Thursday, 16 April 2020

Corona Virus Update: Don't take stories about reinfected cured patients too seriously (part 31)


Prof. Dr. Christian Drosten
The last Corona Virus Update Podacast with specialist for emerging viruses Prof. Dr. Christian Drosten had two main topics. The internationally most important one is about press reports that cured patients would be reinfected or even that people may not become immune after recovering from the disease. ThEN WHat AbOuT hErD iMmUNiTy?

I have seen people who are normally careful and well informed talk about these "reinfections". However, it is very likely just a problem with measurement accuracy when in the final stages of the disease the amount of virus becomes very low and hard to detect, especially in samples taken from the throat.

The other half of the podcast was about a study on the spread of SARS-CoV-2 in the German municipality Heinsberg. A region not too far from Bonn were there was a big early outbreak after a Carnival party. At a press conference some preliminary results were presented without any detail on the methods, on how these results were computed. The numbers suggested less people may die and more may be infected without knowing it.

There was first a wave of publicity praising the results and discussing the political implications. Then after consulting scientists there was a wave of publicity claiming the study was rubbish, while all the scientists had said was that they did not have information on the methods and thus could not comment. Sometimes they explained the kind of information they would need to have and that was spun into the study doing this this wrong, which was not claimed. On social media people started attacking the Heinsberg scientists or those asking for more information, which can only be based on whether they liked the numbers (politically) because they knew about the methods even less. For a day Germany looked like the US culture war. Social media has a mob problem that needs addressing.

It was not a glorious hour for science reporting by (probably mostly) political journalists. Anyway because this is much ado about nothing until we have a manuscript describing the methods and purely German I have skipped this part. I was nodding a lot, yes those are the kinds of problems you have interpreting measurements, yes you really need to know the measurement process well to assess the results. There are so many similarities between sciences.

It may still be fun for the real virology science nerd to learn the kind of details that matter to interpret a study. They can read the German transcript.

The basic problem determining whether someone is ill

Korinna Hennig:
Over the weekend there have been several reports from China and South Korea about patients who were considered to have recovered or were discharged from hospital and have now tested positive again. So this is not about antibodies, but about the actual virus detection in the throat swab, for example, or from the lungs. Is it conceivable that the virus is reactivated? You also examined the course of the PCR tests on the Munich patients.
Christian Drosten:
This phenomenon can be described as follows: A patient is discharged from the hospital, verified as corona negative and as cured. And a moment later - it could be days, three or four days, or even up to seven or eight days - the patient is tested again. And suddenly he is positive for the virus in the PCR. It is said that the patient may have become newly infected, or in reality he was not immune at all, although he survived the disease. Or the virus has come back again, and you know certain infectious diseases, herpes viruses are the prime example, which can always come back.

One asks the question: is this perhaps the case with this new virus? Unfortunately, there are still very few precise descriptions in the scientific literature of how the virus is excreted in patients in different types of samples, for example in swabs taken from the throat or in lung secretion, also known as sputum, or in stool samples - these are all the types of samples we know that the virus is detectable. Only a few studies have so far described how this behaves over time in relation to excretion.

We have made and published one of them. We have made an overview picture of this excretion over time in nine patients from Munich. ... This shows the detection limit of the polymerase chain reaction. And you can see clearly, especially towards the end of the disease process, when the patients recover, that there is still virus present. It is sometimes detectable, sometimes for a few days in a row, then again for a few days in a row it is not detectable. This always jumps above and below the detection limit.

These are simply statistical phenomena that occur. A PCR can only test a certain sample, a certain sample volume for virus. There are statistical distribution phenomena which mean that the virus has in principle been there the whole time, but the test cannot always detect it. You have to picture it like this, I often explain it to students like this: you have a swimming pool full of water and goldfish are swimming in it. And there is no doubt that they are there. But now you take a sample from this paddling pool with a bucket, blindfolded. And then you may have a goldfish in your bucket and sometimes not. Still, one would not deny that there are goldfish in the swimming pool. ...

Reporting of the results

And now the question is simply how to deal with it. I can tell you that here in Germany something like this would not happen, because we have a culture here, where results like this are questioned relatively quickly and rules are always seen with the possibility of an exception. In other words, a German health authority would practically say: well, okay, that's obvious, that's what happened now.

But in the Asian culture of public health there is a much greater strictness in dealing with such rules. That is not so bad. I don't want to criticize it now. It is simply a cultural difference that when such a rule is established, it is adhered to.And when it is then said that we now agree that a patient who has been PCR negative twice in a row, we define him as cured and discharge him. ...

It is a thoroughness to say: No, this rule will not be questioned now, this is no exception, but we just enter it into the table. The patient was tested negative twice and now he is positive again. And now we test a few hundred of such discharge courses and enter all this in the table and discuss it only after we have the table completely. Then we write this together and write a scientific publication about it. This is exactly what happened, several times.

These scientific publications are now in a public resource and readable, but now this discussion process is starting. So, now it's starting with people reading such publications, who perhaps do not know the details and say: What is this? It looks like a reinfection. What is going on with this virus? And it's being spread again through even more discussion channels. This creates excitement and uncertainty.
As a scientist, I would prefer the "Asian" process, that is the cleaner data, where you know exactly what happened. You have to understand the measurement process, but the scientific literature is for scientists.

I like the movement to open science, which makes it easier for people to participate in science and also for scientists to do science, but the scientific literature is not written for normal people and it will lead to problems when people with half-knowledge start reading the scientific literature. In this case it was probably innocent, in many cases bad actors abuse this to mislead the people.

Study one

How the samples were take for one of the studies was not fully clear, as can happen with preprints.
So it may well be that at one point when the patient was discharged, they simply took swabs from the throat, and at another time they may have looked in the lung secretion that someone coughed up. Such things can happen, these are two different types of samples.

And we know well, that the lung secretion stays positive much longer after discharge. And we also believe that it is not infectious for others. Using cell culture virus isolation studies, which we also did in our publication we tried this. We already believe it's no longer infectious. We've never been able to isolate an infectious virus. ...

Study two

In the other study it is actually more interesting, it is a bit more explicit. They examined 172 patients beyond the point of discharge. In 25 of them, the test was positive again, on average after 5.23 days after discharge. There it is also clearly stated, the discharge criterion was two negative throat swabs in a row.

So: The patient had to have a negative throat-swab twice, then he was discharged as cured. But we know exactly that the throat-swab is the sample that becomes negative earliest in patients. So in the second week of illness, many patients no longer have a positive throat-swab on most of the days that one tests, while stool and sputum are still reliably almost always positive.

And then it is said that of these 25 patients, 24 patients had severe histories. For me, this indicates that if someone has a severe history, he will of course be discharged later. Then he will be treated in hospital for a longer time. And especially with these patients we know that the virus in their throat is almost always completely gone. So the virus in the throat has had time to be eliminated. So in severe cases, the throat swab is no longer positive after this long time.
Let me set a break here to let this sink in. If it were really a problem of people being re-infected because they did not acquire immunity, it would be the patients who got most ill, who did not acquire immunity. If it really were a matter of immunity, the opposite would be more logical.
Then it is said that 25 patients have been diagnosed as positive. But in 14 of them, the laboratory test was positive again after they had been discharged from the stool, i.e. not from the throat-swab, and this tells me that we have exactly this mix-up here. For we know that the stool samples in particular remain positive for the virus for a long time, and I have to say that here too, by the way, we have not found any infectious virus in them. This is probably again only dead, excreted virus.

And with others it was throat swabs, which then tested positive again. But then we have to say again, a throat swab can also contain naturally coughed up lung mucus. You cough up the stuff and it sticks to the back of your throat.

You can see from the way in which it was done methodically and from the samples in which it was found, and also from the type of patients, that people say that these are patients who have been seriously ill for a long time, that there is a risk of falling into this trap, into this confusion. I would even suspect that the authors themselves simply know that this "mistake" could be present here. ...


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 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 21: Corona Virus Update: tests, tests, tests and how they work.

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

This Corona Virus Update podcast and its German transcript. Part 31.

All podcasts and German transcripts of the Corona Virus Update.

Roman Wölfel, Victor M. Corman, Wolfgang Guggemos, Michael Seilmaier, Sabine Zange, Marcel A. Müller, Daniela Niemeyer, Terry C. Jones, Patrick Vollmar, Camilla Rothe, Michael Hoelscher, Tobias Bleicker, Sebastian Brünink, Julia Schneider, Rosina Ehmann, Katrin Zwirglmaier, Christian Drosten & Clemens Wendtner, 2020: Virological assessment of hospitalized patients with COVID-2019. Nature. https://doi.org/10.1038/s41586-020-2196-x

Ye, G., Pan, Z., Pan, Y., Deng, Q., Chen, L., Li, J., Li, Y., & Wang, X., 2020: Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation. The Journal of infection, 80(5), e14–e17. Advance online publication. https://doi.org/10.1016/j.jinf.2020.03.001

Jing Yuan, MD, Shanglong Kou, PhD, Yanhua Liang, MS, JianFeng Zeng, MS, Yanchao Pan, PhD, Lei Liu, MD, 2020: PCR Assays Turned Positive in 25 Discharged COVID-19 Patients. Clinical Infectious Diseases, ciaa398. https://doi.org/10.1093/cid/ciaa398

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