Cytokine release syndrome (CRS)

INTRODUCTION — Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction. CRS is most often associated with chimeric antigen receptor (CAR)-T cell therapy, but it also occurs in association with bispecific T cell engager therapy, other monoclonal antibody-based therapy, haploidentical allogeneic transplantation, and other settings. Immune effector cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome that can occur in some patients who are treated with immunotherapy, which may or may not accompany CRS.

This topic discusses the clinical presentation, diagnosis, and management of CRS.

Related topics include:

●(See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Remission induction'.)

●(See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Chimeric antigen receptor T cell therapy'.)

●(See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Chimeric antigen receptor T cells'.)

●(See "Treatment of relapsed or refractory follicular lymphoma", section on 'Chimeric antigen receptor T cells'.)

●(See "Multiple myeloma: Treatment of second or later relapse", section on 'Bispecific antibodies'.)

Clinical presentation, diagnosis, and management of macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) and related systemic inflammatory reaction syndromes are discussed separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

TERMINOLOGY

●Cytokine release syndrome (CRS) – An acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction that is generally associated with some form of immunotherapy.

●Immune effector cell-associated neurotoxicity syndrome (ICANS) – Also called cytokine release encephalopathy syndrome (CRES), ICANS is a neuropsychiatric syndrome that occurs in patients treated with immunotherapy. (See 'ICANS (neurologic syndrome)' below.)

EPIDEMIOLOGY — CRS occurs in patients treated with various types of immunotherapy or haploidentical allogeneic hematopoietic cell transplantation (HCT). The incidence of CRS varies with the causative treatment, underlying malignancy, and because of different and evolving definitions of the syndrome.

Treatments, procedures, and disorders that can cause CRS include:

●Chimeric antigen receptor (CAR)-T cell therapy – Significant CRS occurs in one-quarter to one-half of patients treated with CAR-T cell therapy for relapsed/refractory (r/r) acute lymphoblastic leukemia/lymphoma (ALL/LBL), but less severe manifestations are present in nearly all such patients [1]. The incidence is lower in patients treated with CAR-T therapy for non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) [2].

●Bispecific T cell engager therapy – CRS is less common after treatment with blinatumomab (a CD19-CD3 bispecific antibody for r/r B cell ALL/LBL) or elranatamab (a BCMA-CD3 bispecific antibody for r/r MM). In a study of 189 patients with r/r ALL/LBL who were treated with blinatumomab, significant CRS was reported in 2 percent [3]. CRS was reported in 58 percent of patients treated with elranatamab; 44 percent of cases were grade 1, 14 percent were grade 2, and 0.5 percent were grade 3 [4].

●Haploidentical hematopoietic cell transplantation (HCT) – In a series of 75 patients who underwent haploidentical HCT with T cell-replete peripheral blood grafts, significant CRS was reported in 12 percent, but a milder CRS was reported in 75 percent [5].

●Other immune therapies – CRS has been reported infrequently following treatment with anti-thymocyte globulin (ATG) and conventional monoclonal antibodies, including rituximab, obinutuzumab, alemtuzumab, brentuximab, nivolumab, and others [6-13].

●Severe infections – A CRS-like syndrome ("cytokine storm") can develop in association with a severe viral infection, including COVID-19 (caused by SARS-CoV-2) or influenza [14-16]. (See "COVID-19: Clinical features", section on 'Acute course and complications'.)

CRS occurs most often following targeted cellular immunotherapy for B cell ALL/LBL, NHL, CLL, and MM; it is less common following immunotherapy for treatment of solid tumors [2,17-20]. A CRS-like syndrome in association with viral infection or treatment with nonprotein-based drugs, such as oxaliplatin and lenalidomide, should be referred to as cytokine storm rather than CRS, per se [21-24].

PATHOPHYSIOLOGY — CRS is a supraphysiologic response to immune therapy that activates or engages T cells and/or other immune effector cells. The systemic reaction is associated with increased levels of inflammatory cytokines and activation of T lymphocytes, macrophages, and endothelial cells. However, the contributions of the individual cellular components and cytokines to the cause and severity of CRS are not well defined.

CRS severity has been associated with the disease burden (antigen load) of acute lymphoblastic leukemia/lymphoma in patients treated with chimeric antigen receptor (CAR)-T cell therapy [25-27]. The dose of CAR-T cells may also affect the severity of CRS, but a dose-toxicity relationship is not well defined within the dose ranges that are currently used; this may be because the infusion dose does not accurately predict the final expansion and persistence of the CAR-T lymphocytes [28]. Other contributing factors include the molecular design of the CAR (eg, CD28 versus 4-1BB as the costimulatory domain), the nature and intensity of lymphodepletion prior to cell infusion, and the degree of T cell activation and overall condition ("fitness") of the cellular product [17,25-27]. CRS can develop in the absence of tumor if the target antigen is expressed on normal cells, as in the severe CRS that occurred in healthy volunteers after treatment with a CD28 superagonist (TGN1412) [7]. For haploidentical hematopoietic cell transplantation, the source of the graft (ie, peripheral blood versus bone marrow) may influence the risk of CRS, as discussed separately. (See "HLA-haploidentical hematopoietic cell transplantation", section on 'Selection of graft type'.)

Cytokines contribute importantly to the pathophysiology and clinical manifestations of CRS [29]. In the setting of T cell-engaging immunotherapies, CRS is triggered by release of interferon gamma (IFN-g) by activated T cells or tumor cells. IFN-g activates macrophages, which produce excessive interleukin (IL)-6, tumor necrosis factor alpha (TNF-a), and IL-10. IL-6 binds to the soluble form of the IL-6 receptor (IL-6R) that has been cleaved from the cell surface by metalloproteinases, and the IL-6/IL-6R complex binds to gp130 and activates cell types that ordinarily do not express membrane-bound IL-6R. IL-1, IL-5, IL-8, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are also consistently elevated in CRS and may also contribute to the pathophysiology of CRS.

Cytokines are thought to contribute to many of the clinical manifestations of CRS [25,30-32]. Examples include IL-6, which is associated with vascular leakage, activation of the complement and coagulation cascades, disseminated intravascular coagulation (DIC), and cardiomyopathy; IFN-g, which is associated with fever, chills, headache, dizziness, and fatigue; and TNF-a, which can cause flu-like symptoms with fever, malaise, watery diarrhea, vascular leakage, cardiomyopathy, lung injury, and production of acute phase proteins. The pathophysiologic centrality of IL-6 to CRS is indicated by the often rapid abrogation of the syndrome by interruption of IL-6 signaling with the IL-6R antagonist, tocilizumab. (See 'CAR-T cell-associated CRS' below.)

Various cell types contribute to CRS. T cell activation is an essential component of CRS, monocyte/macrophages amplify and expand the repertoire of cytokines and the inflammatory response, and endothelial cells contribute to capillary leakage, hypertension, and coagulopathy [33,34].

CLINICAL PRESENTATION

Time course — The onset and duration of CRS is variable, but it can progress very rapidly.

CRS typically begins within 1 to 14 days (median, 2 to 3 days) after chimeric antigen receptor (CAR)-T cell therapy, within 1 to 3 days after haploidentical hematopoietic cell transplantation (HCT), and may occur within minutes to hours after infusion of conventional therapeutic or bispecific antibodies [5,7,8,25,31,35,36]. More severe manifestations typically present earlier; factors that influence the severity of CRS are described above. (See 'Pathophysiology' above.)

The duration of CRS is variable, but it typically resolves within a few days to two to three weeks after CAR-T infusion and within days after other causes [37].

Clinical manifestations — Clinical manifestations of CRS can range from mild, flu-like symptoms to a severe life-threatening systemic inflammatory response syndrome (SIRS) [37].

By definition, fever (≥38.0°C) must be present at the onset of CRS. With mild CRS, fever may be accompanied by fatigue, headache, rash, diarrhea, arthralgia, and myalgia. The syndrome may progress with fever to 40.5°C (105°F) or higher [33,37]. In more severe CRS, patients may have hypotension and uncontrolled SIRS with circulatory collapse, vascular leakage, peripheral and/or pulmonary edema, renal failure, cardiac dysfunction, and multiorgan system failure.

Grading of the severity of CRS is described below. (See 'Grading' below.)

Neuropsychiatric findings may develop, including aphasia, altered level of consciousness, impaired cognitive skills, motor weakness, seizures, and cerebral edema [37]. In most cases, neurologic toxicity occurs two to four days after the onset of severe CRS, may be progressive, and can occur after the resolution of CRS symptoms. Neurologic toxicity associated with immunotherapy is referred to as immune effector cell-associated neurotoxicity syndrome (ICANS) or cytokine release encephalopathy syndrome (CRES). (See 'ICANS (neurologic syndrome)' below.)

Laboratory — Laboratory findings reflect the systemic inflammatory response, but the abnormalities are highly variable and are influenced by the type of immune therapy, status of the underlying malignancy, and aspects of management.

●Hematology – Leukocytosis may be present as a response to the systemic inflammatory response or treatment with glucocorticoids. In addition, activated or abnormal lymphocytes may appear in peripheral blood after CAR-T cell therapy (picture 1); it is important to distinguish this expansion of CAR-T cells from progressive leukemia.

Conversely, there may be leukopenia, neutropenia, or thrombocytopenia as a result of lymphodepleting chemotherapy, the underlying malignancy, and/or subsequent treatment. Abnormalities of renal or liver function tests are common.

●Chemistries – Electrolyte abnormalities are common in CRS. In a study of 78 patients who received CAR-T cell therapy, CRS occurred in 85 percent and the following electrolyte abnormalities were reported: hypophosphatemia (75 percent), hypokalemia (56 percent), and hyponatremia (51 percent) [38]. Other kidney toxicity associated with CAR-T cell therapy is discussed separately. (See "Nephrotoxicity of molecularly targeted agents and immunotherapy", section on 'CAR-T cell therapy'.)  

Laboratory abnormalities may also reflect manifestations of tumor lysis syndrome (eg, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia) and/or macrophage activation syndrome, which are discussed separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Clinical manifestations' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features'.)

●Markers of inflammation – Nonspecific markers of inflammation (eg, C-reactive protein [CRP], ferritin) are universally elevated in CRS; inflammatory cytokines (eg, interferon gamma, interleukin [IL]-6, IL-10, soluble IL-2R alpha) are also elevated, but testing is limited to specialized laboratories [25,26,28,30,35,39]. In general, the degree of elevation of cytokines and markers of inflammation correlate with the severity of the clinical syndrome. Dramatic elevation of IL-6 is a supportive finding for the diagnosis of CRS. Importantly, CRP is not specific for CRS and changes in CRP may lag behind clinical changes by ≥12 hours [40]. CRP generally falls quickly after administration of tocilizumab and is not a reliable biomarker in that setting.

EVALUATION — The evaluation should promptly establish the presence and severity of CRS and identify other conditions that may contribute to the clinical presentation. The evaluation of suspected CRS includes history, physical examination, laboratory tests, and imaging. Other studies may also be required, depending on the nature and severity of the clinical presentation.

●History – The history should report the nature and time course of CRS-associated clinical findings, including fever, dyspnea, fatigue, headache, confusion, rash, arthralgia, myalgias, and baseline neurologic function. The underlying malignancy, disease status (eg, remission, relapse, treatment-refractory), and disease burden should be noted. The type, dose, and schedule of immunotherapy and use of any preventive measures (eg, glucocorticoids) must be documented. (See 'Clinical manifestations' above.)

●Physical examination – The physical examination should document blood pressure, temperature, and examination of the skin, heart, and lungs to assess manifestations of the systemic inflammatory reaction syndrome. A neurologic examination should document anxiety, tremor, aphasia, delirium, or other findings that may be related to an associated immune effector cell-associated neurotoxicity syndrome (ICANS) or can be manifestations of the systemic inflammatory response. (See 'ICANS (neurologic syndrome)' below.)

It is critically important to exclude potential infections during the initial evaluation, because patients are typically immunosuppressed or neutropenic from lymphodepleting chemotherapy. Neutropenic patients should be empirically treated with broad-spectrum antibiotic coverage while cultures are pending, as described separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Empiric therapy'.)

Laboratory studies should include:

●Hematology – Complete blood count (CBC) with differential count.

●Coagulation – Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrin D-dimer.

●Chemistry – Serum electrolytes, kidney and liver function, uric acid, lactate, lactate dehydrogenase (LDH).

●Oxygenation – Pulse oximetry or arterial blood gas.

●Markers of inflammation – C-reactive protein (CRP), ferritin; cytokines (eg, interferon gamma, interleukin 6) may be measured, if available.

●Microbiologic testing – Specific studies to evaluate infection, especially in a neutropenic or immunosuppressed patient typically include blood cultures, urinalysis/urine culture, and other tests, as informed by clinical findings, exposure history, and other patient-specific factors. (See "Diagnostic approach to the adult cancer patient with neutropenic fever", section on 'Patient evaluation'.)

●Imaging – Chest radiograph.

Additional testing is often needed to identify other processes that may contribute to the clinical presentation. (See 'Differential diagnosis' below.)

Examples of other testing that may be helpful include:

●Heart – Evaluate dyspnea, edema, or hypotension due to reduced cardiac output or excess fluid accumulation. Testing should include brain natriuretic peptide (BNP), electrocardiogram (ECG), echocardiogram, and/or cardiac telemetry to detect heart failure, pericardial effusion, or dysrhythmias, as described separately. (See "Heart failure: Clinical manifestations and diagnosis in adults".)

●Computed tomography (CT) – CT can clarify the pattern, extent, and location of radiographic abnormalities and can help to assess underlying or contributing infections. CT can also identify pleural or pericardial effusions and may be helpful to guide bronchoscopic evaluation. Use of CT to evaluate respiratory insufficiency is described separately. (See "Approach to the patient with dyspnea", section on 'Chest computed tomography'.)

●Bronchoscopy/bronchoalveolar lavage (BAL) – Bronchoscopy/BAL can be helpful for evaluation of a pulmonary infection or hemorrhage but is generally reserved for patients who require intubation. BAL can usually be performed safely even in a patient with thrombocytopenia and/or coagulopathy. When possible, the area of lung with the greatest degree of radiographic abnormalities should be lavaged and the specimen should be processed as described separately. (See "Basic principles and technique of bronchoalveolar lavage".)

Laboratory studies are not required for the diagnosis of CRS, but CRP, ferritin, and/or cytokine levels may provide supportive data for the diagnosis and may be useful for monitoring the course of CRS, as described below. (See 'Diagnosis' below and 'Monitoring and resolution' below.)

DIAGNOSIS — CRS should be suspected in a patient treated with immunotherapy who has fever, with or without tachypnea, tachycardia, hypotension, hypoxia, or other findings. CRS is most commonly seen after treatment with chimeric antigen receptor (CAR)-T cell therapy, but it can also occur after treatment with a bispecific T cell engager therapy, other monoclonal antibody therapy, and when post-transplant cyclophosphamide is used for prophylaxis of graft-versus-host disease (GVHD), especially after haploidentical allogeneic hematopoietic cell transplantation (HCT). A high index of suspicion is necessary to diagnose CRS and to distinguish it from other conditions that occur in these settings. (See 'Differential diagnosis' below.)

CRS is a clinical diagnosis that requires fever (≥38.0°C), with or without variable degrees of hypotension, hypoxia, and/or other end-organ dysfunction that develops hours to days after treatment with immune therapy [37]. The temporal relationship to the triggering immune therapy is important for establishing the diagnosis of CRS. Laboratory studies are not required to diagnose CRS, but they may help to distinguish CRS from other conditions that can cause similar findings. (See 'Clinical presentation' above.)

The method used to grade CRS depends on the cause of the syndrome, as described below. (See 'Grading' below.)

Immune effector cell-associated neurotoxicity syndrome (ICANS; also called cytokine release encephalopathy syndrome) that develops after immunotherapy is specifically excluded from the definition of CRS but is frequently associated with CRS [37]. (See 'ICANS (neurologic syndrome)' below.)

DIFFERENTIAL DIAGNOSIS — CRS is manifest as an initial fever and a constellation of nonspecific clinical findings that may also be caused by infection/sepsis, disease progression, heart failure, pulmonary thromboembolism, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, or other processes. These other conditions have different causes, kinetics, and clinical and laboratory features that can help to distinguish them from CRS, but they may also be present concurrently with CRS.

Sepsis — Infection/sepsis can present with fever, hypotension, respiratory distress, and/or radiographic pulmonary opacities. Infections cannot be definitively distinguished from CRS based on routine initial laboratory testing and chest radiography. The evaluation for infection should include peripheral blood cultures and other studies that are informed by the clinical presentation, such as stains and cultures of sputum; nasal swab for viral polymerase chain reaction; other serum and urine tests for bacterial, fungal, and viral infections; and/or other specialized studies (eg, flexible bronchoscopy with bronchoalveolar lavage). Empiric antibiotic therapy is often initiated while results of laboratory studies are processed. Evaluation and management for infection/sepsis in related clinical settings are discussed separately. (See "Diagnostic approach to the adult cancer patient with neutropenic fever" and "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Empiric therapy'.)

Tumor progression — Progression of the underlying malignancy may cause tumor-associated fever and other clinical, metabolic, and imaging abnormalities that resemble those of CRS. Tumor lysis syndrome (TLS) (table 1) is an oncologic emergency with metabolic disorders (eg, release of potassium, phosphate, uric acid) and renal dysfunction that may be caused by rapid tumor growth or treatment with lymphodepleting therapy. TLS may also result from a response to treatment with chimeric antigen receptor (CAR)-T cell therapy or a therapeutic antibody. Tumor progression is documented by progressive changes in blood counts, bone marrow examination, or tumor masses. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Definition and classification'.)

Heart failure — Heart failure can be a consequence of the systemic inflammatory syndrome of CRS or it may be caused by other conditions (eg, anthracycline-associated cardiomyopathy, ischemic heart disease, myocarditis, pericardial effusion). Clinical evaluation, measurement of brain natriuretic peptide (BNP), echocardiography, and/or computed tomography (CT) should distinguish heart failure due to left ventricular dysfunction, pericardial effusion, or dysrhythmia from other findings of CRS. (See "Heart failure: Clinical manifestations and diagnosis in adults".)

Thromboembolism — Clinical features of pulmonary embolism (PE)/deep vein thrombosis (DVT), such as dyspnea, hypoxia, hypotension, peripheral edema, leg swelling, or hemoptysis may resemble CRS. PE should be suspected in patients with evidence of DVT affecting an extremity or central venous catheter, and in patients with hypoxemia that is out of proportion to the extent of radiographic opacities. Evaluation of DVT/PE is described separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

Allergic reaction — Allergic reactions including severe drug reactions can cause fever, rash, capillary leak, and dyspnea. Evaluation of the patient suspected of a severe drug allergy, such as drug reaction with eosinophilia and systemic symptoms (DRESS), is discussed separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) — HLH and MAS share many clinical and laboratory features with CRS. Both CRS and HLH/MAS have activation of macrophages and the reticuloendothelial system that is initiated by T cell-mediated inflammation. Indeed, most patients with moderate to severe CRS have laboratory features that meet criteria for HLH/MAS, although patients with CRS may or may not have hepatosplenomegaly, lymphadenopathy, or evidence of hemophagocytosis. We consider that many of the clinical findings that occur after immune therapy should be designated CRS, rather than HLH/MAS. Clinical manifestations and diagnosis of HLH/MAS are discussed separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Immune effector cell-associated HLH-like syndrome (IEC-HS) is a distinct pathological/biochemical hyperinflammatory syndrome, which is independent from CRS and ICANs, that is attributable to immune effector cell therapy and is associated with the progression or new onset of cytopenias, hyperferritinemia, coagulopathy with hypofibrinogenemia, and/or transaminitis; diagnostic and grading criteria for IEC-HS have been proposed [41].

GRADING — The method used to grade CRS depends on the cause of the syndrome.

Grading CAR-T CRS — Grading of CRS associated with chimeric antigen receptor (CAR)-T cell therapy utilizes a distinctive scoring system. It should be recognized that various grading scales for CRS have been used previously and the published literature includes diverse grading scales.

We favor grading of CRS that is associated with CAR-T cell therapy according to the criteria of the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation [ASBMT]) [37]. This consensus approach is based on the degree and type of interventions that are required for patient management, rather than strict laboratory parameters. As examples, rather than defining a specific level of oxygen saturation, the type of oxygen delivery device serves as a surrogate for the severity of the oxygenation deficit. Similarly, hypotension is graded by the number of vasopressors that are required to maintain adequate blood pressure, rather than a specific blood pressure measurement.

ASTCT Consensus Grading for CRS:

●Grade 1 – Temperature ≥38°C (see note below) and no hypotension and no hypoxia. Patients may have malaise, myalgias, or arthralgias, but the severity of these constitutional symptoms does not affect the grade of CRS.

●Grade 2 – Temperature ≥38°C plus hypotension that does not require vasopressors and/or hypoxia that requires low-flow nasal cannula (≤6 L/minute or blow-by oxygenation). See the notes below regarding aspects of the management of hypotension and hypoxia that may affect grading.

●Grade 3 – Temperature ≥38°C plus hypotension that requires one vasopressor (with or without vasopressin) and/or hypoxia requiring high-flow nasal cannula (≥6 L/minute), facemask, non-rebreather mask, or Venturi mask that is not attributable to any other cause.

●Grade 4 – Temperature ≥38°C plus hypotension that requires multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure (eg, continuous positive airway pressure [CPAP], bilevel positive airway pressure [BPAP], intubation and mechanical ventilation).

The following should be noted with regard to grading CRS [37]:

●Fever must not be attributable to any other cause. In patients who have CRS and then receive antipyretic or anticytokine therapy (eg, tocilizumab, glucocorticoids), fever is no longer required to grade subsequent CRS toxicity; in such a case, CRS grading is driven by the management of hypotension and/or hypoxia.

●CRS grade is determined by the more severe event (ie, hypotension or hypoxia).

●Hypotension is not graded based on use of vasopressin alone, if vasopressin is not being used in response to worsening hypotension. Some critical care practitioners administer vasopressin simultaneously with other vasopressors to capitalize on its vasoconstrictive effects, mitigate capillary leak, or minimize norepinephrine dose requirements; such use of vasopressin is not considered to be in response to escalating toxicity. Also, the use of the inotrope milrinone, which may be used to aid in cardiac contractility, does not affect the grade of CRS.

●Hypoxia is defined by a requirement for supplemental oxygen to correct a deficit in oxygenation rather than a specific level of oxygen saturation.

●Intubation of a patient for reasons other than hypoxia (eg, airway protection or to enable a procedure), alone, is not a criterion for grade 4 CRS.

●Other organ toxicities associated with CRS may be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 [42], but they do not influence CRS grading.

Grading for other causes of CRS — CRS caused by other types of immune intervention (eg, bispecific antibodies, haploidentical allogeneic transplantation) should be graded according to the NCI CTCAE v5.0 [42], as follows:

●Grade 1 – Fever, with or without constitutional symptoms.

●Grade 2 – Hypotension responding to fluids. Hypoxia responding to <40 percent FiO₂.

●Grade 3 – Hypotension managed with one pressor. Hypoxia requiring ≥40 percent FiO₂.

●Grade 4 – Life-threatening consequences; urgent intervention needed.

MANAGEMENT

Key principles — The following principles are important for management of CRS:

●Grading differs according to cause of CRS – The grading systems to assess the severity of CRS differ according to the cause of the syndrome (ie, the type of immunotherapy). (See 'Grading' above.)

●Management of severe CRS depends on the cause – Management of severe CRS varies according to the type of immunotherapy that was administered, as described in the sections that follow.

For chimeric antigen receptor (CAR)-T cell therapy, details of management depend on the specific agent, with details provided in the US Food and Drug Administration Risk Evaluation and Mitigation Strategy (REMS) program, as described below. (See 'CAR-T cell-associated CRS' below.)

●Need for intensive care for severe CRS – Patients with severe CRS may require management in an intensive care unit or other setting where they can simultaneously receive aggressive management of hypotension (eg, fluids, vasopressors), oxygenation (eg, supplemental oxygen, mechanical ventilation), cardiac telemetry, infection (eg, routine empiric antibiotics), and other conditions.

●Control CRS without extinguishing the immunotherapeutic benefit – The goal of management is to prevent life-threatening toxicity from CRS while sustaining the antitumor effects of the immunotherapy. Treatment as described below, generally lessens CRS toxicity without abrogating the benefit of CAR-T cells; theoretical concerns about eradicating the CAR-T clone are unproven, at present. (See 'CAR-T cell-associated CRS' below.)

●Concurrent disorders – CRS may be present along with other serious medical conditions (eg, infection/sepsis, tumor progression, heart failure). It is important to promptly diagnose both CRS and coexisting disorders to provide timely, specific, and life-saving treatment. (See 'Differential diagnosis' above.)

Mild CRS — The definition of mild CRS, which generally refers to fever with or without mild associated findings, depends on the specific causal agent and the grading system that is used to score its toxicity, as described above. (See 'Grading' above.)

Regardless of the underlying cause of mild CRS, we suggest symptomatic treatment with antihistamines, antipyretics, intravenous fluids, and close monitoring. For patients with mild CRS, the balance of benefit and toxicity with symptomatic treatment is more favorable than with high dose glucocorticoids, tocilizumab, or interruption of the infusion.

For patients who have mild CAR-T cell-associated CRS, suggestions for symptomatic treatment vary with the individual CAR-T product. The REMS program for the specific agent should be consulted for specific aspects of management.

For patients with mild CRS that progresses or deteriorates while receiving symptomatic treatment, we suggest treatment for severe CRS, according to the precipitating cause, as described below. (See 'Severe CRS' below.)

Severe CRS

CAR-T cell-associated CRS — For CAR-T cell-associated CRS, we consider severe CRS to include patients with grades 3 and 4 disease, and some patients with grade 2. Grading of CAR-T cell-associated CRS is based on the interventions that are required to manage the patient rather than specific laboratory values; as a result, there is some overlap between grades 2 and 3. Whether a patient with grade 2 CRS has severe disease versus milder disease should be judged on a case-by-case basis. Grading and management of milder CAR-T cell-associated CRS is described above. (See 'Grading CAR-T CRS' above and 'Mild CRS' above.)

For severe CRS (grades 3 and 4) caused by CAR-T cell therapy, we suggest initial treatment with tocilizumab plus a glucocorticoid rather than either agent alone. Treatment with tocilizumab plus a glucocorticoid appears to achieve more rapid and complete control of CRS than either agent alone, and use of the suggested doses and duration of therapy provide an acceptable balance of control of CRS manifestations versus toxicity.

Some experts favor initial treatment of less severe CAR-T cell-associated CRS (eg, grade 2) with tocilizumab alone to minimize toxicity. At present, the risk of depleting CAR-T cells and abrogating the clinical benefit with either tocilizumab or glucocorticoids is unproven, and we consider that treatment with the doses and brief duration of glucocorticoid treatment that are suggested generally add benefit without undue depletion of the cells.

Tocilizumab and glucocorticoid should be administered concurrently.

●Tocilizumab – Tocilizumab should be administered intravenously over one hour as follows [43]:

•For patients <30 kg – Tocilizumab 12 mg/kg

•For patients ≥30 kg – Tocilizumab 8 mg/kg; the total tocilizumab dose should not exceed 800 mg

●Glucocorticoid – Examples of glucocorticoid doses are hydrocortisone 100 mg every eight hours, dexamethasone 10 mg up to four times daily, or methylprednisolone 1 mg/kg/day. Glucocorticoid treatment is given until there is improvement in CRS.

If there is no clinical improvement in oxygenation, hypotension, fever, and other manifestations of CRS after the first dose of tocilizumab, it may be repeated after ≥8 hours. Tocilizumab treatment should not exceed four doses in total [43].

Use of commercially available CAR-T cell products in the United States is regulated by the US Food and Drug Administration REMS program. Guidelines for treatment of CAR-T cell-associated CRS varies according to the specific product, and REMS guidelines should be consulted for specific details of management of CRS.

No randomized trials have compared tocilizumab plus a glucocorticoid versus either alone for severe CRS. Treatment suggestions are derived from prospective and retrospective studies that included a wide variety of underlying diseases and various prevention strategies, grading scales, and definitions of response [1]. One study reported that early treatment with tocilizumab reduced fevers and other CRS symptoms within one to three days, but did not dampen expansion of CAR-T cells in peripheral blood; in contrast, high dose glucocorticoids rapidly reversed CRS symptoms but ablated CAR-T cells and were associated with recurrence of disease after an initial response to CAR-T therapy [26].

In one study, early use of tocilizumab reduced the incidence of severe CRS but was associated with a higher incidence of immune effector cell-associated neurotoxicity syndrome, including patients with mild CRS; it is unclear at present if early use of tocilizumab may have contributed to the increased risk of neurologic complications [44]. Importantly, for patients who have delirium or other neurologic findings consistent with ICANS without active CRS, initial treatment with glucocorticoids is preferred, as tocilizumab does not appear to be effective for the neurologic syndrome. (See 'ICANS (neurologic syndrome)' below.)

Management of mild CRS, monitoring the response to treatment, and management when CRS that does not improve clinically within 24 to 72 hours are described below and above. (See 'Monitoring and resolution' below and 'Persistent or worsening CRS' below and 'Mild CRS' above.)

Bispecific T cell engager-associated CRS — Severe CRS caused by bispecific T cell engager therapy (eg, blinatumomab, elranatamab) refers to grades 3 and 4 in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 scoring system, as described above. (See 'Grading for other causes of CRS' above.)

For severe bispecific T cell engager therapy-associated CRS, we suggest interrupting the infusion plus treating with a glucocorticoid rather than either approach alone. This approach offers a favorable balance of rapid improvement and acceptable toxicity, whereas continuing the infusion risks further worsening of the syndrome. There are only limited data, but tocilizumab appears to be less effective than glucocorticoids in this setting.

We suggest the following for bispecific T cell engager-associated CRS [45]:

●Grade 4 – Discontinue the bispecific antibody permanently. Administer dexamethasone 8 mg (or 5 mg/m² if <45 kg; maximum: 8 mg) intravenously or orally every eight hours for up to three days, then taper over four days.

For patients with an inadequate response to these measures, tocilizumab (8 mg/kg intravenously, once) can be given.

●Grade 3 – Management is guided by the agent.

•Blinatumomab – Interrupt blinatumomab therapy. Administer dexamethasone 8 mg (or 5 mg/m² if <45 kg; maximum: 8 mg) intravenously or orally every eight hours for up to three days, then taper over four days.

Upon resolution, resume blinatumomab at 9 mcg daily (or 5 mcg/m²/day if <45 kg). Increase dose to 28 mcg daily (or 15 mcg/m²/day if <45 kg) after seven days if toxicity does not recur.

CRS generally occurs only with the initial dose of blinatumomab. Blinatumomab can usually be resumed with dose adjustment, as described in the package insert [45].

•Elranatamab – Withhold elranatamab until the resolution of CRS and provide supportive care, which may require intensive care. For the next dose of elranatamab, the patient should be hospitalized for 48 hours and pretreatment medications administered [4].

For recurrence of grade 3 CRS, discontinue elranatamab permanently and provide supportive care.

Management of grade 1 or 2 CRS is described in the package label [4].

The clinical and laboratory status should be reassessed regularly to determine if the response is adequate. As an example, we treat with glucocorticoids until vasopressors and high-flow oxygen are no longer needed, and then taper the glucocorticoid over several days as guided by the clinical response. If there is no clinical improvement in oxygenation, hypotension, fever, and other CRS manifestations within 24 to 72 hours, we suggest management for persistent or worsening CRS, as described below. (See 'Persistent or worsening CRS' below and 'Monitoring and resolution' below.)

Haploidentical HCT associated — Severe CRS caused by haploidentical allogeneic hematopoietic cell transplantation (HCT) refers to NCI CTCAE v5.0 grades 3 and 4, as described above. (See 'Grading for other causes of CRS' above.)

For severe CRS associated with haploidentical HCT, we suggest treatment with a glucocorticoid because there are few reports of tocilizumab treatment in this setting.

Details of glucocorticoid dose, duration, and toxicity are described above. (See 'Bispecific T cell engager-associated CRS' above.)

There are limited reports of using tocilizumab to treat severe CRS after haploidentical HCT. Severe CRS is associated with increased blood stream infections (BSIs) in the early post-transplant period, but one study reported no evidence that tocilizumab was independently associated with increased BSIs [46]. In another study, the treatment of 11 patients with tocilizumab for haploidentical HCT-associated CRS was associated with more chronic graft-versus-host disease (GVHD) at one year, compared with 21 matched patients who developed CRS after haploidentical HCT but did not receive tocilizumab [47]. There was no difference in overall survival, disease-free survival, relapse rate, or nonrelapse mortality at one year, and there were no CRS-related deaths in either group. Rates of acute GVHD and engraftment of platelets or neutrophils were similar between groups.

MONITORING AND RESOLUTION — We consider that CRS has resolved when there is sustained resolution of fever and there is no longer a need for oxygen supplementation to relieve hypoxia nor vasopressors to maintain blood pressure. However, there is no consensus regarding when CRS is considered resolved, nor an optimal protocol, schedule, or duration of monitoring response to CRS therapy.

It is important to note that normalization of temperature alone does not define resolution of CRS, because treatments for CRS (eg, tocilizumab, steroids, antipyretics) may lead to rapid resolution of fever while other severe manifestations of CRS including hypotension or hypoxia persist.

Monitoring should reflect the severity of illness:

●Patients with severe CRS and some cases of grade 2 CRS may require management in an intensive care setting, with monitoring of clinical status and laboratory studies performed at least daily. As the patient improves, the intensity of the monitoring and setting can decrease, but the patient should not be discharged from the hospital until clinically stable.

●For patients with mild CRS, clinical and laboratory monitoring should initially be performed daily, with the intensity of monitoring and tapering informed by clinical findings as the patient improves.

The duration of monitoring should reflect the clinical condition and the likely duration of CRS, as described above. (See 'Time course' above.)

Laboratory tests should be used to monitor the patient's hematologic, coagulation, metabolic, and oxygenation status. However, it is important to note that C-reactive protein (CRP) cannot be used as an indicator of the severity of inflammation after treatment with tocilizumab, because blockade of the interleukin 6 signaling pathway rapidly decreases the level of CRP.

PERSISTENT OR WORSENING CRS — For a patient with a persistent or worsening clinical condition after initial treatment of CRS, we suggest re-evaluation for other contributing conditions. It is particularly important to reassess the patient for coexisting infectious, cardiac, thromboembolic, and other complications. (See 'Differential diagnosis' above.)

For patients who do not improve within 8 to 24 hours after initial treatment, subsequent management is informed by the severity of the patient's clinical condition and the treatment that was initially administered.

●For all patients who were previously treated with a single dose of tocilizumab, we suggest repeating the same dose of tocilizumab ≥8 hours later (up to a total of four doses) and adding a corticosteroid, as described above. (See 'CAR-T cell-associated CRS' above.)

The number of tocilizumab treatments needed to control severe CRS may vary with the causative immune therapy. In the authors' experience, one dose of tocilizumab (or occasionally two doses) can provide an optimal clinical response after treatment with tisagenlecleucel or lisocabtagene maraleucel, but up to three to four doses may be needed for patients treated with axicabtagene or brexucabtagene autoleucel.

●For patients with persistent, severe CRS of any cause, who were previously treated with steroids alone, we suggest adding tocilizumab, as described above. (See 'CAR-T cell-associated CRS' above.)

●For patients with severe CRS (generally grade 3 to 4) who fail to improve after repetitive treatment with both tocilizumab and steroids, we generally add a high-dose corticosteroid (eg, methylprednisolone 2 mg/kg up to 1 gram daily for three days).

●Anakinra is commonly used as a third-line agent for refractory CRS [48].

There is very limited experience with other agents, but options include the following [40,49,50]:

•Etanercept (blockade of TNF alpha)

•Cyclophosphamide

•Ruxolitinib

•Dasatinib

•Anti-thymocyte globulin (ATG)

•Alemtuzumab

•Ibrutinib

•Monoclonal antibodies against interleukin (IL)-6 (eg, siltuximab, clazakizumab); however, the benefit from these agents after treatment with tocilizumab (which directed against the IL-6 receptor) is unproven.

PREVENTIVE THERAPY — Preventive treatment for CRS must balance reducing the incidence or severity of CRS against potential interference with the therapeutic effect of treatment. There is no proven role for any strategy for ameliorating CRS.

●CAR-T cells – Disease burden is a risk factor for CRS, so debulking chemotherapy prior to chimeric antigen receptor (CAR)-T cell therapy or reducing the CAR-T cell dose may lessen the frequency and/or severity of CRS [29].

•Glucocorticoids – CAR-T cells must expand in vivo after infusion and there are concerns that prophylactic glucocorticoids may interfere with expansion of the CAR-T cell clones and adversely impact the clinical benefit.

In cohort 6 of the Zuma-1 study of axicabtagene ciloleucel for diffuse large B cell lymphoma (DLBCL), 40 patients were given oral dexamethasone 10 mg immediately prior to CAR-T cell infusion and again daily for two days [51]. Compared with patients in earlier cohorts who did not receive prophylactic dexamethasone, the incidence of grade 3 or 4 CRS was reduced, the onset of CRS was delayed, and there was less exposure to steroids over the course of care. However, the contribution of dexamethasone to reducing CRS is uncertain because other aspects of CRS management had also evolved in the course of the trial.

•Tocilizumab – There is no demonstrated role for prophylactic tocilizumab, and tocilizumab may be associated with an increased risk of neurologic toxicity. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

●Bispecific T cell engager therapy – Bispecific T cell engager therapy can be stopped and restarted with dose adjustments, if needed, in response to toxicity.

•Blinatumomab – The initial dose of blinatumomab can be reduced to 9 mg/day, with subsequent doses adjusted based on presence and severity of CRS [52]. Other approaches include pretreatment cytoreduction with cyclophosphamide and/or dexamethasone.

•Elranatamab – Elranatamab should be discontinued permanently for grade 4 or recurrent grade 3 CRS. Elranatamab should be withheld until the resolution of CRS for grades 1, 2, and or a first occurrence of grade 3 CRS; further actions are provided by the package label [4].

ICANS (NEUROLOGIC SYNDROME) — Immune effector cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome that occurs in patients treated with immunotherapy (eg, chimeric antigen receptor T cell therapy and bispecific antibody therapy). ICANS has also been called cytokine release encephalopathy syndrome (CRES). ICANS can occur alone, concurrently with CRS, or following resolution of CRS [53].

Details of the clinical presentation, evaluation, diagnosis, grading, and management of ICANS are presented separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)  

SUMMARY AND RECOMMENDATIONS

●Description – Cytokine release syndrome (CRS) is an acute systemic inflammatory response syndrome characterized by fever, with or without multiple organ dysfunction that is associated with chimeric antigen receptor (CAR)-T cell therapy, bispecific T cell engager therapy, or haploidentical hematopoietic cell transplantation (HCT).

●Pathophysiology – CRS is a supraphysiologic response to immune therapy that activates T cells and/or other immune effector cells. CRS is associated with increased levels of inflammatory cytokines and activation of T lymphocytes, macrophages, and endothelial cells. (See 'Pathophysiology' above.)

●Clinical manifestations – Fever, which may be accompanied by fatigue, headache, rash, diarrhea, arthralgia, and myalgia. Milder CRS can progress with hypotension, hypoxia, and uncontrolled systemic inflammatory response with circulatory collapse, vascular leakage, peripheral and/or pulmonary edema, renal failure, cardiac dysfunction, and multiorgan system failure. (See 'Clinical presentation' above.)

●Evaluation – Includes history, physical examination, laboratory tests, imaging, and other studies, as clinically indicated. (See 'Evaluation' above.)

●Diagnosis – CRS should be suspected in a patient with fever, which may be accompanied by tachypnea, tachycardia, hypotension, hypoxia, or other findings after receiving immune therapy or haploidentical HCT. (See 'Diagnosis' above.)

CRS is a clinical diagnosis based on fever (≥38.0°C), with or without hypotension, hypoxia, and/or other end-organ dysfunction that develops hours to days after immune therapy. (See 'Diagnosis' above.)

●Differential diagnosis – Findings overlap with infections, heart failure, drug reactions, pulmonary venous thromboembolism, and other severe illnesses in this setting. (See 'Differential diagnosis' above.)

●Grading – Depends on the cause of CRS:

•CAR-T cell therapy (see 'Grading CAR-T CRS' above)

•Other – Bispecific T cell engager therapy (eg, blinatumomab, elranatamab) or haploidentical HCT (see 'Grading for other causes of CRS' above)

●Mild CRS – For mild CRS of any cause, symptomatic treatment with antihistamines, antipyretics, and fluids is typically sufficient.

●Severe CRS – For severe CRS, we suggest (see 'Severe CRS' above):

•CAR-T cell therapy – For severe CRS caused by CAR-T cell therapy, we suggest initial treatment with tocilizumab plus a glucocorticoid rather than either agent alone (Grade 2B). Higher doses or prolonged glucocorticoid therapy may deplete or eradicate CAR-T cells. (See 'CAR-T cell-associated CRS' above.)

•Bispecific antibody therapy – For severe CRS caused by a bispecific antibody, the treatment should be interrupted and supportive care provided, which may require intensive care; other management is based on the agent and severity of CRS. (See 'Bispecific T cell engager-associated CRS' above.)

Tocilizumab may be added for an inadequate response.

•HCT – For severe CRS when using post-transplant cyclophosphamide as prophylaxis for graft-versus-host disease (eg, after haploidentical HCT), we treat with a corticosteroid or tocilizumab (as for CRS associated with a therapeutic antibody). (See 'Bispecific T cell engager-associated CRS' above.)

●Persistent or worsening CRS – Management is informed by the severity and initial treatment, as described above. (See 'Persistent or worsening CRS' above.)

●Immune effector cell-associated neurotoxicity syndrome (ICANS) – A neuropsychiatric syndrome that can occur in some patients who are treated with immunotherapy, which may or may not accompany CRS, as described separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)