The immune system is both our greatest enemy and our best hope in fighting the virus
Gerry Gajadharsingh writes:
“Another great article from Tom Whipple from The Times. We have been hearing a lot about the so-called cytokine storm and the article goes a great way in helping people understand exactly what this is. Whilst the emphasis is more to do regarding the use of drugs targeting this extreme inflammation going on as a consequence of COVID-19, it’s important again to emphasise there are ways for us as individuals to manage our systemic inflammation, obesity and of course medical conditions like Type II diabetes which is now accepted to be able to be reversed with adequate dietary and lifestyle change.
For over 12 years we have been providing appropriate patients with a bespoke Metabolic Balance individualised nutritional plan, the main aim of which is to reduce inflammatory load, improve chemical messengers within the body and often successfully managing weight and reducing obesity and overweight patients.
The principles of this program are open to everybody, by the way the program was designed by endocrinologist in Germany.
For further information you can go to.”
The immune system, what a simple concept, but what complexity. Like much of medicine and health there are often paradoxes. We want a great immune system to fight viruses and other pathogens (bugs) and yet we don’t want our own immune systems to overwhelm us we it starts to fight the virus.
The real enemy, by the time you reach intensive care, is yourself. The coronavirus is the trigger. It invades your body, hijacks your cells and begins the work of replicating in the millions. But it is in your body’s response to that invasion that the most severe danger lies — and in controlling that response that the most effective treatment may yet be found.
Around the world, scientists are looking for antiviral drugs to defeat coronavirus. This makes sense. Antivirals attack the weak points of the virus. By stopping it reproducing and impeding its travel, they assist your body in expelling this invader.
There is another class of drugs entirely, though, which initially make less sense — but which are already being tested on patients in the UK. Their job is not to empower the immune system but to impede it.
They are needed because the people in ICU around the world are not there because the virus is attacking their lungs. They are there, scientists are increasingly convinced, because the immune system is. The patients are suffering from what is called a “cytokine storm”.
To understand what that is, and how to defeat it, requires appreciating the exquisite complexity of the immune system.
The innate immune response
Immunity is not just about antibodies. Long before your body has developed these proteins which can lock onto a new pathogen, or pathogen-infected cells, tagging them for destruction, it has a whole suite of less targeted, but speedier, responses.
The first kicks in almost immediately. When a virus invades a cell, it injects its genetic material — in the case of coronavirus a molecule called RNA — in an attempt to hijack the cellular processes to its own ends. Even at this stage, cells can fight back. On seeing RNA where it shouldn’t be, they send out molecules called cytokines that alert the immune system to invaders.
These molecules are messengers, bringing in immune cells which in turn release their own cytokines. Through a chain of such processes, the body escalates its response.
Much like the country itself, which has had to resort to lockdown until a vaccine can be found, these cruder methods are a way to try to suppress the growing infection until the body can develop the more sophisticated tools that will give it immunity.
As in the country as a whole, where lockdown means we face a historic recession, plunging cancer diagnoses and vulnerable children out of school, this process is not without collateral damage.
“The immune system is always attempting this balancing act where it destroys cells that harbour a virus while sparing healthy cells that look very similar,” says Dan Davis, professor of immunology at Manchester University. For the majority of people this works well: the immune system wins, and the virus is cleared. But for some, it fails catastrophically.
The cytokine storm
“Storm” is the right word for it. No one is sure precisely what happens but amid the delicate checks, balances and feedback loops, the production of cytokines goes into overdrive, the cascade of chemicals spiralling out of control. “There seems to be a trigger point a few days after people arrive at hospital,” says Rav Seeruthun, medical director at Roche UK. “Some people do well, and those are the ones who have a better chance of quick recovery. However in others, we see a cytokine storm.”
A maelstrom of dozens of different molecules buffets and batters the body, calling in a flood of reinforcements. Then, like a householder who complains that the fire brigade’s hoses did more damage than the blaze they were responding to, the protection becomes the danger.
Like an army churning up the roads, they clog the blood vessels. Fluid swamps the lungs. Many of the processes are themselves still not understood, with some cells simply self-destructing in response to the chemical signals. Pneumonia develops, and people struggle to breathe on their own.
Elsewhere, with the immune system in a frenzy, other organs begin to suffer damage. Secondary infections can develop — and progress unchecked.
This means that people progress from wards to intensive care, and from intensive care to ventilators. Stopping that second step is, says Dr Seeruthun, what the drug they are currently testing aims to achieve.
“When the immune system goes into hyperdrive, it is vital that we try and calm it.”
It is this cytokine storm that killed in the Spanish flu, that killed in the 2003 Sars outbreak, and that kills today.
Each storm, though, is different. In 1918, this cytokine storm affected the young. Today, it affects the old. At least some cytokines at high levels in people with Sars are not the same as in coronavirus. Why? We don’t totally know. Perhaps this should not be such a shock, says Professor Davis, author of The Beautiful Cure, a book about the immune system.
“The immune system is amazingly complicated. On the face of it, unnecessarily so. But then you think about what it has to do,” he says.
“Last year this virus did not exist. Yet this is a system that has to find a way to recognise it. So you’ve got to have a system that can detect something dangerous that has never existed before in the universe.
“The second thing it has to do is spot danger with exquisite precision. That’s not trivial. For instance, the same bacteria that does good in your intestine causes harm elsewhere in your body. So it has to know when something is doing harm. It’s not surprising we don’t understand it all.”
What we do know is that some of the cytokines are unusually elevated in coronavirus. We also know that others are, in general, more important — acting like hubs for a freewheeling molecular cascade that starts with rogue RNA and ends in intensive care. Take out the hubs, and the spokes drop away.
How do we take out the hubs? With antibodies. An antibody is a Y-shaped molecule. On the fork of the Y is an atomic structure that is the perfect negative of its target, allowing the two to dock together. Eventually, through immunisation or infection, our hope is that in all our bodies there will be antibodies whose Ys match the surface of a virus, flagging it, and any of our infected cells, for destruction.
Until that happens though, we can use antibodies for something else entirely. Because while an antibody’s target can be a virus, in the past 20 years scientists have shown it can also be literally anything else at all.
If it has a structure, we can make an antibody to latch onto it.
This means that these days, pharmaceutical companies develop drugs by going fishing for antibodies. Do you want to attack a particular cancer? Then put that cancer cell on your molecular fishing rod, dip it into a lake of a 100 billion synthetic antibodies, and whichever of them you pull out is the antibody that will attack that cancer.
The most successful of these antibody treatments — in fact the most successful drugs in the world — have been used not for cancer but for rheumatoid arthritis.
They seek and destroy the molecules that lead to inflammation in the limbs. And what are those inflammatory molecules? Cytokines.
When this virus arrived it was completely novel. The immune response, though, was not.
Doctors realised that in anti-inflammatory drugs we may already have the tools to keep people out of intensive care.
Trials are well under way using rapidly repurposed immune modifier drugs.
Tocilizumab, Roche’s drug, was originally built to suppress the immune system for people with rheumatoid arthritis.
Currently, in dozens of patients across Britain, it is instead suppressing — hopefully — the cytokines of Covid-19 patients.
In their ravaged immune systems, manmade antibodies may already be latching onto the eye of the storm, calming the hurricane of swirling chemical messengers.
It is one irony of this infection that in order to control its worst effects, we have to control the very immune system that is meant to destroy it.
It is another irony altogether that the best way we have found to control that natural immune response is by attacking it with an artificial one.