Table 2.

Definitions for Immune Checkpoint Inhibitor Associated Myocarditis

CTCAE Version 5*
A disorder characterized by inflammation of the muscle tissue of the heart.
Grade 2 Symptoms with moderate activity or exertion	Grade 3 Severe with symptoms at rest or with minimal activity or exertion; intervention indicated; new onset of symptoms	Grade 4 Life-threatening consequences; urgent intervention indicated (e.g., continuous IV therapy or mechanical hemodynamic support)
Bonaca et al.
Definitive	Pathology OR Diagnostic CMR + syndrome +biomarker or ECG OR Echo WMA + syndrome + biomarker + ECG + negative angiography
Probable	Diagnostic CMR (no syndrome, ECG, biomarker) OR Suggestive CMR with either syndrome, ECG or biomarker OR Echo WMA and syndrome (with either biomarker or ECG) OR Syndrome with PET scan evidence and no alternative diagnosis
Possible	Suggestive CMR with no syndrome, ECG or biomarker OR Echo WMA with syndrome or ECG only OR Elevated biomarker with syndrome or ECG and no alternative diagnosis
IC-OS 2021 Consensus
Either pathohistological diagnosis: Multifocal inflammatory cell infiltrates with overt cardiomyocyte loss by light microscopy of cardiac tissue samples
Or clinical diagnosis # §: A troponin elevation (new, or significant change from baseline) with 1 major criterion or a troponin elevation (new, or significant change from baseline) with 2 minor criteria after exclusion of acute coronary syndrome or acute infectious myocarditis based on clinical suspicion
Major Criterion • CMR diagnostic for acute myocarditis (modified Lake Louise criteria)
Minor Criteria • Clinical syndrome (including any one of the following: fatigue, muscle weakness, myalgias, chest pain, diplopia, ptosis, shortness of breath, orthopnea, lower extremity edema, palpitations, lightheadedness/dizziness, syncope, cardiogenic shock) • Ventricular arrhythmia and/or new conduction system disease • Decline in cardiac (systolic) function, with or without regional WMA in a non-Takotsubo pattern • Other immune-related adverse events, particularly myositis, myopathy, myasthenia gravis • Suggestive CMR (meeting some but not all of the modified Lake Louise citeria)
Both troponin I and troponin T can be used; however, troponin T may be falsely elevated in those with concomitant myositis. #Clinical diagnoses should be confirmed with CMR or endomyocardial biopsy if possible and without causing delays of treatment §In a patient that is clinically unwell, treatment with immunosuppression should be promptly initiated while awaiting further confirmatory testing.
Modifiers
Severity of Myocarditis
Severe	Hemodynamic instability, heart failure requiring non-invasive or invasive ventilation, complete or high-grade heart block, and/or significant ventricular arrhythmia
Non-Severe (clinically significant)	Symptomatic but hemodynamically and electrically stable, may have reduced LVEF, no features of severe disease
Smoldering (sub-clinical)	Incidentally diagnosed myocarditis without any clinical signs or symptoms
Steroid Refractory	Non-resolving or worsening myocarditis (clinical worsening or persistent troponin elevation after exclusion of other etiologies) despite high dose methylprednisolone
Recovery from Myocarditis
Complete Recovery	Patients with complete resolution of acute symptoms, normalization of biomarkers and recovery of LVEF after discontinuation of immunosuppression are considered to have achieved complete recovery. CMR may still show LGE or elevated T1 due to fibrosis but any suggestion of acute edema should be absent.
Recovering	Ongoing improvement in patient clinical symptoms, signs, biomarkers and imaging parameters, but not yet normalized, while on tapering doses of immunosuppression.

CMR, cardiac magnetic resonance; CTCAE, Common Terminology Criteria for Adverse Events; cTn, cardiac troponin; ECG, electrocardiogram; Echo, echocardiogram; EMB, endomyocardial biopsy; IC-OS, International Cardio-Oncology Society; IV, intravenous; LBBB, left bundle branch block; LGE, late gadolinium enhancement; LV, left ventricular; LVEF, left ventricular ejection fraction; PET, positron emission tomography; RBBB, right bundle branch block; WMA, wall motion abnormalities.

*Grade 5 = death.