Cytokine release syndrome

Overview

Cytokine release syndrome (CRS) is a potentially life-threatening systemic inflammatory condition caused by a rapid and excessive release of cytokines, small proteins that regulate immune responses, into the bloodstream. CRS is most commonly seen as a side effect of certain immunotherapies, particularly chimeric antigen receptor (CAR) T-cell therapy and monoclonal antibody treatments. While cytokines are essential for fighting infections and controlling immune responses, their uncontrolled release can result in widespread inflammation, multi-organ dysfunction, and in severe cases, death.

Causes

CRS occurs when the immune system is excessively activated, leading to the overproduction of cytokines such as interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). Common causes include:

• CAR T-cell therapy: One of the most frequent causes, especially in the treatment of hematologic cancers like leukemia and lymphoma.

• Monoclonal antibody therapies: Such as blinatumomab, which can activate T-cells and cause CRS.

• Bispecific T-cell engagers (BiTEs): Agents that link T-cells to cancer cells, triggering immune activation.

• Infections: Particularly severe viral infections, including COVID-19, can cause CRS-like inflammatory responses.

• Sepsis: Although distinct, severe cases may show overlapping cytokine profiles with CRS.

Symptoms

The symptoms of CRS can range from mild flu-like symptoms to severe multi-organ dysfunction. Symptoms often appear within a few hours to several days after treatment initiation. Common clinical features include:

• Fever and chills

• Fatigue and malaise

• Nausea and vomiting

• Muscle and joint pain

• Low blood pressure (hypotension)

• Rapid heart rate (tachycardia)

• Difficulty breathing or low oxygen levels

• Organ dysfunction: Such as elevated liver enzymes, kidney injury, or neurological symptoms (confusion, seizures)

CRS is graded by severity (Grades 1–4), with higher grades involving life-threatening complications such as shock, severe hypoxia, and multi-organ failure.

Diagnosis

CRS is primarily a clinical diagnosis, often made in the context of recent immunotherapy. Diagnostic steps include:

• Patient history: Recent CAR T-cell therapy, monoclonal antibody use, or infections

• Physical examination: To assess for fever, respiratory distress, and neurological changes

• Laboratory tests:

  • Elevated inflammatory markers (CRP, ferritin)

  • High serum cytokines (especially IL-6)

  • Abnormal liver and kidney function tests

  • Elevated D-dimer and coagulation abnormalities

• Imaging: Chest X-rays or CT scans to rule out infections or assess lung inflammation

• Exclusion of other causes: Such as sepsis, tumor lysis syndrome, or allergic reactions

Treatment

The treatment of CRS depends on its severity. Supportive care and targeted therapy to block specific cytokines are central to management:

• Mild cases (Grade 1): Managed with supportive care—fluids, antipyretics, and close monitoring

• Moderate to severe cases (Grades 2–4): Require:

  • Tocilizumab: An IL-6 receptor antagonist, FDA-approved for CRS; rapidly reduces inflammation

  • Corticosteroids: Such as dexamethasone or methylprednisolone for patients not responding to tocilizumab

  • Oxygen therapy: For hypoxia or respiratory distress

  • Vasopressors: To support blood pressure in hypotensive patients

  • ICU care: For patients with shock, respiratory failure, or multi-organ dysfunction

• Infection control: Antibiotics may be used if infection is suspected or cannot be ruled out

Prognosis

With prompt recognition and treatment, the prognosis of CRS is generally good. Most patients with mild to moderate CRS recover fully with supportive therapy and cytokine-blocking agents. Severe cases, particularly those requiring ICU admission, carry a higher risk of complications and mortality. The prognosis also depends on the underlying cause, for example, patients receiving CAR T-cell therapy may have better outcomes if CRS is managed effectively without halting the cancer treatment. Long-term follow-up is often needed to monitor for late complications and immune system recovery.