Diagnostic algorithm for clozapine-induced myocarditis: A systematic review

Table 4 Summary of the significance of various tests for both clozapine-induced myocarditis and clozapine-induced pneumonia

Test	CIM sensitivity/specificity	CIP sensitivity/specificity	Dynamic monitoring	Comments
EKG changes	Non-specific and seen in 78% of patients[21]	Non-specific[40]	NA	Feasible in all settings
				Non-specific changes (e.g., ST changes, T-wave inversion) in CIM; normal in 22% of cases
				Limited use in CIP
cTnl	34%/89%	Elevated by 52%[43]	Cornerstone for CIM screening; elevated in CIP	Feasible in all settings
				Repeating testing is critical for trends (> 20% rise suggests escalation)
CRP	52%/81%[22]	Elevated in 75%[44]	Yes (24-48 hours) in CIM Repeat testing (e.g., > 50 mg/L) informs interim management	Feasible in all settings
Echo changes	Nonspecific and seen in 30-60%[23]	Likely normal	Yes (48 hours-5 days)	Feasible in most settings
				Detects wall motion defects in CIM, normal in CIP. Serial testing is key in resource-limited settings (echo-only pathway)
Chest X-ray	NA	51% sensitivity	NA	Feasible in most settings
				Misses CIP in approximately 50% of cases; used in resource-limited settings. Normal X-ray requires clinical correlation
Chest CT	NA	90.7%	NA	Gold standard for CIP; critical for excluding CIP in CIM workup
				Limited to well-resourced settings due to cost (300 dollars-1000 dollars)
Endomyocardial biopsy	60%/80%[28]	NA	NA	Gold standard for CIM; invasive, rarely used. Feasible only in specialized centers with severe cases
Cardiac MRI	88%/91%[32]	NA	NA	Non-invasive, highly sensitive for CIM
				Limited by cost (1000 dollars-3000 dollars) and access (2-4-week wait)
				Preferred in well-resourced settings

Dynamic monitoring: Indicates whether serial testing (e.g., 24-48 hours for biomarkers, 48 hours to 5 days for echocardiography) enhances diagnostic precision, as per the interim management strategy in Figure 2. Resource availability: Chest X-ray, electrocardiogram, echocardiography, and biomarkers are feasible in resource-limited settings; however, chest computed tomography and cardiac magnetic resonance imaging are typically limited to well-resourced settings. Differentiation: Clozapine-induced pneumonia exclusion via chest computed tomography (or X-ray in resource-limited settings) is critical before clozapine-induced myocarditis (CIM) confirmation. Echocardiography and cardiac magnetic resonance imaging are key for CIM, with serial testing improving reliability in resource-limited settings. Sensitivity and specificity data for CIM are primarily derived from viral myocarditis studies[4,30]. CIM-specific data are limited and require validation. cTnl: Cardiac tropinin; CRP: C-Reactive protien; CT: Computed tomography; MRI: Magnetic resonance imaging; CIM: Clozapine-induced myocarditis; CIP: Clozapine-induced pneumonia; NA: Not available.