Immune checkpoint inhibitor associated myocarditis occurs in both high-grade and low-grade forms.

Immune checkpoint inhibitor therapy for malignancy has been associated with adverse events including myocarditis. It has been unclear if there are distinct pathologic grades of this myocarditis that are associated with distinct clinical outcomes. Cardiac tissue from ten patients with immune checkpoint inhibitor myocarditis (nine biopsies and one autopsy) were evaluated using immunohistochemistry for CD3, CD8, CD68, tryptase, PD-L1, and C4D. The immune checkpoint inhibitor myocarditis cases were classified as either high grade (>50 CD3+ cells/hpf) or low grade (≤50 CD3+ cells/hpf). The densities of macrophages, T cells, eosinophils, necrotic myocytes, and PD-L1+ macrophages and myocytes were compared between the two groups and with 13 cases of grade 2R acute cellular allograft rejection. Three patients were classified as high-grade myocarditis and seven as low grade. There were higher densities of CD3+ cells and CD8+ cells in high-grade immune checkpoint inhibitor myocarditis and rejection compared with low-grade myocarditis. The number of CD68+ macrophages was higher in high-grade myocarditis compared with low-grade myocarditis and rejection. For both grades of myocarditis, there was a higher CD68/CD3 ratio and a higher density of PD-L1+ macrophages and myocytes compared with rejection. Clinically, there were trends toward higher serum troponin levels and shorter interval from first immune checkpoint inhibitor treatment in the high-grade myocarditis group compared with the low-grade group. All the patients with high-grade myocarditis died, while all the patients with low-grade myocarditis were still living. These data suggest that immune checkpoint inhibitor myocarditis occurs in two forms, a high-grade form with increased inflammatory cell infiltration and a more fulminant clinical course, and a low-grade form with a lower degree of inflammatory cell infiltration and a more indolent clinical course. Compared with acute cellular rejection, immune checkpoint inhibitor myocarditis is characterized by a more lymphohistiocytic inflammatory infiltrate with an increased CD68/CD3 ratio and increased PD-L1+ macrophages and myocytes.