Inflammatory Cell Profiles in Early- and Late-Manifestation Immune Checkpoint Inhibitor Myocarditis

Immune checkpoint inhibitor (ICI) myocarditis typically develops soon after treatment initiation (<90 days) but may also occur as a delayed complication after discontinuation of ICI therapy. The clinical and histopathologic differences between early- and late-manifestation ICI myocarditis remain unclear.

This study sought to compare the clinical features and myocardial histopathology of early- versus late-manifestation ICI myocarditis.

We conducted a retrospective national cohort study of patients diagnosed with myocarditis after ICI initiation who underwent endomyocardial biopsy. Biopsy samples were analyzed for inflammatory cell infiltration, severity of myocardial inflammation, and collagen volume fraction.

Among 35 patients (mean age: 66 ± 13 years; 71.4% male), 26 (74.3%) developed early-manifestation myocarditis (<90 days), whereas 9 (25.7%) had late-manifestation myocarditis (≥90 days). Early-manifestation cases showed significantly more severe myocardial inflammation; higher levels (median [Q1-Q3]) of CD3⁺ T cells (432 [173-1,381] vs 121 [43-400] cells/mm²; P = 0.036), CD8⁺ T cells (289 [73-994] vs 86 [21-168] cells/mm²; P = 0.019), and CD 68⁺ macrophages (307 [116-841] vs 57 [36-200] cells/mm²; P = 0.008); and higher CD4⁺ T-cell levels that did not reach statistical significance (P = 0.054). There were no significant differences in regulatory T cells or collagen volume. Clinically, early-manifestation myocarditis was characterized by higher cardiac biomarker levels and older age, whereas left ventricular ejection fraction was similar between groups. Mortality due to myocarditis occurred in 2 early-manifestation cases and in no late-manifestation cases. Conversely, cancer-related mortality was more frequent in the late-manifestation group (n = 3) than in the early-manifestation group (n = 2). ICI therapy was reinitiated in only 2 patients overall.

Late-manifestation ICI myocarditis may represent a temporally distinct or partially attenuated inflammatory phase. Despite a milder inflammatory profile, higher cancer-related mortality was observed, suggesting that cautious ICI reinitiation may warrant consideration in selected patients within this subgroup.