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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
  1. ADL activities of daily living, TSH thyroid-stimulating hormone, CMV cytomegalovirus, BAL bronchoalveolar lavage, MRI magnetic resonance imaging, BNP Brain natriuretic peptide, CPK creatine phosphokinase, CRP C-reactive protein, MP methylprednisolone or equivalent, EMG electromyogram, ANCA Antineutrophil cytoplasmic antibodies, TPO thyroid peroxidase, AKI acute kidney failure, PHN Paroxysmal nocturnal hemoglobinuria, ADAMTS 13 a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, DRESS drug reaction with eosinophilia and systemic symptoms, HIV human immunodeficiency virus