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1/7 As of 19.03.2020
NDR.DE/CORONA UPDATE
CORONAVIRUS UPDATE
CONSEQUENCE
S 17
1 ANJA MARTINI SCIENCE EDITOR, NDR INFO
2 CHRISTIAN DROSTEN
VIROLOGIST, CHARITE
BERLIN
Anja Martini
It is serious, those were the words of Chancellor Angela
Merkel last night. Her appeal to all of us: please stick to
the measures and stay at home. She did not use the
word curfew, but the scenario also seems possible. It
was Merkel's first unscheduled television address in her
15-year term of office. Mr Drosten, from a virologist's
point of view: was this speech appropriate?
Christian Drosten
Yeah, well, you don't have to be a virologist to have
anything to say about that. This is, of course, a situation
in which you can look at the neighbouring countries and
see that there are actual curfews. And that is something
we don't want in our society. We must interpret what Mrs
Merkel has done here as an attempt to get things done
in Germany without curfews. And we must now see
whether the population understands that. If they don't,
perhaps we'll have to think about curfews at some point.
But for many of the current regulations, there is of
course no scientific data to say that you need a curfew,
or that you perhaps need a school closing time and so
on. There are starting dates for all these individual
measures, but in the end all these things are, of course,
political decisions. A curfew in neighbouring countries,
which we have, has certainly not been imposed now,
because the scientists there are smarter and have
recommended to their governments that you have to
impose a curfew, because then the cases are so much
better controlled by so many percentages. Nobody
knows that. But this is a political decision, even under
the emotional impression of a very high number of
casualties. And of a care system that is slowly coming to
its knees, as we are already seeing regionally in France.
Italy is no longer the only country. And of course we do
not yet have to make these political decisions, let us say
after the emotional impression we have in Germany at
the moment. But we are running into this situation if not
many people in the population understand and follow
this, that you just don't go into public anymore. Even if
you are not immediately prosecuted by the police if you
do.
Anja Martini
There is also news from the scientific community.
From Marseilles, to be precise. They're doing
experiments with a malaria drug. What do you know
about that?
Christian Drosten
Yes, the chloroquine is a well-known malaria drug. One
that's not without side effects. And we've known for a
long time that chloroquine works against the old SARS
coronavirus in cell culture. And it is not only effective
against the SARS corona virus, but against many other
viruses that have a few similar principles in their ejection
from the cell as the corona viruses. The question is, of
course, can this also help patients? In SARS, this has
not been tried with patients. In principle, this finding only
came up after the epidemic. However, we know from
basic research that if you look at a substance in cell
culture and see that it helps against a virus, then you
can simply give the same substance to a patient and he
is cured. This is all much, much more complicated.
One reason why this is not so simple is that a drug has
to be administered to the lungs, where the virus is. And
we swallow it and have it in our intestines or we
substantiate it and have it in our blood. But the cells of
the lungs, where the virus replicates, have to take up this
substance. Often it is not the substance itself that is in
the tablet, but it has to be metabolized again in order to
produce the effective metabolic product in the infected
cell. And the infected cell in the human body has a
different metabolism than a cell in a cell culture dish.
This cannot be compared with each other, only very
roughly. And under this impression we must always be
sceptical when we get a hit in cell culture, i.e. when we
find a substance that is effective against a virus.
Nevertheless, cell culture is always the first step in the
discovery of such substances. In part, structural
chemists say that we look at a molecule in a virus and
make a small molecule that binds somewhere or blocks
some important site. So that would be a targeted design
of a drug substance. Or the other way is, and it is often
successful...
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has been in the past that one takes certain collections of
active ingredients that the chemical industry has
produced for other things, some of which also occur in
nature. So there are also collections of natural
substances that were initially shown to be effective
against certain enzymes, i.e. certain proteins that are
also found in viruses. Nature, for example, has such
molecules available, for example in plants or fungi,
because these organisms also have bacteria and
viruses. And these bacteria and viruses have enzymes.
And you think to yourself, aha, maybe there are defence
molecules and such collections of natural substances
exist. And then there are also chemical collections.
There are even collections of substances that have been
approved in the past - for example for other viruses or
other diseases, where people simply say that this is a
collection of active substances of approved drugs. Such
so-called libraries, i.e. libraries, substance libraries, can
also be obtained. Some of these can be bought or
exchanged in the chemical industry.
Anja Martini
But does this mean that this malaria drug is not a
source of hope at the moment?
Christian Drosten
Right. So that's where this reflection begins. With the
malaria drug, it's just that...
is an approved substance. And virologists saw almost
15 years ago that chloroquine is one of the hits. The
researchers are trying to find out what happens when
cell culture cells are infected with the virus, certain
substances are added and then the viral replication in
cell culture is measured. Sometimes you can see that
the virus replication suddenly drops. And an important
criterion is the molarity, the effective concentration. And
in principle, this is only a rule of thumb, but in principle it
is good to find substances that are already effective in
the low nanomolar range in cell culture. So mole, that is
a number of particles. And in the case of chloroquine, it
is now the case that the old SARS corona virus was
used to show that slightly more than one micromolar, i.e.
a thousand nanomoles per litre, is required in the cell
culture medium to achieve approximately 50 per cent
viral replication, i.e. 50 per cent reduction of the virus.
That is already at the upper limit, that is already a
concentration, one would say that this is at least the B-
list or even the C-list of hits. That is not something that
makes me excited, you have to follow up immediately.
That was the original finding. But of course chloroquine
is now an available substance, you can try it out. It was
done here in Marseilles by a group that
2/7 As of 19.03.2020
NDR.DE/CORONA UPDATE
I've had patients. And the question with such a clinical
study is always: What does this publication tell us? And
what was actually measured there? And of course, in a
clinical study for such a disease, we would like to know:
Did it benefit the patients? But this is not so easy in a
disease like this, where the majority of patients heal
anyway, even without medication. So with all the bad
pictures on TV we still have to keep reminding ourselves
that most patients infected with the SARS-2 virus still
heal all by themselves. And of course most of them have
this without even having a severe course on the way.
And there are many, many patients who don't feel well
when they are on the road, but who get well again
without further action - after about two weeks.
Now it is relatively difficult to ask in such a group of
patents, for example: Who has survived? Then you
would have to look specifically at very difficult cases.
And I don't think that was the case in this situation - as I
read in this study - that there were so many very difficult
cases. So what you were looking at here is a mixture of
cases. So there are easy cases, there are fewer severe
cases. And there are even a few asymptomatic cases,
whatever that means. And then in these clinical trials, in
the simplest case - and this trial is the simplest case -
you treat patients and you don't treat another group of
patients. There's a control group that doesn't get any
treatment and one group that gets treatment. And then,
of course, you would like to have these two groups put
together in about the same way. The patients should be
of the same age, the disease should look the same, or
at least the proportion of mildly and seriously ill patients
should be the same in both groups. And then the next
thing you have to ask yourself is: What is the end point?
So what do we measure now? What is our criterion,
whether
a drug worked or not? And what the authors of this
study have now done They measured how much virus is
detectable in these patients. So that is the criterion. This
is not about the clinical outcome of the disease, this is
simply a virus measurement.
STUDY IS PROBLEMATIC
Now we have described in principle how the study is
designed. And now we come into the problem area.
Unfortunately, there are several things in this study
where we really have to discuss whether we can do it
that way. The first thing that has been done is that the
groups have been thrown together and set up, and this
has not been completely in line with the
3/7 As of 19.03.2020
NDR.DE/CORONA UPDATE
Leave it to chance. So this was not a randomized trial,
as they say, a randomized trial. Where the coin is
actually flipped when a patient comes in and they say:
Okay, in your case the coin indicates that you're getting
the substance. And for you, the coin indicates you don't
get the substance. But we ourselves, we clinicians and
you, the patient, we both don't know whether the tablet
we are giving now contains the substance. So we have
pills, they look exactly the same. And only the study
director, who does not talk to us, who only evaluates it at
the end, who knows who is getting the substance here.
So it's a double-blind study. This is often done to
eliminate certain influences in such studies. Where you
later have to statistically start questioning all this, that is
not what has been done here.
This is a study that was done the way patients came in.
And there's just a group of patients in a hospital, you did
that, that was your hospital. And then there were other
patients who were taken from another hospital, and
there was no authorization to do that. And then you
didn't give them the substance, because you didn't have
permission. And so it is that these groups are now very
different, who were looked at here. The patients treated
are on average older, they are 51 years old, compared
to the non-treated patients, who are 37 years old on
average. That is a very big difference. It is also the case
that there are only two asymptomatic patients in the
treated group and four asymptomatic patients in the
non-treated group. Asymptomatic means that the
patients have no symptoms at the time of inclusion in
the study.
And you have to look at all these things a second time
and think about them a second time. What does it mean
when the age of such a mixture of patients is so
different? It can mean that the basic conditions in
patient recruitment are completely different. It means
that in one hospital it is very easy to get a PCR test for
patients. And in another hospital it is more difficult, so
patients wait longer until they are seriously ill before
they go to hospital. And then they are older on average,
because on average the older people get more
seriously ill.
So you can see that things are already biting their tails.
It's all connected. And it's not so easy to say that this is
all a fair comparison. Another thing you have to realize
is: Why are the patients admitted to the hospital? We
are still in a situation here at the moment where there
are two very different reasons for hospitalization. One
reason is isolation. So the patients are not sick at all,
but the health authorities have
said: Please go to hospital, because the virus is still
rare in the population and we want to prevent its
spread. And the other reason is disease. The patient is
sick and needs treatment. These are very different
basic conditions, which lead to the fact that patients
are seen on different days. And now it is the case that,
apparently, if you look at the symptoms, a conservative
patient selection has taken place here. It is already
getting complicated here.
But let me explain. You can put such a study in such a
way that it looks as if the treated group has worse
starting conditions than the non-treated group. This is
based on the principle that if the drug works and we see
that we have treated a group of patients who have
worse starting conditions, because they are more
seriously ill, because they are older and so on, and it still
works, but the virus still goes away faster in them, then it
must work all the more. Because right from the start, the
drug has been more difficult to use than those that have
not been treated. And so it is here also somewhat
placed. So the patients are older and the patients have
fewer asymptomatic ones in the cohort.
Here comes the big "but". And you may need to know a
little bit about the patients of this disease to understand
it. And I am sure that many clinicians, who will read this
study now, or also non-physicians, who do not
understand the background, will think that this is a very
big news, a very big encouragement to give all patients
this chloroquine from now on. But there is a big catch to
this study, and that is the time scale on which all this is
written. So the question is: on what day do we actually
measure whether the virus has gone? And on which day
do we actually describe how the patients entered the
study at the beginning and how they came out at the
end? This time scale on which the study is written is not
the day of the disease, but this time scale is the day of
inclusion in the study.
We have here a phenomenon where we have two
different cohorts of patients, and this is strongly
indicated by a very different age at inclusion, 51 versus
37 years. This sounds the alarm bell for me and leads
me to take a closer look at why this age difference
exists here. If I then look again that in one group there
are only two asymptomatic people in the treated group
and in the untreated group there are four asymptomatic
people, then a picture comes together which tells me
that the treated group here is in reality simply already
more advanced in its course. And no matter when you
take the
included in the study, the first day of study inclusion is
probably a more advanced day of disease progression
in the treated group than in the non-treated group.
pe. And this leads us to compare apples with oranges in
this study here. Because we have an additional problem
here. What is measured here is the virus concentration
and the virus detection rate not in the lungs, where the
disease takes place, but in the throat. In the whole study
the virus is not measured in the lungs, but in the throat.
And that is the biggest misconception in this entire
study.
STUDY VS. EXPERIENCES
We have a lot of experience. We have made the most
accurate description of an untreated patient co-hearing
in Munich patients. And in the Munich group we saw
how the virus concentration in the throat and lungs
behaves over time. And we can say that at the
beginning of the disease the virus is in the throat and it
goes away by itself over, let's say, the first ten days of
the disease. After that a lot of patients have very little
or only irregularly detectable virus in their throat.
But that has nothing to do with how the virus behaves in
the lungs. In the lungs, the virus is only truly replicative,
especially in the severe cases. And we can also say that
what the patient has in his throat has nothing to do with
how the disease progresses clinically, whether the
patient gets well quickly or whether he has to go through
a difficult phase. So what is measured in this whole
clinical trial has nothing to do with the course of the
disease, with the symptoms, but is only an initial
indicator of how the disease starts. In all patients the
virus concentration goes down in the first week, but if
you now imagine that the group that is being treated is
included a little later and the untreated group is included
earlier in this study, then it is in the nature of things that
in this later included group - they are already further in
the elimination of the virus from the throat - the virus
then goes down the throat faster. It disappears faster
because they have simply been in the disease process
longer.
Whether this is now additionally due to the fact that
they are treated, cannot be said at all on the basis of
this entire study. Maybe if the groups had been put
together like this, but if they had not been given
chloroquine but some kind of headache tablet, the
study would have ended the same way.
Anja Martini
This means that we simply have to wait for a new
drug or for a possible drug. There is not much in
sight yet.
Christian Drosten
Yeah, I don't want to be so absolute about this either.
I want to say two things. First, it's possible that...
4/7 As of 19.03.2020
NDR.DE/CORONA UPDATE
the authors do not know this at all, because there are many
doctors at the moment who are now facing this dilemma of
having to treat such patients, and they know too little about
the disease. This has all happened so quickly and this will
also apply to the first clinical trials. So it may be that the
colleagues there in Marseilles do not even know that they
are barking up the wrong tree when it comes to evaluation.
And they actually think that we have found a solution here.
They only mean well. I'm not accusing them of anything. I
just want to say that, given what we know about this
disease, we believe that something else should have been
measured, namely the climatic outcome. I cannot even say
that the lung viral load should have been measured; that
would have been better. But I cannot say that that would
have been optimal either. For me, the best criterion for
assessing treatment for this disease at the moment is still
the clinical outcome. It's not that we have very strict
laboratory criteria. We're just working on them now. That's
the one thing I'm trying to say. And the other: I'm not saying
chloroquine won't work. What I'm saying is, the way this
study was done, we're not any smarter. Unfortunately, this
is often the case in clinical research, so that the truth has a
second and sometimes also a third level. And you have to
be very careful. It was important for me to say this right now
because I know how it works. Today, clinicians all over
Germany and perhaps also all over the world will look at
this study and discuss it. And many of them will do so with
little knowledge about the course of the disease, about the
course of the laboratory work, which has been a laboratory
criterion, but many of them are not aware of the course of
the disease. They will think that this is totally convincing.
Anja Martini
As long as this conviction is not present in a study,
however, that actually means that we must continue to
take care of ourselves and do what we have already
been told as measures: Please do not go out as much.
And I think there is a group that is drawing a lot of
attention to itself with the hashtag "risk groups", which
includes a large number of young risk patients. Can you
explain to us why it is very important for them that we all
don't go out and protect not only the elderly, as we have
said many times before, but also the young people.
What can happen to them?
Christian Drosten
In principle, patients who have a basic risk should not
be infected at the moment. We should protect them
from infection. These are the older ones, from the idea
of retirement age. But of course, in younger ones...
Age groups also include patients with a special ri-siko,
with heart disease, lung disease and so on, metabolic
diseases. And of course, all these patients, we can
summarize them as risk patients, no matter whether
they are at risk because of age and related diseases or
other diseases that are present
- no matter how old, they have a right to be protected in
society. There is, of course, the possibility of direct
protection. You can simply say that they should stay at
home and everyone else can continue to live as before.
We discussed yesterday, using this major modelling
study from England, that it is not that simple. That if we
calculated what would happen if they were to be put in
isolation at home, the elderly, the group at greatest risk,
would hardly benefit from strict home isolation. You
would still have a demand of eight times as much beat
capacity as you have in reality. That would be a direct
entry into this situation, which we now have in Italy, for
example. In other words, there is no point in simply
protecting these risk groups. They cannot be protected
after all. This modelling study also took into account the
fact that not everyone is exactly involved and that it is
not possible to isolate everyone completely in detail.
That is the way it is.
Anja Martini
And that means that it is really a social task.
Christian Drosten
Right, exactly. That is to say, this direct protection, this
direct idea: well, then the risk patients should simply lock
themselves up at home, it doesn't work that way. It is a
task for society as a whole to also provide indirect
protection by reducing the number of infections in the
population. Hence the social distance, hence the school
closures and so on that have now been decided on as a
precautionary measure. This is a challenge and a
message which Mrs Merkel also expressed very clearly
again yesterday. It is also an appeal to reason and to the
social behaviour of the individual in society. It must
happen now that the incidence of infection is reduced.
To achieve this, there must be social distancing. And
one can only hope that our society is mature and
thoughtful enough - also altruistically enough - to realise
that this social distancing ultimately protects the weakest
in society and is also aimed at them.
Anja Martini
Now, when you walk through the streets or go to the
supermarket, there are some things you see. The
cashiers, for example.
5/7 As of 19.03.2020
NDR.DE/CORONA UPDATE
protected. They still have that direct contact. I saw
yesterday, there were plastic walls set up in front of
them and they had gloves on and all that, but no
respirators. Is that any good? Does that give them some
protection, given the contagious nature of the virus?
Christian Drosten
I think so. Well, I didn't go shopping yesterday or the day
before yesterday. I saw it on TV. I think it's a good idea to
set up things like that that can really block something like a
wet pronunciation or a coughing. And that leads perhaps a
little to the effect that it would have if everyone, but also
everyone in the public eye, would wear such a mask, like
the one in Asia
is in fact. It's probably not so easy to implement in our
country. So this protection that the mask provides, by
the infected person wearing the mask. Not that I protect
myself from others with my mask, that's a common
thought, but that in public the mask actually protects
when the infected person wears it. And by the way, can I
just say again, we have already talked about masks,
and something has been misunderstood.
I have been contacted by people who have said, does
that mean that all this is of no use at all if we as nurses
wear a mask? It's not like that. That's not what we
discussed. What we discussed was the mask in public.
And that's the effect we need the infected person to
wear the mask. And for that, everybody, everybody,
everybody in the public eye needs to have a mask. If
everybody would do this now, if everybody would buy
these masks now, which has been discussed in public
for weeks, there would not be enough masks on the
market for the medical staff anymore. And in the
medical staff, it is different. There it is really the effect: I
wear the mask and I am protected, because the
exposure level, the duration of exposure, the proximity
to infected persons, the probability of meeting an
infected person in daily business, all this is completely
different in the work situation in hospitals. And where
you are really exposed with a high probability, for
example where you are directly coughed on, where you
sit opposite people, where saliva flies and so on, you
need such a mask alone as a splash guard for the oral
mucosa, not necessarily as inhalation protection. And
these are situations that we don't have in everyday life,
but we do in hospital. And that's why the evaluation of
masks in hospitals is completely different from that in
the supermarket.
Anja Martini
One group is also a little worried. We have learned
this from our emails, namely
6/7 As of 19.03.2020
NDR.DE/CORONA UPDATE
Dentists. Some are already considering closing their
practices because they are afraid and do not have
enough masks. Is there any other way they can protect
themselves? Do you have any advice for them?
Christian Drosten
Honestly, it's not my field. There's a specialty called
hospital hygiene. They deal with that sort of thing, and
they're occupational medicine. There is also an overlap
in the treatment of problems between these two
subjects. These are actually the experts you have to
ask, not the virologists. I can say relatively little about
this. I am almost a private person, if I say so. Well, as a
virologist I can say one thing: yes, this virus replicates in
the throat. We also know that the oral mucosa also has
the receptor for the virus. And I would expect that this
virus also replicates on the mouth, on the inside and
perhaps even on the tongue. And if aerosol is generated
by these drills, where water mist is sprayed, we have all
been to the dentist, something also sprays out of the
mouth, I am not sure whether wearing such a simple
mask at the dentist really protects the dentist well. But
as I said, I am not an expert.
Anja Martini
Today in the lab, what kind of questions are you likely
to have today? What kind of topics are there?
Christian Drosten
Yeah, so in the lab, we were just talking about this
clinical trial. And of course we're also doing things that
go in that direction: That we are testing substances that
we think could be used against the virus, because they
are already approved drugs. We're doing that kind of
thing. And then, of course, there is always this helping
research going on, that is, that we give colleagues the
virus or give them reagents. Then we have a relatively
large amount to discuss, as far as the management of
diagnostics is concerned, how to make better use of
diagnostics as a tool. And then of course the evaluation
of sequences and the improvement of logistic processes
in order to keep bioinformatics up to date with sequence
evaluation. In other words, comparing the results of the
sequences with those already available and asking
oneself: Does this indicate anything? Are there
transmission clusters? Is there a certain virus that
spreads faster than another?
Anja Martini
If we look again at the daily routine of the labs. Do
you think the labs are now working on their
have reached their performance limit? Or could we
theoretically do more and do more tests?
Christian Drosten
Yeah, you're talking about lab diagnostics now. Here at
the Research Institute, of course, that is only a very
small part. We have a large routine laboratory here in
Berlin, i.e. Labor Berlin, which is the large routine
laboratory of the Charité, one of the largest supplying
laboratories for hospital beds, because they supply not
only the Charité, but also the entire Vivantes clinics here
in Berlin and many other hospitals around Berlin. And
there are also hospitals all over Germany that are
supplied. Of course, we have a very large diagnostics
company there where PCR testing, i.e. genetic testing
for the virus, is involved. We have been at the limits of
our capacity for weeks now. And we are certainly one of
the largest laboratories in Germany in terms of
throughput. About 600, 700 samples a day are tested
here. And now we can see that we can hardly keep up.
At the same time, other laboratories in Germany are
also increasing their throughput in this area. There are
now many laboratories in Germany that test 500
samples a day, and many small laboratories that test
100 or 200 samples a day. If I take this as an estimate,
and there are still no clear figures - the RKI is working
together with medical structures, with the associations of
panel doctors, to collect the figures. We had already
talked about that. This weakness of the German system,
that we actually do not know how much we are testing,
is in fact its strength, because so many laboratories can
and are allowed to test. Nevertheless, we can make an
estimate. So my private personal estimate is that we
probably do 100,000 or more tests per week in
Germany. And I am curious what the official figures will
say then. They are still very provisional at the moment. I
once read a figure that only referred to the outpatient
sector, but all the hospitals and university clinics are
missing. I would assume a figure like that. And the
decisive question is now, as the epidermia continues
and more and more patients are being treated, will we
be able to continue with the testing afterwards? And the
answer is..: No, we can't get there, because the
epidemic is growing exponentially. And equipping the
labs, that is still a very linear process.
Anja Martini
So devices, people.
Christian Drosten
Right. So in other words, even doubling that now is
virtually impossible. I think we can get another 30, 40
percent on top of it, with the greatest effort, across the
board, mind you. Some laboratories are of course in a
better position, but area-wide certainly not more than
that. But while every scant week, every scant week, the
number of infected people doubles - that is, of course, a
situation in which it is inevitable to say that we will no
longer be able to cope. We must therefore soon
consider using diagnostics in a more targeted way, in
other words, using diagnostics more as a tool for risk
groups too. For example, it is no longer necessary for
every young patient with compatible symptoms to have a
PCR test in the outpatient area. At some point people
will say: "Well, symptoms at this time of year, influenza
season is over, at this age, that will be the infection. And
then you can also say in principle, in which household
does the infected person live? Is there a family? If so, all
members of the household, i.e. the family or the whole
flat share, can be defined as positive. Because we know
that the transmission rate in the household is high, very
high. And here we can say in principle, all those who live
in a household where a first infected, a first known case
has occurred, this household is considered a quarantine
household and must remain in quarantine for 14 days
without us testing.
OTHER HANDLING OF TESTING
But while in another situation - for example, when a
terminally ill or elderly patient has symptoms - we
absolutely have to have certainty. There we need the
right of way for the diagnosis. Because these patients,
even if they do not yet go to hospital, in principle the
family doctor must call at least once every two days and
ask: How is the air? We now know - as intensive care
doctors who know their stuff tell me - that this illness can
be left out too long at home. So it can be that if you
breathe worse and worse, you should have been in
hospital and spent too long sitting on the sofa at home.
And when you come to the hospital, you suddenly have
a situation where you almost have to be ventilated, even
if you are still walking around and say: Oh yes, I'll sit
here and wait a moment, I'll hang up my handbag here.
A patient like that, when you look at the lungs, for
example in a CT or something like that, it can look quite
dramatic. And then you are close to the point where a
patient needs oxygen. And then it can also happen that it
gets even worse, that you have to go to the intensive
care unit. And that shouldn't happen too late. That
means it will be the task of family doctors to know these
patients,
7/7 As of 19.03.2020
NDR.DE/CORONA UPDATE
To know that one of my patients, whom I know in
primary care, has been positively diagnosed and is at
an age or with an underlying disease that opens up a
risk case here, and I have to stay on the line, albeit over
the phone.
Anja Martini
So many changes, also in diagnostics, in laboratory
diagnostics, so to speak, which could still be coming
up?
Christian Drosten
Right. I just want to sketch this out as a typical
example. And we have other use cases. We don't have
to discuss everything right now. Maybe we can discuss
this on another occasion, what else can be done with
laboratory diagnostics, which are used in a more
targeted way.
FURTHER INFORMATION
ndr.de/corona update

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NDR Corona Virus Podcast with German Virologist Christian Drosden Episode 17

  • 1. 1/7 As of 19.03.2020 NDR.DE/CORONA UPDATE CORONAVIRUS UPDATE CONSEQUENCE S 17 1 ANJA MARTINI SCIENCE EDITOR, NDR INFO 2 CHRISTIAN DROSTEN VIROLOGIST, CHARITE BERLIN Anja Martini It is serious, those were the words of Chancellor Angela Merkel last night. Her appeal to all of us: please stick to the measures and stay at home. She did not use the word curfew, but the scenario also seems possible. It was Merkel's first unscheduled television address in her 15-year term of office. Mr Drosten, from a virologist's point of view: was this speech appropriate? Christian Drosten Yeah, well, you don't have to be a virologist to have anything to say about that. This is, of course, a situation in which you can look at the neighbouring countries and see that there are actual curfews. And that is something we don't want in our society. We must interpret what Mrs Merkel has done here as an attempt to get things done in Germany without curfews. And we must now see whether the population understands that. If they don't, perhaps we'll have to think about curfews at some point. But for many of the current regulations, there is of course no scientific data to say that you need a curfew, or that you perhaps need a school closing time and so on. There are starting dates for all these individual measures, but in the end all these things are, of course, political decisions. A curfew in neighbouring countries, which we have, has certainly not been imposed now, because the scientists there are smarter and have recommended to their governments that you have to impose a curfew, because then the cases are so much better controlled by so many percentages. Nobody knows that. But this is a political decision, even under the emotional impression of a very high number of casualties. And of a care system that is slowly coming to its knees, as we are already seeing regionally in France. Italy is no longer the only country. And of course we do not yet have to make these political decisions, let us say after the emotional impression we have in Germany at the moment. But we are running into this situation if not many people in the population understand and follow this, that you just don't go into public anymore. Even if you are not immediately prosecuted by the police if you do. Anja Martini There is also news from the scientific community. From Marseilles, to be precise. They're doing experiments with a malaria drug. What do you know about that? Christian Drosten Yes, the chloroquine is a well-known malaria drug. One that's not without side effects. And we've known for a long time that chloroquine works against the old SARS coronavirus in cell culture. And it is not only effective against the SARS corona virus, but against many other viruses that have a few similar principles in their ejection from the cell as the corona viruses. The question is, of course, can this also help patients? In SARS, this has not been tried with patients. In principle, this finding only came up after the epidemic. However, we know from basic research that if you look at a substance in cell culture and see that it helps against a virus, then you can simply give the same substance to a patient and he is cured. This is all much, much more complicated. One reason why this is not so simple is that a drug has to be administered to the lungs, where the virus is. And we swallow it and have it in our intestines or we substantiate it and have it in our blood. But the cells of the lungs, where the virus replicates, have to take up this substance. Often it is not the substance itself that is in the tablet, but it has to be metabolized again in order to produce the effective metabolic product in the infected cell. And the infected cell in the human body has a different metabolism than a cell in a cell culture dish. This cannot be compared with each other, only very roughly. And under this impression we must always be sceptical when we get a hit in cell culture, i.e. when we find a substance that is effective against a virus. Nevertheless, cell culture is always the first step in the discovery of such substances. In part, structural chemists say that we look at a molecule in a virus and make a small molecule that binds somewhere or blocks some important site. So that would be a targeted design of a drug substance. Or the other way is, and it is often successful... Subscribe to DeepL Pro to edit this document. Visit www.DeepL.com/Pro for more information.
  • 2. has been in the past that one takes certain collections of active ingredients that the chemical industry has produced for other things, some of which also occur in nature. So there are also collections of natural substances that were initially shown to be effective against certain enzymes, i.e. certain proteins that are also found in viruses. Nature, for example, has such molecules available, for example in plants or fungi, because these organisms also have bacteria and viruses. And these bacteria and viruses have enzymes. And you think to yourself, aha, maybe there are defence molecules and such collections of natural substances exist. And then there are also chemical collections. There are even collections of substances that have been approved in the past - for example for other viruses or other diseases, where people simply say that this is a collection of active substances of approved drugs. Such so-called libraries, i.e. libraries, substance libraries, can also be obtained. Some of these can be bought or exchanged in the chemical industry. Anja Martini But does this mean that this malaria drug is not a source of hope at the moment? Christian Drosten Right. So that's where this reflection begins. With the malaria drug, it's just that... is an approved substance. And virologists saw almost 15 years ago that chloroquine is one of the hits. The researchers are trying to find out what happens when cell culture cells are infected with the virus, certain substances are added and then the viral replication in cell culture is measured. Sometimes you can see that the virus replication suddenly drops. And an important criterion is the molarity, the effective concentration. And in principle, this is only a rule of thumb, but in principle it is good to find substances that are already effective in the low nanomolar range in cell culture. So mole, that is a number of particles. And in the case of chloroquine, it is now the case that the old SARS corona virus was used to show that slightly more than one micromolar, i.e. a thousand nanomoles per litre, is required in the cell culture medium to achieve approximately 50 per cent viral replication, i.e. 50 per cent reduction of the virus. That is already at the upper limit, that is already a concentration, one would say that this is at least the B- list or even the C-list of hits. That is not something that makes me excited, you have to follow up immediately. That was the original finding. But of course chloroquine is now an available substance, you can try it out. It was done here in Marseilles by a group that 2/7 As of 19.03.2020 NDR.DE/CORONA UPDATE I've had patients. And the question with such a clinical study is always: What does this publication tell us? And what was actually measured there? And of course, in a clinical study for such a disease, we would like to know: Did it benefit the patients? But this is not so easy in a disease like this, where the majority of patients heal anyway, even without medication. So with all the bad pictures on TV we still have to keep reminding ourselves that most patients infected with the SARS-2 virus still heal all by themselves. And of course most of them have this without even having a severe course on the way. And there are many, many patients who don't feel well when they are on the road, but who get well again without further action - after about two weeks. Now it is relatively difficult to ask in such a group of patents, for example: Who has survived? Then you would have to look specifically at very difficult cases. And I don't think that was the case in this situation - as I read in this study - that there were so many very difficult cases. So what you were looking at here is a mixture of cases. So there are easy cases, there are fewer severe cases. And there are even a few asymptomatic cases, whatever that means. And then in these clinical trials, in the simplest case - and this trial is the simplest case - you treat patients and you don't treat another group of patients. There's a control group that doesn't get any treatment and one group that gets treatment. And then, of course, you would like to have these two groups put together in about the same way. The patients should be of the same age, the disease should look the same, or at least the proportion of mildly and seriously ill patients should be the same in both groups. And then the next thing you have to ask yourself is: What is the end point? So what do we measure now? What is our criterion, whether a drug worked or not? And what the authors of this study have now done They measured how much virus is detectable in these patients. So that is the criterion. This is not about the clinical outcome of the disease, this is simply a virus measurement. STUDY IS PROBLEMATIC Now we have described in principle how the study is designed. And now we come into the problem area. Unfortunately, there are several things in this study where we really have to discuss whether we can do it that way. The first thing that has been done is that the groups have been thrown together and set up, and this has not been completely in line with the
  • 3. 3/7 As of 19.03.2020 NDR.DE/CORONA UPDATE Leave it to chance. So this was not a randomized trial, as they say, a randomized trial. Where the coin is actually flipped when a patient comes in and they say: Okay, in your case the coin indicates that you're getting the substance. And for you, the coin indicates you don't get the substance. But we ourselves, we clinicians and you, the patient, we both don't know whether the tablet we are giving now contains the substance. So we have pills, they look exactly the same. And only the study director, who does not talk to us, who only evaluates it at the end, who knows who is getting the substance here. So it's a double-blind study. This is often done to eliminate certain influences in such studies. Where you later have to statistically start questioning all this, that is not what has been done here. This is a study that was done the way patients came in. And there's just a group of patients in a hospital, you did that, that was your hospital. And then there were other patients who were taken from another hospital, and there was no authorization to do that. And then you didn't give them the substance, because you didn't have permission. And so it is that these groups are now very different, who were looked at here. The patients treated are on average older, they are 51 years old, compared to the non-treated patients, who are 37 years old on average. That is a very big difference. It is also the case that there are only two asymptomatic patients in the treated group and four asymptomatic patients in the non-treated group. Asymptomatic means that the patients have no symptoms at the time of inclusion in the study. And you have to look at all these things a second time and think about them a second time. What does it mean when the age of such a mixture of patients is so different? It can mean that the basic conditions in patient recruitment are completely different. It means that in one hospital it is very easy to get a PCR test for patients. And in another hospital it is more difficult, so patients wait longer until they are seriously ill before they go to hospital. And then they are older on average, because on average the older people get more seriously ill. So you can see that things are already biting their tails. It's all connected. And it's not so easy to say that this is all a fair comparison. Another thing you have to realize is: Why are the patients admitted to the hospital? We are still in a situation here at the moment where there are two very different reasons for hospitalization. One reason is isolation. So the patients are not sick at all, but the health authorities have said: Please go to hospital, because the virus is still rare in the population and we want to prevent its spread. And the other reason is disease. The patient is sick and needs treatment. These are very different basic conditions, which lead to the fact that patients are seen on different days. And now it is the case that, apparently, if you look at the symptoms, a conservative patient selection has taken place here. It is already getting complicated here. But let me explain. You can put such a study in such a way that it looks as if the treated group has worse starting conditions than the non-treated group. This is based on the principle that if the drug works and we see that we have treated a group of patients who have worse starting conditions, because they are more seriously ill, because they are older and so on, and it still works, but the virus still goes away faster in them, then it must work all the more. Because right from the start, the drug has been more difficult to use than those that have not been treated. And so it is here also somewhat placed. So the patients are older and the patients have fewer asymptomatic ones in the cohort. Here comes the big "but". And you may need to know a little bit about the patients of this disease to understand it. And I am sure that many clinicians, who will read this study now, or also non-physicians, who do not understand the background, will think that this is a very big news, a very big encouragement to give all patients this chloroquine from now on. But there is a big catch to this study, and that is the time scale on which all this is written. So the question is: on what day do we actually measure whether the virus has gone? And on which day do we actually describe how the patients entered the study at the beginning and how they came out at the end? This time scale on which the study is written is not the day of the disease, but this time scale is the day of inclusion in the study. We have here a phenomenon where we have two different cohorts of patients, and this is strongly indicated by a very different age at inclusion, 51 versus 37 years. This sounds the alarm bell for me and leads me to take a closer look at why this age difference exists here. If I then look again that in one group there are only two asymptomatic people in the treated group and in the untreated group there are four asymptomatic people, then a picture comes together which tells me that the treated group here is in reality simply already more advanced in its course. And no matter when you take the included in the study, the first day of study inclusion is probably a more advanced day of disease progression in the treated group than in the non-treated group.
  • 4. pe. And this leads us to compare apples with oranges in this study here. Because we have an additional problem here. What is measured here is the virus concentration and the virus detection rate not in the lungs, where the disease takes place, but in the throat. In the whole study the virus is not measured in the lungs, but in the throat. And that is the biggest misconception in this entire study. STUDY VS. EXPERIENCES We have a lot of experience. We have made the most accurate description of an untreated patient co-hearing in Munich patients. And in the Munich group we saw how the virus concentration in the throat and lungs behaves over time. And we can say that at the beginning of the disease the virus is in the throat and it goes away by itself over, let's say, the first ten days of the disease. After that a lot of patients have very little or only irregularly detectable virus in their throat. But that has nothing to do with how the virus behaves in the lungs. In the lungs, the virus is only truly replicative, especially in the severe cases. And we can also say that what the patient has in his throat has nothing to do with how the disease progresses clinically, whether the patient gets well quickly or whether he has to go through a difficult phase. So what is measured in this whole clinical trial has nothing to do with the course of the disease, with the symptoms, but is only an initial indicator of how the disease starts. In all patients the virus concentration goes down in the first week, but if you now imagine that the group that is being treated is included a little later and the untreated group is included earlier in this study, then it is in the nature of things that in this later included group - they are already further in the elimination of the virus from the throat - the virus then goes down the throat faster. It disappears faster because they have simply been in the disease process longer. Whether this is now additionally due to the fact that they are treated, cannot be said at all on the basis of this entire study. Maybe if the groups had been put together like this, but if they had not been given chloroquine but some kind of headache tablet, the study would have ended the same way. Anja Martini This means that we simply have to wait for a new drug or for a possible drug. There is not much in sight yet. Christian Drosten Yeah, I don't want to be so absolute about this either. I want to say two things. First, it's possible that... 4/7 As of 19.03.2020 NDR.DE/CORONA UPDATE the authors do not know this at all, because there are many doctors at the moment who are now facing this dilemma of having to treat such patients, and they know too little about the disease. This has all happened so quickly and this will also apply to the first clinical trials. So it may be that the colleagues there in Marseilles do not even know that they are barking up the wrong tree when it comes to evaluation. And they actually think that we have found a solution here. They only mean well. I'm not accusing them of anything. I just want to say that, given what we know about this disease, we believe that something else should have been measured, namely the climatic outcome. I cannot even say that the lung viral load should have been measured; that would have been better. But I cannot say that that would have been optimal either. For me, the best criterion for assessing treatment for this disease at the moment is still the clinical outcome. It's not that we have very strict laboratory criteria. We're just working on them now. That's the one thing I'm trying to say. And the other: I'm not saying chloroquine won't work. What I'm saying is, the way this study was done, we're not any smarter. Unfortunately, this is often the case in clinical research, so that the truth has a second and sometimes also a third level. And you have to be very careful. It was important for me to say this right now because I know how it works. Today, clinicians all over Germany and perhaps also all over the world will look at this study and discuss it. And many of them will do so with little knowledge about the course of the disease, about the course of the laboratory work, which has been a laboratory criterion, but many of them are not aware of the course of the disease. They will think that this is totally convincing. Anja Martini As long as this conviction is not present in a study, however, that actually means that we must continue to take care of ourselves and do what we have already been told as measures: Please do not go out as much. And I think there is a group that is drawing a lot of attention to itself with the hashtag "risk groups", which includes a large number of young risk patients. Can you explain to us why it is very important for them that we all don't go out and protect not only the elderly, as we have said many times before, but also the young people. What can happen to them? Christian Drosten In principle, patients who have a basic risk should not be infected at the moment. We should protect them from infection. These are the older ones, from the idea of retirement age. But of course, in younger ones...
  • 5. Age groups also include patients with a special ri-siko, with heart disease, lung disease and so on, metabolic diseases. And of course, all these patients, we can summarize them as risk patients, no matter whether they are at risk because of age and related diseases or other diseases that are present - no matter how old, they have a right to be protected in society. There is, of course, the possibility of direct protection. You can simply say that they should stay at home and everyone else can continue to live as before. We discussed yesterday, using this major modelling study from England, that it is not that simple. That if we calculated what would happen if they were to be put in isolation at home, the elderly, the group at greatest risk, would hardly benefit from strict home isolation. You would still have a demand of eight times as much beat capacity as you have in reality. That would be a direct entry into this situation, which we now have in Italy, for example. In other words, there is no point in simply protecting these risk groups. They cannot be protected after all. This modelling study also took into account the fact that not everyone is exactly involved and that it is not possible to isolate everyone completely in detail. That is the way it is. Anja Martini And that means that it is really a social task. Christian Drosten Right, exactly. That is to say, this direct protection, this direct idea: well, then the risk patients should simply lock themselves up at home, it doesn't work that way. It is a task for society as a whole to also provide indirect protection by reducing the number of infections in the population. Hence the social distance, hence the school closures and so on that have now been decided on as a precautionary measure. This is a challenge and a message which Mrs Merkel also expressed very clearly again yesterday. It is also an appeal to reason and to the social behaviour of the individual in society. It must happen now that the incidence of infection is reduced. To achieve this, there must be social distancing. And one can only hope that our society is mature and thoughtful enough - also altruistically enough - to realise that this social distancing ultimately protects the weakest in society and is also aimed at them. Anja Martini Now, when you walk through the streets or go to the supermarket, there are some things you see. The cashiers, for example. 5/7 As of 19.03.2020 NDR.DE/CORONA UPDATE protected. They still have that direct contact. I saw yesterday, there were plastic walls set up in front of them and they had gloves on and all that, but no respirators. Is that any good? Does that give them some protection, given the contagious nature of the virus? Christian Drosten I think so. Well, I didn't go shopping yesterday or the day before yesterday. I saw it on TV. I think it's a good idea to set up things like that that can really block something like a wet pronunciation or a coughing. And that leads perhaps a little to the effect that it would have if everyone, but also everyone in the public eye, would wear such a mask, like the one in Asia is in fact. It's probably not so easy to implement in our country. So this protection that the mask provides, by the infected person wearing the mask. Not that I protect myself from others with my mask, that's a common thought, but that in public the mask actually protects when the infected person wears it. And by the way, can I just say again, we have already talked about masks, and something has been misunderstood. I have been contacted by people who have said, does that mean that all this is of no use at all if we as nurses wear a mask? It's not like that. That's not what we discussed. What we discussed was the mask in public. And that's the effect we need the infected person to wear the mask. And for that, everybody, everybody, everybody in the public eye needs to have a mask. If everybody would do this now, if everybody would buy these masks now, which has been discussed in public for weeks, there would not be enough masks on the market for the medical staff anymore. And in the medical staff, it is different. There it is really the effect: I wear the mask and I am protected, because the exposure level, the duration of exposure, the proximity to infected persons, the probability of meeting an infected person in daily business, all this is completely different in the work situation in hospitals. And where you are really exposed with a high probability, for example where you are directly coughed on, where you sit opposite people, where saliva flies and so on, you need such a mask alone as a splash guard for the oral mucosa, not necessarily as inhalation protection. And these are situations that we don't have in everyday life, but we do in hospital. And that's why the evaluation of masks in hospitals is completely different from that in the supermarket. Anja Martini One group is also a little worried. We have learned this from our emails, namely
  • 6. 6/7 As of 19.03.2020 NDR.DE/CORONA UPDATE Dentists. Some are already considering closing their practices because they are afraid and do not have enough masks. Is there any other way they can protect themselves? Do you have any advice for them? Christian Drosten Honestly, it's not my field. There's a specialty called hospital hygiene. They deal with that sort of thing, and they're occupational medicine. There is also an overlap in the treatment of problems between these two subjects. These are actually the experts you have to ask, not the virologists. I can say relatively little about this. I am almost a private person, if I say so. Well, as a virologist I can say one thing: yes, this virus replicates in the throat. We also know that the oral mucosa also has the receptor for the virus. And I would expect that this virus also replicates on the mouth, on the inside and perhaps even on the tongue. And if aerosol is generated by these drills, where water mist is sprayed, we have all been to the dentist, something also sprays out of the mouth, I am not sure whether wearing such a simple mask at the dentist really protects the dentist well. But as I said, I am not an expert. Anja Martini Today in the lab, what kind of questions are you likely to have today? What kind of topics are there? Christian Drosten Yeah, so in the lab, we were just talking about this clinical trial. And of course we're also doing things that go in that direction: That we are testing substances that we think could be used against the virus, because they are already approved drugs. We're doing that kind of thing. And then, of course, there is always this helping research going on, that is, that we give colleagues the virus or give them reagents. Then we have a relatively large amount to discuss, as far as the management of diagnostics is concerned, how to make better use of diagnostics as a tool. And then of course the evaluation of sequences and the improvement of logistic processes in order to keep bioinformatics up to date with sequence evaluation. In other words, comparing the results of the sequences with those already available and asking oneself: Does this indicate anything? Are there transmission clusters? Is there a certain virus that spreads faster than another? Anja Martini If we look again at the daily routine of the labs. Do you think the labs are now working on their have reached their performance limit? Or could we theoretically do more and do more tests? Christian Drosten Yeah, you're talking about lab diagnostics now. Here at the Research Institute, of course, that is only a very small part. We have a large routine laboratory here in Berlin, i.e. Labor Berlin, which is the large routine laboratory of the Charité, one of the largest supplying laboratories for hospital beds, because they supply not only the Charité, but also the entire Vivantes clinics here in Berlin and many other hospitals around Berlin. And there are also hospitals all over Germany that are supplied. Of course, we have a very large diagnostics company there where PCR testing, i.e. genetic testing for the virus, is involved. We have been at the limits of our capacity for weeks now. And we are certainly one of the largest laboratories in Germany in terms of throughput. About 600, 700 samples a day are tested here. And now we can see that we can hardly keep up. At the same time, other laboratories in Germany are also increasing their throughput in this area. There are now many laboratories in Germany that test 500 samples a day, and many small laboratories that test 100 or 200 samples a day. If I take this as an estimate, and there are still no clear figures - the RKI is working together with medical structures, with the associations of panel doctors, to collect the figures. We had already talked about that. This weakness of the German system, that we actually do not know how much we are testing, is in fact its strength, because so many laboratories can and are allowed to test. Nevertheless, we can make an estimate. So my private personal estimate is that we probably do 100,000 or more tests per week in Germany. And I am curious what the official figures will say then. They are still very provisional at the moment. I once read a figure that only referred to the outpatient sector, but all the hospitals and university clinics are missing. I would assume a figure like that. And the decisive question is now, as the epidermia continues and more and more patients are being treated, will we be able to continue with the testing afterwards? And the answer is..: No, we can't get there, because the epidemic is growing exponentially. And equipping the labs, that is still a very linear process. Anja Martini So devices, people. Christian Drosten Right. So in other words, even doubling that now is virtually impossible. I think we can get another 30, 40
  • 7. percent on top of it, with the greatest effort, across the board, mind you. Some laboratories are of course in a better position, but area-wide certainly not more than that. But while every scant week, every scant week, the number of infected people doubles - that is, of course, a situation in which it is inevitable to say that we will no longer be able to cope. We must therefore soon consider using diagnostics in a more targeted way, in other words, using diagnostics more as a tool for risk groups too. For example, it is no longer necessary for every young patient with compatible symptoms to have a PCR test in the outpatient area. At some point people will say: "Well, symptoms at this time of year, influenza season is over, at this age, that will be the infection. And then you can also say in principle, in which household does the infected person live? Is there a family? If so, all members of the household, i.e. the family or the whole flat share, can be defined as positive. Because we know that the transmission rate in the household is high, very high. And here we can say in principle, all those who live in a household where a first infected, a first known case has occurred, this household is considered a quarantine household and must remain in quarantine for 14 days without us testing. OTHER HANDLING OF TESTING But while in another situation - for example, when a terminally ill or elderly patient has symptoms - we absolutely have to have certainty. There we need the right of way for the diagnosis. Because these patients, even if they do not yet go to hospital, in principle the family doctor must call at least once every two days and ask: How is the air? We now know - as intensive care doctors who know their stuff tell me - that this illness can be left out too long at home. So it can be that if you breathe worse and worse, you should have been in hospital and spent too long sitting on the sofa at home. And when you come to the hospital, you suddenly have a situation where you almost have to be ventilated, even if you are still walking around and say: Oh yes, I'll sit here and wait a moment, I'll hang up my handbag here. A patient like that, when you look at the lungs, for example in a CT or something like that, it can look quite dramatic. And then you are close to the point where a patient needs oxygen. And then it can also happen that it gets even worse, that you have to go to the intensive care unit. And that shouldn't happen too late. That means it will be the task of family doctors to know these patients, 7/7 As of 19.03.2020 NDR.DE/CORONA UPDATE To know that one of my patients, whom I know in primary care, has been positively diagnosed and is at an age or with an underlying disease that opens up a risk case here, and I have to stay on the line, albeit over the phone. Anja Martini So many changes, also in diagnostics, in laboratory diagnostics, so to speak, which could still be coming up? Christian Drosten Right. I just want to sketch this out as a typical example. And we have other use cases. We don't have to discuss everything right now. Maybe we can discuss this on another occasion, what else can be done with laboratory diagnostics, which are used in a more targeted way. FURTHER INFORMATION ndr.de/corona update