Presentation
Presented at: Oncology Nursing Society 40th Annual Congress; April 22-26, 2015; Orlando, FL. [theoncologynurse.com]
Neurotoxicity, presenting as headache, altered mental status, delirium, aphasia, hallucinations, or seizures, is now often considered an event separate from CRS, he said. [mdedge.com]
Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T-cells [published online February 26, 2019]. [cancertherapyadvisor.com]
Fc receptors present on the surface of antibody opsonised target cells bind with Fc region of antibody followed by signal transduction and massive release of cytokines. Drugs like rituximab and alemtuzumab act via this mechanism. [microbiologyjournal.org]
Case Presentation: A 43-year-old male with advanced gastric cancer was treated with nivolumab as a third-line chemotherapy. He had no history of allergies. [karger.com]
Entire Body System
- Inflammation
Now, this is seen in haploidentical transplants where there is only a half match between donor and recipient, and there is an outpouring of inflammation due to this recognition. [managingmyeloma.com]
MONMOUTH JUNCTION, N.J., Sept. 16, 2019 / PRNewswire / — CytoSorbents Corporation (NASDAQ: CTSO), a critical care immunotherapy leader commercializing its CytoSorb ® blood purification technology to treat deadly inflammation in critically-ill and cardiac [cytosorbents.com]
However CRP is also increased in various infections, so it lacks specificity on demarking infections associated with inflammation from infectious inflammation 27. [microbiologyjournal.org]
IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010; 6 (4):232–241. doi: 10.1038/nrrheum.2010.4. [ PubMed ] [ CrossRef ] [ Google Scholar ] [ncbi.nlm.nih.gov]
This pattern of organ impairment may be consistent with a generalized multiorgan response to inflammation or critical illness. 9,10 However, the rapid onset and concordance of the lung injury among patients seemed unusual, and in the presence of high [nejm.org]
- Weakness
The nurse should tell the patient to let her know right away if she experiences any of the following symptoms: weakness, dizziness, shortness of breath, hives, swelling of the lips, low blood pressure, scratchy throat, itchiness, nausea, or hoarse voice [theoncologynurse.com]
Mental status changes, delirium Aphasia Hallucinations Dysmetria Seizures, altered gait Skin rashes CRES Early signs: diminished attention, language disturbance, impaired handwriting Agitation, aphasia Somnolence Tremors Severe signs Seizures Motor weakness [pepidconnect.com]
Renal Electrolyte imbalances, azotemia, renal injury due to reduced renal perfusion [11,15] Nervous Headache, confusion, hallucination, dysphasia, tremor, seizure, facial nerve palsy, altered gait [8] Musculoskeletal Elevated creatine kinase, myalgias, weakness [microbiologyjournal.org]
Over the next 30 days, all patients had generalized desquamation (most marked in Patients 5 and 6) and muscle weakness on discharge from the ICU. [nejm.org]
- Malaise
Toxicity See Evidence for grading organ toxicity and definitions of high-dose pressors Symptoms not life-threatening; only symptomatic treatment required (fever, nausea, fatigue, headache, myalgias, malaise) Moderate intervention required for response [mdcalc.com]
His symptoms, including high fever, tachycardia, appetite loss and malaise, without any obvious infection, were similar to the symptoms of CRS that we have observed after TCR-Gene Transduced T Cell Transfer therapy [ 5 ]. [karger.com]
Table (1): Symptoms associated with CRS and sites of body affected Organ systems affected Symptoms Constitutional Fever, headache, anorexia, malaise, myalgias, rigors [11, 12] Integument Skin rashes [11] Blood Cytopenias (anaemia, leucopenia, lymphopenia [microbiologyjournal.org]
Some patients experience a severe inflammatory syndrome, including Vascular leak Hypotension Pulmonary edema Coagulopathy Results in multiorgan system failure CRES Confusion, disorientation, delirium Physical Exam/Signs CRS Constitutional High fever, malaise [pepidconnect.com]
- Sepsis
On behalf of the Hellenic Sepsis Study Group, Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. [scielo.cl]
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992 ;20: 864 - 874 9. [nejm.org]
CRS. [2] It appears that interleukin 6 is a key mediator of CRS. [2] Severe CRS or cytokine storms can occur in a number of infectious and non-infectious diseases including graft-versus-host disease (GVHD), acute respiratory distress syndrome (ARDS), sepsis [en.wikipedia.org]
The third international consensus definitions for Sepsis and septic shock (Sepsis-3) JAMA. 2016; 315 :801–810. doi: 10.1001/jama.2016.0287. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ] 48. [ncbi.nlm.nih.gov]
- Hypoxemia
CRS causes various symptoms, such as fever, hypotension, hypoxemia, tachycardia, liver injury and neurological disorders. [karger.com]
Perform tests before initiation of CAR-T-cell therapy if infection suspected Delay CAR-T cell therapy until infection has been controlled/ruled out Cardiovascular Tachycardia/hypotension Capillary leak Cardiac dysfunction Respiratory Tachypnea, hypoxemia [pepidconnect.com]
Subsequent Events After an initial recovery, Patient 6 became hypotensive (blood pressure, 65/40 mm Hg), and 12 hours after infusion, he had metabolic acidosis and marked respiratory distress with hypoxemia that was refractory to treatment with supplemental [nejm.org]
Respiratoric
- Respiratory Distress
However, some patients may exhibit more severe symptoms which may cause life-threatening complications, such as cardiac dysfunction, acute respiratory distress syndrome or multiple organ failure. [creative-biolabs.com]
However, some patients experience more severe symptoms that may lead to potentially life-threatening complications such as cardiac dysfunction, acute respiratory distress syndrome or multi-organ failure. 1 About Actemra/RoActemra (tocilizumab) Actemra [roche.com]
Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995 ;151: 293 - 301 10. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ. [nejm.org]
distress syndrome (ARDS), sepsis, Ebola, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS). [7] Hemophagocytic lymphohistiocytosis and Epstein-Barr virus-related hemophagocytic lymphohistiocytosis are caused by extreme elevations [en.wikipedia.org]
distress and renal dysfunction Ultimately required dialysis Following Sx onset (day 1), all subjects were treated with corticosteroids Within 3 days, cytokines returned to normal levels Two subjects experienced prolonged organ dysfunction despite return [pepidconnect.com]
- Dyspnea
CRS is characterized by symptoms such as fever, nausea, chills, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea. [theoncologynurse.com]
Cytopenias (anaemia, leucopenia, lymphopenia, thrombocytopenia), increase in D-dimer, hypofibrinogenemia [10, 13] Cardiovascular Mild: Tachycardia with fever Severe: Hypotension, decreased cardiac output, arrhythmias, cardiac arrest [14,15] Pulmonary Hypxia, dyspnea [microbiologyjournal.org]
[…] had further signs of respiratory deterioration: all six had signs of tachypnea, use of accessory muscles, inability to complete spoken sentences, and bilateral pulmonary infiltrates on chest radiography ( Figure 2A and 2B ), and two had symptoms of dyspnea [nejm.org]
- Pneumonia
Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia. [scielo.cl]
Patient 2 was also successfully treated for presumed nosocomial Klebsiella pneumoniae bacteremia, isolated on day 6 after TGN1412 infusion. Patients 5 and 6 had a more complex course, as detailed in the Supplementary Appendix. [nejm.org]
Gastrointestinal
- Loss of Appetite
[…] of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rashes, fast breathing, rapid heartbeat, low blood pressure, seizures, headache, confusion, delirium, hallucinations, tremor, and loss of coordination. [2] Lab tests and clinical monitoring [en.wikipedia.org]
Cardiovascular
- Hypotension
His system defines grade 2 CRS as hypotension responsive to one low-dose pressor or to fluid therapy and hypoxia responsive to less than 40% oxygen therapy. [mdedge.com]
mild respiratory symptoms (hypoxia), grade 2 organ toxicity Moderate therapeutic interventions required For hypotension: -fluids or vasopressors (Low Dose) For hypoxia: – low flow oxygen ( 3 High grade hypotension, hypoxia, grade 3 organ toxicity like [microbiologyjournal.org]
CRS was characterized by high fevers, encephalopathy, hypotension, hypoxia, hepatic dysfunction, and evidence of coagulopathy, and resolved after infusion of the interleukin‐6 inhibitor tocilizumab and corticosteroids. [onlinelibrary.wiley.com]
Perform tests before initiation of CAR-T-cell therapy if infection suspected Delay CAR-T cell therapy until infection has been controlled/ruled out Cardiovascular Tachycardia/hypotension Capillary leak Cardiac dysfunction Respiratory Tachypnea, hypoxemia [pepidconnect.com]
Symptoms not life-threatening; only symptomatic treatment required (fever, nausea, fatigue, headache, myalgias, malaise) Moderate intervention required for response: oxygen requirement Aggressive intervention required for response: oxygen requirement ≥40%, hypotension [mdcalc.com]
- Tachycardia
CRS causes various symptoms, such as fever, hypotension, hypoxemia, tachycardia, liver injury and neurological disorders. [karger.com]
CRS is characterized by symptoms such as fever, nausea, chills, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea. [theoncologynurse.com]
Among patients with r/r ALL who had CRS, key manifestations included fever (96%), hypotension (67%), hypoxia (20%), and tachycardia (30%). CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. [hcp.novartis.com]
Symptoms Constitutional Fever, headache, anorexia, malaise, myalgias, rigors [11, 12] Integument Skin rashes [11] Blood Cytopenias (anaemia, leucopenia, lymphopenia, thrombocytopenia), increase in D-dimer, hypofibrinogenemia [10, 13] Cardiovascular Mild: Tachycardia [microbiologyjournal.org]
Perform tests before initiation of CAR-T-cell therapy if infection suspected Delay CAR-T cell therapy until infection has been controlled/ruled out Cardiovascular Tachycardia/hypotension Capillary leak Cardiac dysfunction Respiratory Tachypnea, hypoxemia [pepidconnect.com]
Skin
- Skin Rash
Table (1): Symptoms associated with CRS and sites of body affected Organ systems affected Symptoms Constitutional Fever, headache, anorexia, malaise, myalgias, rigors [11, 12] Integument Skin rashes [11] Blood Cytopenias (anaemia, leucopenia, lymphopenia [microbiologyjournal.org]
rashes CRES Early signs: diminished attention, language disturbance, impaired handwriting Agitation, aphasia Somnolence Tremors Severe signs Seizures Motor weakness Incontinence Mental obtundation Increased ICP Papilledema Cerebral edema Biphasic First [pepidconnect.com]
Neurologic
- Confusion
However, a potential limitation to the use of these treatments include 2 relatively common adverse effects: cytokine release syndrome (CRS) and neurotoxicity, with symptoms of the latter ranging from mild confusion to cerebral edema with coma and, potentially [cancertherapyadvisor.com]
[…] cytokines from cells targeted by antibody/immune effector cells recruited to the area Most common toxicity associated with CART-19 and blinatumomab CAR-T Related Encephalopathy Syndrome (CRES) Second most occurring event Toxic encephalopathy/neurotoxicity Confusion [pepidconnect.com]
[…] the six subjects experienced severe CRS. [2] [4] Symptoms [ edit ] Symptoms include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rashes, fast breathing, rapid heartbeat, low blood pressure, seizures, headache, confusion [en.wikipedia.org]
[…] mechanical ventilation required in some cases [5,16] Gastrointestinal Diarrhoea, abdominal pain, colitis, hyperbilirubinemia, transaminitis [17,18] Renal Electrolyte imbalances, azotemia, renal injury due to reduced renal perfusion [11,15] Nervous Headache, confusion [microbiologyjournal.org]
- Dizziness
The nurse should tell the patient to let her know right away if she experiences any of the following symptoms: weakness, dizziness, shortness of breath, hives, swelling of the lips, low blood pressure, scratchy throat, itchiness, nausea, or hoarse voice [theoncologynurse.com]
It causes symptoms such as: fever (high temperature) dizziness due to low blood pressure difficulty breathing This syndrome might happen in the first week of treatment. You can have treatment to reverse the syndrome. [about-cancer.cancerresearchuk.org]
The most common neurological toxicities observed in r/r ALL studies included headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%), sleep disorders (10%), dizziness (6%), tremor (9%), and peripheral neuropathy (4%). [hcp.novartis.com]
- Asthenia
CRS is characterized by symptoms such as fever, nausea, chills, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea. [theoncologynurse.com]
Workup
Serum
- Cytopenia
Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. [hcp.novartis.com]
HLH is a rare immune disorder characterized by cytopenias, prolonged fever, hyperferritinemia, hypertriglyceridemia, spleenomegaly, coagulopathy, decreased efficacy of natural killer cells and elevation in cytokine level 36. [microbiologyjournal.org]
Treatment
It confirms that Actemra® does have treatment effect on such symptom. [creative-biolabs.com]
Actemra is the first approved treatment for CRS in this setting. In Japan, Actemra is also approved for the treatment of Castleman’s Disease and Takayasu Arteritis. [roche.com]
Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. [e-cancer.fr]
Children and young people may be able to travel to England for treatment. This treatment has not been approved in Scotland for adults with lymphoma. [about-cancer.cancerresearchuk.org]
CytoSorb ® has been used in more than 67,000 human treatments to date. [cytosorbents.com]
Prognosis
The ultimate goal is to avoid grade 4 CRS, he said, which involves grade 4 organ toxicity, requires mechanical ventilation, and yields a poor prognosis despite vigilant supportive care, tocilizumab, and corticosteroids. Dr. [mdedge.com]
T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J. Clin. Oncol. 36(22), 2267–2280 ( 2018 ). Crossref, Medline, CAS, Google Scholar 16. [futuremedicine.com]
Etiology
Major efforts are ongoing to characterize the pathogenesis and etiology of CRS and CRES. Mouse models have been established to… CONTINUE READING [semanticscholar.org]
[…] levels to baseline CRES : biphasic manifestation of toxic encephalopathy Mechanism yet to be determined; 2 postulates Passive diffusion of cytokines into the brain (e.g., IL-6, IL-15) Migration of T-cells into the CNS (detection of CAR-T cells in CSF) Etiology [pepidconnect.com]
Epidemiology
CRS and guide dosing for Phase I trials, and regulatory agencies expect to see results of such tests in investigational new drug applications. [4] [10] A modified chandler loop model can be used as a preclinical tool to assess infusion reactions. [1] Epidemiology [en.wikipedia.org]
T-cells into the CNS (detection of CAR-T cells in CSF) Etiology/Risk Factors CRS has classically been associated with Therapeutic mAb infusions Most notably anti-CD3 (OKT3) Anti-CD52 (alemtuzumab) 19 anti-CD20 (rituximab) CD28 super-agonist, TGN1412 Epidemiology [pepidconnect.com]
Pathophysiology
Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. [scielo.cl]
Neurotoxicity: temporal & pathophysiological relationship with CRS Neurotoxicity is a life-threatening complication associated with CAR T cells and BiTEs. [futuremedicine.com]
CAR-T-cell-related encephalopathy syndrome (CRES) Fulminant CRS may be life-threatening CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH) Also known as macrophage-activation syndrome (MAS) Management of CRS and CRES can be life saving Pathophysiology [pepidconnect.com]
Prevention
Earlier seems to be better, although we do not yet know if prophylactic tocilizumab or corticosteroids can prevent CRS symptoms before they start.” For hypotensive patients on pressors, Dr. [mdedge.com]
Management Monitoring and aggressive supportive care should be considered in order to prevent irreversible end-organ damage. Consider ICU setting (1:1 nursing care). Consider involving expert consultative services. [mdcalc.com]
Recently, considerable developments have been achieved with regard to the prevention or control of this syndrome. In this review it is aimed to summarize the clinical approach to cytokine release syndrome and associated conditions. [journalofoncology.org]
It binds to the IL-6 receptor, preventing IL-6 from activating end-stage cells or endothelial cells, inflammatory cells, and a variety of things that can be upregulated in terms of inflammation by IL-6. [managingmyeloma.com]
Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. [e-cancer.fr]