From the WebMD Archives

June 18, 2020 -- Low-dose chest radiation, usually given in a single treatment, may reduce inflammation in the lungs of severely ill COVID-19 patients enough to wean them off a ventilator or avoid it altogether. Several clinical trials of the treatment are underway or launching in the U.S. and elsewhere.

The radiation works to offset an immune system overreaction known as a “cytokine storm” that happens in some patients with COVID, says Arnab Chakravarti, MD, a professor and chair of radiation oncology at Ohio State University. In a cytokine storm, the body starts to attack its own cells and tissues rather than just fighting off the virus.

Coronavirus in Context: The Role of Cytokine Storm in COVID-19WebMD's Chief Medical Officer, John Whyte, speaks with Maximilian F. Konig, MD. Division of Rheumatology, The Johns Hopkins University School of Medicine about the role of cytokine storm in COVID-19.867

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JOHN WHYTE: You're watching

Coronavirus in Context.

I'm Dr. John Whyte, Chief

Medical Officer at WebMD.

Today I'm joined

by rheumatologist Dr. Maximilian

Konig at Johns Hopkins School

of Medicine,

where he's going to talk

about his interest

in cytokine storm.

Dr. Konig, thanks for joining

me.



MAXIMILLIAN KONIG: Doctor Whyte,

it's a pleasure to be here.

Thank you so much for having me.



JOHN WHYTE: Now, you're

a rheumatology fellow

and you're studying

cytokine storm.

Tell us how that all happened.



MAXIMILLIAN KONIG: That's a very

good question observation,

you know?

Most people who are in the field

of r-- rheumatology probably

do not study COVID-19

at the moment.

Uh, for me, the path to actually

being interested

in cytokine storm

is a little bit of a long--

is a longer one.



I started to be

interested in cytokine storm

in the context of patients

with rheumatic disease

that have a similar presentation

at times that is referred

to as macrophage activation

syndrome, which has a lot of--



JOHN WHYTE: What would--

what would those conditions be?

Rheumatoid arthritis, lupus,

what would they be?



MAXIMILLIAN KONIG: Historically,

it's most common in a condition

called Still's disease,

or adult onset Still's disease.

Some patients

with that condition

develop a very fulminant

immune response that has a lot

of similarities to what we're

currently seeing in COVID-19,

but obviously has a lot

of differences in the sense

that it's not driven

by a viral infection in most

of the case.



I started working in a cancer

lab at Johns Hopkins,

being interested in diseases

and mechanisms of disease

related to cancer

and immune responses in cancer.

Particularly, I'm

interested in studying how

the immune system can be used

to target cancer and treat

the disease.



In that context,

the lab that I joined,

led by Dr. Vogelstein, Dr.

Kingsley, and Dr. Bettegowda,

is interested in using CAR T

cell therapies to treat cancer.

And I'm particularly

interested in using

a similar approach to treat

cancer,

but also potentially autoimmune

rheumatic disease.



It turns out that our lab had

an interest a couple of years

ago in better understanding

severe complications

of CAR T cell therapy,

including something that's

called cytokine release

syndrome.

And in that context,

we started to look particularly

in immuno responses that are

hyperactive, including ones that

mimic cytokine storm.

So that's kind of--



JOHN WHYTE: So what

is cytokine-- what

is cytokine storm?

Can you explain that

to a consumer audience?



MAXIMILLIAN KONIG: Absolutely.

So cytokine storm is a concept

that's actually pretty poorly

defined.

When physicians talk

about cytokine storm, they often

refer to a state

of immune activation

that's more than it should be.



So for example, when any of us

has a viral infection,

be it influenza,

or in this case, SARS CoV-2,

the cause of COVID-19,

an appropriate immune response

is necessary to clear the virus

and protect

from future infection.



What we're seeing in a subset

of patients with COVID-19,

unfortunately,

is that this immune response

becomes disregulated.



And in these patients,

instead of, um, having

an appropriate immune response

that, afterwards, is lowered

and resolves,

we see that the immune response,

a couple of weeks

after initial infection,

starts to ramp up.

And that is associated

with a lot of the disease's

morbidity and mortality

that we're seeing

in this disease.



JOHN WHYTE: Several of the drugs

that are being studied

for COVID-19 are also drugs used

for arthritis.

Not just hydroxychloroquine,

but there's a few others

as well.

Does that surprise you?



MAXIMILLIAN KONIG: Well, it

doesn't surprise me in a sense

that, given the similarities

that we observed to diseases

like macrophage activation

syndrome

and another condition called

HLH, it is naturally that people

would be thinking of applying

a similar repertoire

of medicines

to treat the disease.



Hydroxychloroquine is not

necessarily one of them,

but many of the drugs that we

currently use to treat

rheumatoid arthritis

and other autoimmune rheumatic

diseases are currently being

investigated as a treatment

of people who have

either severe or critical

COVID-19.



And that includes drugs that

target specific cytokines,

inflammatory molecules,

including IL-6, but also IL-1

and a plethora

of other cytokines and immune,

uh, cytokines

and immune mediators

that potentially,

um, are associated

with worsening disease

and severe outcomes in COVID-19.



JOHN WHYTE: What are some

of those other drugs that are

being studied?



MAXIMILLIAN KONIG: So if you

look at the moment,

uh, it's almost an endless list

of drugs.

Anything that you can think

of that probably has been used

in the treatment

of rheumatic disease

is investigated in some form.



A lot of centers

around the world have focused

on drugs that target the IL-6

axis.

IL-6 is an important cytokine,

and has been found to be

elevated in patients

with COVID-19.

Probably more importantly, IL-6

is elevated in patients early

on who have poor outcomes.



So in a paper that was re--

reported early on from China,

it said that if you looked

at patients who have

poor outcomes

and eventually died,

IL-6 levels were, early on,

already elevated compared

to those who survived.



There are a couple

of other cytokines

that follow a similar pattern,

and that has guided,

I think, initial interests

in-- in investigating drugs that

could be potentially

interfering with that

up regulation

of inflammatory markers.



In that context, there are drugs

that are used, for example,

for rheumatoid arthritis,

but also sometimes used

in Still's

disease that I mentioned

earlier, which has

this phenotype

of macrophage activation

syndrome.



One of them

is called tocilizumab.

It's an antibody that blocks

IL-6 receptor.

But there are similar drugs

in that same--



JOHN WHYTE: That also has

anti-inflammatory properties

as well, does it not?



MAXIMILLIAN KONIG: It-- it has,

right?

So the antibody is neutralizing

to IL-6 in a sense that it binds

the IL-6 receptor, and therefore

IL-6 cannot signal anymore.

So it's

a potent anti-inflammatory drug.



And usually when we use it,

we see a rapid decline

in inflammatory markers

in patients who get the drugs as

early as one or two

days after administration.



JOHN WHYTE: But those drugs also

have significant risks as well.

And this is the challenge,

is it not, in terms of targeting

drugs that impact cytokine

storm, specifically IL-6

and some of the others?



MAXIMILLIAN KONIG: It-- it's

an absolutely important

observation that you're making.

And I cannot stress enough that,

at the moment, we know very

little to what degree using

these drugs, be it IL-6

inhibitors, IL-6 in--

receptor inhibitors,

or other potent

immunosuppressive drugs,

is going to be

helpful or harmful depending

when they're given

and to what patient

they are given.



So that's why it is so important

that we're currently pursuing

clinical trials around the world

to help figure out what the risk

benefit ratio is.

There are encouraging

early results that suggests

that some patients may get

benefit, but it's probably

not the case across the board.



So it's going to be very

important to differentiate

at what point

you should be giving that drugs

and to what patient population.

The risks that you mentioned

is potentially important

to consider.



We know that patients who have

severe COVID-19, and those are

patients that end up being

in the hospital,

often intubated, and often

in the ICU where they are

at high risk

of secondary infection,

would be getting these drugs.



And due to the long half life

of many of these agents,

including, for example,

tocilizumab, it is possible

that we would be giving a drug

to a patient who could have

significant side effects

from being immunosuppressed

for prolonged period of time.



In that same context,

it's important to consider

that we're giving the drug

to somebody who doesn't have

sterile inflammation.

What I mean by that

is that we're giving the drug

to a patient who doesn't have

rheumatoid arthritis

or other forms of inflammation

that's driven

by your own immune system

in the context of being

overactive,

not necessarily in the context

of fighting

a virus

or a bacterial infection.



JOHN WHYTE: What that relates

to, is there any belief

that COVID-19 could have

some element of auto

immune disease?



MAXIMILLIAN KONIG: I-- I think

at the moment,

we have no evidence of that.

But it's important to realize

that for some reason that we

still poorly understand,

the immune system starts

to become into overdrive.



There are very few data that I

could think of that would

suggest that there's

any mechanism underlying this

that's autoimmune in nature,

but we know too little to really

understand for sure.



JOHN WHYTE: With the release

of all these cytokines, and it's

a, you know,

which cames first,

their underlying condition

or the overreaction of the body.

But obviously, cytokine storm

is-- is a contributor

in and of itself

to-- to someone's, um,

condition, is it not?



MAXIMILLIAN KONIG: Yes.

So that's actually what we think

is going on.

If you look at the trajectory

of patients

get admitted to the hospital

for severe COVID-19, what we

often see that patients

in the first week or 1 and 1/2

weeks of disease have symptoms,

but they're not critically ill.



And somewhere

within the second and third week

in a subset of patients,

and we don't fully understand

what subset that is

and what influences that risks,

the immune system becomes

overactive and then leads to all

the complications that we think

are associated

with poor outcomes in COVID-19.



JOHN WHYTE: Is that

unusual for a virus?



MAXIMILLIAN KONIG: It has been

reported with other viruses.

So if we look back

in-- in the literature,

there are reports of patients

with influenza, um, specifically

influenza

like the H1N1 epidemic, um,

several years back,

where similar presentations had

been reported.



Patients that would have

severe disease to the degree

that would-- they would be

in a kind of cytokine storm.

And it's actually known

from prior coronavirus diseases,

including SARS and MERS,

prior illnesses that were

described within the last 10

years, where we saw similar, um,

manifestations of cytokine storm

after infection.



JOHN WHYTE: What do you hope

to know six months from now

that you don't know today?



MAXIMILLIAN KONIG: That's

a great question.

So first of all, at the moment,

a lot of the efforts

are focused on treating patients

that already have

severe disease.

I think it's very important

to understand better what

the right drugs will be

to interfere

with-- in the process.



And it's going to be incredibly

important to understand when

these drugs need to be given

in the disease course.

If we give it too late,

the concern is that patients

will not have

the appropriate benefit anymore,

because there is already

enough organ damage.



If we give it too early,

the hypothetical risk is that we

interfere with the body's

ability to actually interfere,

clear, and fight the virus.

So timing is going to be

important.

And at the moment,

I don't understand where

the right window of opportunity

is.



The second thing that I would

really like to understand,

thinking about cytokine storm,

is how we can prevent

cytokine storm from happening

in the first place.

And that's where a lot

of research efforts that I'm

interested are currently going.



Ideally, we would be

able to prevent the progression

of patients who come in

with mild symptoms

to go

through the second and third

phase of the disease

where they accrue more and more

inflammatory

damage, which includes

the development of ARDS,

severe lung injury,

and potentially other organ

systems that fail afterwards.



So those are two

critical questions.

That's all embedded

with many other strategies that

are currently pursued.

You mentioned a couple of them

that might be focusing

on targeting the virus itself,

and other strategies that might

be important to prevent the risk

of infection with the virus

by blocking receptors.



And ultimately, I think there

is, uh, the greatest interest

of finding a vaccine that could

potentially prevent us

from getting

the virus and the infection

in the first place.

But it seems like that is

nothing that we will have

answered in the next six months.



JOHN WHYTE: Do you get

any weird responses from people

when you're a rheumatologist

studying an infectious disease?



MAXIMILLIAN KONIG: Well, I think

it is fascinating to observe

what a diverse group of people

is currently coming together,

tackling and trying to tackle

this epidemic.

And pandemic.



It is fascinating, for example,

that I get emails

from patients--

from other physicians

who might be plastic surgeons

at a different part

of the United States

who have ideas and contributions

to actually contribute to this.



Um, so I think there is strength

in an approach where very

different specialties are coming

together to tackle a-- a similar

and-- and shared goal.



In our group, for example, we

have oncologists, neurologists,

neurosurgeons, rheumatologists,

and a bunch of other incredibly

talented research statisticians

and even economists working

together to try to find answers.

I think it's an incredibly

inspiring time,

and to be part of it

is fantastic.



JOHN WHYTE: Well Dr. Konig, I

want to thank you for sharing

your insights today.



MAXIMILLIAN KONIG: It's

my pleasure.

Thank you so much for having me.



JOHN WHYTE: And I want to thank

you for watching Coronavirus

in Context.

I'm Dr. John Whyte.



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John Whyte, MD, MPH. Chief Medical Officer, WebMD. Maximilian F. Konig, MD. Division of Rheumatology, The Johns Hopkins University School of Medicine/delivery/aws/38/0a/380ad66f-2beb-398f-b88a-e432f7b56811/Konig_042920b_,4500k,2500k,1000k,750k,400k,.mp405/07/2020 14:36:0018001200Maximilian Konig/webmd/consumer_assets/site_images/article_thumbnails/video/covid19-images/Konig_042920_1800x1200.jpg091e9c5e81eec824

Chakravarti is leading two clinical trials -- one will test the treatment in patients already on a ventilator, and the other will give the treatment to patients on oxygen to try to prevent the need for a ventilator.

"Radiation at these low doses usually doesn't have a direct antiviral effect," he says. "But it does reduce inflammation. And when the inflammation is reduced, the acute [ill] effects of the byproducts of pneumonia also subside," says Chakravarti, who is also the Klotz Family chair of cancer research at OSU's Comprehensive Cancer Center -- Arthur G. James Cancer Hospital.

Researchers at Emory University's Winship Cancer Institute are also testing the therapy. In their early analysis of five COVID-19 patients treated with radiation therapy, three were taken off supplemental oxygen within 24 hours of the treatment, and a fourth after 96 hours. The patients were 64 to 94 years old. The results are reported in a preprint, which is not yet peer-reviewed.

Researchers in Italy, India, Iran, and Spain are also studying the treatment.

The treatment was used after the 1918 influenza pandemic to treat flu-related viral pneumonia, Chakravarti says, and has also been used for arthritis.

The dose for COVID-19 patients ''would be a little higher than the dose of a typical CT scan, but magnitudes lower than when it is used to treat lung cancer," he says. "At these very low doses, the treatment should be safe for most patients, but it really should be done in a clinical trial."

How did the treatment come into play again for COVID-19? "Many of the thought leaders in radiation oncology thought if these ultra-low doses work for influenza-mediated viral pneumonia, why wouldn't it work for COVID-19-mediated pneumonia as well," Chakravarti says.

The study to test the therapy in ventilated patients, called VENTED, will only be done at Ohio State, with a goal of enrolling 24 patients. The study testing the therapy to prevent the need for a ventilator, called PREVENT, will include up to 21 hospitals across the country, Chakravarti says. Varian Medical Systems, which makes radiation oncology treatments, provided funding for the PREVENT study.

William Small Jr., MD, chair of the Radiation Oncology Commission for the American College of Radiology, called radiation therapy “another tool to try.”

He says he hopes to join the multi-center study led by Chakravarti.

In his prior research, Small has found that radiation therapy can prevent kidney transplant rejection by effecting the immune system.

In late April, researchers from Iran reviewed radiation treatment for COVID-19 in a radiation oncology journal, cautioning that "there is limited knowledge about the interaction of low dose radiation therapy and viruses." They warned that some research has reported the spread of some viruses after radiation treatment, but the studies they cite did not involve the coronavirus that causes COVID-19.

WebMD Health News

Sources

medRxiv: "Low-Dose Whole-Lung Radiation for COVID-19 Pneumonia: Planned Day-7 Interim Analysis of a Registered Clinical Trial." 

William Small Jr., MD, chair, Radiation Oncology Commission, American College of Radiology; chair of radiation oncology and director, Cardinal Bernardin Cancer Center, Loyola University, Chicago.

Arnab Chakravarti, MD, professor and chair, radiation oncology and Klotz Family chair of cancer research, OSU Comprehensive Cancer Center -- Arthur G. James Cancer Hospital, Columbus, OH.

News release, Emory University: "Low dose chest radiation for COVI-19 patients."

Radiotherapy & Oncology: "Low dose radiation therapy for COVID-19 pneumonia: A double-edged sword."

Clinical Trials.gov: "Radiation Eliminates Storming Cytokines and Unchecked Edema as a 1-Day Treatment for COVID-19 (RESCUE1-19)."

Clinical Trials.gov: "Low Dose While Lung Radiation Therapy for Patients With COVID-19 and Respiratory Compromise (VENTED)."

American Journal of Clinical Oncology: "Radiotherapy for Rejection of Renal Transplant Allografts Refractory to Medical Immunosuppression." 

 

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