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Microteaching English Learning Area peer feedback sheet v2 (1)

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Updated August 07, 2020 12:46:30

In the quest to find life-saving COVID-19 treatments, scientists are trying everything from using the blood of coronavirus survivors to recycling old HIV drugs. What's working - and how?

On March 16, 50-year-old Damian Fawkner cancelled his regular blood donation to the Red Cross because he wasn't feeling well.

Within two days, he couldn't get out of bed.

"I woke up and just felt like my bones were being squeezed and my muscles were being squeezed," he says. "It was just an ache all over my body. I didn't have the energy to move."

Damian, a general manager from the NSW Central Coast, didn't imagine then that he would become part of the quest to outwit the coronavirus.

After fighting off the virus, Damian has become a corona "super-donor".

The blood plasma extracted from his arm is now being injected into sick coronavirus patients as part of a clinical trial.

It may sound radical, medieval even, to inject the blood of recovered coronavirus patients into those who are sick.

But with no vaccine, this and hundreds of other potential cures are the only hope for preventing more deaths from COVID-19.

But is a cure even a realistic goal?

Three types of treatments are being explored for coronavirus. All have shown promise, but this virus is also proving hard to outsmart:

The century-old 'bag of blood' approach relying on altruistic people like Damian

Drugs already being used to treat other diseases, which might also work on COVID-19, and

The much-hyped, but not thoroughly tested, new anti-viral

To beat the virus, researchers first need to understand how patients like Damian recover from a coronavirus infection. Here's how it happens.

The coronavirus isn't alive, so it needs to infect the cells of a patient like Damian before it can replicate itself.

Think of the cell as a factory and the virus as a burglar trying to get inside.

But the virus doesn' t even need to break into the factory. It has a key - the spike protein.

The spike binds to a receptor on the surface of healthy cells, and the virus slips quietly inside.

Before long, the factory has been taken over and is spitting out lots of new virus particles.

But the cell doesn't just give up when the virus gets inside. Its early warning system is activated.

It releases a cascade of chemical messengers called cytokines.

It's as if the alarm goes off and the security guards come running.

The security guards are white blood cells - they fight the virus.

One of the most important cytokines in a viral infection is called Interleukin-6.

The surprising catch is that Interleukin-6 doesn't just ring the body's alarm bells.

It can also make you really sick.

Ten days into his illness with COVID-19, Damian Fawkner started feeling even worse.

"I've never been that sick in my life. I was staying in bed for 15 to 16 hours a day," he says.

He was so crook he went to the hospital emergency department where they ran a battery of tests.

Despite what you might think, his symptoms were not caused by the virus itself. They were caused by the body's response to the virus.

Cytokines, including Interleukin-6, were the culprits responsible for Damian's extreme tiredness.

Doctors gave Damian oxygen to help him breathe and by the end of the day, let him go home.

A couple of days later, he got a call to say his coronavirus test was negative. His positive diagnosis would not come until later.

World-first research into one of the first Australian coronavirus cases by Melbourne's Doherty Institute reveal that around day 10, the time when Damian Fawkner went to hospital, populations of immune cells start to appear in the blood.

One of the cells that kicks into gear is a type of white blood cell called a T cell.

T cells are one of the factory security guards that combat the viral invader.

Some T cells are killers.

They latch onto cells infected with the virus and kill them.

But other T cells are helpers.

They recruit another white blood cell - B cells, and tell them to start making antibodies.

Antibodies are the secret to taking down the virus.

They bind to the virus's spike, meaning it can no longer break into healthy cells to reproduce.

The T and B cell security guards can clone themselves.

For the rest of their lifespan, they will hang out in the body, ready to spot the coronavirus spike protein and annihilate the virus the next time it invades.

This means the body's response to any further coronavirus attack will be fast - it will not take a couple of weeks.

In early May, nearly two months after Damian first felt sick, the hospital called to say it had found antibodies specific to coronavirus in his blood sample.

Those antibodies were the key to his recovery.

Damian was back at work two and a half weeks after he first got sick, but when he resumed his mountain biking hobby, he discovered the virus had taken a longer-term toll.

"What I found was as soon as I started exercising, I'd lost something in the lungs. Probably about 10 per cent or thereabouts, but I certainly felt it," he says.

It was four weeks before he felt completely well again.

Not everyone responds the way Damian did. In some people, the immune response goes crazy.

Cells rush into the lungs, filling them to the point where the patient needs a ventilator to breathe.

Some will eventually die.

The impacts are felt all over the body. The heart is particularly at risk.

Immune cells ramp up production of cytokines, especially Interleukin-6, but they go too far and the inflammatory response gets out of hand.

Researchers think this "cytokine storm" might be causing some severely ill patients to die.

For the people who don't mount a proportionate immune response, the challenge is to find treatments that will give them a helping hand.

A bag of blood

Could receiving blood from corona survivors help save sick patients?

What if we could harvest antibodies from someone like Damian, and give them to a sick patient?

That's how a treatment known as "convalescent plasma" works. It has been used to treat Spanish flu, measles, Ebola and SARS.

It was first used in the 1890s, when doctors took blood plasma from horses injected with the bacteria that causes diphtheria and used it to treat patients.

These days, it's the same concept, but a lot more refined.

The idea of convalescent plasma is it acts like an immediate booster - the antibodies from the donor's blood plasma help the recipient fight the virus, until their own immune system gets up to speed.

Damian Fawkner has been a blood donor for 30 years.

When he read that the Red Cross was looking for donors who had recovered from coronavirus, he didn't hesitate.

"It's no different to how I've always felt about it. If my plasma can help someone who needs it, I'm absolutely happy to give it away," he says.

It turns out Damian is what researchers call a "super donor". Coronavirus antibody levels in his blood are 69 times higher than required for the trials using donated blood.

So far, 454 recovered Australians have made 990 donations of 450 mls of blood, around a beer glass full, to Australian Red Cross Lifeblood.

They are very keen to have more recovered patients donate, but only 28 days after their respiratory symptoms have gone away.

Zoe McQuilten, a haematologist at Monash University, is testing whether blood plasma can save lives in two big Australian trials.

Associate Professor McQuilten's team separates the antibody-rich plasma from the red blood cells and transfuses a donation into sick patients, then another one a day later.

Convalescent plasma was given to 10 severely ill Chinese patients and all their symptoms disappeared or improved within three days, a compelling result, but one that needs to be confirmed in larger studies.

The blood can be frozen for up to 12 months, but only plasma from men is used.

"That's to reduce one of the complications from plasma transfusion, called transfusion-related acute lung injury," Associate Professor McQuilten says. "It's a very rare complication but its more likely to occur with plasma from female donors."

Donations from recovered female patients won't go to waste, though.

Australian company CSL will use donations from women and men, in their "hyper-immune globulin", a purified mix of anti-coronavirus antibodies.

Stop over-reacting

When the body's response to the virus is worse than the virus itself

An alternative to giving antibodies would be to throw a bucket of water on the over-excited immune response that makes some people sick.

Interleukin-6, that critical chemical messenger, sometimes causes all the immune cells to rush into the lungs to fight a coronavirus infection.

It's one of the key targets of this treatment approach.

IL-6 binds to a receptor on T and B cells.

That causes more cytokines to be made, and still more immune cells to come running.

Stopping IL-6 from sounding the alarm could dampen down that response.

Enter tocilizumab.

It's a drug that has been around since 2010 and is used to treat people with rheumatoid arthritis and other inflammatory diseases.

It's been engineered in the lab to attach to cells' IL-6 receptor.

That stops IL-6 from binding and wreaking havoc.

If tocilizumab works, it should stop the out-of-control rush of immune cells into the lungs.

In the first days of the pandemic, doctors from Milan to Wuhan threw everything from blood thinners to steroids into sick patients in a desperate attempt to stem the deaths.

Chinese doctors gave tocilizumab to 21 patients in early February.

They responded well and after three weeks, they were all back home.

So, you might be wondering, if tocilizumab works so well, why not use it in all severely ill coronavirus patients?

Well, the answer is that this small study didn't meet the gold standard for deciding to use a drug more widely - a randomised, controlled trial.

That means treating thousands of patients, comparing them to no treatment or a dummy treatment, called a placebo, after randomly allocating patients to each group.

Steven Tong is a researcher at Melbourne's Peter Doherty Institute for Infection and Immunity.

He says a big randomised clinical trial is the only way to work out whether any treatment might do more harm than good.

Tocilizumab is being tested in one of the largest randomised controlled trials ever run - the 7,000-patient REMAP CAP trial.

Tocilizumab targets the runaway immune response in very sick patients. But what about people who are less sick, or haven't caught the virus yet?

Enter the anti-viral drugs.

Hydroxy hype

Trump says he took it, but the science is still out on this one

Hydroxychloroquine was quickly touted as a miracle treatment for coronavirus infection - Donald Trump says he has been taking it, and Australia's own Clive Palmer bought nearly 33 million doses and spruiked it in full-page newspaper ads.

Hydroxychloroquine is a cheap drug used to treat malaria and autoimmune diseases for more than 50 years.

To see how it works, we're going inside the cell "factory".

Once the coronavirus attaches to a healthy cell, it buds off to form a bubble inside the cell.

The bubble, with the virus inside, is called an endosome.

Hydroxychloroquine gets into a cell and builds up in the endosome, making it less acidic.

This build-up causes the endosome to swell and it stops the virus from being released.

If the virus can't get out of the endosome, it can't use the cell machinery to replicate itself and make lots of new viruses.

Essentially, the drug forces the factory to grind to a halt.

But that' s not all hydroxychloroquine can do. It also calms down the over-excited immune response in very sick patients.

Sounds like a wonder drug, right?

Well, hydroxychloroquine certainly wins the prize for most investigated coronavirus treatment - it is being tested in trials involving more than 120,000 people.

That's a lot of hope riding on an old drug that was designed to treat other diseases, and it didn't take long for the first scientific scandal to erupt around it.

Dodgy data: When the scientific method gets messy

On May 22, eminent British journal The Lancet published a study on 100,000 patients with coronavirus, comparing those who were treated with hydroxychloroquine to usual hospital care.

It was not a randomised trial, but a backward look at how patients across six continents had responded.

It showed that the patients who took hydroxychloroquine were actually more likely to die than those who didn't, and more prone to heart problems.

In Australia, Associate Professor Tong and the team running the Australian and New Zealand AustralaSian COVID-19 Trial (ASCOT) in 2,400 patients, suspended enrollment of patients in the hydroxychloroquine arm and got to work analysing the data from the Lancet paper.

Their statistician noticed that the Australian data could not possibly be accurate.

The Lancet study relied on data collected from Surgisphere, a small data analytics company, which would not release its data to peer reviewers.

Peer reviewers are fundamental to the integrity of scientific research - they are independent scientists, working in the same field, who review studies before they are published in scientific journals.

More problems emerged, and the authors were forced to withdraw the study.

By June 4, patient recruitment to hydroxychloroquine treatment in the Australian ASCOT trial was back on, but on July 30, it was abandoned after overseas trials failed to find a benefit.

That's not the end of the road for hydroxychloroquine, though.

Marc Pellegrini, an infectious diseases doctor at Australia's Walter and Eliza Hall Institute, is testing whether it can prevent healthcare workers from getting the virus in a trial evocatively named COVID SHIELD.

"Some of our most successful [influenza] drugs ... are pretty pathetic at treating influenza, but they are absolutely phenomenal in preventing people from getting infected," he says.

"The same drug can be incredibly important in managing an infection if given at the right time."

Professor Pellegrini says hydroxychloroquine, used by thousands of people with rheumatoid arthritis, is reasonably safe.

However, it's not without risks - it can get into heart cells and affect how the heart beats.

All patients in the COVID SHIELD trial will get an electrocardiogram, a test to check that their heartbeat is normal, before being given the drug.

No copying

This old HIV drug aims to stop the virus from replicating itself

Hydroxychloroquine and tocilizumab aren't the only older drugs that offer hope.

Researchers think a 20-year-old HIV drug combination of lopinavir and ritonavir could also work on coronavirus.

To understand exactly how these drugs come into the picture, we're going to have to delve deeper into the science of RNA and exactly how viruses clone themselves.

Deep breath. You've got this...

After the virus gets inside the cell, the endosome opens and lets out the viral RNA.

The RNA is like the virus's design package.

It directs the cell to make the proteins that will generate the new viruses.

The virus uses the cell's 3D printer, called a ribosome, to do that.

The RNA feeds into the 3D printer....

...and two strings of viral proteins, called polyproteins, come out.

The string needs to be chopped up into its individual proteins.

The virus, unfortunately for us, is like a Swiss Army Knife.

It has its own pair of scissors, called a protease, for just this job.

Lopinavir, an old HIV drug, is a protease inhibitor.

When it is lurking in the cell, it binds to the viral protease...

... and stops the string of proteins from being cut up.

It is used with ritonavir, which acts like a bodyguard to help protect lopinavir.

Like hydroxychloroquine, nearly all the data showing how these HIV drugs act on coronavirus comes from the test tube.

In a small randomised trial in 200 patients in China, people who got the drug recovered one day faster than others, but the difference was not statistically significant.

That means it could have been due to chance.

Still, researchers included the HIV combo in seven trials in more than 20,000 patients.

It's a measure of how desperately a treatment is needed to defeat coronavirus.

Microscopic mimic

With a dash of trickery, could this drug jam the virus's photocopier?

Another anti-viral, remdesivir, is possibly the best hope yet for a reliable treatment.

It was picked up by screening a thousand small molecules for anti-viral activity against the Ebola virus in a test tube. Unlike other potential coronavirus treatments, it has never been used in patients outside of a clinical trial.

Like lopinavir, it acts to prevent the virus from replicating itself. But it tackles the job a little differently.

Remdesivir acts at the second stage of viral replication - when the virus tries to copy its RNA.

Remember those viral proteins made by the infected cell?

The virus uses them to assemble its own RNA photocopier.

It's called a replication complex.

To make the new RNA, the virus steals the cell' s building blocks, called nucleotides.

New full-length viral RNA strands come out the other side.

Remdesivir acts at this stage. It mimics one of the cell' s building blocks and inserts itself into the new RNA strand.

This causes the RNA photocopier to jam and a short, incomplete RNA to be made.

Not only is the dodgy building block inserted into the viral RNA, but remdesivir also seems to be able to fool the virus's proofreading capacity, which would overcome the blockage.

Every day counts in race for effective treatments

The desperate, hurried search for a coronavirus treatment has thrust the arcane world of clinical research into the limelight.

Results are being announced at press conferences even before trials are finished.

Remdesivir became Australia's first approved coronavirus treatment and has already been used to treat patients, even though the clinical trial has not finished.

And the interimresult that drove that decision?

Patients taking remdesivir recovered after 11 days, compared to 15 days for patients not getting it.

Eight per cent in the remdesivir group died compared with 12 per cent in the control group, though the difference was not statistically significant.

"If after a thousand patients, you don't have statistical significance, that means the difference is not going to be very large," Associate Professor Tong says. "It is an important difference and I'd take the drug if it was offered, but it's not going to save everyone's life".

The most exciting breakthrough so far has come from the UK RECOVERY trial.

Helped by floods of patients, it is the fastest-growing trial in medical history, enrolling 1,000 patients at 132 hospitals in its first 15 days.

It includes hydroxychloroquine, lopinavir and ritonavir, and an antibiotic.

But it was dexamethasone, an old, cheap corticosteroid that caused a stir on June 16.

Dexamethasone helps put a brake on the out-of-control immune response by suppressing those cytokine "alarms".

In around 2,000 patients, dexamethasone lowered the death rate in patients on ventilators by a third but had no benefit in patients who didn't need help to breathe.

To put that result in context, dexamethasone would prevent one death in eight ventilated patients or one death in 25 patients on oxygen.

'They are not going to be perfect'

These differences may not seem like much, but they might be the best we can hope for.

A "cure" is unlikely.

"It's fair to say, none of these will be a game-changer," Associate Professor Tong says.

David Paterson, director of the University of Queensland centre for clinical research, is working on the ASCOT trial.

"I think we'll find something that's better than nothing," he says.

"We don't use that word cure, we talk about treatments. I don't think there's going to be a universal cure but I think there will be things that do improve outcomes but we have to accept they are not going to be perfect."

Damian Fawkner's convalescent plasma is just one of the many treatments that might help us outwit the virus.

"If it doesn't work, at least they have tried it," he says. "I'm happy to be the person who supplies it. And if it does help, that's great."

Credits

Topics: covid-19, epidemics-and-pandemics, pharmaceuticals, medical-research, academic-research

First posted August 06, 2020 04:59:22

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Outwitting the virus - the treatments that just might do it

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Updated August 07, 2020 12:46:30 In the quest to find life-saving COVID-19 treatments, scientists are trying everything from using the blood of coronavirus survivors to recycling old HIV drugs. What's working - and how? On March 16, 50-year-old Damian Fawkner cancelled his regular blood donation to the Red Cross because he wasn't feeling well.