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Cytokine Release Syndrome

Introduction

A 56 year old female was brought in by her spouse for acute onset of confusion. She has metastatic kidney cancer (renal cell carcinoma with bilateral adrenal metastases as well as DVT/PE on enoxaparin) and she started an experimental drug trial with a drug and had the infusion roughly 4 days prior at the cancer hospital. Following the infusion, the patient developed chills, coughing, vomiting, increasing fatigue and confusion. She was not febrile. The patient is able to state she has back pain but otherwise provides no meaningful history. Her spouse states her urine output and stool output has decreased over the last 48 hours as well.
On exam, the patient is afebrile, heart rate 104, respiratory rate 22, pulse ox 94% (room air) and blood pressure is approximately 90/50. She is altered, somnolent and not following most commands. Her abdomen is mildly tender. CT Chest shows right sided ground glass opacities suspicious for pneumonia. Initial treatment includes IV fluids and she was started on broad spectrum antibiotics as sepsis is high on the differential

Labs
– Na 131
– K 5.3
– HCO3 18
– Cr 5.0 (recent was 1.1 to 1.5)
– AST 556
– ALT 470
– High sensitivity troponin 1658
– B-Type Natriuretic Peptide (BNP) 959
– White blood cell count 13.3
– Hemoglobin 12.
– Uric Acid 14.4
– Arterial Blood Gas (ABG): 7.23, pO2 51, pCO2 58

Oncology is consulted in the ED. They further clarify that she was diagnosed about 2 years prior, and has had a right radical nephrectomy, median sternotomy for transatrial IVC thrombectomy. She was previously treated with pembrolizumab/lenvatinib but had disease progression so she was put in the experimental trial with XTX202 (novel IL-2 meant to reduce off-target IL-2 toxicity). Oncology is concerned with severe cytokine release syndrome (CRS). They initiate Tocilizumab and dexamethasone for CRS protocol. The patient was started on rasburicase and allopurinol for hyperuricemia. The patient is placed on BiPap for hypercapnic and hypoxic respiratory failure and is admitted to the Medical ICU.

Discussion

Cytokine Release syndrome (CRS) is a systemic inflammatory response triggered by infections and certain drugs. The term “cytokine release syndrome” was first coined in the early 90s with the introduction of the anti-T-cell antibody muromonab-CD3 (OKT3)1Chatenoud L , Ferran C , Reuter A , Legendre C , Gevaert Y , Kreis H , et al . Systemic reaction to the anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-gamma [corrected]. N Engl J Med. 1989;320:1420–1421. doi:10.1056/NEJM198905253202117 Since then, CRS has been described after an infusion of a wide variety of antibody-based therapies including rituximab, brentuximab among others as well as some cancer drugs such as oxaliplatin and lenalidomide. CRS has also been described in stem cell transplant and graft-versus-host disease. 2Abboud R , Keller J , Slade M , DiPersio JF , Westervelt P , Rettig MP , et al . Severe cytokine-release syndrome after T cell–replete peripheral blood Haploidentical donor transplantation is associated with poor survival and anti–IL-6 therapy is safe and well tolerated. Biol Blood Marrow Transplant. 2016;22:1851–1860. doi:10.1016/j.bbmt.2016.06.010 pmcid:5070661 It has also been proposed as a pathomechanism of severe viral infections like influenza.
Clinical Manifestations of Cytokine Release Syndrome
Clinical Manifestations of Cytokine Release Syndrome1Shimabukuro-Vornhagen, Alexander, et al. "Cytokine release syndrome." Journal for immunotherapy of cancer 6 (2018): 1-14.
CRS can present along a continuum of disease ranging from mild and flu-like to severe and life threatening. Mild symptoms include fever, fatigue, headache, rash, arthralgia, myalgias. In more severe cases, hemodynamic instability begins to manifest including hypotension, hyperthermia and subsequently uncontrolled inflammatory response. Patients may require vasopressor agents, develop disseminated intravascular coagulation and multi organ failure. Laboratory findings cytopenia (anemia, thrombocytopenia, leukopenia), acute liver injury, acute kidney injury, coagulation dysfunction and elevated inflammatory markers.

Differential Diagnosis
– Severe sepsis/ septic shock
– Cardiogenic shock
– Cytokine Release Syndrome
– Tumor Lysis Syndrome
– Immune effector cell-associated neurotoxicity syndrome (ICANS)
– Multi-organ Dysfunction Syndrome
– Hemophagocytic Lymphohistiocytosis (HLH)/ Macrophage Activation Syndrome (MAS)

Epidemiology depends largely on the type of immunotherapeutic agent being administered. Onset occurs from days to weeks after infusion. Most monoclonal antibodies have a low incidence, however, the T-cell engaging immunotherapies carry a much higher risk of CRS. The risk of CRS is influenced by factors related to the type of therapy, the underlying disease, and characteristics of the patients. The so-called “first-dose effect” can be seen where patients have a severe response to the first administration but not subsequently.3Klinger M , Brandl C , Zugmaier G , Hijazi Y , Bargou RC , Topp MS , et al . Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012;119:6226–6233. doi:10.1182/blood-2012-01-400515 The strength of the T cell activation and degree of T cell expansion seems to correlate with severity. Children are at higher risk of developing CRS.4Lee DW , Kochenderfer JN , Stetler-Stevenson M , Cui YK , Delbrook C , Feldman SA , et al . T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–528. doi:10.1016/S0140-6736(14)61403-3
Reported inducers of cytokine release syndrome
Reported inducers of cytokine release syndrome2Shimabukuro-Vornhagen, Alexander, et al. "Cytokine release syndrome." Journal for immunotherapy of cancer 6 (2018): 1-14.
The pathophysiology of CRS is incompletely understood. IL-6, IL-10 and interferon (IFN)-Υ are the core cytokines typically found elevated in CRS. In T-cell targeting therapies, IFN-Υ is released en masse by the activated T-cells themselves. Subsequently, additional immune cells (macrophages) release a further cascade of cytokines causing the systemic symptoms. IL-6 seems to be key to CRS as it is typically highly elevated in these patients and contributes to many of the key symptoms.5Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154-7. Teachey et al found that IL-6, soluble IL-6 receptor, IFN-γ, and sgp130 correlated with the risk of severe CRS6Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;
the pathomechanism of cytokine release syndrome
the pathomechanism and grading system of cytokine release syndrome3Shimabukuro-Vornhagen, Alexander, et al. "Cytokine release syndrome." Journal for immunotherapy of cancer 6 (2018): 1-14.
Management of CRS remains challenging given the novelty of the immunotherapies which induce the syndrome and the many subsequent unanswered questions. Current treatment guidelines are based on expert opinion. The national cancer institute has developed a CRS grading system (see illustration). In critically ill patients, management requires collaboration of emergency medicine, critical care, oncology, neurology and radiology.
Low grade CRS is treated symptomatically with antihistamines, antipyretics and fluids. Given the differential, additional diagnostic testing should be performed and admission may be indicated depending on the clinical picture. If infection can not be ruled out, empiric antibiotics should be administered.
Life threatening CRS requires aggressive management in the intensive care unit. Tocilizumab binds IL-6 is considered the gold standard for treatment of CRS. Significant resolution of symptoms can occur within the first few hours up to two days after administration. Corticosteroids are indicated in neurological manifestations of CRS as tocilizumab does not cross the blood brain barrier. In patients who do not respond to these two agents, TNF-α blockade (etancercept) or siltuximab (IL-6 monoclonal antibody) should be considered.7Chen F , Teachey DT , Pequignot E , Frey N , Porter D , Maude SL , et al . Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods. 2016;434:1–8. doi:10.1016/j.jim.2016.03.005 pmcid:5490247 Other immunosuppressive agents have been used in case reports. Critically ill patients should also be placed on empiric antibiotics pending cultures and require other supportive measures as indicated.

Case Conclusion

The patient’s mentation improved with the treatment for CRS. By the time of discharge she was alert and oriented and only complaining of back pain. She was found to have a new frontoparietal brain mets and developed a facial droop while in the hospital. By hospital day 4 she had improved so much that she was resuming a normal diet and oral medications. No further interventions were made given how quickly she improved. Attempts were made to transfer the patient to the cancer hospital, however she improved enough for discharge prior to transfer. She had close follow up with her oncologist following discharge.

3 Key Points

  1. Cytokine Release syndrome (CRS) is a systemic inflammatory response triggered by infections and certain immune modulating drugs
  2. Symptoms can range from mild and flu-like to severe and critical and life threatening with multi organ dysfunction and hemodynamic instability
  3. Treatment is the IL-6 antagonist Tocilizumab which seems to be the key mediator of CRS
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