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Immune checkpoint inhibitor toxicityMANAGEMENT

HEMATOLOGIC AND ONCOLOGIC PRESENTATIONS · 12 SECTIONS

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738 items

☷ Legend

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Cardiovascular Presentations71▾

Respiratory Presentations52▾

Neurological Presentations83▾

Gastrointestinal Presentations74▾

Genitourinary and Reproductive Presentations48▾

Infectious Disease Presentations148▾

Trauma Presentations89▾

Toxicologic Presentations80▾

Psychiatric Presentations26▾

Musculoskeletal and Rheumatologic Presentations96▾

Dermatology Presentations23▾

Environmental and Exposure Presentations27▾

Hematologic and Oncologic Presentations36▾

Acute chest syndrome Acute Hemolytic Transfusion Reaction Anticoagulant reversal (warfarin, DOAC, heparin)Aplastic Anemia (Crisis)Autoimmune Hemolytic Anemia CAR-T and cytokine release syndrome Coagulopathy Delayed Hemolytic Transfusion Reaction Disseminated Intravascular Coagulation (DIC)Essential Thrombocythemia Febrile Non-hemolytic Transfusion Reaction Graft Versus Host Disease (Acute)Hemolytic Uremic Syndrome (HUS)Hemophilia A (Bleeding Crisis)Heparin-Induced Thrombocytopenia (HIT)Hyperviscosity syndrome Immune checkpoint inhibitor toxicity Immune Thrombocytopenic Purpura (ITP)Leukemoid Reaction Leukostasis Massive transfusion protocol Myelofibrosis Neutropenic enterocolitis (typhlitis)Paroxysmal Nocturnal Hemoglobinuria Polycythemia Vera (Crisis)Pure Red Cell Aplasia Sickle Cell (Acute Chest Syndrome)Sickle Cell (Splenic Sequestration)Sickle cell crisis (vaso-occlusive)Symptomatic anemia Thrombocytopenia (severe)Thrombotic Thrombocytopenic Purpura (TTP)Transfusion-Associated Circulatory Overload (TACO)Transfusion-Related Acute Lung Injury (TRALI)Tumor lysis syndrome Von Willebrand Disease (Bleeding)

Pediatric-Specific Presentations19▾

Endocrine and Metabolic Presentations45▾

ENT and Maxillofacial Presentations27▾

Ophthalmologic Presentations19▾

Obstetric Presentations23▾

Systemic and Miscellaneous Presentations17▾

01Approach to the Critical Patient/attcp104

Immediate priorities

›New symptom in a patient on a checkpoint inhibitor

›Treated as an immune-related adverse event until proven otherwise

›Applies even when disease progression or infection seems more likely

›Applies regardless of which organ system is symptomatic

›Onset window

›Can begin days after the first dose

›Can begin weeks to months after the last dose, including after treatment has been stopped

›No safe interval after discontinuation excludes a new irAE

›Rapid organ-threat screen at triage

›Cardiac screen

›Troponin and 12-lead ECG in any patient with chest symptoms, dyspnea, palpitations, syncope, or new weakness

›Low threshold given disproportionate mortality of myocarditis relative to its incidence

›Respiratory screen

›Pulse oximetry and work of breathing

›New cough, dyspnea, or hypoxia treated as pneumonitis until excluded

›Abdominal screen

›Stool frequency change and peritoneal signs

›Perforation and toxic megacolon as immediate concerns with diarrhea or abdominal pain

›Neurologic screen

›Diplopia, ptosis, dysphagia, ascending weakness, or bulbar symptoms

›Screen for the myocarditis-myositis-myasthenia gravis overlap triad whenever any one component is found

›Endocrine screen

›Unexplained hypotension, hyponatremia, hypoglycemia, or altered mentation

›Treated as possible adrenal crisis pending confirmation

›Oncology team contact

›Contacted early for every suspected irAE

›Confirms agent, regimen, cycle number, and date of last dose

›Confirms baseline organ function and prior irAE history

›Joint decision on holding versus permanently discontinuing therapy

›Emergency clinician should not make permanent discontinuation decisions in isolation

Organ-threat recognition and stabilization

›Airway and breathing

›Bulbar or respiratory muscle weakness from neurologic irAE

›Forced vital capacity and bedside spirometry when myasthenic-crisis-like picture suspected

›Early intubation for declining respiratory mechanics rather than waiting for hypoxia

›Hypoxia from pneumonitis

›Supplemental oxygen titrated to target

›SpO2 target 92 to 96% in patients without chronic hypoxemia

›Individualized lower target in chronic lung disease, pulmonary hypertension, or known baseline hypoxemia from underlying malignancy

›Circulation

›Shock disproportionate to apparent trigger

›Consider adrenal crisis from hypophysitis or primary adrenalitis

›Consider fulminant myocarditis with cardiogenic shock

›Empiric hydrocortisone when adrenal crisis suspected

›Hydrocortisone 100 mg IV bolus, IM if no IV access

›Given before confirmatory cortisol and ACTH results, not delayed for labs

›Hemodynamic monitoring

›Continuous telemetry when myocarditis, thyrotoxicosis, or adrenal crisis suspected

›Arterial line for refractory shock requiring vasopressor titration

›Abdominal and gastrointestinal threat

›Perforation and toxic megacolon recognition

›Peritoneal signs, distension, or hemodynamic instability with severe colitis

›Antimotility agents avoided, see Treatment

›Volume resuscitation for GI losses

›Isotonic crystalloid titrated to hemodynamics and urine output

Iatrogenic harms from routine ED interventions

›Intubation and sedation

›Induction agent selection

›Etomidate avoided or used cautiously when adrenal insufficiency is suspected or unexcluded

›Ketamine or an alternative induction agent preferred when adrenal axis suppression is a concern

›Neuromuscular blocker selection when myasthenic-crisis-like overlap present

›Increased sensitivity to nondepolarizing agents

›Relative resistance to succinylcholine

›Oversedation risk

›Masks hypercapnia in evolving neuromuscular respiratory failure

›Worsens hypotension in unrecognized adrenal insufficiency

›Fluid loading

›Appropriate for hypovolemic losses from colitis or adrenal crisis

›Reassessed with cardiac imaging before aggressive bolus when myocarditis is suspected

›Reduced ventricular function tolerates volume poorly

›Risk of precipitating pulmonary edema

›Oxygen and ventilatory support

›High-flow or noninvasive support can delay recognition of a patient who actually needs intubation

›Reassess respiratory mechanics, not oxygenation alone, in neuromuscular irAE

›Vasopressors

›Refractory to conventional vasopressors until glucocorticoid given when adrenal crisis is the driver

›Hydrocortisone administration restores vasopressor responsiveness

›Mechanical circulatory support

›Intra-aortic balloon pump or VA-ECMO considered for fulminant myocarditis with cardiogenic shock

›Bridge to recovery, not a substitute for immunosuppression

›IABP less effective with complete heart block or malignant arrhythmia from active myocarditis, favoring VA-ECMO in that setting

›Anticoagulation

›Cancer-associated venous thromboembolism anticoagulation reassessed against active colitis

›Active GI bleeding or suspected perforation is a reason to hold anticoagulation

›Multidisciplinary decision when both thromboembolic and bleeding risk are high

›Fibrinolysis

›Recent or active GI bleeding from colitis is a contraindication

›Neurologic deficits are worked up for irAE and other mimics before fibrinolysis is given for presumed stroke

›Analgesia

›Opioids for abdominal pain

›Morphine 2 to 4 mg IV every 4 hours as needed, lowest effective dose

›Risk of masking peritoneal signs and worsening ileus in active colitis

›NSAIDs relatively avoided

›Ibuprofen 400 to 600 mg PO every 6 to 8 hours as an example dose if used

›Increased GI bleeding risk with active colitis and renal risk with concurrent nephritis

Escalation and consults

›Subspecialty consultation by organ

›Gastroenterology for colitis or hepatitis

›Pulmonology for pneumonitis

›Endocrinology for hypophysitis, thyroid dysfunction, or adrenal insufficiency

›Cardiology for suspected myocarditis

›Neurology for neuromuscular or CNS irAE

›Nephrology for nephritis

›Dermatology for severe cutaneous reactions

›Critical care involvement

›ICU admission for any grade 4 irAE

›ICU admission for myocarditis regardless of stated grade given mortality risk

02History/hx61

ICI treatment history

›Agent and regimen

›Agent class

›Anti-PD-1 (nivolumab, pembrolizumab, cemiplimab)

›Anti-PD-L1 (atezolizumab, durvalumab, avelumab)

›Anti-CTLA-4 (ipilimumab)

›Combination anti-PD-1/PD-L1 plus anti-CTLA-4

›Indication and cancer type

›Cycle number and date of most recent dose

›Time since last dose, since toxicity can present weeks to months later

›Prior irAE history

›Organ affected, severity, and whether therapy was resumed after

›Response to prior steroid or immunosuppressive treatment

›Concurrent oncologic therapy

›Combined with chemotherapy or targeted therapy

›Overlapping toxicity profile consideration

›Concurrent or recent radiation

›Radiation recall or radiation pneumonitis overlap

Organ-system symptom screen

›Gastrointestinal

›Stool frequency change from baseline

›Blood or mucus in stool

›Abdominal pain character and location

›Hepatic

›Jaundice, dark urine, or pale stool

›Right upper quadrant discomfort

›Pruritus

›Pulmonary

03Physical Exam/exam54

Vital signs and general appearance

›Hemodynamic snapshot

›Hypotension

›SBP < 100 mmHg or >= 20 mmHg below documented baseline

›Exception: chronic hypotension at baseline in advanced malignancy requires comparison to the patient's own baseline, not a fixed cutoff

›Tachycardia or bradycardia

›Tachycardia from thyrotoxicosis, shock, or fever

›Bradycardia or heart block from myocarditis

›Oxygenation and respiratory rate

›Hypoxia

›SpO2 below 92% on room air

›Exception: cyanotic congenital heart disease, chronic lung disease, or pulmonary hypertension may have a lower individualized baseline

›Tachypnea

›Adult threshold above 20 breaths per minute

›Temperature

›Fever

›May reflect infection, thyrotoxicosis, or the irAE itself

›Absence of fever does not exclude a severe irAE

Organ-targeted exam

›Abdomen

›Distension, tenderness, or peritoneal signs

›Guarding and rebound raise concern for perforation

›Bowel sounds

›Hypoactive or absent bowel sounds with toxic megacolon

›Skin and mucosa

›Rash morphology and body surface area

›Maculopapular, lichenoid, or bullous pattern

›Mucosal involvement

04Differential Diagnosis/ddx52

irAE mimics by organ system

›Gastrointestinal

›Infectious colitis

›Clostridioides difficile

›Cytomegalovirus colitis, especially with steroid exposure

›Bacterial enteritis

›Neutropenic enterocolitis (typhlitis) with concurrent chemotherapy

›Ischemic colitis

›Hepatic

›Viral hepatitis A, B, C, or E

›Drug-induced liver injury from other medications

›Hepatic metastases or disease progression

›Biliary obstruction

›Pulmonary

›Infectious pneumonia, including Pneumocystis with prior steroid exposure

›Lymphangitic carcinomatosis or malignant pleural disease

›Pulmonary embolism

›Cardiogenic pulmonary edema

›Radiation pneumonitis with prior thoracic radiotherapy

›Cardiac

›Acute coronary syndrome

›Stress cardiomyopathy

›Malignant pericardial disease

›Prior anthracycline cardiotoxicity

›Neurologic

›Brain metastases or leptomeningeal disease

›Paraneoplastic neurologic syndrome

›Stroke

05Laboratory Tests/lt52

Core labs

›Complete blood count

›Anemia from GI blood loss or chronic disease

›Eosinophilia supporting an immune-mediated process

›Cytopenias from marrow involvement or concurrent chemotherapy

›Comprehensive metabolic panel

›Electrolytes

›Hyponatremia and hyperkalemia suggesting adrenal insufficiency

›Glucose mmol/l, hypoglycemia in adrenal crisis, hyperglycemia with steroid therapy

›Renal function

›Creatinine rise from nephritis or prerenal loss

›Urinalysis with sterile pyuria or white cell casts suggesting interstitial nephritis

›Liver enzymes and bilirubin

›AST and ALT trend

›Grading based on multiple of the upper limit of normal

›Total bilirubin

›Cholestatic versus hepatocellular pattern

›Lipase

›Elevated with irAE pancreatitis, an uncommon but recognized presentation

Endocrine and cardiac labs

›Adrenal axis

›Random cortisol

›Under 5 µg/dl strongly suggests adrenal insufficiency in the acutely unwell patient

›ACTH

›Low or low-normal in secondary adrenal insufficiency from hypophysitis

›Elevated in primary adrenalitis, which is rare

›Do not delay hydrocortisone for these results when crisis is suspected

›Thyroid axis

06Diagnostic Tests/dt77

Scoring Systems

›CTCAE grading framework, version 5

›Grade 1

›Mild, asymptomatic or clinical findings only

›Grade 2

›Moderate, minimal or local intervention indicated, limiting instrumental activities of daily living

›Grade 3

›Severe or medically significant, hospitalization indicated, limiting self-care activities of daily living

›Grade 4

›Life-threatening, urgent intervention indicated

›Grade 5

›Death related to the adverse event

›Organ-specific grading anchors

›Colitis by stool frequency above baseline

›Grade 1: fewer than 4 stools per day above baseline

›Grade 2: 4 to 6 stools per day above baseline

›Grade 3: 7 or more stools per day above baseline, incontinence, or hospitalization indicated

›Grade 4: life-threatening, perforation, or hemodynamic collapse

›Hepatitis by transaminase elevation

›Grade 1: AST or ALT less than 3 times the upper limit of normal

›Grade 2: AST or ALT 3 to 5 times the upper limit of normal

›Grade 3: AST or ALT 5 to 20 times the upper limit of normal

›Grade 4: AST or ALT greater than 20 times the upper limit of normal

›Pneumonitis by symptoms and oxygen requirement

›Grade 1: radiographic changes only, asymptomatic

›Grade 2: symptomatic, not requiring supplemental oxygen

›Grade 3: severe symptoms, supplemental oxygen required, hospitalization indicated

›Grade 4: life-threatening, respiratory failure requiring ventilatory support

›Nephritis by creatinine rise

›Grade 1: creatinine rise greater than baseline up to 1.5 times baseline

›Grade 2: creatinine 1.5 to 3 times baseline

›Grade 3: creatinine greater than 3 times baseline or hospitalization indicated

›Grade 4: life-threatening, dialysis indicated

MRI

›Pituitary MRI for suspected hypophysitis

›Findings

›Diffuse pituitary gland enlargement and stalk thickening early in the course

›Gland can appear normal or atrophic later, so a normal scan does not exclude hypophysitis

›Timing

›Obtained after hormonal axis testing and initial stabilization, not before empiric hydrocortisone when crisis is suspected

›Brain MRI for neurologic irAE

›Excludes brain metastases, leptomeningeal disease, and stroke

›Typically normal in isolated peripheral neuromuscular irAE

›Cardiac MRI when myocarditis suspected and the patient is stable enough

›Late gadolinium enhancement and myocardial edema patterns

›Limited sensitivity early in fulminant presentations

›A normal cardiac MRI does not exclude myocarditis in a patient with strong clinical and biomarker suspicion

›Chest CT

›Ground-glass opacities and organizing pneumonia pattern in pneumonitis

›Excludes pulmonary embolism, progression, and infection

›Abdomen and pelvis CT

›Colonic wall thickening, mesenteric stranding, or free air in colitis

›Free air or extraluminal contrast mandates emergent surgical consultation

›Toxic megacolon

›Colonic dilation with loss of haustration

›CT head

›When altered mental status or focal deficit raises concern for an alternative diagnosis

Ultrasound

›Point-of-care cardiac ultrasound

›Global or regional wall motion abnormality in myocarditis

›Pericardial effusion

›Point-of-care volume assessment

›IVC collapsibility to guide fluid resuscitation in adrenal crisis or GI losses

›Lung ultrasound

›B-lines supporting an interstitial process or pulmonary edema

›Consolidation suggesting an infectious alternative

Electrocardiography

›Obtained in anyone with cardiac symptoms or vague symptoms such as fatigue or myalgias in the overlap syndrome

›New conduction abnormality

›Complete heart block is a recognized presentation of ICI myocarditis

›Ventricular arrhythmia

›Warrants continuous telemetry and urgent cardiology involvement

›Serial ECGs

›Trended alongside troponin while myocarditis is being excluded or treated

›Electrolyte-shift correlates

›Hyperkalemia from adrenal crisis

›Peaked T waves and widened QRS before treatment

›Resolves as hydrocortisone and fluid resuscitation correct the underlying deficiency

›Hypokalemia from high-dose or pulse-dose corticosteroid therapy

›U waves and arrhythmia risk during pulse methylprednisolone for myocarditis

›Potassium trended alongside ECG during pulse-dose courses

07Disposition/dispo20

Level of care and admission criteria

›ICU admission

›Any grade 4 irAE

›Suspected or confirmed myocarditis regardless of stated grade

›Respiratory failure or impending ventilatory failure from neuromuscular or pulmonary irAE

›Refractory shock

›Ward admission

›Grade 3 irAE requiring IV corticosteroids and organ-specific workup

›Grade 2 irAE with inability to tolerate oral intake or manage symptoms as an outpatient

›Outpatient management candidates

›Grade 1 irAE with reliable follow-up and oncology involvement

›Close interval reassessment arranged before discharge

Consults, transfer, and oncology contact

›Oncology team notified for every suspected irAE before disposition is finalized

›Confirms hold versus continue decision

›Arranges outpatient immunotherapy toxicity clinic follow-up where available

›Transfer criteria for non-tertiary EDs

›Suspected myocarditis without on-site cardiology or advanced heart failure support

›Fulminant colitis with surgical abdomen without on-site gastroenterology or surgery

›Neuromuscular respiratory failure without ICU or neurology capability

›Transfer timing

›Initiated in parallel with stabilization, not after it is complete

08Treatment/t204

Grading-based management ladder and escalation immunosuppression

›General principle

›Grade 1

›Continue ICI therapy with close monitoring for most organ systems

›Exception: cardiac and most neurologic irAEs are held even at grade 1 given their risk of rapid deterioration

›Grade 2

›Hold ICI therapy

›Prednisone or equivalent 0.5 to 1 mg/kg/day

›Grade 3

›Hold ICI therapy, with permanent discontinuation for some organ systems

›Methylprednisolone 1 to 2 mg/kg/day IV

›Hospitalization for most grade 3 irAEs

›Grade 4

›Permanently discontinue ICI therapy

›Exception: isolated endocrinopathy with adequate hormone replacement may allow cautious continuation per oncology and endocrinology

›Methylprednisolone 1 to 2 mg/kg/day IV, higher pulse dosing for myocarditis, see below

›Escalate to a second-line agent if no improvement within 48 to 72 hours

›Escalation agents

›Infliximab

›5 mg/kg IV, may repeat at 2 weeks if incomplete response

›Contraindicated in hepatitis due to hepatotoxicity risk

›Contraindicated with active or suspected perforation, sepsis, or moderate to severe heart failure

›Vedolizumab

›300 mg IV at weeks 0, 2, and 6

›Gut-selective, an alternative for colitis when infliximab is contraindicated or ineffective

›Mycophenolate mofetil

›1000 mg PO or IV twice daily

›Preferred steroid-refractory second-line agent for hepatitis, since infliximab is contraindicated there

›Intravenous immunoglobulin

›0.4 g/kg/day for 5 days, or a total of 2 g/kg divided over 2 to 5 days

›Used for neurologic irAE and as an adjunct in myocarditis

›Plasma exchange

›5 exchanges over 7 to 14 days, 1 to 1.5 plasma volumes per exchange

›Used for severe neurologic irAE, particularly myasthenic-crisis-like presentations

Colitis and gastrointestinal toxicity

›Diagnostic confirmation before escalation

›Stool studies to exclude Clostridioides difficile

›Flexible sigmoidoscopy or colonoscopy with biopsy, including CMV immunohistochemistry, before starting biologic immunosuppression when feasible

›Grade-based treatment

›Grade 1

›Supportive care and continued monitoring

›Grade 2

›Hold ICI, prednisone 1 mg/kg/day

›Grade 3 or 4

›Permanently discontinue ICI

›Methylprednisolone 1 to 2 mg/kg/day IV

›Infliximab 5 mg/kg IV if no improvement within 3 days, or vedolizumab as an alternative

›Perforation risk

›Any severe colitis carries perforation and toxic megacolon risk

›Surgical consultation for peritoneal signs or imaging evidence of perforation

›Antimotility agents

›Loperamide 4 mg once then 2 mg after each loose stool, maximum 16 mg/day, is the typical antidiarrheal dose

›Avoided in irAE colitis

›Masks worsening disease severity

›Increases risk of toxic megacolon and perforation by slowing transit in an actively inflamed colon

›Analgesia caution

›Opioids and NSAIDs carry the same masking and bleeding concerns described in Approach to the Critical Patient and are minimized

Hepatitis

›Diagnostic exclusion before treatment

›Viral hepatitis serologies

›Autoimmune hepatitis antibodies

›Hepatology consultation, liver biopsy when diagnosis is unclear

›Grade-based treatment

›Grade 1

›Continue ICI with weekly liver enzyme monitoring

›Grade 2

›Hold ICI, prednisone 0.5 to 1 mg/kg/day

›Grade 3 or 4

›Permanently discontinue ICI

›Methylprednisolone 1 to 2 mg/kg/day IV

›Mycophenolate mofetil 1000 mg PO or IV twice daily if no improvement within 3 days

›Infliximab not used because of hepatotoxicity risk

›Analgesic and antipyretic dosing adjustment

›Acetaminophen maximum reduced to 2000 mg/day in active hepatitis or hepatic impairment, from the usual 3000 to 4000 mg/day maximum

Pneumonitis

›Diagnostic workup

›Chest CT for ground-glass or organizing pneumonia pattern

›Bronchoscopy with bronchoalveolar lavage to exclude infection, especially before high-dose immunosuppression

›Grade-based treatment

›Grade 1

›Hold ICI, repeat imaging in 3 to 4 weeks before resuming

›Grade 2

›Hold ICI, prednisone 1 mg/kg/day

›Grade 3 or 4

›Permanently discontinue ICI

›Methylprednisolone 2 to 4 mg/kg/day IV, hospitalization

›Infliximab, mycophenolate, or IVIG if no improvement within 48 hours

›Cyclophosphamide, approximately 500 to 1000 mg/m2 IV monthly, reported for refractory cases

›Monitoring and troubleshooting

›Daily oxygen requirement and work of breathing while inpatient

›Not-improving trigger

›Escalating oxygen requirement or no radiographic improvement by 48 to 72 hours prompts escalation and re-evaluation for infection

Endocrinopathies

›Hypophysitis

›Presentation

›Headache, visual field defect, fatigue

›Hormone axis evaluation before hormone replacement

›Cortisol and ACTH, TSH and free T4, LH/FSH and sex hormones, prolactin

›Sequencing rule

›Glucocorticoid replacement with hydrocortisone always precedes levothyroxine initiation

›Giving levothyroxine before treating unrecognized adrenal insufficiency accelerates cortisol clearance and can precipitate adrenal crisis

›High-dose steroids for mass effect

›Methylprednisolone 1 to 2 mg/kg/day for severe headache or visual symptoms, tapered once symptoms resolve

›Hormone replacement itself is typically lifelong and does not require stopping ICI

›Thyroid dysfunction

›Thyrotoxic phase

›Usually a transient destructive thyroiditis rather than true hyperthyroidism

›Propranolol 10 to 20 mg PO every 6 to 8 hours, or atenolol 25 to 50 mg PO daily, for symptomatic control

›Antithyroid drugs such as methimazole generally not indicated unless a Graves-like picture is confirmed

›Hypothyroid phase

›Levothyroxine 1.6 mcg/kg/day, started at a lower dose in older adults or cardiac disease

›Adrenal insufficiency

›Life-saving priority

›Suspected or confirmed adrenal insufficiency is treated with stress-dose hydrocortisone immediately

›This decision precedes and is not superseded by the steroid dose or agent chosen for any other concurrent irAE

›Acute dosing

›Hydrocortisone 100 mg IV bolus, IM if no IV access, not delayed for confirmatory labs

›Maintenance 200 mg per 24 hours as a continuous infusion, or 50 mg IV every 6 hours

›Reduced to 100 mg per day after 24 hours, guided by clinical response

›Oral transition at 2 to 3 times the eventual maintenance dose once tolerating PO, tapered to maintenance over 2 to 3 days

›Agent selection when adrenal insufficiency is in the differential

›Hydrocortisone preferred over dexamethasone

›Dexamethasone lacks mineralocorticoid activity and does not cover coexisting aldosterone deficiency

Myocarditis and cardiac toxicity

›Diagnostic approach

›Troponin and ECG in anyone with cardiac or vague systemic symptoms

›Echocardiogram for wall motion and ejection fraction

›Cardiac MRI when stable enough, with the caveat that a normal study does not exclude myocarditis

›Endomyocardial biopsy considered the reference standard when diagnosis remains uncertain

›Overlap syndrome

›Myocarditis, myositis, and myasthenia gravis-like weakness can occur together

›CK, aldolase, and neuromuscular exam obtained in every suspected myocarditis case

›Highest mortality when all three components are present

›Grade-based treatment

›Any grade

›Permanently discontinue ICI therapy

›Pulse-dose corticosteroids

›Methylprednisolone 1000 mg IV daily for 3 to 5 days, then taper

›Steroid-refractory or hemodynamically unstable disease

›Abatacept, weight-tiered IV dosing similar to its rheumatologic dosing table, reported in case series for refractory ICI myocarditis

›Antithymocyte globulin, dosed as in transplant-rejection protocols in reported cases, approximately 1.5 mg/kg/day IV

›Ruxolitinib, approximately 5 to 10 mg PO twice daily, reported in case reports

›Mycophenolate mofetil 1000 mg PO or IV twice daily

›IVIG or plasmapheresis as adjuncts, dosed as in the escalation agents above

›Monitoring cadence

›Continuous telemetry for arrhythmia and conduction abnormality

›Serial troponin trended alongside clinical status

›Avoid QT-prolonging medications

›Mechanical circulatory support

›IABP or VA-ECMO for fulminant cardiogenic shock, a bridge that does not replace immunosuppression

›Not-improving trigger

›Rising troponin, worsening ejection fraction, or new arrhythmia despite pulse steroids prompts immediate escalation

›Long-term

›ICI therapy is not resumed after confirmed myocarditis in almost all cases given the mortality risk on rechallenge

Neurologic toxicity and overlap syndrome

›Myasthenic crisis-like presentation

›Often antibody-negative or with a different antibody profile than idiopathic myasthenia gravis

›Screen for the myocarditis-myositis overlap in every case

›Treatment

›Permanently discontinue ICI

›IVIG 0.4 g/kg/day for 5 days, or plasma exchange as above

›Pyridostigmine 30 to 60 mg PO every 4 to 6 hours for symptomatic control

›Corticosteroids used cautiously, since steroid initiation can transiently worsen weakness, favoring ICU-capable monitoring when started

›Guillain-Barre-like syndrome

›Ascending weakness and areflexia

›Albuminocytologic dissociation on lumbar puncture

›Treatment

›Permanently discontinue ICI

›IVIG or plasma exchange, dosed as above

›Corticosteroids have less established benefit here than in idiopathic GBS but are often used given the immune-mediated ICI etiology

›Other neurologic irAEs

›Aseptic meningitis and encephalitis

›Peripheral neuropathy

›Transverse myelitis

›Monitoring cadence

›Serial forced vital capacity and bedside spirometry while respiratory status is uncertain

Nephritis and severe cutaneous reactions

›Nephritis

›Most common pattern is acute interstitial nephritis

›Diagnostic workup

›Urinalysis with sterile pyuria or white cell casts

›Renal biopsy when diagnosis is unclear or grade 2 or higher

›Grade-based treatment

›Grade 1

›Continue ICI with monitoring

›Grade 2

›Hold ICI, prednisone 1 mg/kg/day

›Grade 3 or 4

›Permanently discontinue ICI

›Methylprednisolone 1 to 2 mg/kg/day IV

›Mycophenolate mofetil 1000 mg PO or IV twice daily for steroid-refractory disease

›Severe cutaneous reactions

›Stevens-Johnson syndrome and toxic epidermal necrolysis

›Permanently discontinue ICI

›Burn-unit level supportive care for significant body surface area involvement

›IVIG considered as an adjunct

›High-dose systemic steroids used more cautiously here than in other irAEs given mixed evidence in TEN generally

›Bullous pemphigoid

›Topical or oral corticosteroids

›Doxycycline 100 mg PO twice daily as a steroid-sparing option

›Dapsone 25 to 100 mg PO daily as a steroid-sparing option

›Rituximab 375 mg/m2 IV weekly for 4 doses for refractory disease

Steroid taper and infection prophylaxis

›Taper duration

›Corticosteroids tapered over a minimum of 4 to 6 weeks for most irAEs

›Myocarditis often requires a longer taper given relapse risk, individualized with cardiology

›Rapid taper risks rebound flare of the irAE

›Pneumocystis prophylaxis

›Indicated for prednisone 20 mg/day or equivalent for 4 or more weeks

›Trimethoprim-sulfamethoxazole single strength (80/400 mg) PO daily, or double strength (160/800 mg) PO three times weekly

›Additional prolonged-steroid precautions

›Bone protection and gastric protection per usual prolonged-steroid protocols

›Glucose monitoring for steroid-induced hyperglycemia

09Special Populations/sp28

Pregnancy

›ICI use in pregnancy

›Generally avoided when possible given limited safety data and placental transfer of IgG antibodies later in pregnancy

›irAE management considerations

›Hydrocortisone preferred over dexamethasone for adrenal-related irAEs, consistent with general adrenal insufficiency management, since dexamethasone crosses the placenta more readily

›Infliximab and other biologics used only after multidisciplinary maternal-fetal medicine discussion

›Fetal and neonatal considerations

›Neonatal monitoring for transient effects when biologic therapy was used near delivery

Geriatric

›Presentation differences

›Fatigue and functional decline may be the only presenting symptom of a significant irAE

›Delirium as a presentation of adrenal crisis, thyroid dysfunction, or hypercapnia

›Therapy risks

›Higher risk of steroid-related delirium, hyperglycemia, and infection

›Lower levothyroxine starting dose given cardiac risk

›IVIG thrombosis risk higher, with volume overload risk during infusion

›Disposition bias

›Lower threshold for admission given reduced physiologic reserve and atypical presentation

Pediatrics

›Use context

›ICI therapy is used less commonly in pediatrics, mainly for melanoma, Hodgkin lymphoma, and selected sarcomas

›Neonates are not a relevant risk population for this therapy

›Dosing considerations

›Weight-based hydrocortisone for adrenal crisis

›50 mg/m2 IV bolus or 2 mg/kg, then 50 to 100 mg/m2 per day divided

›Verify against current pediatric guideline before use

›IVIG dosing

›0.4 g/kg/day for 5 days for pediatric neurologic irAE

10Background/b46

Epidemiology

›Any-grade irAE frequency by regimen

›Anti-PD-1 or anti-PD-L1 monotherapy, roughly 65 to 70%

›Anti-CTLA-4 monotherapy, roughly 80 to 90%

›Combination anti-PD-1 plus anti-CTLA-4, approaching 95 to 100%

›Grade 3 or 4 irAE frequency by regimen

›Anti-PD-1 or anti-PD-L1 monotherapy, roughly 10 to 15%

›Anti-CTLA-4 monotherapy, roughly 20 to 30%

›Combination therapy, roughly 55 to 60%

›Organ-specific frequency

›Colitis more common with anti-CTLA-4, roughly 30% any grade versus roughly 10% with anti-PD-1

›Hepatitis roughly 5% with monotherapy, higher with combination therapy

›Pneumonitis roughly 5%, higher in lung cancer populations

›Hypothyroidism roughly 10% with anti-PD-1 monotherapy, higher with combination therapy

›Hypophysitis more common with anti-CTLA-4, roughly 10% at higher historical doses versus under 1% with anti-PD-1 monotherapy

›Primary adrenal insufficiency or adrenalitis, under 1%

›Myocarditis roughly 0.1 to 1%, up to approximately 2% with combination therapy

›Nephritis roughly 1 to 2% any grade

›Neurologic irAEs roughly 1 to 3% overall, with myasthenic-crisis-like and Guillain-Barre-like presentations each well under 1%

›Mortality

›Myocarditis carries the highest case fatality among irAEs, reported as high as 25 to 50%

›Colitis and pneumonitis account for the largest share of fatal irAEs overall by absolute number, since they are far more common than myocarditis

Pathophysiology

›Mechanism of immune checkpoint blockade

›Loss of T-cell inhibitory signaling that normally maintains peripheral self-tolerance

›Off-target activation against normal tissue antigens shared with tumor antigens

›Organ-specific mechanisms

›Colitis

11Patient Discharge Instructions/pdi26

copy discharge instructions

›Immune checkpoint inhibitor toxicity education

›Any new symptom while on this medication, or for months after your last dose, should be reported promptly

›Do not assume a new symptom is from your cancer or from a routine side effect

›Symptoms needing urgent reassessment

›New or worsening diarrhea, blood in the stool, or severe abdominal pain

›Yellowing of the skin or eyes, dark urine, or pale stool

›New shortness of breath or cough

›Chest pain, palpitations, or fainting

›New weakness, drooping eyelid, double vision, or difficulty swallowing

›Severe rash, blistering, or mouth sores

›Confusion, severe fatigue, or dizziness on standing

›Medication safety

›Do not stop prescribed steroids suddenly once started for this problem

›Acetaminophen up to 650 to 1000 mg every 6 hours, maximum 3000 to 4000 mg per day, or 2000 mg per day maximum if you have liver problems, for fever or pain

›Avoid over-the-counter anti-diarrheal medicine unless specifically told it is safe for you

›Steroid course reminders

›Your steroid dose will be tapered gradually over a minimum of 4 to 6 weeks, do not adjust it on your own

›You may need an additional medication to prevent a lung infection while on a prolonged steroid course

Follow-up plan

›Oncology follow-up

›Contact your oncology team within 24 to 48 hours of this visit

›Bring a list of all new medications started during this visit

›Subspecialty follow-up as arranged

›Gastroenterology, pulmonology, endocrinology, cardiology, neurology, nephrology, or dermatology as applicable

›Return to ED criteria

›Any of the urgent symptoms above

›Any rapid worsening of your original symptom despite treatment

12References/r14

Clinical guidelines and consensus

›ASCO Clinical Practice Guideline, Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy, updated 2021

›Grading and organ-specific management algorithms

›NCCN Clinical Practice Guidelines in Oncology, Management of Immunotherapy-Related Toxicities

›Widely used US oncology reference for irAE management

›ESMO Clinical Practice Guideline, Management of Toxicities from Immunotherapy

›European consensus grading and treatment algorithms

›Society for Immunotherapy of Cancer (SITC) Clinical Practice Guideline on Immune-Related Adverse Events

›Multidisciplinary consensus recommendations

Landmark trials and evidence sources

›Postow, Immune-Related Adverse Events Associated with Immune Checkpoint Blockade, New England Journal of Medicine, 2018

›Comprehensive review of irAE spectrum and management principles

›Moslehi, Increased Reporting of Fatal Immune Checkpoint Inhibitor-Associated Myocarditis, Lancet, 2018

›Correspondence establishing the disproportionate fatality of ICI myocarditis relative to its incidence

›Wang, Fatal Toxic Effects Associated with Immune Checkpoint Inhibitors, JAMA Oncology, 2018

›Systematic review finding myocarditis had the highest case fatality rate among fatal irAEs, while colitis and pneumonitis accounted for the largest absolute number of fatalities

Evidence & Review

Reviewed by SymptomDx Medical Team · Last reviewed September 13, 2026

SymptomDx is an educational tool for medical professionals. It does not replace clinical judgment. Verify all clinical data and drug dosages with authoritative sources.