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

Champion, Samantha N; Stone, James R.

doi:10.1038/s41379-019-0363-0

Cited by 78 publications

(83 citation statements)

References 40 publications

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“…In some previous studies not related to COVID-19, particularly involving endomyocardial biopsies, such pathology was regarded as myocarditis. 22 , 23 However, the significance of these lymphocytic infiltrates with no to only focal myocardial injury in the COVID-19 autopsy population is currently unclear and may not be indicative of myocarditis.…”

Section: Discussionmentioning

confidence: 99%

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study

Basso

Leone

Rizzo

et al. 2020

European Heart Journal

411

365

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Aims Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described. Methods and results In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified. Conclusions In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.

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Section: Discussionmentioning

confidence: 99%

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study

Basso

Leone

Rizzo

et al. 2020

European Heart Journal

411

365

View full text Add to dashboard Cite

show abstract

“…These cells subsequently attack the myocardium, resulting in the accumulation of CD3 + CD8 + T cells, macrophages, and neutrophils in the heart. 33,34 The prevalence rate of cardiac side effects of checkpoint inhibitors is common, which can reach 25% or more. 35 Although the prevalence rate of FM from checkpoint inhibitors is <1% and is much lower than other targets, its fatality rate is as high as 40~70%.…”

Section: Etiologymentioning

confidence: 99%

Fulminant myocarditis: a comprehensive review from etiology to treatments and outcomes

Hang

Chen

Seubert

et al. 2020

Sig Transduct Target Ther

103

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Fulminant myocarditis (FM) is characterized by a rapid progressive decline in cardiac function and a high mortality rate. Since the first report of FM patients in the 1980s, several clinical trials and research studies have been published increasing our knowledge regarding FM. Currently, the diagnosis of FM depends on various techniques including electrocardiography, echocardiography, endomyocardial biopsy, and cardiac magnetic resonance. The development of mechanical circulation support (MCS) devices and progress in our understanding of the pathophysiological mechanisms underlying FM, treatment regimens have evolved from simple symptomatic treatment to a life support-based comprehensive treatment approach. The core mechanism underlying the development of FM is the occurrence of an inflammatory cytokine storm. This review provides a comprehensive account of the current understanding of FM pathophysiology and knowledge regarding its etiology, pathophysiology, treatments, and outcomes.

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“…The skin, endocrine system and gastrointestinal (GI) tract are among the most common systems involved by IRAEs, 1 and their pathological findings frequently mimic those of idiopathic or autoimmune diseases, such as inflammatory bowel disease (IBD), 2–5 lupus nephritis, 6 myocarditis, 7,8 hypophysitis, 9 pancreatitis, and autoimmune thyroiditis 1 . Expression of checkpoint ligands in non‐tumoral tissues affected by IRAEs has been described in the pituitary gland of patients with checkpoint inhibitor‐associated hypophysitis [cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4)], 9,10 myocytes of patients with ICI‐related programmed death‐ligand 1 (PD‐L1) myocarditis (PD‐L1), 7,8 and renal tubules of patients with ICI‐related acute interstitial nephritis (PD‐L1) 11 . This may play a direct role in the pathogenesis of IRAEs, as is the case for hypophysitis, in which direct binding of anti‐CTLA4 to CTLA4‐bearing pituitary endocrine cells leads to complement activation, macrophage infiltration, and tissue injury (type II hypersensitivity reaction), as well as later infiltration with autoreactive T cells (type IV hypersensitivity) 9,10 ; or it may represent a secondary response to further limit T‐cell‐mediated injury 12 .…”

Section: Introductionmentioning

confidence: 99%

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

et al. 2020

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Aims Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of advanced malignancies by boosting immune‐mediated destruction of neoplastic cells, but are associated with side effects stemming from generalised immune system activation against normal tissues. Checkpoint ligand expression in non‐tumoral cells of tissues affected by immune‐related adverse effects has been described in ICI‐associated hypophysitis, myocarditis, and acute interstitial nephritis. We aimed to investigate the tissue expression of the immune checkpoint receptor programmed cell death‐1 (PD‐1) and its ligand, programmed death‐ligand 1 (PD‐L1), in PD‐1 inhibitor‐associated colitis (PD1i colitis). Methods and results PD‐1 and PD‐L1 immunohistochemical expression levels were analysed in 15 cases of PD1i colitis and potential mimics—infectious colitis and inflammatory bowel disease (IBD). Increased epithelial expression of PD‐L1 was observed in PD1i colitis as compared with normal colon and infectious colitis, but the expression level was lower than that in IBD. Conversely, PD‐1 expression in inflammatory cells was higher in infectious colitis, intermediate in IBD, and minimal or absent in normal colon and in patients receiving PD‐1 inhibitors. Conclusions Although our results do not justify the use of PD‐L1 as a discriminatory marker of PD1i colitis against other entities within the differential diagnosis, they support the concept that PD1i colitis and IBD have similar pathogenetic mechanisms. They also highlight the fact that PD‐L1 epithelial overexpression is a commonly used mechanism of the gastrointestinal tract mucosa to protect itself from inflammatory‐mediated damage resulting from different aetiologies, which probably underpins the high incidence of gastrointestinal immune‐related adverse effects in patients receiving ICI therapies, in whom this mechanism is disrupted.

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

Cited by 78 publications

References 40 publications

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study

Fulminant myocarditis: a comprehensive review from etiology to treatments and outcomes

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

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