Cytokine Storm

What is a Cytokine Storm?

A cytokine storm occurs when the body releases too many cytokines into the blood too quickly causing a severe immune reaction. Cytokines are an important part of a normal immune response, but can be extremely harmful when a large amount of them are released into the body. A cytokine storm can occur as a result of an infection, autoimmune condition, or other disease. Signs and symptoms of a cytokine storm can include high fever, inflammation (redness and swelling), severe fatigue and nausea. Sometimes, a cytokine storm may be severe or life threatening and lead to multiple organ failure as seen in the most severe cases of Castleman disease. For more information, check out our review article on Cytokine Storm in NEJM.

What is Castleman disease?

Overview

Castleman disease (CD) describes a group of rare disorders that involve enlarged lymph nodes with a similar lymph node appearance under the microscope and a broad range of inflammatory symptoms and laboratory abnormalities. There are four main subtypes of CD:

  1. Unicentric Castleman disease (UCD)

  2. POEMS-associated multicentric Castleman disease (POEMS-MCD)

  3. HHV-8-associated multicentric Castleman disease (HHV-8+MCD)

  4. HHV-8-negative/idiopathic multicentric Castleman disease (iMCD)

Disease overview

Castleman disease (CD) describes a group of rare disorders that involve enlarged lymph nodes and a broad range of inflammatory symptoms and laboratory abnormalities. The lymph nodes, and the cells that reside in them (lymphocytes and stromal cells), are an integral part of our immune system that help us fight invading organisms and cancer. In a healthy individual, the cells of the immune system become activated to fight off invading organisms or cancer and then return to a surveillance mode. In CD, the cells of the immune system become hyper-activated, overproduce cytokines and other inflammatory compounds, and fail to return to a surveillance mode.

Approximately 4,300-5,200 cases of CD are diagnosed in the US each year; CD can occur in people of any age, gender, or ethnicity. All forms of CD involve a constellation of microscopic abnormalities in the lymph node tissue that can be observed following a lymph node biopsy. Whether Castleman disease should be considered an autoimmune disease, cancer, or infectious disease is currently unknown. The symptoms, causes, and treatments vary greatly for each subtype of CD. 

Learn more about the signs and symptoms of Castleman disease here.

Learn more about diagnosing and treating Castleman disease here.

Cytokine Storm and Castleman disease

Castleman disease patients in flare experience a hyper-response from their immune system. This cytokine storm in their bodies causes immune dysregulation characterized by constitutional symptoms, systemic inflammation, multi-organ dysfunction that can lead to multi-organ failure, and in the most severe cases, even death.

Castleman disease patients with the most severe subtype (iMCD TAFRO) suffer from thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly and have the most severe cytokine storms. Patients with iMCD have no known cause of their disease but interleukin-6 is the driver of pathogenesis in a large portion of patients. 

First-line treatment for idiopathic multicentric Castleman disease is anti-IL-6 therapy with siltuximab (or tocilizumab, if siltuximab is not available). Siltuximab (Sylvant) is the only FDA-approved treatment for iMCD and patients who responded to siltuximab tend to have long-term responses. This drug targets a specific protein (interleukin-6) that is highly involved in inflammation. Unlike traditional chemotherapy, anti-IL6 therapy is more targeted and doesn’t result in the elimination of any cell types so the side effects are milder.

 

For patients who do not respond to first line therapy, the CSTL has worked to uncover several other treatment approaches in CD including:

  1. Siltuximab for iMCD - supported the initial approval, recommend it first line in guidelines, and have continued to support this through running a study to help maintain its approval in Europe

  2. Sirolimus for iMCD - discovered that sirolimus may be effective, treated patients effectively, and launched a clinical trial. Learn more about this trial here.

  3. Ruxolitinib for iMCD - discovered that ruxolitinib may be effective, treated patients effectively, and launched a clinical trial

  4. Rituximab for iMCD - collaborated on a retrospective study indicating that it can be used as a second or third line treatment

  5. Velcade-dexamethasone-thalidomide - collaborated on a clinical trial indicating that it can be used as a second or third line treatment

  6. Thalidomide-cyclophosphamide-prednisone - collaborated on a clinical trial indicating that it can be used as a second or third line treatment

 

Other potential drugs identified from our research that need further investigation:

  • Siltuximab for unresectable UCD

  • Rituximab for unresectable UCD

  • Embolization for unresectable UCD

  • Eculizumab for iMCD

  • Trametinib for iMCD

  • Sapanisertib for iMCD

  • Anti-CXCL13/CXCR5 therapies for iMCD

 

You can learn more about the Diagnostic criteria and treatment guidelines for iMCD here.

Relevant publications:

NEJM cytokine storm paper

Overview of CD in Blood Advances