This syndrome occurs unfortunately every day in ICUs, both in pediatrics and adults across the planet, as a result of a whole variety of conditions that go under-diagnosed and therefore under-treated. However, COVID-19 is changing that - Dr. Randy Cron
image by: José Mário Tran
When we get sick we trust our immune system to protect us, but what happens when that system goes awry and ends up killing patients? COVID-19 is shedding new light on how viruses can kick some patient’s immune system into overdrive to deadly effect in what is known as a cytokine storm syndrome.
In short, our immune system by and large is incredibly effective at working around the clock to keep a myriad of infections and diseases at bay while simultaneously being able to identify between outside invaders and our own cells and effectively prioritise what to attack and what to protect. However, occasionally, either due to genetic factors or rampant viral infections like COVID-19, our immune system can become overzealous and go rogue - attacking and killing everything in sight, including healthy cells in the body. When that happens it is referred to as a cytokine storm and it may be killing around half of severe COVID-19 patients.
“Cytokines are inflammatory immunologic proteins that are there to fight off infections and ward off cancers,” says Randy Cron, M.D., Ph.D, at the University of Alabama at Birmingham, “But when they are out of control, they can make you very ill.”
Immune Response And COVID-19
It is important to note that many things have to happen before a potential COVID-19 related cytokine storm is triggered, which is why the majority of COVID-19 patients will never have to deal with the syndrome. According to the Centers for Disease Control (CDC), “This first preliminary description of outcomes among patients with COVID-19 in the United States indicates that fatality was highest in persons aged:
- ≥85, ranging from 10% to 27%,
- followed by 3% to 11% among persons aged 65–84 years,
- 1% to 3% among persons aged 55-64 years,
- <1% among persons aged 20–54 years,
- and no fatalities among persons aged ≤19 years.”
Which means that odds are if you contract COVID-19 you will be able to ride it out at home. You can thank the immune system for that because it does not just have one means for defending you against disease, but many many tools in its tool belt to keep you alive.
Dr. Randy Cron, of the University of Alabama, is a leading researcher of cytokine storm syndrome. He explains “The data out of China, as well as elsewhere, suggests that about 80% of patients can ride COVID-19 out at home because they are either asymptomatic or feel like their having something like a horrible case of the flu.” Continuing, “However, about 20% require hospitalization and of those 20% that are being hospitalized, it's entirely unknown what percentage have a cytokine storm so it makes it hard to gauge the mortality of COVID-19 related cytokine storms.”
Dr. Cron goes on to explain that the typical mortality rates in adults who develop the syndrome ranges from 50% to 80%. Until further research is done to track COVID-19 related cytokine storm indicating symptoms along with positive cytokine indicating tests we will not yet know just how prevalent cytokine storms are in COVID-19 patients.
Our immune systems are far from simple and have a number of safe guards to keep invaders out. This can be broken down into our innate immune system and our active immune system, which is contributes to our adaptive immune response, as well as our passive immune system, which is "borrowed" from another source and lasts for a short time (for example, antibodies in a mother's breast milk give a baby temporary immunity to diseases the mother has been exposed to).
Put (very) simply, the innate immune system response relies on the use of physical barriers like our skin and mucous membranes, coupled with our first responder defenders like phagocytes, antimicrobial proteins, and attack cells. The innate immune system response is why, for example, we get a stuffy nose and sneeze when we have a cold, or why a scrapped knee gets red, hot and inflamed, as well as sometimes filled with pus. By and large, this first defense is effective and may be why many people who contract COVID-19 are asymptomatic.
However, when the innate immune system isn’t enough it calls on our second line of defense; the active immune system. This is typically when the inflammatory response gets kicked into higher gear and you develop a fever, which triggers a number of your body’s chemical alarms that call the active immune system to action and increases the metabolic rates in cells, thus allowing them to heal faster, as well as making it easier for a variety of immune response cells and proteins to do their jobs faster and more effectively. This is also when people start feeling body aches associated with COVID-19 and other viral infections.
The active immune response is both complex and elegant and (again put very simply) not only identifies and fights off viruses like COVID-19, it also remembers these viruses so it can quickly and effectively combat and neutralize them in the future, thus creating immunity. This is why vaccines are one of the more amazing developments of modern medicine. So if all goes well (or relatively well), then our immune system will protect us and we will live to tell the tale, but what happens when things start going awry?
Cytokine Storms And COVID-19
Viruses like COVID-19 have a devious trick up their sleeve when it comes to making us sick; in a sense, they use human cells to shelter and reproduce. When COVID-19 is searching the body for a cellular host to attach to it is fairly exposed and it is easier for our active immune response to target and kill them. COVID-19 wants to do three things when it enters our body; find protection, reproduce and spread. Our cells offer the perfect environment for COVID-19 to do all three. So COVID-19, which targets the respiratory system, attaches and infiltrates our respiratory cells where it can more effectively hide from our immune system early on and reproduce. The infected cell will then spit out more of the COVID-19 virus that will repeat the process. This is where the battle royale of our immune response kicks off with our cellular immune response.
Yet again put very simply, our body has a special cell called the T-Cell, which has a variety of forms that it exists in to combat infection. When T-Cells are activated they release cytokines (yes, that cytokine), which trigger additional T-Cells to be made, which then release even more cytokines. One type of T-cells that are created are called cytotoxic T-cells. Cytotoxic T-cells are the cells that are able to roam the body and mercy kill infected cells who are chemically calling out to be killed and ideally to stop the increased production of viruses like COVID-19.
When your body responds the way it is supposed to, the cytotoxic T-cells will only target infected cells to be killed and move along. Additionally, the immune response also has a chemical indicator that ideally tells overzealous immune response cells to stand down once the threat has been neutralized. It is when we are in the throes of a cytokine storm that those systems start to get overwhelmed and malfunction. In essence, our body’s immune response gets so amped up that it stops differentiating between infected and healthy cells and attacks everything in its path. For obvious reasons, this is very bad for patients because not only is the COVID-19 virus killing the cells in our bodies, now our immune system is too.
Dr. Randy Cron and his colleagues began recognizing instances of cytokine storm syndrome in the early Chinese reports of COVID-19. “The way we are seeing cytokine storms manifest in COVID-19 patients are that we are typically seeing a fever and some degree of respiratory distress.” He says, “However, we are also seeing patients who look like they're in septic shock and become hypotensive as they get sicker.” He explains that many COVID-19 patients also have bleeding or clotting abnormalities as well saying, “COVID-19 seems to have a really high propensity to lead to clots either in deep veins or in the brain or in the lungs, for example.”
However, most notably, COVID-19 patients are most often dying of acute respiratory distress syndrome (ARDS), which indicates that COVID-19 related cytokine storms, like the virus, are focused in the lower lung. This leads to the instances of acute pneumonia and the need for intubation and ventilator use. It also means that patients are dying of cytokine storms faster in instances of COVID-19 than other infections.“Most cytokine storm related deaths happen as a result of multi-organ failure, which is why it has such a high mortality rate.” Says Dr. Cron, “However, with COVID-19 we are seeing people die from pulmonary complications typically before the multi-organ failure can set in. It may just be that patients are getting so sick with their lungs that they're already deathly ill before the rest of the syndrome develops. No one really knows.”
Identification And Treatment Of COVID-19 Related Cytokine Storms
Our understanding of cytokine storms is relatively young within the medical field and most of the literature around the syndrome did not take off until the 1990’s. “There are a lot of people who, both in the lay community and the medical community (particularly if they were trained a longer time ago), that are unfamiliar with cytokine storm syndrome.” says Dr. Cron, “This syndrome occurs unfortunately every day in ICUs, both in pediatrics and adults across the planet, as a result of a whole variety of conditions that go under-diagnosed and therefore under-treated.” However, COVID-19 is changing that.
Luckily, the tests to diagnose cytokine storms are often cheap and readily available in hospitals. Dr. Cron explains that when patients are in throes of a cytokine storm, “You will notice an elevation in the serum ferritin, a protein in the blood. Usually the value is less than 200 nanograms per ML and for COVID-19 related cytokine storms, it tends to run between 500 to the low thousands.” The test to measure serum ferritin is cheap, readily available in most hospitals, and has a fast turn-around time. If a patient’s serum ferritin results are elevated, then it is a good early indicator that further testing is needed.
“A complete blood count or CBC is a really common standard test.” says Dr. Cron, “And COVID-19 patients, for whatever reason, seem to be very lymphopenic, meaning their lymphocyte count tends to be less than a thousand per microliter.” Continuing that, “We don't know if it's more of a cytokine storm feature or just the virus itself, but it certainly suggests that you're not going to do well.”
Cytokine storms also can be indicated by liver enzyme abnormalities. “The liver gets very unhappy with the cytokine storms and as a result liver enzymes will go up,” says Dr Cron, “We see also an increase in a protein called D dimers and lactate dehydrogenase (LDH) levels also tend to go up as well.” So luckily, despite the relative youth of the field, there are relatively straightforward indicators to diagnose and therefore treat cytokine storms.
There are also a few effective treatments for cytokine storms despite the fact that we still do not know exactly which treatments will ultimately be developed and recommended across the board for COVID-19 related cytokine storms. “There's always kind of this push pull between doing no harm and trying therapies that haven't been tried for this disease because it's new to mankind.” says Dr. Cron, “It's hard to watch people dying in front of you so if you can intervene in some way to help stop that, then that's what doctors are going to do and why some of our colleagues are trying to treat COVID-19 related cytokine storms with just any approach that seems reasonable based on how they’ve treated other cytokines storms in the past.”
Among other therapies, a few that have recently gotten attention (controversially or otherwise) are hydroxychloroquine and a drug called Actemra. While hydroxychloroquine has been touted by President Trump repeatedly, hospitals have reported mixed results. As Forbes contributor, Anita Bartholomew explains, “One of the most dramatic press reports of apparent success came from a skilled nursing facility for veterans in Lebanon, Oregon. A doctor treated eight elderly veterans with a combination of hydroxychloroquine and azithromycin (an antibiotic that’s been used in tandem with the anti-malarial, and in a French study, showed better results than hydroxychloroquine alone). One died, but the others recovered, including a 103-year old who was “seriously declining” prior to getting the medication, and survived to celebrate his 104th birthday on April 1, 2020.”
Actemra is a drug that was designed to treat rheumatoid arthritis, but was also approved in 2017 to treat cytokine storms in cancer patients. Actemra was recently successfully used to save a Seattle emergency room doctor who was near death after he contracted COVID-19.
Additionally, “There are both broadly immunosuppressive approaches, such as high-dose corticosteroids, and more novel targeted approaches that go after inflammatory cytokine proteins,” Dr. Cron said in a Q&A, “While we are attempting to develop vaccines for COVID-19 and are trialing novel or re-purposed anti-viral therapies for COVID-19, let us also not forget to treat the patient with all we have to offer to help save lives. We need to address the immediate needs for the significant numbers of patients becoming critically ill in the current pandemic.”
While cytokine storms are admittedly terrifying, there is still some hope for COVID-19 patients who develop the syndrome. Now that physicians are more aware of the syndrome and how to identify and treat it we are on track to develop more effective therapies and fail safes that can save more and more patients as the COVID-19 pandemic develops and (eventually) subsides.
Source: Clary Estes, What Is The Cytokine Storm And Why Is It So Deadly For Coronavirus Patients?, Forbes, April 16, 2020.