{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T05:21:25Z","timestamp":1787721685615,"version":"build-2784847793"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitor (ICI)-associated myocarditis (ICI-M) is a rare but potentially lethal immune-related adverse event (irAE). Early identification of fulminant (severe) cases remains challenging, and the peripheral immune derangements underlying ICI-M are incompletely characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The disproportionality analysis was performed using the FDA Adverse Event Reporting System (FAERS) database (2015\u20132026) for patients treated with eight ICIs. A retrospective cohort of 100 patients who developed ICI-M was stratified into severe and non-severe groups. Peripheral blood cells and their derived ratio index were analyzed. A severity-predictive nomogram was developed using features selected by three machine learning methods, and was evaluated by calibration, receiver operating characteristic, and decision curve analyses. Single-cell RNA-seq data from peripheral blood mononuclear cells were analyzed to explore immune landscape alterations for ICI-M.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      FAERS analysis revealed strong signals for ICI-M across all eight ICIs, with &amp;gt;80% of cases occurring within three months of therapy. Associations between peripheral blood cells\/derived ratio indexes and ICI-M were identified: the (neutrophil + monocyte) to lymphocyte ratio (NMLR), cTnI, and NT-proBNP were identified as key predictors of severe ICI-M. The 3-feature-based exploratory nomogram demonstrated a relatively good predictive performance (Area under curve = 0.849) with internal validation performed via 1000 bootstrap samples. Single-cell profiling identified monocyte expansion and lymphocyte contraction for ICI-M and its severity. The pseudotime ordering, ligand\u2013receptor inference, subcluster differential abundance analysis, and pathway enrichment analyses associated a distinct\n                      <jats:italic>FCGR3A<\/jats:italic>\n                      + monocyte subset with a potential role in ICI-M development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides a multi-dimensional view of ICI-M, integrating clinical and single-cell immune profiling analysis of peripheral blood cells as well as pharmacovigilance data. The developed nomogram may serve as a potential tool for identifying severe ICI-M, although external validation in independent cohorts is warranted. Insight into the immune landscape may inform future therapeutic strategies targeting specific cell\u2013cell interactions in ICI-M.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1834913","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:43:27Z","timestamp":1787719407000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral blood cells and immune checkpoint inhibitor-associated myocarditis: a retrospective clinical study with pharmacovigilance and single-cell analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhenli","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]},{"name":"Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University International Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zipei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]},{"name":"Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piaoran","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]},{"name":"Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengkun","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]},{"name":"Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyan","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]},{"name":"Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiezhu","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaozhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenghui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]},{"name":"Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]},{"name":"Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingtao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Hospital of Hebei Medical University\/The Tumor Hospital of Hebei Province","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-18-0367","article-title":"Fundamental mechanisms of immune checkpoint blockade therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discov"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2025.4543","article-title":"Immune checkpoint inhibitor-associated cardiovascular toxic effects: International Cardio-Oncology Society position statement","volume":"12","author":"Herrmann","year":"2026","journal-title":"JAMA Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2025.103011","article-title":"Immune checkpoint inhibitor-related neurotoxicity: Incidence and management. A systematic review and meta-analysis","volume":"140","author":"Nielsen","year":"2025","journal-title":"Cancer Treat Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz026","article-title":"Cardiovascular toxicities associated with immune checkpoint inhibitors","volume":"115","author":"Hu","year":"2019","journal-title":"Cardiovasc Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyaf285","article-title":"Immune checkpoint inhibitor-related myocarditis: a comprehensive analysis of clinical manifestations and prognostic factors","volume":"30","author":"Fan","year":"2025","journal-title":"Oncologist"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.102536","article-title":"Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective","volume":"70","author":"Gougis","year":"2024","journal-title":"EClinicalMedicine"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/ehjcvp\/pvag006","article-title":"Cardiac adverse events associated with dual immune checkpoint inhibitors: a pharmacovigilance analysis from the FDA adverse event reporting system","volume":"12","author":"Xia","year":"2026","journal-title":"Eur Heart J Cardiovasc Pharmacother"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.120.018306","article-title":"Decreased absolute lymphocyte count and increased neutrophil\/lymphocyte ratio with immune checkpoint inhibitor-associated myocarditis","volume":"9","author":"Drobni","year":"2020","journal-title":"J Am Heart Assoc"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.36660\/abc.20250047","article-title":"Prognostic value of troponin to lymphocyte ratio in patients with immune checkpoint inhibitor-associated myocarditis","volume":"122","author":"Chen","year":"2025","journal-title":"Arq Bras Cardiol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1762144","article-title":"Integrated risk stratification for ICI-associated myocarditis: a baseline hematological profile and a combined ECG and enzymatic signature at onset","volume":"17","author":"Zheng","year":"2026","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.21037\/cdt-24-556","article-title":"Development of peripheral biomarker-based prognostic nomograms for short-term and long-term survival in immune checkpoint inhibitor-associated myocarditis","volume":"15","author":"Guan","year":"2025","journal-title":"Cardiovasc Diagn Ther"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1597427","article-title":"Association of inflammatory index with the severity of disease in patients with acute myocarditis: a retrospective observational study","volume":"16","author":"Wang","year":"2025","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.121.056730","article-title":"Identification of pathogenic immune cell subsets associated with checkpoint inhibitor-induced myocarditis","volume":"146","author":"Zhu","year":"2022","journal-title":"Circulation"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08105-5","article-title":"Immune responses in checkpoint myocarditis across heart, blood and tumour","volume":"636","author":"Blum","year":"2024","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaccao.2023.09.004","article-title":"Severe vs nonsevere immune checkpoint inhibitor-induced myocarditis: Contemporary 1-year outcomes","volume":"5","author":"Itzhaki Ben Zadok","year":"2023","journal-title":"JACC CardioOncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.7460","article-title":"Early identification of severe immune checkpoint inhibitor associated myocarditis: From an electrocardiographic perspective","volume":"13","author":"Gao","year":"2024","journal-title":"Cancer Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2147\/jir.s592827","article-title":"High-sensitivity troponin I and NT-proBNP as early indicators of disease severity and prognostic markers in immune checkpoint inhibitor-associated fulminant myocarditis","volume":"19","author":"Zhou","year":"2026","journal-title":"J Inflammation Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2024.2446430","article-title":"Real-world analysis of medications inducing meibomian gland dysfunction: based on the FDA adverse event reporting system database","volume":"25","author":"Li","year":"2026","journal-title":"Expert Opin Drug Saf"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac244","article-title":"2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)","volume":"43","author":"Lyon","year":"2022","journal-title":"Eur. Heart J"},{"key":"B20","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1161\/CIRCULATIONAHA.118.034497","article-title":"Myocarditis in the setting of cancer therapeutics: Proposed case definitions for emerging clinical syndromes in cardio-oncology","volume":"140","author":"Bonaca","year":"2019","journal-title":"Circulation"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab674","article-title":"Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement","volume":"43","author":"Herrmann","year":"2022","journal-title":"Eur Heart J"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1177\/00033197231201929","article-title":"Immune-checkpoint inhibitor-related myocarditis: Where we are and where we will go","volume":"75","author":"Vergara","year":"2024","journal-title":"Angiology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1515\/oncologie-2025-0378","article-title":"Survival predictive nomograms for non-surgical lung squamous-cell carcinoma patients with brain metastases: a SEER-based retrospective cohort study with external validation","volume":"28","author":"Cui","year":"2026","journal-title":"Oncologie"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1698566","article-title":"Single-cell transcriptomics reveals systemic immune dysregulation in non-segmental vitiligo","volume":"16","author":"Xiao","year":"2025","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0694-x","article-title":"Lineage tracking reveals dynamic relationships of T cells in colorectal cancer","volume":"564","author":"Zhang","year":"2018","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.140793","article-title":"Integration of single-cell and bulk RNA sequencing data using machine learning identifies oxidative stress-related genes LUM and PCOLCE2 as potential biomarkers for heart failure","volume":"300","author":"Li","year":"2025","journal-title":"Int J Biol Macromol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s12672-025-04002-z","article-title":"Single-cell transcriptomic analysis reveals the heterogeneity and functional characteristics of macrophage subpopulations in colon cancer","volume":"17","author":"Zhao","year":"2025","journal-title":"Discov Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1302\/0301-620x.107b3.bjj-2024-1220.r1","article-title":"Machine-learning models for the prediction of ideal surgical outcomes in patients with adult spinal deformity","author":"Wang","year":"2025","journal-title":"Bone Joint J"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2025.1658896","article-title":"Development and validation of a novel nutrition-inflammation prognostic score for predicting 30-day mortality in critically ill stroke patients","volume":"12","author":"Li","year":"2025","journal-title":"Front Nutr"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13770","article-title":"Single-cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor-related myocarditis","volume":"172","author":"Lou","year":"2024","journal-title":"Immunology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-025-07896-w","article-title":"Muscle expression of PD1 and PD-L1 may predict the severity and outcomes of neuromuscular immune-related adverse events caused by immune checkpoint inhibitor treatment","volume":"45","author":"Yang","year":"2026","journal-title":"Clin Rheumatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2025-011636","article-title":"Single-cell RNA sequencing of baseline PBMCs predicts ICI efficacy and irAE severity in patients with NSCLC","volume":"13","author":"Kim","year":"2025","journal-title":"J Immunother Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1615\/critrevimmunol.2022045956","article-title":"The novel diagnostic index based on HLA-DRB1 genotype and PD-L1 expression can predict severe irAEs in patients with metastatic melanoma taking immune checkpoint inhibitors. The results of the pilot study","volume":"42","author":"Zhukova","year":"2022","journal-title":"Crit Rev Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s40959-026-00458-2","article-title":"Enhanced predictive value of post-treatment lymphocyte-based immunoinflammatory biomarkers for cancer therapy-related cardiac dysfunction in anthracycline-treated breast cancer patients","volume":"12","author":"Zhang","year":"2026","journal-title":"CardioOncology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaf315","article-title":"Immune checkpoint inhibitor-associated myocarditis: a novel risk score","volume":"47","author":"Power","year":"2025","journal-title":"Eur Heart J"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-023-01400-4","article-title":"Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer","volume":"41","author":"Xu","year":"2023","journal-title":"Invest New Drugs"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.7233","article-title":"Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study","volume":"13","author":"Zheng","year":"2024","journal-title":"Cancer Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002553","article-title":"Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis","volume":"9","author":"Puzanov","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvac052","article-title":"Neutrophil inhibition improves acute inflammation in a murine model of viral myocarditis","volume":"118","author":"Carai","year":"2023","journal-title":"Cardiovasc Res"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1038\/s41598-020-79397-6","article-title":"Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events","volume":"11","author":"Matsukane","year":"2021","journal-title":"Sci Rep"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvae133","article-title":"Central memory CD4+ T cells play a protective role against immune checkpoint inhibitor-associated myocarditis","volume":"120","author":"Yu","year":"2024","journal-title":"Cardiovasc Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/cells14171397","article-title":"Distinct inflammatory responses of hiPSC-derived endothelial cells and cardiomyocytes to cytokines involved in immune checkpoint inhibitor-associated myocarditis","volume":"14","author":"Conte","year":"2024","journal-title":"Cells"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21072399","article-title":"Programmed cell death-1: Programmed cell death-ligand 1 interaction protects human cardiomyocytes against T-cell mediated inflammation and apoptosis response in vitro","volume":"21","author":"Tay","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B44","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1161\/circulationaha.122.062551","article-title":"Expansion of pathogenic cardiac macrophages in immune checkpoint inhibitor myocarditis","volume":"149","author":"Ma","year":"2024","journal-title":"Circulation"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-22-1180","article-title":"Abatacept\/ruxolitinib and screening for concomitant respiratory muscle failure to mitigate fatality of immune-checkpoint inhibitor myocarditis","volume":"13","author":"Salem","year":"2023","journal-title":"Cancer Discov"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1834913\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:43:36Z","timestamp":1787719416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1834913\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2026.1834913"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1834913","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"article-number":"1834913"}}