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Cancer Immunotherapy Related Adverse Events (irAEs)

This bedside tool is available in our emPOC app. Available exclusively to ACEP Members.

Section IconHistory & Physical
Assess Clinical Stability
Acutely unstable presentation -> resuscitate as necessary
If on immunotherapy in the past year (immune checkpoint inhibitor [ICI]), Chimeric Antigen Receptor T cell therapy [CAR T) consider an immune related adverse event (irAE).
Chief Complaint/History of Presentation
Immune related adverse events (irAE) can involve ANY organ system and can mimic common emergency and autoimmune conditions. Cardiopulmonary and neurologic adverse events have highest mortality.
Delayed toxicity is the rule, can occur weeks, months or even over a year after treatment.
Clinical syndromes/symptoms related to immunotherapy type, organ system can overlap and co-exist. Abbreviations available in glossary.
Endocrine – nonspecific fatigue, electrolyte disturbances, nausea/vomiting. Vital Sign abnormalities
Adrenalitis- adrenal insufficiency
Thyroiditis- thyrotoxicosis or hypothyroidism
Diabetes Mellitus (DM) +/- Diabetic Ketoacidosis (DKA)
Hypophysitis (Pituitary)- headache, multiple endocrinopathies
Parathyroiditis - rare
Cardiac- chest pain, short of breath, palpitations, syncope-high mortality
Myocarditis +/- Congestive Heart Failure, Arrythmia
Pericarditis +/- effusion
Thyrotoxicosis
Thromboembolism (DVT/PE, MI)
Pulmonary- cough, short of breath. Common, high mortality
Pneumonitis
Sarcoid like granulomas
Pleural effusion
Gastrointestinal - abdominal pain, vomiting, diarrhea, jaundice
Pancreatitis
Diarrhea / colitis
Hepatitis
Enteritis +/- Small Bowel Obstruction, perforation
Renal- often asymptomatic, but nephrotic symptoms (edema) may occur
Nephritis (hematuria, proteinuria) +/- Acute Kidney Injury (AKI)
Dermatologic- may include mouth and hair symptoms
Pruritus without rash
Maculopapular rash
Mucositis
Alopecia
Bullous lesions
Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)
Ocular – visual symptoms, eye pain
Uveitis
Episcleritis
Blepharitis
Extraocular muscle myopathy
Optic neuritis
Neurological-rare, high morbidity and mortality
Central Nervous System: headache +/- altered mental status, seizure, stroke
  • Aseptic meningitis
  • Encephalitis
  • ICANS*- Immune Effector Cell-Associated Neurotoxicity syndrome from CAR-T*
  • CRS* (Cytokine Release Syndrome): common, from CAR T
  • HLH* -(Hemophagocytic Lymphohistiocytosis): rare, deadly, from ICI
  • RPLS*-Reversible Posterior Leukoencephalopathy Syndrome (AKA PRES-posterior reversible encephalopathy syndrome)
  • Thromboembolism (CVA)
Cranial nerve/Spine/Neuromuscular weakness/sensory loss
  • Myasthenia gravis
  • Transverse myelitis
  • Myositis (can be associated with myocarditis and myasthenia gravis)
  • Guillain-Barre syndrome
  • Peripheral and autonomic neuropathies
Hematologic-abnormal bleeding, weakness, fatigue, petechiae, infection
Autoimmune hemolytic anemia
TTP - Acquired thrombotic thrombocytopenic purpura,
HUS- hemolytic uremic syndrome
Neutropenia/lymphopenia
ITP - Immune thrombocytopenia
PRCA *- Pure Red Cell Aplasia
Aplastic anemia (2 or 3 cell line involvement)
CRS* or HLH *
Rheumatological- joint pains, swelling, myalgias
Arthralgia without swelling
Rheumatoid arthritis
Sicca (Sjogren’s) syndrome
Polymyalgia
Myositis (often associated with myocarditis and myasthenia gravis)
Thromboembolism (DVT)
Severe Multi-organ symptoms – fever, tachycardia +/- hypotension, neuro, hepatic, renal, GI and cardiopulmonary complaints
Thyroid Storm
CRS* or HLH*
Review past medical history/medications
Broaden differential to include immune adverse event if on immunotherapy in the past year.
Obtain detailed oncology history
Current cancer status: new diagnosis, active treatment, surveillance, remission
Obtain treatment history:
  • Radiation Treatments
  • Surgical History
  • Cytotoxic Chemotherapy
Immunotherapy within the past year. Learn More (PDF)
Immune checkpoint inhibitors (ICI)
  • PD-1
    • Pembrolizumab (Keytruda)
    • Nivolumab (Opdivo)
    • Cemiplimab (Libtayo)
  • PDL-1
    • Atezolizumab (Tecentriq)
    • Avelumab (Bavencio)
    • Durvalumab (Imfinzi)
  • CTLA4
    • Ipilimumab (Yervoy)
CAR T - T cell infusion
  • Tisagenlecleucel (Kymriah™)
  • Axicabtagene ciloleucel (Yescarta™)
  • Brexucabtagene autoleucel (Tecartus™)
  • lisocabtagene maraleucel (Breyanzi®)
  • Idecabtagene vicleucel (Abecma®)
Bi-specific T-cell engagers (BITE) - Blinatumomab (Blincyto®)
Prior autoimmune conditions increase chances of ICI toxicities.
History of previously diagnosed & treated IRAEs
Patient Information sources:
  • Targeted chart review of oncology notes if available
  • Ask patient if they have any treatment wallet cards
  • Identify patient’s treating oncologist
Review Physical Exam & Vital Signs
Complete targeted exam
  • Attention to abnormal vital signs, pulse oximetry, mental status
  • Abnormal heart and lung sounds
  • Subtle weakness in cranial nerves or limbs
  • Skin/mouth for cyanosis, hypoperfusion, petechiae, bullae, jaundice
  • Evaluate access sites/central venous access
References
  1. Yeung SJ, Qdaisat A, Chaftari P, et al. Diagnosis and management of immune-related adverse effects of immune checkpoint therapy in the emergency department. JACEP. 2020;1:1637-59.
  2. Hryniewicki AT, Wang C, Shatsky RA, Coyne CJ. Management of Immune Checkpoint Inhibitor Toxicities: A Review and Clinical Guideline for Emergency Physicians. J Emerg Med. 2018 Oct;55(4):489-502. doi: 10.1016/j.jemermed.2018.07.005. Epub 2018 Aug 16. PMID: 30120013.
  3. Cooksley, T; Stutman, R; Klotz, A. Emergency management of immune-related toxicity, Current Opinion in Oncology: July 2020 - Volume 32 - Issue 4 - p 274-281
  4. Girotra M, Hansen A, Farooki A, Byun DJ, Min L, Creelan BC, Callahan MK, Atkins MB, Sharon E, Antonia SJ, West P. The current understanding of the endocrine effects from immune checkpoint inhibitors and recommendations for management. JNCI Cancer Spectrum. 2018 Jul;2(3):pky021.
  5. Win MA, Thein KZ, Qdaisat A, Yeung SCJ. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. The American journal of emergency medicine. 2017;35(7):1039.e5-1039.e7. doi:10.1016/j.ajem.2017.02.048
  6. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71:1755-1764.
  7. Bonaca MP, Olenchock BA, Salem JE, et al. Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology. Circulation. 2019;140:80-91.
  8. Giustozzi M, Becattini C, Roila F, Agnelli G, Mandalà M. Vascular events with immune checkpoint inhibitors in melanoma or non-small cell lung cancer: A systematic review and meta-analysis. Cancer treatment reviews. 2021;100:102280-102280. doi:10.1016/j.ctrv.2021.102280
  9. Chuzi S, Tavora F, Cruz M, et al. Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis. Cancer Manag Res. 2017;9:207-213.
  10. Rajha E, Chaftari P, Kamal M, Maamari J, Chaftari C, Yeung S-CJ. Gastrointestinal adverse events associated with immune checkpoint inhibitor therapy. Gastroenterol Rep. 2020;8(1):25-30.
  11. Izzedine H, Mateus C, Boutros C, et al. Renal effects of immune checkpoint inhibitors. Nephrol Dial Transplant. 2017;32:936-942.
  12. Sibaud V. Dermatologic Reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. 2018;19:345-361.
  13. Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint inhibitor immune therapy: systemic indications and ophthalmic side effects. Retina. 2018;38:1063-1078.
  14. Reynolds KL, Guidon AC. Diagnosis and management of immune checkpoint inhibitor-associated neurologic toxicity: illustrative case and review of the literature. Oncologist. 2019;24:435-443.
  15. Rogers BB, Zawislak C, Wong V. Management of Hematologic Adverse Events Associated With Immune Checkpoint Inhibitors. J Adv Pract Oncol. 2021 May;12(4):392-404.
  16. Moreira A, Loquai C, Pfohler C, et al. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019;106:12-23.
  17. Gupta R, Roach C, Hryniewicki AT, Vilke GM, Shatsky RA, Coyne CJ. Management of Chimeric Antigen Receptor (CAR) T-Cell Toxicities: A Review and Guideline for Emergency Providers. J Emerg Med. 2020 Jul;59(1):61-74.
  18. Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M. et al. Cytokine release syndrome. j. immunotherapy cancer 6, 56 (2018).
  19. Wang DY, Salem J, Cohen JV, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018;4(12):1721–1728. doi:10.1001/jamaoncol.2018.3923
  20. Bischof JJ, Presley CJ, Caterino JM. Addressing New Diagnostic and Treatment Challenges Associated with a New Age of Cancer Treatment. Ann Emerg Med. 2019 Jan;73(1):88-90.
  21. Sengsayadeth, S, Savani, BN, Oluwole, O, Dholaria, B. Overview of approved CAR-T therapies, ongoing clinical trials, and its impact on clinical practice. eJHaem. 2022; 3(Suppl. 1): 6– 10. https://doi.org/10.1002/jha2.338
Section IconTesting
Common ED test results that may suggest irAE - interpret along with clinical presentation and other supporting evidence.
Immune-oncology terms with “*” such as CRS and HLH explained further in glossary definitions document.
CBC abnormalities (rare, unlike in chemotherapy)
Anemia-isolated
  • Autoimmune hemolytic anemia (most common heme irAE)
  • PRCA (Pure Red Cell Aplasia)
Thrombocytopenia-isolated
  • ITP -Immune thrombocytopenia)
  • TTP (Thrombotic thrombocytopenic purpura) or HUS (Hemolytic Uremic Syndrome) without hemolytic anemia. AKI seen with both. Fever and neurologic changes seen with TTP.
Neutropenia/ lymphopenia-isolated (antibodies/macrophages target marrow leukocytes)
Multiple cytopenias
  • TTP with anemia and thrombocytopenia, + Fever, AKI, or neurological symptoms
  • HUS with anemia and thrombocytopenia –Diarrhea, no fever or neuro symptoms, otherwise like TTP
  • Aplastic anemia
  • HLH* (Hemophagocytic lymphohistiocytosis) or CRS* (cytokine release syndrome): Similar, resemble severe sepsis-Fever, tachy, +/- hypotension, multi-organ dysfunction, splenomegaly, elevated ferritin, coagulopathy, low fibrinogen
PT/INR elevated
Immune hepatitis with liver failure
Acquired hemophilia
CRS* with DIC due CAR-T
HLH* with DIC due to ICI
CRP, ferritin, lactate elevated, fibrinogen low
CRS
HLH
Hyponatremia
Adrenal insufficiency/hypophysitis
Hypothyroidism
Hyperkalemia
Adrenal insufficiency/hypophysitis
Nephritis with AKI
Rhabdomyolysis/myositis
Diabetic Ketoacidosis (DKA)
Hemolysis
Hypokalemia
Colitis
Nephritis
Metabolic acidosis (low HCO3)
Colitis
Immune type 1 DM with DKA
Nephritis/AKI
CRS*, HLH* (lactic acidosis)
Hyperglycemia +/- anion gap acidosis
Immune Type 1 DM +/-DKA
Hyperosmolar hyperglycemia
Hypoglycemia
Adrenal insufficiency
Myxedema coma
AKI (acute kidney injury)
Nephritis
Rhabdomyolysis/myositis
TTP/HUS
CRS*, HLH*
Hypercalcemia
Sarcoid like syndromes
Hypocalcemia
Hypoparathyroidism
LFT (liver function test)
AST/ALT, Alk P, GGT, +/- T. bilirubin - hepatitis. CRS*, HLH*.
Hypoalbuminemia, otherwise normal LFT – nephritis with nephrotic syndrome
Isolated AST/ALT – consider rhabdomyolysis (add CPK)
Isolated elevated LDH– hemolysis (attention indirect bilirubin), rhabdomyolysis (add CPK)
Elevated lipase – immune pancreatitis
Urinalysis
Urine ketones -DKA, starvation due to GI toxicity
Urine protein– nephritis/nephrotic syndrome
Urine blood – nephritis, HUS, myositis (if no RBCs on microscopy)
Elevated CPK, Troponin, BNP
Myocarditis
Consider concomitant myositis and myasthenia gravis
AKI can artificially elevate these.
Hypoxemia on Pulse Ox or ABG
Pneumonitis
Myocarditis with CHF
CRS*
HLH*
EKG with conduction block, tachy- or brady-dysrhythmias, ST changes, electric alternans
Myocarditis
Pericarditis +/- effusion
Thyrotoxicosis or hypothyroidism
Electrolyte disturbances above
Chest x-ray/CT chest infiltrates
Pneumonitis
Myocarditis with CHF
CRS or HLH with pulmonary involvement
Clinical Syndromes: Presentations that may prompt additional testing considerations and interpretations.
The diagnostic workup should be broad, with consideration of other life-threatening illnesses based on the judgment of the treating physician. The information presented is not intended to suggest a standard of care. Once IRAE is identified – contact consulting oncologist or primary oncologist. Immune-oncology terms with “*” such as CRS and HLH explained further in glossary definitions document.
Undifferentiated shock/hypotension- consider:
Cortisol - (adrenal insufficiency)
EKG/POC echo - (pericarditis with tamponade)
CRP, ferritin, lactate PT/INR (High); low fibrinogen - CRS* or HLH*
TSH/TFT’s - hypothyroidism
Sepsis like syndrome (fever, tachycardia, +/- hypotension)- consider:
High CRP, ferritin, lactate, PT/INR; low fibrinogen - CRS* or HLH*
TSH/TFT’s thyrotoxicosis
Cytopenia(s)– CRS*,HLH*, neutropenic fever, TTP
Short of breath/hypoxia – consider
High resolution CT chest (pneumonitis)
EKG, Echocardiogram, cardiac MRI (myocarditis)
High CRP, ferritin, lactate, PT/INR; low fibrinogen - (CRS* or HLH*
Bedside PFT/NIF/VC - (myasthenia, myositis, GBS)
Short of breath without hypoxia– consider:
Severe metabolic acidosis (DKA, AKI, CRS*, HLH*)
Severe anemia (hemolytic anemia, aplastic anemia, TTP, HLH*, CRS*)
Bedside PFT/NIF/VC - (myasthenia, myositis, guillain barre)
Altered mental status- standard workup, including ammonia and head CT, then consider:
AKI or LFT’s - (metabolic encephalopathy, CRS*,HLH*)
Abnormal CBC +/- AKI – peripheral smear and labs for hemolysis (TTP,HUS)
High CRP, ferritin, lactate, PT/INR; low fibrinogen – CRS*, HLH*
MRI – specific findings in irAE encephalitis, RPLS*, ICANS*
ICE tool if recent Car T-cell treatment - ICANS
EEG- non-convulsive seizures can mimic altered mental status.
LP often abnormal with encephalitis/meningitis–CSF lymphocytosis and elevated protein.
Headache (with normal mental status)– CT scan, LP to rule out other causes as indicated. If severe or associated with hypotension, fatigue, meningismus, consider:
TSH/T4, cortisol +/- (if available) ACTH, LH, FSH, Prolactin, testosterone, estradiol - Hypophysitis with panhypopituitarism.
MRI - best way to image Hypophysitis
LP abnormal in irAE meningitis – CSF lymphocytosis and elevated protein.
MRI might show meningeal enhancement in irAE meningitis (not common).
Neurological motor weakness/muscle pain – determine CNS vs cranial nerve vs spine vs peripheral etiology; workup as usual and consider
CPK, aldolase - (myositis, can be associated with myocarditis and myasthenia)
Anti-AChR antibodies - (myasthenia)
Anti-muscle-specific tyrosine kinase antibodies - (Guillain-Barre)
EKG, troponin, BNP - (myocarditis)
MRI spine - (transverse myelitis)
Bedside PFT’s/NIF/VC if suspect myositis, myasthenia or GBS
Fatigue - consider
Anemia (bleeding, hemolysis, immune heme toxicities, CRS*, HLH*
Cortisol - (adrenal insufficiency, hypophysitis)
TSH/T4-hypothyroidism
Electrolyte abnormalities - interpret in context of symptoms
MRI brain/pituitary (hypophysitis)
Nausea/vomiting
Cortisol - (adrenal insufficiency, hypophysitis)
Anion gap, low pH, ketones, glucose elevation – DKA
Lipase - (irAE pancreatitis)
EKG - conduction block, tachy or brady dysrhythmias, ST changes, electric alternans suggest Myocarditis
CRS* or HLH* if sepsis like features
Abdominal pain – usual workup, consider
Lipase - (immune pancreatitis)
LFT’s - (autoimmune hepatitis)
Low threshold for CT – small bowel obstruction, perforation due to checkpoint inhibitor enteritis is rare but deadly
Consider DKA and adrenal insufficiency
Diarrhea - usual workup plus
CT abdomen -very low threshold, can be diagnostic of colitis
Send stools for lactoferrin, calprotectin
CRS* or HLH* in proper context
Eye complaints
MRI – if considering immune neurotoxicity or ophthalmitis
Abnormal bleeding if abnormal CBC, coagulation profile, consider
Peripheral smear (schistocytes), Comb’s, haptoglobin, LDH – hemolysis from hemolytic anemia, TTP, or HUS.
Reticulocyte count low - (marrow failure due to aplastic anemia, PRCA*)
DIC (elevated INR, low platelets + fibrinogen) – CRS*or HLH*
References
  1. Yeung SJ, Qdaisat A, Chaftari P, et al. Diagnosis and management of immune-related adverse effects of immune checkpoint therapy in the emergency department. JACEP. 2020;1:1637-59.
  2. Hay KA. Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy. British journal of haematology. 2018;183(3):364-374. doi:10.1111/bjh.15644
  3. Blackmon JT, Viator TM, Conry RM. Central nervous system toxicities of anti-cancer immune checkpoint blockade. J Neurol Neuromed. 2016;1:39-45.
  4. Gupta R, Roach C, Hryniewicki AT, Vilke GM, Shatsky RA, Coyne CJ. Management of Chimeric Antigen Receptor (CAR) T-Cell Toxicities: A Review and Guideline for Emergency Providers. J Emerg Med. 2020 Jul;59(1):61-74.
  5. Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M. et al. Cytokine release syndrome. j. immunotherapy cancer 6, 56 (2018).
  6. Rogers BB, Zawislak C, Wong V. Management of Hematologic Adverse Events Associated with Immune Checkpoint Inhibitors. J Adv Pract Oncol. 2021 May;12(4):392-404.
Section IconManagement
Immune Checkpoint Inhibitor irAE Grading and Management
irAE is a diagnosis of exclusion; work up and treat other conditions as indicated
Resuscitate a patient as appropriate per Emergency Medicine training
Management based on grading schemes.
For all grades consult oncologist for co-management and additional treatment recommendations.
For organ specific treatments, seek expert consultation familiar with published guidelines.
CAR T related CRS Grading and Management:
Cytokine Release Syndrome (CRS) symptoms resemble sepsis due to cytokine storm:
  • General - fever, malaise, fatigue, weakness
  • Neurological-Headache, AMS, seizures, focal deficits, delirium, tremors
  • Pulmonary - Tachypnea, dyspnea, pulmonary edema
  • Cardiac - Tachycardia, hypotension, reduced ejection fraction, dysrhythmias
  • Renal - Acute kidney injury,
  • Heme - Anemia, cytopenias, DIC
  • GI - Nausea, vomiting, diarrhea
  • Liver - LFT elevations, encephalopathy
  • Other – splenomegaly, elevated ferritin, lactate
CAR T related ICANS Grading and Management:
Immune Effector Cell-Associated Neurotoxicity syndrome (ICANS): presentation can vary from mild ( headache, fatigue) to severe and life-threatening ( seizures, elevated intracranial pressure, and coma).
Findings determine grading/treatment
  • ICE (Immune Effector Cell-associated Encephalopathy) Score – measures Cognition
    • Orientation: year, month, city, hospital (4 points, 1 point each)
    • Naming: name 3 objects (3 points, 1 point each)
    • Following commands: (1 point)
    • Writing: ability to write a standard sentence (1 point)
    • Attention: count backwards from 100 by 10s (1 point)
  • Level of Consciousness
  • Seizure
  • Motor findings – hemi or paraparesis automatically Grade 4
  • Edema of brain on imaging
If mixed findings, worst score determines the Grade (and treatment).
References
  1. Immunotherapy to Treat Cancer. National Cancer Institute website. Updated September 24, 2019. Accessed June 1, 2020. http://www.cancer.gov
  2. Yeung SJ, Qdaisat A, Chaftari P, et al. Diagnosis and management of immune-related adverse effects of immune checkpoint therapy in the emergency department. JACEP. 2020;1:1637-59.
  3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;4:625-638.
  4. Conde Royo D, Juarez-Salcedo LM, Dalia S. Management of adverse effects of new monoclonal antibody treatments in acute lymphoblastic leukemia. Drugs in Context. 2020.
Section IconDisposition
IRAE Disposition Grading:
The disposition of patients experiencing an irAE is based on the grading severity of the symptoms(1-Mild, 2-Moderate, 3-Severe, 4-Life Threatening) and findings of impaired Activities of Daily Living (ADL’S). Lack of clinical resources should prompt consideration of transfer to a higher level of care facility. The following link is a flowchart that illustrates the dynamic between symptoms, and considerations that influence appropriate treatment and disposition, any of which may conservatively upgrade a patient’s disposition.
References
  1. Yeung SJ, Qdaisat A, Chaftari P, Lipe D, Merlin J, Rajha E, Wechsler A, Sandoval M, Viets J, Al-Breiki A, Shah M, Pandey R, Kamal M, Khattab O, Toale K, Wattana M, Elsayem A, Gaeta S, Brock P, Reyes-Gibby C, Alagappan K. Diagnosis and management of immune-related adverse effects of immune checkpoint therapy in the emergency department. J Am Coll Emerg Physicians Open. 2020 Aug 30;1(6):1637-1659. doi: 10.1002/emp2.12209. PMID: 33392573; PMCID: PMC7771833.
  2. Hryniewicki AT, Wang C, Shatsky RA, Coyne CJ. Management of Immune Checkpoint Inhibitor Toxicities: A Review and Clinical Guideline for Emergency Physicians. J Emerg Med. 2018 Oct;55(4):489-502. doi: 10.1016/j.jemermed.2018.07.005. Epub 2018 Aug 16. PMID: 30120013.
  3. Cooksley, Tim; Stutman, Robin; Klotz, Adam Emergency management of immune-related toxicity, Current Opinion in Oncology: July 2020 - Volume 32 - Issue 4 - p 274-281 doi: 10.1097/CCO.0000000000000635.
Section IconImmunotherapy Pearls
Remember:
History of autoimmune conditions increase chances of ICI toxicities.
Obtain detailed ROS -varied immunotherapy related conditions can co-exist.
Immediate infusion reactions occur, but delayed toxicity (weeks, months or even over a year) is the rule.
Common:
  • Maculopapular rash or pruritus.
  • Mucositis.
  • Endocrine (thyroiditis, adrenalitis, hypophysitis, type 1 diabetes).
  • Diarrhea/colitis.
  • Hepatotoxicity.
  • Pneumonitis – high morbidity and mortality.
  • Nonspecific headache - common, but beware of hypophysitis if there is hypotension, hyponatremia or vomiting.
Rare, unlikely to miss
  • Acute kidney injury.
  • Pancreatitis.
  • Ophthalmic.
  • Rheumatologic.
Rare, high morbidity/mortality (cannot afford to miss)
  • SJS/TEN (look for Nikolsky’s sign).
  • Myocarditis (ACS like syndrome, CHF, arrythmias); often associated with myositis.
  • Thromboembolism (DVT/PE, MI, CVA)
  • Parathyroiditis (hypocalcemia)
  • Neuro - Guillain-Barre, myasthenia, meningoencephalitis, transverse myelitis, autonomic/cranial/peripheral neuropathies, RPLS* (Reversible Posterior Leukoencephalopathy Syndrome)
  • Hematologic - aplastic anemia, hemolytic anemia, leukopenia, ITP, TTP/HUS, HLH*, CRS*
CRS (CYTOKINE RELEASE SYNDROME) and HLH (HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS) are induced by different forms of immunotherapy, but are clinically similar and share many findings, including fever, tachycardia, hypotension, cardiopulmonary, GI, renal, hepatic and neurological symptoms, cytopenia’s, DIC, splenomegaly, lactic acidosis. Very elevated ferritin and CRP levels are very suggestive, but procalcitonin not yet studies in this setting.
CRS (CYTOKINE RELEASE SYNDROME) onset within 2 weeks, ICANS within 4 weeks of CAR T-cell. They can co-exist, some symptoms may overlap, wax and wane.
Even mild CRS (CYTOKINE RELEASE SYNDROME) or ICANS requires seizure prophylaxis.
Hypotension – consider CRS (CYTOKINE RELEASE SYNDROME), HLH (HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS), adrenal crisis in addition to usual causes
Hypoxia – consider pneumonitis, myocarditis, CRS*, HLH*
Nonspecific fatigue – consider adrenal insufficiency, hypothyroidism in addition to traditional causes.
Beware of rare but deadly muscle weakness mimicking fatigue– Guillain-Barre (ascending paralysis), myasthenia (difficulty holding head up from weak neck muscles), transverse myelitis at cervical level (4 extremity weakness).
Myositis, common and usually painful, can also mimic fatigue if painless. Furthermore, it can co-exist with myasthenia (cranial nerves) and myocarditis, both with high morbidity and mortality.
Assessment of musculoskeletal weakness should include pulmonary mechanics including NIF and vital capacity.
Headache is common irAE but if headache is associated with severe fatigue, hypotension, hyponatremia, or vomiting, consider hypophysitis (panhypopituitarism) and get MRI brain/pituitary.
Fever/sepsis picture- consider CRS* or HLH*
Cardiopulmonary symptoms– myocarditis and pneumonitis can mimic ACS/AMI, CHF, pneumonia. Thromboembolism with DVT/PE, MI and stroke also can be due to ICI.
Altered mental status–consider CRS or HLH, ICANS, ICI encephalitis, RPLS (Reversible Posterior Leukoencephalopathy Syndrome)
Colitis: detailed number of bowel movements per day above baseline (<4, 4-6, or >6) will be relevant for severity grading, treatment and disposition.
Heme irAE’s rare, but some are life threatening and can be easily missed; HLH, TTP .
Even mild irAE’s may require hospital observation or admission if adverse comorbidities, multi-system involvement or psychosocial factors are present.
Some patients get treatment at institutions far from home and may present to local ED with these complications. Unavailability of local expertise or resources may necessitate transfer of even mild cases to higher level of care.
References
  1. Immunotherapy to Treat Cancer. National Cancer Institute website. Updated September 24, 2019. Accessed June 1, 2020. Learn More
  2. Yeung SJ, Qdaisat A, Chaftari P, et al. Diagnosis and management of immune-related adverse effects of immune checkpoint therapy in the emergency department. JACEP. 2020;1:1637-59.
  3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;4:625-638
  4. .
  5. Rogers BB, Zawislak C, Wong V. Management of Hematologic Adverse Events Associated With Immune Checkpoint Inhibitors. J Adv Pract Oncol. 2021 May;12(4):392-404. doi: 10.6004/jadpro.2021.12.4.4. Epub 2021 May 1. PMID: 34123476; PMCID: PMC8163252.
  6. Sadaat M, Jang S. Hemophagocytic lymphohistiocytosis with immunotherapy: brief review and case report. Journal for ImmunoTherapy of Cancer 2018;6:49. doi: 10.1186/s40425-018-0365-3
  7. Gupta R, Roach C, Hryniewicki AT, Vilke GM, Shatsky RA, Coyne CJ. Management of Chimeric Antigen Receptor (CAR) T-Cell Toxicities: A Review and Guideline for Emergency Providers. J Emerg Med. 2020 Jul;59(1):61-74. doi: 10.1016/j.jemermed.2020.04.021. Epub 2020 May 28. PMID: 32473867.
  8. Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M. et al. Cytokine release syndrome. j. immunotherapy cancer 6, 56 (2018). https://doi.org/10.1186/s40425-018-0343-9
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Glossary of Terms
  • ICI – immune checkpoint inhibitor
  • CAR T - Chimeric Antigen Receptor T cell therapy
  • irAE: immune-related adverse event
  • DM – Diabetes mellitus
  • DKA -Diabetic Ketoacidosis
  • DVT- Deep venous thrombosis
  • PE- Pulmonary embolism
  • CVA – Cerebrovascular accident
  • MI – Myocardial infarction
  • CHF–Congestive heart failure
  • AKI – Acute kidney injury
  • SJS - Stevens-Johnson Syndrome
  • TEN -Toxic Epidermal Necrolysis
  • ICANS* - Immune Effector Cell-Associated Neurotoxicity syndrome
  • CRS* - Cytokine Release Syndrome
  • HLH*- Hemophagocytic Lymphohistiocytosis
  • RPLS*-Reversible Posterior Leukoencephalopathy Syndrome
  • PRES- Posterior reversible encephalopathy syndrome
  • TTP - Acquired thrombotic thrombocytopenic purpura
  • HUS- Hemolytic uremic syndrome
  • ITP - Immune thrombocytopenia
  • PRCA* - Pure Red Cell Aplasia
  • DIC-Disseminated intravascular coagulation
  • CRP - C-reactive protein
  • PT/INR–prothrombin time/international normalized ratio
  • PTT–partial thromboplastin time
  • AST/ALT- Aspartate transaminase/ alanine aminotransferase
  • Alk P -alkaline phosphatase
  • LDH lactate dehydrogenase
  • CPK - creatine phosphokinase
  • GGT- gamma-glutamyl transferase
  • BNP-beta natriuretic peptide
  • ABG–arterial blood gas
  • EKG–electrocardiogram
  • POC-point-of-care
  • TSH-thyroid stimulating hormone
  • TFTs–thyroid function tests
  • CBC-complete blood count
  • CT-computed tomography
  • MRI-magnetic resonance imaging
  • PFT -pulmonary function test
  • NIF - Negative Inspiratory Force
  • VC- Vital Capacity
  • AChR-acetylcholine receptor
  • ICE*- Immune effector cell–associated encephalopathy
  • AMS -altered mental status
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Acknowledgments

Developed by the ACEP Expert Panel on Immuno-Oncology Toxicity
Reviewed by the ACEP Clinical Resource Review Committee

Support made possible by AstraZeneca and Bristol Myers Squibb

 

CONTRIBUTORS
Jason J. Bischof, MD, FACEP (co-chair) Marcelo A. Sandoval, MD (co-chair) Kumar Alagappan, MD, FACEP Christopher Coyne, MD, MPH Sarah Bui Dubbs, MD, FACEP Emily A. Highsmith, PharmD, BCCCP Divya Koura, MD Mark A. Melrose, DO, FACEP

 

ACEP Staff
Liz Muth, CAE

 

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