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onc.irae-management.core.v1

Immune-related adverse events (irAE) — checkpoint inhibitor toxicity management

oncologyacuteadultgeriatricoutpatientacuteinpatient
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Cross-disease ICI-toxicity management engine — covers PD-1 (nivolumab, pembrolizumab, cemiplimab), PD-L1 (atezolizumab, durvalumab, avelumab), CTLA-4 (ipilimumab), LAG-3 (relatlimab), alone or combined. 7 organ-system regimen axes (colitis, pneumonitis, hepatitis, myocarditis, endocrinopathy, neurologic, other) with NCCN 2024 + ASCO 2021 + ESMO 2022-anchored grade-stratified IS escalation. Critical safety rules embedded: empirically treat any ICI patient with troponin rise (Mahmood JACC 2018 PMID 29567210); INFLIXIMAB CONTRAINDICATED in cardiac irAE with HF (abatacept preferred salvage); INFLIXIMAB CONTRAINDICATED in ICI hepatitis (MMF preferred — TNF-alpha hepatotoxicity); replace CORTISOL before THYROID HORMONE in panhypopituitarism. 7 severity triggers covering all life-threatening organ-specific subtypes plus the combined Triple-M syndrome. 10 immunosuppressant + endocrine replacement RxCUIs RxNav-verified 2026-05-26 (methylprednisolone IN 6902, prednisone 8640, infliximab 191831, vedolizumab 1538097, MMF 68149, abatacept 614391, tocilizumab 612865, levothyroxine 10582, hydrocortisone 5492, IVIG 1426680). All 4 evidence PMIDs PubMed-MCP-verified 2026-05-26. Three candidate PMIDs from the prompt dropped as wrong-article (35550581 = fiber-optic inclinometer; 31075455 = ruptured AAA survival; 29420041 = chemistry synthesis paper — none used).

Entry points (7)

  • medication
    Active checkpoint inhibitor therapy (PD-1/PD-L1/CTLA-4/LAG-3) with new symptom or laboratory abnormality of any organ system — irAE until proven otherwise (NCCN 2024)
    active_ici_with_new_symptom
  • lab_abnormality
    Any troponin elevation in an ICI patient — STAT cardiology + STAT empiric methylprednisolone 1 g IV (Mahmood JACC 2018 PMID 29567210)
    troponin_rise_in_ici_patient
  • symptom
    Diarrhea >4 stools above baseline, or any bloody stool, in an ICI patient — suspect colitis (NCCN 2024)
    persistent_diarrhea_or_bloody_stool_on_ici
  • symptom
    New dyspnea, cough, hypoxia in an ICI patient — suspect pneumonitis; HRCT chest (NCCN 2024)
    new_dyspnea_or_cough_on_ici
  • lab_abnormality
    AST/ALT >3x ULN or >5x baseline in an ICI patient — suspect hepatitis (NCCN 2024)
    lft_elevation_on_ici
  • lab_abnormality
    Abnormal TSH, low cortisol, hyperglycemia in an ICI patient — suspect endocrinopathy (NCCN 2024)
    tsh_or_cortisol_abnormality_on_ici
  • symptom
    New motor weakness, ptosis, diplopia, sensory deficit, confusion in an ICI patient — suspect Guillain-Barre / myasthenia / encephalitis (NCCN 2024)
    neurologic_symptom_on_ici

Required inputs (14)

  • specific_ici_agent_and_combination_statusrequired
    medication • used at FRAME
    PD-1 vs PD-L1 vs CTLA-4 vs combination; combination ipi+nivo carries 2-3x irAE severity (CheckMate-067)
  • days_since_last_ici_doserequired
    history • used at FRAME
    Time-since-dose helps differentiate irAE timing; peak myocarditis 4-6 wk; colitis often after cycle 2-3; thyroiditis at any cycle
  • prior_irae_episodesrequired
    history • used at CONTEXT
    Prior irAE increases recurrence risk; multi-organ pattern (Triple-M) requires aggressive workup
  • cancer_diagnosis_and_prognosisrequired
    history • used at CONTEXT
    Cancer prognosis informs decision on permanent ICI discontinuation
  • concomitant_autoimmune_disease
    history • used at CONTEXT
    Pre-existing autoimmune disease (IBD, RA, SLE) baseline state and flare risk
  • cbcrequired
    lab • used at INITIAL_WORKUP
    Baseline cytopenia; rules out concurrent neutropenia
  • lftrequired
    lab • used at INITIAL_WORKUP
    AST/ALT/bilirubin/ALP for hepatitis grading (CTCAE v5)
  • creatininerequired
    lab • used at INITIAL_WORKUP
    eGFR baseline; nephritis screen; steroid dose adjustment
  • troponin_if_cardiac_suspicion
    lab • used at INITIAL_WORKUP
    High-sensitivity troponin is most sensitive ICI myocarditis screen; treat any elevation empirically (Mahmood JACC 2018 PMID 29567210)
  • tsh_cortisol_glucose
    lab • used at INITIAL_WORKUP
    Endocrinopathy screen — thyroiditis most common; hypophysitis primarily ipi; adrenal crisis screen
  • ck_total
    lab • used at INITIAL_WORKUP
    CK rises in myositis; combined irAE with myocarditis common (Triple-M)
  • lipase
    lab • used at INITIAL_WORKUP
    Lipase elevation suggests pancreatitis irAE
  • ecg_if_cardiac_suspicion
    imaging • used at INITIAL_WORKUP
    ECG for AV block, ventricular ectopy — characteristic in ICI myocarditis
  • cxr_or_hrct_chest_if_resp_symptoms
    imaging • used at INITIAL_WORKUP
    COP-like or NSIP-like patterns common in ICI pneumonitis

12-phase flow (12)

  1. 1FRAME
    Identify ICI class + combination status + time-since-dose; flag prior irAE; flag known autoimmune comorbidity. Combination ipi+nivo carries 2-3x irAE severity vs monotherapy (CheckMate-067 PMID 28889792)
    inputs: specific_ici_agent_and_combination_status, days_since_last_ici_dose
    advance: ICI exposure profile documented (NCCN 2024)
  2. 2ENTRY
    Capture trigger: new symptom (dyspnea, diarrhea, weakness, headache) or new lab abnormality (LFT, TSH, cortisol, troponin, glucose) in an ICI patient — irAE until proven otherwise (NCCN 2024)
    advance: Trigger documented; organ-system suspicion noted (NCCN 2024)
  3. 3CONTEXT
    Cancer diagnosis + prognosis; prior irAE history; concomitant autoimmune disease; concomitant immunosuppressants/steroids; baseline performance status (NCCN 2024)
    inputs: cancer_diagnosis_and_prognosis, prior_irae_episodes
    advance: Context for risk-benefit of immunosuppression vs cancer control documented (NCCN 2024)
  4. 4RED_FLAGS
    Myocarditis (any troponin rise — STAT methylpred 1 g IV); fulminant pneumonitis with hypoxia <90% on RA; grade 4 hepatitis (ALT >20x ULN or bilirubin >3x ULN); grade 4 colitis with perforation or megacolon; encephalitis; new DKA from T1DM; adrenal crisis from hypophysitis. ALL require immediate inpatient escalation (NCCN 2024 + Mahmood JACC 2018 PMID 29567210)
    inputs: troponin_if_cardiac_suspicion
    actions: panel.cardiac
    advance: Red flags screened; emergent treatment + admission triggered if positive (NCCN 2024)
  5. 5INITIAL_WORKUP
    Universal: CBC + CMP + LFTs + lipase + UA; organ-targeted: ECG + troponin (cardiac), TSH + free T4 + AM cortisol + glucose (endocrine), HRCT chest (pulmonary), CK + LDH (muscle); infectious workup BEFORE immunosuppression for colitis (C diff, CMV, EBV) and hepatitis (HBV/HCV/HEV serologies) (NCCN 2024 / ASCO 2021 PMID 34724392)
    inputs: cbc, lft, creatinine
    actions: panel.cbc, panel.lft, panel.renal, panel.cardiac, panel.thyroid
    advance: Baseline labs + organ-targeted imaging + infectious-screen documented (NCCN 2024)
  6. 6BRANCHING_WORKUP
    Organ-specific deep workup: cardiac MRI Lake Louise + endomyocardial biopsy if life-threatening myocarditis; HRCT with COP/NSIP pattern for pneumonitis; flex sig + biopsy + stool studies for colitis; MRI pituitary for hypophysitis suspicion; liver biopsy for hepatitis grade >=3 if equivocal etiology; LP for encephalitis; NCS + ACh-receptor Ab for myasthenia; spirometry / DLCO for pneumonitis recovery (NCCN 2024 + ESMO 2022 PMID 36270461)
    advance: Organ-system diagnosis confirmed and infection ruled out (NCCN 2024)
  7. 7DIFFERENTIAL
    irAE vs disease progression vs infection vs other drug toxicity vs metastasis; multi-organ "Triple-M" syndrome (myocarditis + myositis + myasthenia) — recognise early as it worsens prognosis (NCCN 2024)
    advance: irAE confirmed and graded (CTCAE v5) per organ (NCCN 2024)
  8. 8RISK_STRATIFICATION
    CTCAE v5 grading per organ: G1 monitor, G2 hold ICI + low-dose pred, G3 hold ICI + high-dose IV steroid + 2nd-line IS if no response 3-5 d, G4 permanent d/c + maximal IS. Combined irAE elevates grade by 1 level for management intensity (NCCN 2024)
    advance: Grade assigned per organ; combined irAE status documented (NCCN 2024)
  9. 9TREATMENT
    Stepwise per organ + grade: Colitis G2 budesonide / oral pred, G3-4 IV methylpred 1-2 mg/kg + infliximab 5 mg/kg if no response 3-5 d, then vedolizumab for steroid-dependent / refractory. Pneumonitis G3-4 IV methylpred 2-4 mg/kg + infliximab or MMF. Hepatitis G3+ IV methylpred 1-2 mg/kg + MMF (AVOID infliximab — hepatotoxic). Myocarditis empiric methylpred 1 g IV + abatacept if refractory (INFLIXIMAB CONTRAINDICATED for cardiac with HF). Endocrinopathy: levothyroxine for hypothyroid (continue ICI), hydrocortisone stress-dose for adrenal crisis. Neurologic: methylpred 1 g IV + IVIG 2 g/kg over 2-5 d +/- plasmapheresis. Steroid taper over 4-6 wk minimum with PJP prophylaxis if pred >20 mg for >4 wk (NCCN 2024 + ASCO 2021 PMID 34724392 + ESMO 2022 PMID 36270461 + Mahmood PMID 29567210)
    inputs: creatinine
    advance: Per-organ regimen started with grade-appropriate intensity (NCCN 2024)
  10. 10DISPOSITION
    Outpatient for grade 1-2 stable with daily symptom check; admit for grade 3-4, any suspected myocarditis, severe colitis, fulminant hepatitis, neurologic with respiratory weakness, adrenal crisis, DKA. ICU for fulminant myocarditis or encephalitis or grade 4 pneumonitis. (NCCN 2024)
    advance: Care setting matches grade + organ severity (NCCN 2024)
  11. 11MONITORING
    Daily labs during admission (LFT, creatinine, glucose, troponin per organ); weekly outpatient labs during steroid taper; echo at 6 wk if myocarditis; HRCT at 4-6 wk if pneumonitis; flex sig at 4-6 wk if colitis grade >=3; TSH + cortisol q4-6 wk for endocrinopathy surveillance (NCCN 2024)
    actions: panel.cbc, panel.lft, panel.cardiac, panel.thyroid
    advance: Organ-specific surveillance + steroid taper plan documented (NCCN 2024)
  12. 12FOLLOWUP
    Steroid taper over 4-6 wk minimum; PJP prophylaxis (TMP-SMX 3x/wk) if prednisone >20 mg for >4 wk; PPI; calcium + vitamin D + bisphosphonate for long-term steroid; endocrinopathy permanent replacement (levothyroxine, hydrocortisone, insulin); rechallenge decision per NCCN 2024 — most G3 + all G4 myocarditis/pneumonitis/encephalitis/hepatitis permanently discontinue; G2 rechallenge feasible after resolution. Multidisciplinary cancer follow-up with primary oncology team for alternative therapy if permanent d/c (NCCN 2024)
    advance: Steroid taper + prophylaxis + replacement + rechallenge decision + oncology follow-up documented (NCCN 2024)