A book about hemophagocytic lymphohistiocytosis (HLH) — also known as cytokine release syndrome, macrophage activation syndrome — covers information ranging from disease symptoms and their clinical presentation to the most recent therapies and care regimens.
“Cytokine Storm Syndrome” was co-authored by professor Randy Cron, MD, PhD, a professor of pediatrics and medicine at the University of Alabama at Birmingham (UAB). He hopes this work will help to inform physicians of the symptoms and treatment options available to HLH patients.
“We now have a variety of therapeutic options to treat cytokine storm syndrome,” Cron said in a UAB news story. “But especially a lot of the older physicians don’t know what this is.”
This was one of the main reasons why Cron decided to write this book.
“The sooner you recognize it, the better the outcomes,” Cron said. “If we can get people to diagnose this in the ER [emergency room] and the ICU [intensive care unit], that would be ideal.”
HLH is caused by an immune system gone awry, where cells of the immune system produce too much inflammatory molecules – called cytokines – that lead to organ failure and, if not stopped, to death.
“Cytokines are inflammatory immunologic proteins that are there to fight off infections and ward off cancers. But when they’re out of control they can make you very ill,” Cron said.
Researchers believe HLH is related to defects on the perforin pathway. This molecular pathway includes a group of proteins that work together to deliver perforin, a cytotoxic molecule used by immune cells (cytotoxic T-cells and natural killer cells) to destroy invading cells. Perforin creates holes on the walls of infected or cancer cells, allowing immune cells to deliver toxic granzyme B to these cells and causing their self-destruction.
When perforin related-genes are mutated, individuals are known to be at a higher risk for HLH.
According to Cron, about 10 to 15 percent of the population may carry these mutations. But unlike primary HLH, where newborns have two mutated copies (one from each parent) of a gene related to perforin, secondary cases have one mutated gene copy and another normal gene.
“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.”
Besides potential organ failure, HLH symptoms include high fever, an enlarged spleen, excessive bleeding, and low numbers of all blood cell types.
“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.
According to the researcher, there are “a lot of triggers” for the condition, including rheumatic diseases, blood cancers, and viral infections (like the herpes virus family, Ebola, and dengue).
His team’s previous work suggested that HLH could in fact be a contributing factor for the high death rate of the 2009 H1N1 flu epidemic — the outbreak killed nearly 12,500 people and hospitalized over 270,000 in the U.S. (575,000 people died worldwide). The team’s study, published in 2016, found that five out of 14 samples from patients who died during the outbreak carried perforin pathway-related mutations.
HLH has also been reported, although less frequently, in people with rare metabolic disorders, and those who had needed cardiac and respiratory support machines.
More recently, CAR-T cell therapy, used to treat cancer patients, has also been associated to HLH. “In about 20% to 30% of cases, CAR-T saves the patient’s life, but it also triggers [HLH],” Cron said.
But there is hope. A treatment called anakinra that targets cytokines, and is approved to treat autoimmune diseases like rheumatoid arthritis (marketed under the brand name Kineret), has shown promising results, including in a patient Cron knew in Pennsylvania.
He and colleagues developed new animal models to explore the genetics of HLH. Working with Winn Chatham, MD, with the division of clinical immunology and rheumatology at UAB, Cron began a clinical trial in 2016 to test the safety of anakinra in patients with life-threatening inflammation.
Results suggested that anakinra is “remarkably safe,” and the team plans to conduct a larger study to assess its efficacy.
But a correct and fast HLH diagnosis is also urgently needed. In his book, Cron includes information about a simple, inexpensive blood test that can help determine whether a patient is having a cytokine storm.
“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.”
The ICU at Children’s Hospital (at UAB) recently began to perform screens of ferritin in routine blood analysis at Cron’s urging, and results are already positive. “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.
“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,” he said.
Cron hopes his book will help physicians and other healthcare professionals to better understand and manage HLH.
“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?’ 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,” Cron added.