Cytokine release syndrome (CRS)

Also known as cytokine storm.
CRS defined as a supraphysiological response involving any immune therapy that results in the activation or engagement of endogenous, or infused T cells and/or other immune effector cells, such as lymphocytes or myeloid cells.
An acute inflammatory syndrome, characterized by fever, flu like symptoms, and malaise with possible severe manifestations leading to hemodynamic instability, organ injury, or failure and altered mental status.
These effects are induced by binding of the CAR T cell receptor to its antigen, subsequent release of inflammatory cytokines and activation of lymphocytes, macrophages, and endothelial cells.
It is an umbrella term for several disorders of immune dysregulation characterized by constitutional symptoms, systemic inflammation, and multi organ dysfunction.
The typical time to onset for CRS, is 2 to 3 days with a duration of 7 to 8 days.
CRS may occur within hours after CAR T cell infusion and as late as 10 to 15 days post infusion.
The initial drivers of cytokine storm vary both in onset and duration, but late stage clinical manifestations often overlap.

An immediate complication occurring with the use of anti-T cell antibody infusions such as ATG, OKT3 and TGN1412, but also with the CD-20 antibody rituximab, and Blinatumomab.

Multiple cytokines have been implicated in CRS, including: IL-6, IL-1, interferon-gamma, and TNF-alpha.

Cytokine storm, cytokine release syndrome is a life-threatening systemic inflammatory syndrome involving elevated elevated levels of circulating cytokines and immune-cell hyper activation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.
Neutrophils, monocytes, and macrophages respond to pathogens by producing cytokines that engulf pathogens and cells by phagocytosis.
There are other innate immune cells, such as dendritic cells, gamma delta T cells, and natural killer cells that participate in response to pathogens.
Innate immune cells use pattern recognition receptors, which are not specific for any particular antigen, to recognize and respond to microbial invaders by producing cytokines that activate cells of the adaptive immune system.
The innate cells that are most often involved in the pathogenesis of cytokines storm include neutrophils, macrophages, and NK cells.

Neutrophils can produce neutrophil extracellular traps, which are a network of fibers that contribute to thrombi formation and amplify cytokine production during the cytokine storm.

Cytokine release syndrome is it complex process involving interconnected networks of cell types, signaling pathways, and cytokines including interferon-gamma, interleukin-1, interleukin-6, TNF, and interleukin-18 which are cytokines that often have elevated levels and are thought to have a central immuno pathologic role.

Specific CRS manifestations may include: fever, hypertension, tachycardia, hypoxia, chills, and may be associated with cardiac, hepatic, renal dysfunction, and capillary leak syndrome.

Severe cases of cytokine releasing syndrome are known as cytokine storms.

Cardiovascular complications can be severe with hypotension, hypoxia, atrial fibrillation, ventricular, tachycardia, cardiac arrest, and atrial cardiac failure.

A pattern of cytokine elevations resulted on the basis of the microbiome, genetic features, and underlying disorders.

Interferon-gamma is primarily secreted by activated T cells and NK cells and activates macrophages.

When activated macrophages can secrete excessive amounts of cytokines, ultimately causing severe tissue damage that can lead to organ failure.

Hematophagocytic macrophages are often observed in bone marrow biopsy specimens from patients with cytokines storm.

Interferon gamma can induce hemophagocytosis by macrophages and contribute to cytopenias seen in patients with cytokine storm.

NK cells have a decreased function in some cases of cytokine storm and can lead to profound to prolonged antigenic stimulation and difficulty resolving inflammation.

Excess interleukin-6 may mediate the impairment in NK cell function.

Previously referred to as an influenza like syndrome occurring with systemic infection such as sepsis and after immunotherapies, pandemics such as the Black Death, and triggers alveolar macrophages to produce excessive amounts of cytokines, resulting in cytokine storm.
Nearly all patients  with cytokine storm are febrile.
It is the immune response to the pathogen, but not the pathogen itself, that can contribute to multi organ dysfunction.
Immune hyperactivation in  cytokine storm can be due to inappropriate triggering or danger sensing, with a response initiated in the absence of pathogen: Castlemans disease, genetic disorders of inappropriate inflammasome activation, CAR T-cell therapy, an overwhelming pathogen burden as in sepsis, uncontrolled infections, and prolonged immune activation, failure to resolve the immune response and return to homeostasis.
In the above situations there is a failure of negative feedback mechanisms meant to prevent hyperinflammation and overproduction of inflammatory cytokines and soluble mediators: leading to excessive cytokine production with hyper inflammation in multi organ failure.
Anti-inflammatory cytokines such as  Interleukin-10 are important for antagonizing inflammatory cell populations and preventing immune hyperactivity.
Patients may have fever, fatigue, anorexia, headache, rash, diarrhea, arthralgia, myalgia, and neuropsychiatric findings.
Cytokine  induced tissue damage, acute phase physiological changes or immune cell mediated responses lead to symptoms.
Cases can progress to disseminated intravascular coagulation with vascular occlusions or catastrophic hemorrhages, dyspnea, hypoxemia, hypotension, hemostatic i balance,   vasodilatory shock, and death.
Many patients experience respiratory symptoms involving cough, tachypnea, and that can progressed to acute respiratory distress syndrome with hypoxemia and may require mechanical ventilation.
Spontaneous hemorrhage can occur with a combination of hyper inflammation, coagulopathy, and thrombocytopenia.
In severe  cases renal failure, acute liver injury, cholestasis, and stress related stress cardiomyopathy can develop.

The combination of renal dysfunction, endothelial cell death and acute phase hypoalbuminemia can lead to capillary leak syndrome and anasarca.

The process occurs as antibodies bind to the T cell receptor, activating the T cells before they are destroyed.

Th1 exaggerated inflammatory response occurs during cytokines storm.

Th1 cells produce large quantities of interferon gamma, induce delayed hypersensitivity reactions, activate macrophages and are essential for defense against intracellular pathogens.

The cytokines released by the activated T cells produce a systemic inflammatory response similar to that found in severe infection.

Th17 cells have cell function lead to auto immunity and have a major role in host defense, particularly anti-fungal infections. 

TH 17 cells can be drivers of a cytokine storm that is independent of interferon gamma.

B cells are not often associated with cytokine storm, however the cell depletion is effective in treating some cytokines storm disorders, such as human herpesvirus8 associated multicentric Caastleman’s disease: suggesting these cells are capable of initiating or propagating cytokine storm particularly when virally infected.

Iatrogenic causes of cytokines storm involve excessive T cell activation such as CAR T cell and anti-CD28 antibody therapy which point to ability to activate T cells in to initiate cytokines storm.

May be life-threatening or fatal.

Sustained production of cytokine may lead to elevated circulating levels that may be required to appropriately control some disseminated infections.
Increased levels of cytokines can have systemic effects and cause collateral damage to a vital organ system.

The systemic inflammatory response is characterized by hypotension, pyrexia and chills.

May be associated with headache, nausea, asthenia, hypotension, increased ALT, increased AST, increased bilirubin.

DIC, capillary leak syndrome, and hemagophagocytic lymphohistiocytosis/macrophage activation syndrome has been reported.

Can cause life-threatening pulmonary edema.

Neurologic toxicity associated with T-cell immunotherapy is associated with an encephalopathy.
 Neurotoxic effects are often delayed and develop several days after the onset of cytokine storm.
Laboratory findings in cytokine storm are non-specific and include elevated C reactive protein which is universally elevated and correlated with severity.
Elevations in serum inflammatory cytokines levels such as interferon gamma, interleukin-six, interleukin-10, and soluble Interleukin-2 receptor alpha, a marker for T-cell activation are usually present.
Highly elevated serum Interleukin-6 levels are found in CARMT-cell therapy including cytokine storm and several other cytokine storm disorders.
Laboratory abnormalities include commonly hypertriglyceridemia, leukocytosis, leukopenia, anemia, thrombocytopenia, and elevated ferritin and D-dimer levels.

Manifestations can be reduced by slowing the infusion, intravenous administration of an anti-histamine and a corticosteroid, and acetaminophen 500 mg by mouth 1 hour before infusion to prevent fever.

Overhydration must be corrected before the administration of the first dose.

How to manage cytokine release syndrome.

Closely monitoring for cytokine release syndrome and starting anticytokine therapy early can prevent life-threatening organ toxicities in recipients of chimeric antigen receptor (CAR) T-cell therapy.

CRS management includes direct, targeting and nonspecific immunosuppressive strategies to counter the overactive immune cells and increased cytokine levels.

Generally, patients are given tocilizumab and corticosteroids.

No evidence that early anticytokine therapy impairs antitumor response.

Cytokine release syndrome affects multiple organs, explaining its diverse symptomatology.

Evaluating a patient with cytokine storm should accomplish three goals, identifying the underlying disorder, establishing severity, and determining a clinical pathway.
All cases of suspected cytokines storm require work up for infection, and laboratory assessment of kidney and liver functions.
Laboratory evaluation of cytokines storm includes measurement of inflammatory acute-phase biomarkers: CRP, and ferritin, and blood counts should be obtained to correlate with disease activity.
Levels of serum cytokines, most prominently, interferon gamma,  are often more elevated in patients with cytokine storm dure to CAR T-cell therapy than  in patients  with sepsis induced cytokine storm, who often have higher levels of circulating Interleukin-1beta, procalcitonin, and markers of endothelial damage.

Fever and flu-like illness mark its onset of CRS.Life-threatening findings include wide pulse pressures, hypotension, ventricular strain, and capillary leak leading to pulmonary edema and hypoxia, coagulopathy, azotemia, hyperbilirubinemia, transaminitis, flushing, and rash.

Using a consistent CRS severity grading system enables physicians to treat rationally across trials and CAR T-cell therapies.

CRS severity system defines grade 1 CRS as flu-like symptoms and fever up to 41.5 degrees Celsius.

Patients with grade 1 CRS should receive antipyretics and analgesia as needed and should be monitored closely for infections and fluid imbalances.

Hypotension signifies progression beyond grade 1 CRS, and should receive no more than two to three IV fluid boluses and then should receive vasopressors.

Early treatment seems to be better, although it is not yet known if prophylactic tocilizumab or corticosteroids can prevent CRS symptoms before they start.

Grade 2 CRS defined as hypotension responsive to one low-dose pressor or to fluid therapy and hypoxia responsive to less than 40% oxygen therapy.

Patients with grade 2 CRS who also have comorbidities should receive tocilizumab – with or without corticosteroids.

Severe CRS often results from supraphysiologic release of interleukin 6, which induces not only classic IL-6 signaling but also proinflammatory trans-signaling across many cell types.

Tocilizumab reverses this process by binding and blocking the IL-6 receptor

Tocilizumab is the mainstay of treatment for severe cytokine release syndrome.

Patients with grade 3 CRS have hypotension requiring multiple or high-dose pressors and hypoxia requiring oxygen therapy.

The ultimate goal is to avoid grade 4 CRS.

Grade 4 organ toxicity, requires mechanical ventilation, and yields a poor prognosis despite vigilant supportive care, tocilizumab, and corticosteroids.

Siltuximab is an anti-IL-6 anybody approved for the treatment of Castleman’s disease, and is a proposed alternative treatment to tocilizumab.

Corticosteroids play an important role in CRS management, in addition to anti-IL-6 therapy.

Other agents to be considered, include anakinra, JAK inhibitors, cyclophosphamide, extracorporal cytokine absorption with continuous renal replacement therapy,  intravenous IgG, and anti-thymocyte globulin.

Empirical treatment for infection is warranted in patients who are febrile and neutropenic.




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