Table 2 Management of immune-related adverse events according to severity [85].
From: Severe toxicity from checkpoint protein inhibitors: What intensive care physicians need to know?
Immune-related adverse events | Definitions of severe IrAE | Diagnostic workup before treatment | Steroid and other treatment |
|---|---|---|---|
Gastrointestinal Colitis: disorder with inflammation of colon | Grade III: > 7 stools/day or increase in ostomy output, incontinence, need for hospitalization, limited self-care/ADL Grade IV: life-threatening consequences | Metabolic and hematologic panel TSH Clostridium difficile, CMV, parasite CT scan abdomen and pelvis Endoscopy with biopsy | Consider permanently discontinuing CTAL4i. PD/PDL1 agent may be restarted if patient recovered. Consider MP 1–2 mg/kg/day and other immunosuppressive drugs after 3–5 days symptoms |
Lung Pneumonitis: focal or diffuse inflammation of lung parenchyma (no pathognomonic pattern) | Grade III: severe symptoms, need for hospitalization, more than 50% of parenchyma involved, limited self-care/ADL, need for oxygenation Grade IV: acute respiratory failure with life-threatening consequences | Chest X-ray Thoracic CT Nasal swab, sputum culture, blood and urine culture Bronchoscopy and BAL ± biopsy | Permanently discontinue CPI Empirical antibiotics and 1–2 mg/kg/MP Consider other immunosuppressive drugs after 2 days |
Heart Myocarditis, pericarditis, arrhythmia, impaired ventricular function, and vasculitis | Grade III: moderate abnormal testing or symptoms occurring with mild activity Grade IV: moderate to severe decompensation, life-threatening consequences | ECG, troponin, BNP Echocardiogram, chest X-ray Cardiac MRI Cardiac catheterization | Permanently discontinue CPI MP 1–2 mg/kg/day Consider other immunosuppressive agent or MP 1 g/day if no improvement |
Neurological Myasthenia gravis | Grade III–IV: limited self-care, aids warranted, weakness limiting walking, any dysphagia, facial or respiratory weakness or rapidly progressive symptoms | Anti-striated muscle antibody in blood, muscle specific kinase Pulmonary function assessment CPK, CRP ± MRI of spine or brain, EMG | Permanently discontinue CPI Consider MP 2 mg/kg/day MP and plasmapheresis and IVIg 2 g/kg over 5 days |
Guillain–Barré syndrome or peripheral neuropathy | Grade III–IV: severe symptoms, limited self-care, aids warranted, weakness limiting walking, any dysphagia, facial or respiratory weakness or rapidly progressive symptoms | Neurological consultation MRI spine Lumbar puncture EMG Pulmonary function testing | Discontinue CPI Consider MP 1–2 mg/kg/day and plasmapheresis |
Aseptic meningitis | Grade III–IV: severe symptoms, limited self-care, aids warranted | MRI with pituitary protocol Cortisol and ACTH test Lumbar puncture with measurement of opening pressure | Hold CPI until patient stabilization Consider restarting after risk/benefit analysis. MP 0.5–1 mg/kg |
Encephalitis | Grade III–IV: severe symptoms, limited self-care, aids warranted | Neurologic consultation Brain MRI Lumbar puncture EEG CRP, ± , ANCA, TPO, thyroglobulin | Hold CPI until patient stabilization Consider restarting after risk/benefit analysis. Steroid 1–2 mg/kg MP Consider pulse steroids 1 g IV 3–5 days |
Hepatitis | Grade III: symptomatic liver dysfunction, fibrosis by biopsy, cirrhosis, reactivation of chronic hepatitis, ASAT or ALAT 5–20 N, bilirubin 3–10 N Grade IV: decompensated liver function, ASAT or ALAT > 20 N, bilirubin > 10 N | Viral hepatitis, alcohol history, iron study, thromboembolic event Liver ultrasound (metastasis) ± antinuclear antibody, anti-smooth-muscle antibody, ANCA | Permanently discontinue CPI Steroids 1–2 mg/kg/day MP Consider other immunosuppressive agent after 3 days Avoid using Infliximab |
Endocrine Hypothyroidism Hyperthyroidism | Grade III–IV: severe symptoms, unable to perform ADL, life-threatening consequences | TSH and T4 dosage | Hold CPI until patient is stabilized Hormone replacement therapy |
Adrenal insufficiency | Grade III–IV: severe symptoms, unable to perform ADL, life-threatening consequences | ACTH dosage, cortisol level ± ACTH stimulation test | Hold CPI until patient is stabilized Hormone replacement therapy |
Hypophysitis | Grade III–IV: severe symptoms, unable to perform ADL, life-threatening consequences | ACTH dosage, cortisol level +/-ACTH stimulation test TSH and T4 dosage, LH, FSH Brain MRI | Hold CPI until patient has stabilized Hormone replacement therapy |
Diabetes mellitus | Grade III–IV: severe symptoms, unable to perform ADL, life-threatening consequences Grade III: blood sugar 13.9–27.8 mmol/l Grade IV: blood sugar > 27.8 mmol/l | Anti-insulin antibody, anti-islet antibody C peptide levels | Hold CPI until glucose control Initiate Insulin therapy |
Kidney Nephritis | Grade III: creatinine level > 3 × baseline or > 350 µmol/l Grade IV: life-threatening complication, dialysis required | Rule out other causes of AKI Urinary tract infection | Permanently discontinue CPI MP 1–2 mg/kg/day |
Hematologic Autoimmune hemolytic anemia | Grade III: Hb < 8 g/dl, transfusion indicated Grade IV: life-threatening complication | Drug history, insect bites LDH, haptoglobin, bilirubin, reticulocyte count, autoimmune serology PNH Viral or bacterial infection Protein electrophoresis, cryoglobulin analysis G6PD, methemoglobinemia B12, folate, parvovirus, thyroid ± ADAMTS 13 | Permanently discontinue CPI MP 1–2 mg/kg/day Consider other immunosuppressive agent if no improvement. |
Immune thrombocytopenia | Grade III: platelet count < 50/mm3 Grade IV: platelet count < 25/mm3 | HIV, hepatitis B or C, Helicobacter pylori Reticulocyte count, blood smear ± bone marrow | Hold CPI until improvement Steroid oral 1–2 mg/kg/day Consider IVIg Consider permanently discontinue CPI if no improvement |
Skin Rash Bullous dermatoses | Grade III: affects quality of life if no response to treatment (rash) Over 30% of body surface (bullous dermatoses) affected, with pain Over 10% of body surface or mucosal involvement (DRESS, pustulosis) Grade IV: > 30% body surface with electrolyte abnormalities (bullous dermatoses) >10% body surface with blood abnormality (liver function) | Whole body examination Assessment for drug, infection Skin biopsy | Permanently discontinue CPI MP 1–2 mg/kg/day Consider other immunosuppressive agent if no improvement |