Suspected immune-related adverse event (irAE)
Adult with new symptoms or abnormal tests on an immune checkpoint inhibitor (ICI), or after one. irAEs can start months after the last dose.
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Hematology & OncologyManagement
Immune Checkpoint Inhibitor Toxicity (irAE) Management
Immune Checkpoint Inhibitor Toxicity (irAE) Management: Suspected immune-related adverse event (irAE) → Recognise the irAE and the organ involved → Work...
Pathway Overview
20 steps
Algorithm Steps
20 total
01Start 02Action Recognise the irAE and the organ involved
Any organ. Several irAEs can occur together. Timing varies by organ.
- Heart: chest pain, dyspnoea, palpitations, syncope, raised troponin (myocarditis)
- Nerves and muscle: weakness, ptosis, diplopia, bulbar symptoms, neuropathy, confusion
- Endocrine: thyroid dysfunction, hypophysitis, adrenal insufficiency, new diabetes or DKA
- Gut: diarrhoea, colitis (more common with anti-CTLA-4, e.g. ipilimumab)
- Liver: raised ALT/AST or bilirubin
- Lung: cough, dyspnoea, hypoxia (pneumonitis)
- Skin: rash, itch, blistering, mucosal ulcers
- Kidney: rising creatinine; blood: haemolysis, low platelets, cytopenias
03Action Work-up before treatment: confirm irAE and exclude other causes
Exclude infection, cancer progression and drug causes. Do not delay steroids in grade 3-4 while tests are pending.
- All: FBC, UEC, LFTs, glucose, TSH and free T4, morning cortisol
- Heart symptoms, or any muscle or nerve irAE: ECG, troponin, BNP, CK, echo
- Diarrhoea: stool culture and C. difficile; consider calprotectin, endoscopy
- Liver: viral hepatitis serology; review hepatotoxic drugs
- Lung: CT chest; respiratory virus panel; bronchoscopy if unsure
- Endocrine: ACTH, LH/FSH, testosterone or oestradiol; pituitary MRI if hypophysitis
- Before possible infliximab: hepatitis B serology, TB screen (IGRA, chest X-ray)
04Warning Myocarditis, endocrine and neurological irAEs do not follow the grade table
Check these first. Each has its own path below.
- Myocarditis (any grade, even without symptoms): withhold ICI, admit, cardiology, IV methylprednisolone within 24 h. Do not rechallenge.
- Endocrine irAE: hormone replacement or insulin. High-dose steroids do not treat thyroiditis or ICI diabetes. Hydrocortisone before levothyroxine.
- Myasthenia, Guillain-Barre, encephalitis: withhold ICI at any grade; urgent neurology; check FVC, troponin and CK. Severe: start IVIG or plasma exchange with steroids now. Avoid drugs that worsen myasthenia.
05Decision Myocarditis suspected?
Chest pain, dyspnoea, arrhythmia, heart block, syncope, heart failure, or raised troponin
- If Yes
06Action Myocarditis: withhold ICI, admit, start IV steroids within 24 h
Mortality about 50%, even with normal LVEF. Confirmed myocarditis at any grade: stop ICI permanently.
- Admit with telemetry; CCU if troponin raised or conduction disease; urgent cardiology
- Adult: IV methylprednisolone 500-1000 mg once daily for 3-5 days (until troponin falls), then oral prednisolone taper over 4-6 weeks
- No response in 24-72 h: second-line agent with cardio-oncology (e.g. abatacept, mycophenolate, ATG). Do not use infliximab.
- Check for myositis and myasthenia (triple M): CK, ptosis, bulbar and breathing function
- Tests: ECG, troponin, BNP, CK, echo; cardiac MRI or biopsy as cardiology advises
07Action Stop ICI permanently; plan other cancer treatment
Myocarditis at any grade, or rechallenge not appropriate (e.g. most grade 4, severe pneumonitis, Guillain-Barre, severe myasthenia, SJS/TEN).
- Discuss other cancer treatment with the oncologist
- Long-term follow-up: irAEs can persist or start months to years later
- Continue hormone replacement if endocrine irAE
- Multidisciplinary follow-up
08Outcome irAE managed
Continue cancer care and irAE monitoring
If No09Decision Endocrine irAE only?
Thyroid dysfunction, hypophysitis, adrenal insufficiency or ICI diabetes, with no other irAE that needs steroids
- If Yes
10Action Endocrine irAE: replace hormones or give insulin; involve endocrinology
Suspected adrenal crisis: treat now. With adrenal insufficiency or hypophysitis, start hydrocortisone several days before levothyroxine (risk of adrenal crisis).
- Adrenal crisis (adult): hydrocortisone 100 mg IV/IM, then 200 mg per 24 h infusion (or 50 mg IV/IM 6-hourly); sodium chloride 0.9% 1000 mL in the first hour
- ICI diabetes: check glucose, ketones, venous gas; treat DKA with insulin per local protocol. Do not give steroids.
- Hypothyroidism: levothyroxine (lower start dose if older or heart disease). Thyrotoxicosis: beta-blocker for symptoms.
- Hypophysitis: hormone replacement; grade 2 or more also needs a higher steroid dose until symptoms settle (dose with endocrinology)
- Grade 1 thyroid: continue ICI. Adrenal, pituitary, DKA or grade 2+ thyroid: withhold ICI until stable. Replacement is often lifelong.
11Action Resume ICI when criteria met, with close monitoring
Endocrine irAE stable on replacement, or rechallenge judged appropriate.
- Resume when grade 1 or less and prednisolone 10 mg/day or less (physiological replacement is allowed)
- Prefer anti-PD-1 or anti-PD-L1 alone; do not restart anti-CTLA-4 after a high-grade irAE
- The same or a new irAE recurs in a large share of patients: educate and monitor closely
- Generally safe: endocrine irAEs on replacement, most skin irAEs, resolved grade 1-2 irAEs
- Path rejoins step 08Shared downstream outcome
If No12Warning Before steroids: exclude infection, check glucose, exclude perforation
These change treatment. They must not delay steroids in grade 3-4 or in life-threatening irAE.
- Infection can mimic colitis, hepatitis and pneumonitis: send cultures and viral tests; give empirical antibiotics if unsure
- Diabetes: steroids raise glucose. Check glucose at least daily and adjust treatment.
- Suspected GI perforation: no steroids and no infliximab; urgent surgical review
13Decision Other irAEs: grade severity (CTCAE v5.0)
Grade 1 mild; grade 2 moderate, limits instrumental ADLs; grade 3 severe, limits self-care or needs admission; grade 4 life-threatening. Organ-specific criteria apply (e.g. stool count, ALT, creatinine).
- Grade 3-4
14Action Grade 3-4: withhold ICI; usually admit; high-dose IV steroids
Grade 4: usually stop ICI permanently (endocrine irAEs controlled with replacement are an exception). Severe myasthenia, Guillain-Barre or encephalitis: add IVIG or plasma exchange now; do not wait for steroid failure.
- Adult: IV methylprednisolone 1-2 mg/kg/day (max 1 g/day; nephritis max 250 mg/day) for 3 days, then oral prednisolone 1-2 mg/kg/day
- Myasthenia or Guillain-Barre: IVIG or plasma exchange with steroids from the start, with neurology; monitor FVC. Guillain-Barre or encephalitis: pulse IV methylprednisolone 1 g/day for 3-5 days may be used
- Urgent specialist review for the organ involved
- Combination ipilimumab plus anti-PD-1: stop ipilimumab permanently after grade 3-4 colitis
- Hepatitis grade 3-4, nephritis grade 3-4, SJS or TEN: stop ICI permanently
- 1 mg prednisolone = 0.8 mg methylprednisolone
15Decision Steroid-refractory?
No improvement after 48-72 h of high-dose steroids (colitis: after 24 h of IV steroids; hepatitis: after 1-2 days), or relapse on taper
- If Yes
16Action Steroid-refractory: add a second agent with the organ specialist
Continue steroids. Do not give infliximab with myocarditis, heart failure, hepatitis or liver dysfunction, chronic hepatitis B, sepsis or GI perforation.
- Colitis: IV infliximab 5 mg/kg (adult) or IV vedolizumab 300 mg, with gastroenterology
- Hepatitis: mycophenolate or tacrolimus, with hepatology
- Pneumonitis: mycophenolate or IVIG preferred over infliximab (infection risk)
- Myasthenia or Guillain-Barre: IVIG or plasma exchange, with neurology
- Screen for hepatitis B and TB before infliximab, without delaying urgent treatment
- These uses are off-label in Australia
17Action Improved to grade 1 or less: taper steroids over at least 4-6 weeks
Taper slowly; fast tapers cause flares. Pneumonitis: reduce by 5-10 mg/week.
- Watch for relapse during taper; if it flares, increase the dose and taper more slowly
- PJP prophylaxis (e.g. trimethoprim-sulfamethoxazole) if prednisolone 20 mg/day or more for 4 weeks or more
- Monitor glucose, blood pressure and mood; consider gastric and bone protection
18Decision ICI rechallenge appropriate?
Oncologist decision, weighing cancer benefit against risk. Yes (grade 1 or less and prednisolone 10 mg/day or less): resume with close monitoring. No: stop ICI permanently.
- If Yes
- Path rejoins step 11Shared downstream outcome
If No- Path rejoins step 07Shared downstream outcome
If No- No - improving
- Path rejoins step 17Shared downstream outcome
- Grade 2
19Action Grade 2: withhold ICI; steroids for most organs
Colitis, pneumonitis, nephritis: start steroids once infection is excluded. Hepatitis: steroids if symptoms or rising LFTs.
- Adult: oral prednisolone 0.5-1 mg/kg/day (organ-specific; 1 mg/kg/day for colitis; nephritis max 60 mg/day)
- Seek specialist advice for the organ involved
- No improvement in 2-3 days on oral steroids: treat as grade 3-4
- Pneumonitis: prednisolone 1-2 mg/kg/day; recurrent grade 2 pneumonitis: stop ICI permanently
- Path rejoins step 15Shared downstream outcome
- Grade 1
20Action Grade 1: usually continue ICI with close monitoring
Exceptions: withhold ICI for suspected myocarditis, any neurological irAE, uveitis or scleritis (until eye review), and TTP, aplastic anaemia or acquired haemophilia. Pneumonitis: consider withholding until imaging improves.
- Symptomatic treatment (e.g. topical steroid, emollient, fluids)
- Loperamide only with caution: it can mask worsening colitis
- Repeat tests often (e.g. LFTs weekly). Worse or persisting: treat as grade 2.
- Path rejoins step 08Shared downstream outcome
Guideline Source
eviQ: Management of immune-related adverse events (irAEs), ID 1993 v6 (Cancer Institute NSW, 2026); ASCO 2021 irAE guideline update
Clinical Safety Information
Clinical Decision Support — Not a Substitute for Clinical Judgment
Individual patient factors may require deviation from these recommendations.
Known Limitations
- Adults only. Doses and holds are organ-specific; check the organ section of eviQ 1993 and involve the organ specialist.
- Rare irAEs (ocular, haematological, rheumatic, renal detail) are summarised only. Individualise care in frail or older patients.
- Rechallenge after grade 3-4 irAE is an individual oncologist decision.
- Second-line agents (infliximab, vedolizumab, abatacept, mycophenolate, IVIG) are off-label for irAEs in Australia.
Contraindicated Populations
Children: doses are for adults
Applicable Regions
AUNZUSEUUK
AU: eviQ ID 1993 (Cancer Institute NSW) is the Australian reference. Infliximab, vedolizumab, abatacept and ruxolitinib are not TGA-approved for irAEs.
Version 2Next review: 2027-09-30
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Frequently Asked Questions
What is the Immune Checkpoint Inhibitor Toxicity (irAE) Management?
The Immune Checkpoint Inhibitor Toxicity (irAE) Management is a management clinical algorithm for Hematology & Oncology. It provides a structured decision tree to guide clinical decision-making, based on eviQ: Management of immune-related adverse events (irAEs), ID 1993 v6 (Cancer Institute NSW, 2026); ASCO 2021 irAE guideline update.
What guideline is the Immune Checkpoint Inhibitor Toxicity (irAE) Management based on?
This algorithm is based on eviQ: Management of immune-related adverse events (irAEs), ID 1993 v6 (Cancer Institute NSW, 2026); ASCO 2021 irAE guideline update (DOI: 10.1200/JCO.21.01440).
What are the limitations of the Immune Checkpoint Inhibitor Toxicity (irAE) Management?
Known limitations include: Adults only. Doses and holds are organ-specific; check the organ section of eviQ 1993 and involve the organ specialist.; Rare irAEs (ocular, haematological, rheumatic, renal detail) are summarised only. Individualise care in frail or older patients.; Rechallenge after grade 3-4 irAE is an individual oncologist decision.; Second-line agents (infliximab, vedolizumab, abatacept, mycophenolate, IVIG) are off-label for irAEs in Australia.. Individual patient factors may require deviation from these recommendations.
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