many people get infected without noticing it or without having taken it seriously because just a little bit of scratching of the throat? But they are still antibody-positive and, as we can assume, immune, and even then contribute to the 60 or 70 percent of the population that must have become immune or infected before the pandemic wave comes to a halt.

Validation of the ELISA antibody tests

Before introducing antibody tests on a large scale, one needs to study how accurate they are. Unreliable tests would be damage patients and help spread the disease.

Christian Drosten:
There is already the possibility of carrying out [a simpler] antibody tests on a smaller scale in the laboratory. ... We have been able to carry out antibody tests for this virus in our laboratory since mid-January - but only on a small scale because it is a lot of work. ...

For these large mass screenings, where we would like to test thousands of patients, we need an automated ELISA test, and they are all just being set up. ...

There is a German manufacturer, a large well-known manufacturer, whom we have helped from the beginning to both set up and, above all, evaluate these test procedures. So to ask: How does what they have set up there compare to our microscope test carried out at home? So when I say "at home", of course I mean in our own laboratory. ...

But [those validations] closed now, they look good. So we can attest to this manufacturer: Go ahead, start producing these so everyone can use them. Such studies are of course now taking place in many other countries. Other manufacturers are now asking us, too, whether we can help validate this. And of course we do that.

When will ELISA tests be available?

Christian Drosten:
We already have one machine here in the institute, and we will build a much larger machine in two weeks here in our laboratory. And other large laboratories elsewhere in Germany are also doing that these days, so it doesn't necessarily have to take another two or three months.

And these tests can then be sent in via a General Practitioner; a blood sample will be taken by the General Practitioner and the results will be available the next day or the day after next. ...

There are considerations on how to use such tests, which doesn't necessarily have to be the planned visit to grandma and grandpa, but also the question: Can this doctor or nurse actually treat patients with the disease again, maybe even with reduced self-protection, i.e. with reduced protective equipment, because there is immunity? That is a very important question, for example. Or outside in outpatient care, whether a nurse has survived the infection, yes or no, is extreme important for the operational capability.

Rapid antibody tests

Very new on the market are rapid tests, lateral-flow-tests, which look like pregnancy tests.

Christian Drosten:
Then, of course, such tests are now coming onto the market, antibody tests that you can buy yourself, perhaps soon in the pharmacy or even now already on Ebay. These tests have not yet been validated, they come mainly from Asia, especially from China. These are tests that also test for antibodies using a different test principle. At the moment, I simply have to say that this should be treated with caution because we do not yet have good validation studies. However, we are currently testing such tests from several manufacturers and are providing the manufacturers with feedback on how well they work. In the next few weeks we will certainly see publications and first publications about how well such rapid antibody tests work.

That these tests are not validated yet is used on social media to attack China for endangering the West with unreliable tests. I would say: if you are so careless to use such a test now, do not blame China for your Trumpian ignorance.

Other podcasts

Part 28: Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste.

Part 27: Corona Virus Update: tracking infections by App and do go outside

Part 26: Corona Virus Update on Vaccines: clinical trials, various types, for whom and when.

Part 23: Corona Virus Update: need for speed in funding and publication, virus arrival, from pandemic to endemic

Part 22: Corona Virus Update: scientific studies on cures for COVID-19.

Part 20: Corona Virus Update: Case-tracking teams, slowdown in Germany, infectiousness.

Part 19: Corona Virus Update with Christian Drosten: going outside, face masks, children and media troubles.

Part 18: Leading German virologist Prof. Dr. Christian Drosten goes viral, topics: Air pollution, data quality, sequencing, immunity, seasonality & curfews.

Related reading

The German podcast and German transcript of part 21.

All Corona Virus Update Podcasts and their transcripts in German.

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