ICU clinicians tend to a patient in July 2020 at Western Health’s Footscray hospital. Doctors around the world have been sharing notes and tricks to fight COVID since the pandemic started.

ICU clinicians tend to a patient in July 2020 at Western Health’s Footscray hospital. Doctors around the world have been sharing notes and tricks to fight COVID since the pandemic started.Credit:Penny Stephens

How does COVID attack the body?

Most people with COVID recover on their own at home,where rest,fluids and over-the-counter pain medication for fevers and headaches will be the order of the day. But in severe cases,the virus can spread so fast it overwhelms the body’s immune defences,attacking organs and sometimes causing complications such as stroke or heart attacks.

However,with an unfamiliar pathogen such as COVID,the biggest danger is actually an overreaction of the immune system itself,the kind that canspiral into what’s known as a “cytokine storm” where too many virus-fighting proteins are called into battle and our cells become collateral damage. In the lungs,this looks like the inflammation that causes pneumonia. It becomes harder to pump oxygen to the rest of the body – and harder for patients to breathe. “Blood pressure can drop and you can start to tip into multi-system organ failure,” says infectious disease physician Steven Tong at the Royal Melbourne Hospital.

COVID patients generally arrive at wards because they are having trouble breathing. Only,it doesn’t quite look like that ad. Clinicians have been quick to point out that people are not left suffering and struggling to breathe on their own in a bed,as the woman in the ad is. Along with oxygen masks,ventilators and other machines can be used to keep the lungs and organs working.

Are we getting better at treating COVID?

Yes. Even before vaccines arrived, mortality rates worldwide were trending down and better treatment was part of the picture. While the virus and all its strange complications (from strokes and delirium to red “COVID toes”) has challenged the usual infection rule book,clinicians now have a much better idea of what to watch out for. “We see it as a multi-system disease now,” says Tong,who is running Australia’s biggest COVID treatment trial,ASCOT (mostly now in overseas hospitals where there are more cases such as India).

Though the nose and lungs remain ground zero for the virus,it can travel throughout the body via the ACE2 protein,found in the lining of blood vessels and almost every organ. The oxygen levels of patients recovering at home can be monitored remotely in case of a sudden crash. In the pandemic’s first wave,whendoctors in New York began finding dangerous blood clots among a small number of otherwise healthy COVID patients,they quickly made strong blood thinners a preemptive treatment for those in intensive care units. Today,Tong says just what dose to give patients is still a live question – while all patients in ICU will be given a lower,preventative dose,ASCOT is testing a number of blood-thinning tactics at its Indian sites to see if something stronger is best.

Still,the director of the Kirby Institute,Professor Anthony Kelleher,says a lot of the advances in treatments have been more procedural – managing how best to weather the storm of COVID symptoms such as optimising ventilator use or proning (lying patients on their sides or stomachs to redistribute air in the lungs). There has been no breakthrough designer drug against COVID as yet.

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Do existing drugs work against COVID?

So far,most drugs repurposed from the medicine cabinet have failed against COVID – from Donald Trump’s pick,hydroxychloroquine,to the anti-HIV combination lopinavir/ritonavir. The commonantiparasitic drug ivermectin is still being trialed,Tong says. “But in[severe] cases,we now know hydroxychloroquine can even make things worse”. Doctors around the world have often faced a harrowing choice between waiting for treatment trials to finish and offering experimental therapies to the dying patients before them in the meantime.

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Two drugs work well enough that they are now standard in COVID hospital wards,including in Australia:the antiviral remdesivir,formulated to fight Ebola and somewhat effective in stopping the coronavirus replicating in cells,and the inexpensive steroid dexamethasone,which dampens that dangerous immune system overreaction. Dexamethasone is the stand-out,shown to bring down the risk of death by a third for COVID patients on ventilators,and nearly a fifth for those on oxygen therapy (“There’s no silver bullet but we’re very confident that saves lives,” Tong says).

Remdesivir has hadmore disappointing results in terms of reducing mortality,Tong says,but is still considered safe. “Patients will often get both together in hospitals. There’s also another anti-inflammatorytocilizumab that’s directed against a specific cytokine I’ve used for[patients] and that’s been shown to work too.”

Can we just give people the antibodies they need?

Vaccines tell your immune system which antibodies to make to fight off COVID-19;they then gum up the signature spike protein the virus uses to break into cells. But,for someone already infected,or someone with a compromised immune system,doctors can put antibodies directly into the body via transfusion. Before vaccines arrived,this was already being tried by “borrowing” the immunity (antibodies) still active in the blood plasma of recovered COVID patients. But,despite urgent calls for survivors to donate their plasma and a large rollout in hospitals worldwide,Tong says it has since beenfound not to help patients as first hoped. ASCOT halted its own test of plasma transfusions in February of this year.

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Instead,designer antibodies engineered in the lab,known as monoclonals,are proving very effective at stopping patients early on from developing severe disease. “They’re engineered to go after the spike just like the vaccine,” Tong says. The treatment is already approved in the United States and Tong says it would be good tosee it come to Australia,too. “When people test positive who we know are at higher risk of severe disease,those who have[underlying conditions] like diabetes or are older,then we could give it to them proactively.”

Kelleher says that,as with most of the existing drugs tested on COVID,monoclonals have a long safety record,often cooked up for cancers,hepatitis and autoimmune conditions. They work especially well in patients whose immune system does not kick in strongly against COVID.

“Eventually,we might be testing a patient’s initial antibody response and then coming up with the best treatment algorithm from there,” Kelleher says. Kirby Institute researchers are part of a global trial testing newly developed monoclonals in places such as Indonesia and South America,with plans to trial designer anti-viral drugs next.

But monoclonals are also expensive and difficult to make,Kelleher says.They are given intravenously at present,posing a challenge for delivery to early-stage patients outside a hospital. And some already appear vulnerable to evolving variants of the virus.

Although there is some evidence emerging that the more contagious Delta variant also has a higher hospitalisation rate,Tong says it’s not clear yet and overall “we don’t know if the response to treatment varies by variant”. Certainly,therapies focused on dampening the body’s immune response won’t be. And as Kelleher adds:“Not all drugs are aimed at the spike protein,that’s the bit[of the virus that keeps mutating],so they might not be as vulnerable as monoclonals.”

Could we take a pill to stop a bad case of COVID?

That’s the hope. So far a number of candidates have failed. But Pfizer,one of the makers of mRNA vaccines for COVID,is in the late stages of testing an antiviral pill to stop more severe disease developing,which it hopes to have available by the end of the year. The US government has already agreed to pay Merck&Co. $US1.2 billion ($1.6 billion) for the company’s own experimental antiviral molnupiravir if it clears regulators. Preventative nasal sprays that kill the virus as it enters the body via the nose and mouth are also being tested. There’s even work underway by Australian and US scientists onnanoparticles that can be delivered directly to the lungs like “heat-seeking missiles” to stop an infection taking hold there. Meanwhile,the inhaledsteroidal asthma medication budesonide has been shown to reduce the chance of more severe disease if taken early.

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Outside the frenzied focus of a pandemic,new drugs face a similarly slow path to development as vaccines do. But Kelleher notes respiratory viruses are notoriously difficult to make anti-virals and other treatments for,trickier than,say,making antibiotics to fight bacteria. “Even[the influenza antiviral] Tamiflu only reduces the severity of the flu by a couple of days.”Robots have been screening millions of chemical compounds since early 2020 to find the best COVID-fighting potential,but that’s just in labs. “And when you do find something,most will fail in people or have[bad side effects],” Kelleher says.

Tong says treatment development for COVID would benefit from more focus and funding. “We needa pipeline to get therapies into clinical trials earlier and in a more co-ordinated way.” He points to the example of the failed plasma trials. “In the US,in particular,hundreds of thousands of people have had it,often on compassionate grounds[not just in trials] and with great expense,and now the evidence says it doesn’t seem to work. If those trials had been bigger earlier,we might have known sooner.”

Kelleher agrees that the world’s focus on vaccine development is crucial,but treatments for COVID are urgently needed,too. “For those people where the virus has got around the vaccine or their bodies haven’t generated the antibodies as we’d hoped,this is where you save them.”

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