Jayney's Blog

Randy Cron, M.D., Ph.D., professor of paediatrics and medicine at UAB, knows to expect calls from people all over the world at any time.

“Not a week goes by when I don’t get a call from someone on the planet asking, ‘Does this seem like it’s it?’” Cron said. “It” goes by multiple names in medical literature, but the name Cron has used in his new textbook is Cytokine Storm Syndrome.

The calls Cron receives tend to be urgent. A cytokine storm – aka cytokine release syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis – is the result of the immune system getting out of control. Killer cells tend to be defective, which results in increased production of inflammatory proteins which can then lead to organ failure and death.

Cron says that “we now have a variety of therapeutic options to treat cytokine storm syndrome, but especially a lot of the older physicians don’t know what this is.” He said that this was one of his primary motivating factors in writing his book.  “Cytokine Storm Syndrome” offers detailed descriptions of symptoms and clinical presentations, along with the latest treatments and care regimens.

“The sooner you recognize it, the better the outcomes,” Cron said. “If we can get people to diagnose this in the ER and the ICU, that would be ideal.”

Up to 15% of the population

“Cytokines are inflammatory immunologic proteins that are there to fight off infections and ward off cancers,” Cron explained. “But when they’re out of control they can make you very ill.”

The symptoms of cytokine storm syndrome can include high fever, enlarged spleen, excessive bleeding, low counts of all types of blood cells (red, white and platelets) and, potentially, multiple organ failures.

Cron’s research has revealed that cytokine storm syndrome is far more common than was previously thought. Scientists that have been investigating the cause of the syndrome have focussed on the perforin pathway – this is the series of proteins that work together to deliver perforin. Perforin is a key part of the immune system’s cytotoxin T-cells and natural killer cells – they use it to rupture the walls of infected, cancerous, or otherwise undesirable cells. The perforin channels are then used to pour in granzyme B, which induces the undesirable cells to self-destruct. Mutations in the genes responsible for “any one of the 10-plus proteins that get perforin to do what it does” are linked to a higher risk of cytokine storm syndrome, Cron said.

According to Cron’s research, 10% to 15% of the population may carry these mutations. Unlike infants, who tend to have two bad copies of one of the 10+ perforin-associated genes, the people affected have one mutated copy and one normal copy.

“Generally, that’s enough to produce all the killing you need,” Cron said. “But if you get the wrong organism or the wrong inflammatory state it may push you over the edge.”

Danger conditions

“These patients almost always present with fever, something like 96 percent, and they tend to be sicker than you would expect for why they are in the hospital,” Cron said. “Even sepsis patients will get cytokine storm syndrome on top of the sepsis, and if you don’t treat the cytokine storm syndrome, even if you treat the infection causing the sepsis, they may still die.”

Unfortunately, “there are a lot of triggers for this,” Cron said. “In addition to rheumatic diseases, such as juvenile arthritis and lupus, certain types of blood cancers, like leukemias and lymphomas,” can cause cytokine storm syndrome, he said. “And there are a whole slew of infections that can do this, including the herpes virus family (including the bug that causes mono and CMV), Ebola, dengue — there are 80 to 100 bugs that have been associated with it in case reports.” There have also been reported cases of cytokine storm syndrome in patients with rare metabolic disorders and in patients who go on heart-lung bypass machines, such as ECMO. However, this is less common.

More recently, cytokine storms have also been discovered in patients who have been treated with a chimeric antigen receptor T-cell therapy (CAR-T) as immunotherapy for cancer. “They see that in about 20% to 30% of cases,” Cron said. “CAR-T saves the patient’s life, but it also triggers this.”

In a 2016 study, Cron and his colleagues discovered evidence of perforin pathway-related mutations in 5 of the 14 samples that were analysed from patients who had died in the 2009 H1N1 flu outbreak. In the United States, more than 270,000 people were hospitalised and almost 12,500 died during the pandemic. As many as 575,000 people died worldwide, with 80% of them younger than the age of 65. Cron believes that cytokine storm syndrome was a contributing factor in the abnormally high number of deaths in otherwise healthy individuals.

For more information on the H1N1 pandemic,  CMA President, Jayney Goddard’s book “The Survivors’ Guide to Swine Flu: The Complementary Medical Approach”  is currently on offer at Amazon.

‘Magical’ treatment success

The syndrome was first identified (as hemophagocytic lymphohistiocytosis, or HLH) as a rare genetic disease in paediatric patients in the 1950s. The majority of children born with HLH died within a few days to weeks. Even today with the use of chemotherapy and bone marrow transplants, the chances of children with primary HLH living to the age of 5 are only around 50%, according to Cron.

For other patients, new treatments are available and bring remarkable recoveries. Cron and Behrens “both got interested in this through a patient we saw in Pennsylvania,” Cron said. “Probably the sickest patient I ever saw come out of the ICU unscathed.”

The doctors in the unit treated the patient with anakinra, a cytokine-targeting therapy that was approved to treat the autoimmune disease rheumatoid arthritis. “She turned around and it was magical,” Cron recalled. “We’re both research scientists, so he developed a mouse model [of cytokine storm syndrome] and I’ve been studying the genetic and human aspects. We’ve identified new genes not previously described as a part of this genetic workup.”

In 2016, Cron and Winn Chatham, M.D., professor in the Division of Clinical Immunology and Rheumatology, began a clinical trial in order to study the safety of anakinra in patients with signs of severe, potentially life-threatening inflammation. According to Cron, anakinra is “remarkably safe”, and following this initial study, the researchers hope to begin a larger trial in the future.

Cheap, simple test

A cheap, simple test is widely available at most hospitals worldwide which can help to diagnose cytokine storm syndrome, Cron said. “A protein called serum ferritin tends to get very high in this disorder,” he said. “If you are sick enough to be in a hospital and you have a fever, you should get a serum ferritin. It typically comes back in less than 24 hours and almost every hospital can do it, and if it’s high you can work them up for cytokine storm syndrome.”

At Cron’s urging, the ICU at Children’s Hospital recently added serum ferritin screens to its routine procedures. “The day after we did that we identified a patient and we’ve had three kids in the last couple of months that we’ve identified,” Cron said.

Cron hopes that his book “Cytokine Storm Syndrome” will help spread the word of this life-saving knowledge. “We have this thing in medicine called Occam’s Razor, which encourages us to gather the data and come up with one unifying diagnosis for what’s going on,” Cron said. “But this is the opposite — you can have juvenile arthritis, or lupus or T-cell leukemia, and then you have cytokine storm syndrome on top of that. And if you don’t treat the cytokine storm syndrome directly, patients can die.

“If we get to the point where people know about it and don’t have to call me to find out, that would be a success.”