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Diagnosis and management of cytokine release syndrome (CRS)

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Topics: Advanced therapy medicinal productsCautions and contraindicationsGuidancePrescribing

Guidance on the management of CRS in adult patients receiving licensed CAR-T cell products.

This article forms part of a series
  1. Understanding acute CAR-T cell therapy toxicities in adults
    1. Diagnosis and management of cytokine release syndrome (CRS)
    2. Diagnosis and management of ICANS
    3. Medications for treating CRS and ICANS

Contents

  1. Recognition and differential diagnosis
    1. Complications of CRS
  3. Monitoring
  4. Management
    1. CRS treatment algorithm
    2. Alternative description of the CRS treatment algorithm image
    3. Management table for treatment of CRS

Recognition and differential diagnosis

CRS can present as a mild flu-like illness to multi-organ failure. Signs and symptoms can mimic tumour lysis syndrome or sepsis and treatment with broad spectrum antimicrobials, paracetamol and intravenous fluids is required to cover possible concurrent infection.

At onset of fever, and before starting CRS specific treatments, take appropriate cultures and start empirical antibiotic therapy until infection can be ruled out.

Treatments for CRS are immunosuppressive and can exacerbate severe active infection. This must be considered in all patients presenting with CRS symptoms.

Complications of CRS

Potential life-threatening complications of CRS include:

  • cardiac dysfunction
  • acute respiratory distress syndrome
  • neurological toxicity
  • renal failure
  • hepatic failure
  • disseminated intravascular coagulation

Monitoring

Regularly monitor for signs and symptoms of CRS in CAR-T cell therapy in line with the individual product SmPC, and national service specification.

The key symptoms are:

  • fever
  • hypotension
  • hypoxia

Temperature equal or above 38°C, which is not attributable to any other cause, is the distinguishing feature.

Management

The grade of CRS indicates the management and treatment plan.  See Understanding acute CAR-T cell therapy toxicities in adults (SPS page) for more information on how CRS is graded.

CRS management includes tocilizumab, an anti-cytokine therapy, and corticosteroids. In severe and refractory cases, off-label treatments such as anakinra may be used in line with Trust formulary processes.

Temperature often normalises within a few hours after tocilizumab administration whereas the other symptoms of CRS take longer to resolve.

The patient is still considered to have CRS even in the absence of fever, until all signs and symptoms leading to the diagnosis of CRS have resolved.

Once patients have received paracetamol or anti-cytokine therapy, then fever is no longer required and the grading of CRS is driven by hypotension or hypoxia.

CRS treatment algorithm

The figure below outlines the CRS treatment algorithm.

The flowchart illustrates 4 steps in the treatment algorithm:

Step 1

  • Every patient should have baseline and regular monitoring of temperature, blood pressure and oxygen saturation

Step 2

  • If CRS is suspected, immediately contact the CAR-T team.  If concurrent ICANS also follow the ICANS management algorithm.

Step 3

  • If CRS is suspected, the following additional investigations should be performed: ferritin; FBC; U&Es; LFTs; CRP; coagulation; daily ECG; appropriate imaging e.g. chest X-ray; blood and urine cultures; bone profile (if TILS in differential).

Step 4

  • Follow CRS management table
  • Patients must be monitored closely and treatment rapidly escalated if there is lack of clinical response or further deterioration.
  • CAR-T toxicity treatment decisions should be undertaken by the attending consultant or CAR-T team and escalation plan pre-empted where possible to support rapid treatment escalation when required.
  • If part of a clinical trial, contact the clinical trial team and follow the specific trial protocol for management of CRS.

Management table for treatment of CRS

 

CRS treatment algorithm and management table

A printable version of the CRS treatment algorithm and management table.