FROM THE DOC’S LAB by Dr. S A Siraj
July 31, 2020: It’s been seven months since the new coronavirus was detected in Wuhan, China. Along the journey, scientists from around the world have been working at breakneck speed, trying to create a magic drug or vaccine that will tame Covid-19. But the wait continues and it seems it might be longer than many would imagine.
By now, most of us are well aware of things such as the origin of SARS-CoV-2, how it spreads, how to reduce the transmission, how the virus attacks us, and so on.
While the media is focusing on the race for a vaccine, it is equally important to look at how scientists are trying to fight the disease on another front – they’re looking for ways to stop what’s called the ‘cytokine storm’.
By now, cytokine storm has become a household term around the world. It’s basically a severe immune overreaction of the human body to the invading coronavirus in which the body releases too many cytokines, along with phagocytes and natural killer cells, into the bloodstream too quickly for the body to handle.
These substances are released (rather, over-released) as part of the human body’s defence mechanism. They’re comparable to soldiers deployed on the front lines during an emergency.
This overreaction, instead of only killing the coronavirus, kills the host itself by causing one or more of various phenomena such as inflammation, infection, thrombosis or multi-organ failure.
The cytokine storm is well understood. What is less discussed is how scientists are trying out different drugs or a combination of them in order to nip the cytokine storm in the bud.
This is important in the fight against the deadly flu because ironically, more than the coronavirus itself, it’s the human body’s own overreaction to the virus that’s killing the host.
The truth is, every human cell is home to some dangerous traitors (in the form of cytokines and enzymes), which help the coronavirus hijack the human cell.
The scientists’ experimentation in the fight against Covid-19 can be compared to a war front in which the military tries to weed out traitors within the system to weaken the advancing enemy.
While there are several battlefronts on which doctors are experimenting with drugs, here are six areas in which the traitors are being targeted.
TACKLING THE TRAITORS
An important warrior on the battlefront can be anakinra. It’s a drug that can make a big difference. If it clicks, the coronavirus will be packed off before it makes any damage, and the deadly cytokine storm can be nipped in the bud.
Anakinra is sent into the human body through intravenous infusion or drip injection. Now, the human cell has a number of traitors hanging around it that are ready to help this dangerous coronavirus to sneak inside.
So, the mission of this drug is to stop one of those traitors from helping the virus enter the human cell. This particular traitor is called IL1 or Interleuken 1. IL1 is a cytokine substance that is found on the membrane of the human cell.
What anakinra does is, it starts a bio-chemical reaction when the virus tries to penetrate the human cell. The drug secretes chemicals (visualise it as soldiers opening fire) that target IL1 (the traitor) and inactivate it.
As a result, the virus doesn’t get any help from the human cell’s traitor, and its plan to smoothly enter the cell fails. Anakinra is marketed under the trade name Kineret.
WAR ON TRAITORS CONTINUES
Another crucial warrior is called emapalumab, a drug that’s marketed under the trade name Gamifant. The drug is an antibody, basically a protein, which shuts out the production – and hence the negative actions – of interferon gamma right at the moment when the spike glycoprotein of the coronavirus tries to puncture the membrane of the human cell.
Interferon gamma is a cytokine substance which in principle is supposed to play a positive role in the battle against viruses. It is supposed to stimulate human cells infected by viruses and it is also supposed to alert and order nearby human cells to produce proteins that prevent viruses from replicating within them.
But when it comes to an invasion from the coronavirus, interferon gamma strangely ends up acting as a traitor to the human cell.
How? It helps the coronavirus to use one of its spikes to make an entry point on the membrane of the human cell. And this is where emapalumab steps in. It releases certain bio-chemicals (again, imagine soldiers opening fire). The chemicals disable the interferon gamma, which was about to help the virus’ spike make a dent. And the deadly cytokine storm is averted.
Unlike anakinra, emapalumab is sent into the human body through an injection.
A VITALLY IMPORTANT TARGET
Tocilizumab or TCZ, which goes by the prescription name Actemra, is another crucial drug that can play a powerful role in the initial stages of the coronavirus’ invasion.
TCZ can be sent in to the human body through the sub-cutaneous route and intravenous infusion. It is a strong antibody that has a specific mission to serve on the battlefront. It targets a certain traitor called IL6 or Interleuken 6.
Just like IL1 (the traitor that anakinra targets), IL6 is also a cytokine substance that is found on the membrane of the human cell. What TCZ does is, when the coronavirus tries to enter the human cell, the drug steps in and blocks IL6, disabling the traitor from welcoming the virus.
As a result, the cytokine storm doesn’t kick in. Just like in many real-life wars, without the support of traitors present around the human cell (traitor such as IL1 and IL6 cytokines), the coronavirus on its own cannot infect the human cell.
When the cytokine storm begins, there’s something called TNF alpha that gets produced. TNF stands for tumour necrosis factor. Basically, TNF alpha is a protein that sparks inflammation, which can be dangerous for the body.
It’s one of those cytokines that trigger acute reaction when a virus comes knocking on the doors of the human cell. When the coronavirus tries to enter the cell, TNF alpha is produced as a reaction, which, in turn, harms the human cell itself.
To tackle TNF alpha, there are two drugs (or soldiers) that are being tried out on the battlefront: adenosine and glucocorticoids. They are two different things, but they are trained to carry out the same mission.
Adenosine is an organic compound and glucocorticoids are a class of steroid hormones. Both of them are trained and tasked to stop inflammation when the cytokine storm begins following the virus’ attempt to enter the human cell.
In medical lingo, these two drugs are called inhibitors. They can be sent into the human body either through injections or in the form of tablets.
COMBATING THE ENEMY WITHIN
While we learnt earlier that the drug called anakinra is tasked with fighting against IL1, a traitor, there’s another drug that’s also trained to fight the same opponent: it’s called colchicines.
Its eventual objective is to ensure there’s no inflammation. And it does so by aggressively controlling or regulating the production of IL1, a cytokine substance found on the membrane of the human cell. Colchicines can be deployed to ground zero in the form of capsules consumed by mouth.
TACKLING AN EVIL ENZYME
On the membrane of the human cell, there quietly lies yet another traitor that goes by the name ACE2. It’s basically an enzyme.
When the coronavirus tries to make a dent on the membrane of the human cell, the ACE2 enzyme literally acts like a welcoming guide. The virus firmly binds itself to the enzyme, like a tight lock-and-key grip, and enters the human cell.
To knock down this ACE2 enzyme, a set of drugs called catecholamines can work. They are basically hormones released by adrenal glands located on the upper surface of the kidneys with the aim of preparing the human body for a fight. The drugs, which can be applied in the form of tablets, negate the effect of ACE2, thereby preventing the virus from entering the human cell.
EXPERIMENTS WITH TREATMENT
Apart from fighting the traitors within us in order to stop the cytokine storm from happening, scientists are experimenting with various types of treatment.
Many doctors are pushing ahead with steroids to treat Covid-19 patients, especially corticosteroids. But their use is limited to only severe conditions and they are used only in short periods because they can damage the heart and kidneys.
Intravenous infusion of pooled polyclonal immunoglobin from the plasma of healthy patients may have positive effects on severely sick patients. However, thrombosis may occur as a side-effect of this treatment.
Hydroxychloroquine or HCQ – an antimalarial drug famously promoted by US President Donald Trump and Brazil President Jair Bolsonaro – can act as a biochemical antagonist against the IL6 cytokine. But due to its severe side-effects in the treatment against Covid-19, its use is not advised. Its side-effects can include thrombosis or brain edema.
Janus kinase is a protein that’s responsible for a deadly situation called ‘endocytosis’ or human cell death during the start of the cytokine storm. An antiviral called baricitinib is being tried out by doctors to block that protein.
To reduce the chances of thrombosis, injections of low-molecular heparin are being used along with aspirin, a proven blood thinner.
Another treatment option is mesenchymal stem cell therapy, where cells are taken usually from bone marrow. It’s a highly expensive affair, though.
Also, through the process of dialysis, the ‘whole blood’ of the Covid-19 patient gets purified with cytosorb, a substance that removes cytokines in the blood. After it’s purified, the ‘whole blood’ is reintroduced into the bloodstream. But again, this is yet another costly treatment option. The dialysis done in this case is the extracorporeal form, which is the most common type.
Also, a handful of antivirals are being tried out by medical experts globally. The prominent ones that are being experimented with are osaltemivir, TCZ, lopinavir, remdesivir, retanovir and ribovarin.
Some other types of medication are also being trialled, such as IFN alfa/beta, which freezes the fast replication of the RNA of the coronavirus; Ulinastatin, which reduces production of TNF alpha, IL6, IL1 beta and IL8; Eritoran, which acts against severe infection; and Dornase alfa, an inhaler that helps snuff out the severity of the virus’ impact.
Over centuries, pandemics have come and gone. In some cases, medical science has been able to end the killer instinct of those outbreaks, while in many other cases, mankind has just had to keep fingers crossed and let the pathogen die a natural death. It remains to be seen which path we will take in this nightmare journey with Covid-19.
Will we tame this deadly virus, or will it bulldoze us and only then walk away on its own?
Medical science has come a long way since the time of the Black Death or the 1918 Flu. Modern-day scientists don’t want to sit back and think about crossing the bridge when it comes. The best brains are at it. They are trying to play catch-up with the fast-spreading coronavirus, looking for a breakthrough. And if there’s a breakthrough, indeed, before the virus gets the better of us, we’ll live to tell the story.
(Dr S A Siraj is a Kolkata-based doctor who has served as the Additional Director for Health Services in the state govt of West Bengal, India)