In the COVID-19 Pandemic, A Solution For Some Of Us, Is Not A Solution At All: Don’t Ignore CYCLOSPORINE
I am a cellular immunologist. I spent over ten years of my professional and academic life thinking about and researching how different cell populations within the immune system respond to things like viruses and cancers.
So, as the COVID-19 viral pandemic has been ravaging our world and tearing at the fabric of our nation, I’ve been looking at how it’s doing so, carefully. The staggering projected number of deaths from COVID-19’s critical illness promises to grow with the spread of the virus. And though our social distancing and quarantine measures will “flatten the curve”, they also pose an existential danger to our economic national security. This pandemic is threatening everyone’s health in America — and the world.
It is clear that this virus triggers a powerful immune response in its host, which helps rid most people of it. But in a large number of patients the powerful immune response itself is creating what we know of as a “cytokine storm”, which is likely causing COVID-19 patients to become critically ill or die.
From a medical perspective, “Cytokine Storm” is usually caused by hyperactivation of a group of immune cells named Macrophages and T-cells.
In thinking about Cytokine Storm, two known disease entities come to mind: “Macrophage Activation Syndrome” (MAS) and “Hemophagocytic lymphohistiocytosis” (HLH). There are several pathways to developing HLH, some genetic, some triggered by viruses like EBV and the SARS virus, and some as an adverse reaction to treatment with the new class of cancer immunotherapy drugs known as “checkpoint inhibitors”.
COVID-19 disease shares many of the symptoms of HLH — including some very characteristics features: elevated Ferritin level, elevated C-Reactive Protein, Fever, Pneumonitis with Ground Glass Opacities, elevated liver enzymes indicating liver inflammation (i.e., transaminitis), and blood lymphopenia.
In fact, a simple but profound thought experiment for any clinician to do would be the following: pretend he/she did not know about the COVID-19 pandemic and was confronted with the clinical picture of a decompensating patient with Pneumonitis, Transaminitis, elevated Ferritin, elevated CRP and lymphopenia. HLH would be on top of the differential diagnosis list.
So, it is coming into focus that COVID-19’s “kill mechanism” is very likely to be a cytokine storm response involving the host’s Macrophages and T-cells similar, if not identical, to HLH — and one that very likely causes critical illness in some people.
Imagine, a runaway train with no functional brakes, the immune system becomes hyperactivated, and keeps moving fast, until it causes a catastrophic crash — as is the case in HLH syndromes left untreated, and in the case of COVID-19 disease.
It may be a twist of good fortune for humanity in our fight against COVID-19 that there is already significant clinical experience with treatment of “cytokine storm” syndromes, and specifically HLH. We may stand a chance at effectively blocking COVID-19’s “kill mechanism”: An HLH-like hyper-inflammatory syndrome and at times a florid Cytokine Storm syndrome.
Over the past few weeks, as the COVID-19 pandemic has taken root, it’s been proposed that a variety of “immunosuppressive drugs” be used to salvage the critically ill COVID-19 patients by blocking the “cytokine storm”. In fact, some novel, expensive and powerful biologic immunosuppressive drugs are being used, both off-label and in clinical trials. Chief among them is the anti-IL6 antibody, Tocilizumab — or TOCI, for short. There are also a few other novel and expensive “pipe-line” options, like the JAK1/2 inhibitor drugs being tested.
But the trouble with the use of these non-generic immunosuppressive drugs is three-fold. First, they are mostly considered experimental, even for treatment of a classically known syndrome like HLH. Second, they are mostly being applied too late in the critical illness, when most patients are too sick and are no longer salvageable. Third, there is no way from a cost or scalability perspective to produce nearly enough of these drugs to make available to the millions of people and nations world-wide who need it to survive — especially those with insurmountable economic disparities nationally and internationally.
I believe that our overt American focus on the new, untested and “sexy” immune-modulatory drugs to rescue COVID-19 patients with critical illness is misplaced and short-sighted. First, we should be blocking the disease before it becomes critical and lands patients in the ICU. Second, the novel drugs we are currently using will never be scalable enough to protect the millions of people, globally, at risk in the immediate future. And, third, we are not using ANY of the known and classical drugs we can for blockade of cytokine storm in HLH — at least not in any consistent or rational manner.
In fact, it has been sobering for me to observe America’s profound market-failure in touting, testing and haphazardly deploying these rare, new and expensive drugs (worse yet, scientific long-shots, like Hydroxychloroquine) — especially since we have a well-known, safe and effective generic drug alternative in our arsenal to block COVID-19’s HLH-like cytokine storm syndrome. A drug, which we know is capable of specifically blocking Cytokine Storm syndromes caused by T-cells and Macrophages. This drug is CYCLOSPORINE.
CYCLOSPORINE blocks a central T-cell and Macrophage activation pathway known as the Calcineurin pathway. It revolutionized organ transplantation by preventing immunological rejection. It is used frequently to treat several hyperimmune flares in diseases like Ulcerative Colitis, Lupus and Rheumatoid Arthritis. Importantly, it is used as an established and standard approach to blocking cytokine storm in HLH syndromes, which has been used for many years.
Most importantly for public health, CYCLOSPORINE is an inexpensive generic drug, which can be easily and quickly upscaled on a national and global level. So, I find our academic healthcare establishment’s failure to immediately consider this powerful generic option to block COVID-19’s cytokine storm very surprising — in fact, in some highly academic quarters there’s even resistance expressed to the idea. But, I recognize most of this resistance to be caused by either dogmatic professional egos, or by a simple lack of knowledge and understanding about the mechanism of CYCLOSPORINE action and its clinical applications by many clinicians.
I believe that it is a serious failure of our market driven healthcare system to overtly emphasize rare, untested and expensive, but profitable, new drug options over the mechanistically rational, feasible, generic and time-tested options in this national and global emergency.
This is not the time to use our revenue driven pre-COVID19 drug development strategies to try and save the day. We need a mechanistically and scientifically sound, economically feasible and quickly scalable solution that also addresses healthcare inequality, both domestically and internationally — in order to prevent deaths caused by COVID-19 hyperimmunity.
In the COVID-19 pandemic, a solution for some of us, is not a solution at all.
As for CYCLOSPORINE, my good friends and colleagues at the University of Pennsylvania in Philadelphia, PA and at Baylor Medical College in Houston, TX are in the process of rapidly deploying an urgent Phase 2a clinical trial to demonstrate the safety and efficacy of CYCLOSPORINE for blockade of COVID-19 hyperimmunity and cytokine storm. Additionally, Intensive Care physicians in Tehran, Iran, in charge of one of the major COVID-19 treatment centers in that country, have been alerted to the potential key importance of considering CYCLOSPORINE as a treatment for COVID-19 disease — and are doing so.
If we are justified testing and using expensive and powerful immunosuppressive drugs to save some lives in America, certainly we cannot ignore the vastly available CYCLOSPORINE on the list of candidate drugs for every life — especially since this drug in many cases of cytokine storm in HLH disease acts like a literal “off switch”.
My message to the public, to all colleagues and to FDA leaders who are interested in blocking COVID-19’s cytokine storm and hyperimmunity, and in saving American lives and many more globally, is this: Don’t ignore CYCLOSPORINE!
