Combined therapy was so effective doctor offered it to daughter-in-law

In mid-June 2020, the eminent medic Sir Christopher Edwards received a text message from the equally eminent Oxford immunologist Sir John Bell. It contained just three words: “You were right!”

Months earlier, when Sir John was first tasked with finding treatments for the new virus that was sweeping the globe, Sir Christopher urged him to consider the steroid dexamethasone.

Within months, large trials of said drug were shown to cut deaths by a third for people on ventilators, providing the first known treatment for Covid. Sir Christopher had wanted to combine the steroid with a second drug – spironolactone. The combination of the two is now starting to show impressive results in trials.

“I would have been a lot more right if both drugs had been used,” he said.

“I have had a rather large number of sleepless nights thinking about how many people have died that actually didn’t need to die. That’s upsetting.”

It was clear that Covid was causing a very different disease to other respiratory infections. Patients were experiencing loss of taste and smell, while post-mortems revealed blood clotting and fluid in the lungs.

Sir Christopher realised that the mechanisms behind the symptoms and pathologies were the key to understanding how to stop the disease.

“We spent too much time trying to stop the virus, with antivirals and the like,” he said. “If a thief pinches and crashes your car, you don’t get the car going again by chasing after the thief.

“I’m afraid we spent a vast amount of time chasing the thief – the virus. We have spent very little time working out what’s wrong with the car.”

Coronavirus uses spike proteins to latch onto a claw-like receptor on human cells called ACE2. The virus uses this as a taxi to get into the cell.

Once inside Covid hitches a ride in tiny enzyme-holding sacs which recycle cellular waste. These sacs move to the cell surface and allow the virus to escape from the cell.

This cycle is speeded up in Covid because the virus causes cells to lose their “moat” which keeps out the hormone cortisol. Cortisol releases the hijacked lysosomes which carry out the virus as well as the energy molecule ATP. This ATP release proved the clue in understanding this process. When too much is produced in certain locations the body shuts off its sensory receptors as a protective mechanism and also activates specific nerves.

So as coronavirus infects cells in the nose and mouth it sparks a loss of taste and smell, and when released in the lungs, activates the cough reflex – all classic symptoms of Covid.

Sir Christopher realised that using a combination of dexamethasone to suppress cortisol secretion with spironolactone to block the ACE2 could restore the moat around cells.

His work has also suggested why some patients are at much higher risk of lethal complications. This relates to coronavirus entering the cells lining blood vessels. When the virus enters these cells it triggers the release of the Von Willebrand factor which spreads like a spider’s web, forming a mesh that collects key cells in the blood called platelets, causing clotting.

‘We’ve got to wake up. You’ve only got to have a variant, or vaccine resistance, and you’re back to square one’

It also triggers the production of angiopoietin-2 which prevents fluid being cleared from the lungs.

“Look at people dying from Covid and compare them to the lungs of people dying from influenza, there are 10 times as many micro-clots,” he said.

“The body normally has in the alveoli (air sacs) a very clever system where key cells actually produce a substance that acts like a very clever plumber and his job is to seal leaks.

“But when the blood vessels are infected, the plumber stops working because of damage to these cells and angiopoietin-2 released from the infected blood vessel cells produces an incredible series of leaks, and so basically you drown.

“So, when you look at people in intensive care, the higher the levels of the Von Willebrand Factor and angiopoietin-2 the more likely you are to be getting clotting and a lot of fluid.”

The mechanism also explains why older and sicker people are more vulnerable to the disease. Younger people carry ACE2 receptors – the taxi used for cell entry – on key cells that line the nose, tongue and specific cells in the respiratory tract – which is why they suffer largely mild infections.

However, the receptor is virtually absent from cells lining their blood vessels, meaning Covid rarely becomes serious in younger age groups.

Older people and those suffering conditions such as heart disease and diabetes, carry many ACE2 receptors, giving coronavirus an easy ride.

This is where spironolactone becomes a second crucial backstop because it is synergistic with dexamethasone and together they produce a much greater benefit.

Sir Christopher was so convinced by the cocktail that he recommended it to is daughter-in-law when she became infected with Covid and was struggling to breathe. She made a full recovery and now the first results of trials are also revealing a dramatic effect.

Early trials show a combination of dexamethasone and spironolactone (SpiDex) is four times better at keeping patients out of intensive care than dexamethasone alone. A study in Frontiers in Endocrinology showed that 40 Covid patients taking the ‘SpiDex’ regime did better on every clinical, biochemical and radiological measure than 40 patients on high dose dexamethasone. No patients died on SpiDex but there was a death in the dexamethasone-only group.

In 20 out-patients treated with the SpiDex there were no adverse events, and 95 per cent were asymptomatic at 10 days including full recovery of taste and smell.

Not only could it prevent deaths and serious illness, but it could be repurposed as a nasal spray, which might stop cells pumping out new viruses and stop transmission.

“If we can reproduce on a larger scale what these early trials suggest, the benefits could be extraordinary,” added Sir Christopher.

“We all hope the Covid is going to go away, but it’s not going away.

“Spironolactone and dexamethasone are cheap off-patent drugs that could be immediately available, especially for parts of the world that cannot afford expensive anti-viral drugs or antibodies.

“If you look at the number of cases and what’s going on, we’ve all got to wake up. You’ve only got to have a variant, or vaccine resistance, and you’re back to square one. We have to act now.”

Happily, the scientific world may be finally starting to come around to his point of view.