Diagnosis and Treatment of Cytophagic Histiocytic Panniculitis and Cytokine Storm

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• Rare Condition Presentation
• Escalation to Multi-Organ Failure
• Cytokine Storm Diagnostic Criteria
• Initial Treatment Approach
• Anakinra Game-Changing Intervention
• Patient Recovery Outcomes
• Full Transcript

Rare Condition Presentation

Dr. Randy Cron, MD, describes a 14-year-old patient with an extremely rare condition called cytophagic histiocytic panniculitis. This disease involves severe inflammation of the body's fat tissue. The patient had suffered from daily high fevers since six months of age. Chronic inflammation and steroid treatment had severely stunted her growth. By age 14, she was the size of an average seven-year-old.

Escalation to Multi-Organ Failure

The patient's condition rapidly deteriorated after initial treatment with glucocorticoids and cyclosporine. She was admitted to the intensive care unit in multi-organ system failure. Dr. Randy Cron, MD, details her critical state. She experienced heart failure requiring three inotropic drugs, acute respiratory distress syndrome, kidney failure, and pancreatitis. She also developed coagulopathy and fell into a coma after a seizure.

Cytokine Storm Diagnostic Criteria

Dr. Cron confirms the patient met the criteria for a severe cytokine storm. Pro-inflammatory cytokines were markedly elevated in both her blood and cerebral spinal fluid. Oncologists were consulted and initiated a protocol using the chemotherapeutic agent etoposide (VP-16). This treatment aims to wipe out the immune system to control the storm, potentially followed by a bone marrow transplant.

Initial Treatment Approach

Despite aggressive treatment with etoposide, cyclosporine, and steroids, the patient continued to decline. Her ferritin levels and liver enzymes rose sharply. Dr. Randy Cron, MD, and his colleague, Dr. Ed Behrens, were called to consult on the case in the ICU. They recognized the dire prognosis and the need for a novel therapeutic intervention to save her life.

Anakinra Game-Changing Intervention

Inspired by work from colleague Dr. Virginia Pascual, Dr. Cron proposed using anakinra. Anakinra is a recombinant interleukin-1 receptor antagonist. It had shown success in treating children with systemic juvenile idiopathic arthritis, who are also at high risk for cytokine storms. After discussing with the family and care team, they administered the drug as a last resort.

Patient Recovery Outcomes

The response to anakinra was rapid and remarkable. Dr. Randy Cron, MD, reports the patient woke from her coma within two days. She was out of the ICU within six days and discharged from the hospital within two weeks. This case demonstrated the profound potential of targeted cytokine blockade. It personally inspired Dr. Cron to shift his research focus to studying cytokine storm syndromes.

Full Transcript

Dr. Anton Titov, MD: Professor Cron, is there a clinical story, a clinical vignette that you could discuss that illustrates some of the topics that we talked about today?

Dr. Randy Cron, MD: Yeah, maybe we'll go back to the one patient I mentioned that I saw in Philadelphia with my colleague, Dr. Ed Behrens. He was a fellow at the time. He was already a pediatrician, but on his way to becoming a full-fledged pediatric rheumatologist.

We saw this young girl in the clinic. I believe she was 14 at the time. And she had had a chronic, extremely rare condition called cytophagic histiocytic panniculitis. It is something I had never heard of, and hope to never see again.

This unfortunate young girl had fevers since six months of age, every single day of her life, very high, 104, terrible. And as part of that panniculitis, which is an inflammation of her fat, her immune system basically made it so she had no fat.

When we met her at age 14, she was the size average size of a seven-year old. We surmised either from or a combination of just chronic inflammation will stifle your growth and/or glucocorticoids, or steroids to prevent the inflammation, which also will stop your growth.

So she had had a tough life. And she presented to us with belly pain on an exam. She had a big liver. She was inflamed. And so we started her again on glucocorticoids. They are great in the short term.

We started her on steroids; she'd trialed a lot of things. By the time she met us in Philadelphia, she had been to the NIH, in fact, and had tried one of these TNF inhibitors. There was actually concern that it may have caused problems in her brain or central nervous system.

So she was off of that. I think when she met us, she was really only on acupuncture, and maybe for about a year and a half at that point. So we started her on steroids and a drug called cyclosporine, which is somewhere again, in between individual targeted cytokines and steroids, but more on the steroid end. It really blocks a lot of the function of your lymphocyte populations, which make a whole list of cytokines.

So we started her on some broad immunosuppression and she got a little bit better. But unfortunately, within a month, she was back. Except this time she was back in the hospital as an inpatient and quickly made her way to the intensive care unit.

She seized and was comatose after that, and she was in multi-organ system failure. So her heart was failing; she was on three of these inotropic drugs to support her blood pressure and her heart function. She was in acute respiratory distress syndrome.

Her lungs were basically, when you looked at her images, whited out and filled with fluid and on what we call very high ventilatory settings to be able to even get oxygen into her lungs to pass on to her blood. Her kidneys were failing; she had pancreatitis, which is always a bad thing.

Her cell lines were down. So her immune system was really out of whack. She had what's called coagulopathy, or disseminated intravascular coagulation, DIC to the point that she was very prone to bleeding. And again, her central nervous system, she was very sick.

And we could measure some of these pro-inflammatory cytokines, both in her blood and her fluid around her brain or cerebral spinal fluid. For me, personally, she's probably the sickest kid I've ever seen, who eventually came out of the intensive care unit unscathed.

This was back in 2004. So they had called the pediatric oncologist because before we had started using cytokine blockers to treat these cytokine storms, which she met the criteria for the familial or generic form. Often those criteria are too restrictive for the ones that show up later, so you don't necessarily use them because you might miss the diagnosis.

But she was so sick that she easily met those criteria. And so the oncologists, to their credit, over the years have, through open-label studies, been tracking the benefit of this protocol that uses a drug called etoposide, VP-16, which is a chemotherapeutic agent that essentially wipes out your immune system.

Eventually, if you can get the cytokine storm under control, then you set them up to have a bone marrow transplant to kind of reboot their entire immune response. Anyway, she was started on etoposide; they continued the cyclosporine at a bit higher doses, and continued steroids.

And eventually they realized that we had seen her as an outpatient and they called us to come see her in the intensive care unit. But by this point, she was getting worse. And her markers of disease, including her ferritin going up and her liver enzymes getting very sick.

And just clinically she was requiring more support. She was getting worse. And it was around this time that Dr. Virginia Pascual, one of our colleagues in Dallas at the time—she's now in New York—had reported the use of this drug Anakinra, which is this recombinant human protein that blocks the ability of the two interleukins 1, alpha and beta to bind its receptor and signal through this receptor.

And she had reported that this was kind of a life saving, game-changing drug for 10 children who are really sick with the systemic form of juvenile idiopathic arthritis. And so we were aware of this. And at this time, we knew also that that subset of children were at very high risk of getting a cytokine storm, much like this 14 year old girl was experiencing.

And so we reasoned that if it helped these kids in general, that it may also help their cytokine storm. And we were comfortable with the fact that it was a pretty safe drug; it had been tested actually as a rheumatoid arthritis drug. So there were a lot of patient-years of data on this drug.

It turns out not to be a great drug for rheumatoid arthritis, but it was tested very well. And it was actually even tested back in the day for sepsis. And it turns out in retrospect, that if you ferret out or separate out the patients with sepsis—this is where you're growing bacteria in your blood that puts you in the intensive care unit—that those patients who had features of a cytokine storm, actually when you went back and looked at the data, in retrospect, benefited in terms of survival from this drug.

So anyway, we had reason to think that this may help her, but it had never been used, at least to our knowledge, to treat a cytokine storm before. So we spoke with the family. We spoke with the other caring team members who were caring for this child and said, "Can we give this a try?" Because I was convinced she was not going to live.

And within two days, she woke from her coma and within six days she was out of the intensive care unit. Within two weeks she was out of the hospital. And my colleague and I at one point moved down to Birmingham.

But he stayed and remained on faculty at the University of Pennsylvania Children's Hospital in Philadelphia. And he took care of her for a while till she graduated to adult rheumatology.

She didn't have a perfectly easy life after that, but she clearly benefited from Anakinra. And so that was really, for me, actually, personally—I was doing research on other things at the time, lupus and AIDS actually, from an immune standpoint.

But over time, I've transitioned my lab to study the cytokine storm, in part because of that patient. Just the ability to change what was dire situations with just this one drug being added to what she was already receiving.