Elderly patient with squamous cell carcinoma of the lung with irAE-associated hidden myocarditis: A case report

Elderly patient with squamous cell carcinoma of the lung with irAE-associated hidden myocarditis: A case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Elderly patient with squamous cell carcinoma of the lung with irAE-associated hidden myocarditis: A case report Norio Kodaka, Noriyuki Hayashi, Nanae Asakawa, Masahiro Yoshida, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4515177/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Immune checkpoint inhibitors (ICIs) are the standard therapy for various types of cancer. One of them, durvalumab, as a programmed cell death ligand 1 (PD-L1) inhibitor, is commonly used to treat pulmonary malignancies. It has a wide range of known side effects, known as immune-related adverse events (irAEs). Myocarditis as an irAEs is rare but fatal. Currently, there is a paucity of reports on myocarditis as an irAE after durvalumab treatment in elderly patients. Case presentation: The patient was a 79-year-old female with stage Ⅲb squamous cell lung carcinoma and myocarditis as an irAE after durvalumab treatment. She had completed two cycles of carboplatin and TS-1 and received 50 Gy of radiation. After combined chemotherapy and radiotherapy (CCRT), she was administered 10 mg/kg of durvalumab every two weeks as maintenance therapy. After eleven courses over five months of durvalumab, despite the absence of complaints, she experienced a significant decline in cardiac function as observed via echocardiography. Blood tests revealed elevated levels of high-sensitivity cardiac troponin T(hs-cTn). The diagnosis of myocarditis was confirmed through a myocardial biopsy, indicating that it was an irAE following durvalumab therapy. Her myocarditis improved with the discontinuation of durvalumab treatment and the administration of steroid therapy. She has been successfully treated for lung cancer for more than two years without flare-up of myocarditis or lung cancer deterioration, although no treatment for lung cancer has been attempted since the occurrence of myocarditis. Conclusion: In patients on ICIs, especially elderly patients, it is important to pay attention to irAEs and perform periodic electrocardiograms and ECGs, even in asymptomatic persons, for early detection and prognosis improvement. ICIs irAEs PD-L1 myocarditis Figures Figure 1 Figure 2 Figure 3 Background Immune checkpoint inhibitors (ICIs) hold a significant position in lung cancer pharmacotherapy per treatment guidelines. ICIs sustain T-cell activation and exert anti-tumor effects by blocking immunosuppressive signaling from antigen-presenting cells and tumor cells. 1) Thus, unlike conventional cytotoxic anti-cancer agents, ICIs can give rise to a wide range of immune-related adverse events (irAEs). Among these, myocarditis, when identified, has a high mortality rate; thus, it requires prompt diagnosis and treatment initiation. 2) Currently, seven ICIs are approved for the treatment of cancer; they are nivolumab, pembrolizumab as programmed cell death 1 (PD-1) inhibitors, atezolizumab, durvalumab, avelumab as PD-L1 inhibitors, and ipilimumab and tremelimumab as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Among the irAEs, myocarditis has a lower incidence than the others such as thyroid dysfunction or liver dysfunction. To our knowledge, there are fewer reports on PDL-1-related irAEs than on PD-1-related irAEs. To the best of our knowledge, there are only a few reported cases of myocarditis or similar side effects with the use of durvalumab in the PACIFIC regimen. 3) Case presentation A 79-year-old female with a smoking history of at least 50 pack years and a medical history of hypertension had no medical history of diabetes mellitus and dyslipidemia and no family history of coronary artery disease. She had stage Ⅲb (T3N2M0) lung squamous cell carcinoma. The tumor had no associated driver mutation detected, and she had a PD-L1 TPS of <1%. The patient’s performance status was 0, and CCRT + PDL-1 therapy was selected. She had completed two cycles of carboplatin and TS-1 and received 50 Gy of radiation. After five months of bi-weekly durvalumab treatment, periodic echocardiography was performed because the tumor was in contact with the heart on chest CT. (Figure 1A,B) After eleven courses, despite the absence of complaints, she experienced a significant cardiac function decline as observed via echocardiography performed during a regular examination. Echocardiography revealed that her ventricle size was within the normal range (left ventricle end-diastolic dimension 43 mm), atrial enlargement (left atrium dimension LA 43 mm), and a significantly reduced ventricular ejection fraction (left ventricular ejection fraction: 30%), pericardial effusion all-round the heart. The electrocardiogram (ECG) revealed sinus tachycardia, low voltage of all limb and chest leads, T-wave inversion in anterior waves, and the V1-V2 QS type. The new ECG’s findings differed significantly from those of the previous one (Figure 2A, B). She was urgently hospitalized. Upon hospitalization, she was afebrile with a blood pressure of 145/91mm Hg, heart rate of 107 beats/min, respiratory rate of 20 beats/min, and 97% oxygen saturation on room air. Markers of myocardial injury tests revealed elevated NT-proBNP (2064.0), hs-cTn (0.663), and creatine kinase-myocardial band (CK-MB; 18.9). We suspected that the cause of the patient’s pericardial effusion was either lung cancer invasion of the pericardium or durvalumab-induced myocarditis. Myocarditis as irAE diagnosis was confirmed through a myocardial biopsy. The myocardial biopsy enhanced features of iatrogenic myocarditis with inflammatory infiltrates of mononuclear lymphocytes and macrophages. Immunostaining of the tissue revealed an inflammatory cell infiltrate predominantly composed of CD68-positive macrophages and CD3,8-positive T cells, with a slight predominance of CD4-positive T cells in the myocardium with subendocardial and intermyocardial fibers and in the perivascular area. CD20-positive B cell infiltration was poor (Figure 3). We initiated daily methylprednisolone (1000 mg for three days) and intravenous immunoglobulin (IVIg; 400 mg/kg for five days) immediately after the endocardial biopsy, and also started on the beta blocker (carvediol) 2.5 mg and ACE (renibase) 2.5 mg as a diuretic and cardioprotective agent. After that, a glucocorticoid (prednisolone at a dose of 0.5 mg/kg) was administered and tapered off. After one week, Hs-cTn (0.327) and CK-MB (3.8) decreased on blood tests; however, NT-proBNP levels did not decrease. Her myocarditis improved with durvalumab treatment discontinuation and steroid administration. After three weeks, echocardiography revealed that her cardiac ejection fraction (left ventricular ejection fraction: 50%) was improved，and her pericardial effusion had almost completely been resorbed. After discharge, she has not only remained free of cardiac deterioration for the past two years but has also been free of lung cancer flare-ups without using anti-cancer drugs. Discussion and conclusion Herein, we report a rare case of an elderly patient with durvalumab-associated hidden myocarditis. The exact mechanism underlying ICI-induced myocarditis remains poorly understood. Although the incidence of cardiac irAE is relatively low, ranging from 0.27–1.14% 4,5,6) , its fatality rate (50%) is high 7) . However, we were able to confirm that corticosteroids and IVIG are effective treatments for durvalumab-induced myocarditis. However, to the best of our knowledge, evidence of the efficacy of both steroid therapy and IVIG in the treatment of irAE-associated myocarditis is still scarce. Nevertheless, there are reports of the efficacy of IVIGs in the treatment of myocarditis with low cardiac function 8) , and considering the suppressive effects of T cells on IVIG inflammation 9) , it may be effective in irAE-associated myocarditis. Elderly patients sometimes have no symptoms or complaints of dyspnea, which may be clinically atypical for each individual. Even in asymptomatic patients, regular echocardiography tests and ECGs can help to detect the disease at an early stage. casein this case, the condition occurred five months after the administration of an immune checkpoint inhibitor. Although the time between the administration of immune checkpoint inhibitors (ICIs) and the onset of myocarditis is generally considered to be within three months 6,7) , there are only a few reports on the onset of myocarditis more than one year after the first administration of ICIs to the best of our knowledge. 10,11) Myocarditis is an inflammatory disease of the myocardium caused by cancer, viral infection, autoimmunity, drugs, and eosinophil count elevations. 12) Myocarditis is classified as eosinophilic, lymphocytic, giant cell, granulomatous, or pleomorphic based on the type of cells infiltrating the myocardium. ICI-induced myocarditis occurs when ICIs maintain T lymphocyte activity, T lymphocytes infiltrate the myocardium, and the immune response is excessive. Histological analyses of endomyocardial biopsy specimens have revealed myocardial infiltration by CD8-positive lymphocytes and CD68-positive macrophages. 13) The histopathological findings in this case were typical of irAE myocarditis (Fig. 3 ). Several biomarkers, such as troponin, electrocardiography, and CK, have been shown to be useful for cardiac irAE. 14,15) In the present study, hs-cTn and CK-MB levels were also elevated, and they decreased as the patient’s myocarditis improved. However, NT-proBNP did not change significantly, suggesting that NT-proBNP is not a suitable biomarker for cardiac irAE follow-up. The recommended regimen after CCRT is one year of durvalumab maintenance therapy. However, in this case, the patient was treated with durvalumab for only six months; notwithstanding, her lung cancer has not worsened for more than two years. According to several tissue sample analyses, lung cancer patients who experience strong side effects of ICI may also be responsive to ICIs. 16,17) In addition, the patient had a TPS of < 1%; however, the ICI administered was effective because it was an immunostain and not a quantitative test; so, errors in the biopsy pathology specimen analysis may have been a factor. Although there is still insufficient evidence of durvalumab-induced cardiotoxicity, its onset is thought to be dose-independent. Although studies are underway to determine the risk of onset, it is impossible to completely predict the outcome. 18,19) As demonstrated in the present case, the possibility of avoiding death is increased by performing echocardiography regularly to ensure the early diagnosis of myocarditis. In patients on ICIs, especially elderly patients, it is important to pay attention to irAEs and perform periodic electrocardiograms and ECGs, even in asymptomatic persons, for early detection and prognosis improvement. Considering the paucity of clinical evidence of myocarditis related to PD-L1 treatment, we believe the present case report is of clinical value for the treatment and prognosis of PD-L1-relatedmyocarditis. Abbreviations CK: Creatine kinase-myocardial CCRT: Combined chemotherapy and radiotherapy ICIs: Immune checkpoint inhibitors TPS: Tumor proportion score Declarations Ethics approval and consent to participate Not applicable. Consent for publication The patient gave written consent for publication. Availability of data and materials The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors. Competing interests The authors have no conflicts of interest to declare. Funding None. Authors’ contributions NK initiated the study and wrote the manuscript. NK, NH, NA, and MY collected clinical data. KW and HM reviewed the manuscript. All authors have read and approved author. Clinical Trial Number Not applicable. Acknowledgments We would like to thank Enago (https://www.enago.jp) for reviewing and editing this manuscript for English language. References Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398:535–54. Wong SK, Nebhan CA, Johnson DB. Impact of patient age on clinical efficacy and toxicity of checkpoint inhibitor therapy. Front Immunol. 2021;12:786046. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377:1919–29. Hu JR, Florido R, Lipson EJ, Naidoo J, Ardehali R, Tocchetti CG, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 2019;115:854–68. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749–55. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71:1755–64. Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19:1579–89. Goland S, Czer LS, Siegel RJ, Tabak S, Jordan S, Luthringer D, et al. Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature. Can J Cardiol. 2008;24:571–4. Hori A, Fujimura T, Murakami M, Park J, Kawamoto S. Intravenous immunoglobulin (IVIg) acts directly on conventional T cells to suppress T cell receptor signaling. Biochem Biophys Res Commun. 2020;522:792–8. Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391:933. Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, et al. Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity. Circulation. 2017;136:2085–87. Kodaka N, Nakano C, Oshio T, Hirouchi T, Satou M, Moroi M, et al. Successful treatment of an elderly patient with severe eosinophilic asthma and eosinophilic myocarditis using benralizumab. Geriatr Gerontol Int. 2022;22:175–6. Sobol I, Chen CL, Mahmood SS, Borczuk AC. Histopathologic characterization of myocarditis associated with immune checkpoint inhibitor therapy. Arch Pathol Lab Med. 2020;144:1392–6. Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune checkpoint inhibitor myocarditis: pathophysiological cha teristics, diagnosis, and treatment. J Am Heart Assoc. 2020;9:e013757. Vasbinder A, Chen Y, Procureur A, Gradone A, Azam TU, Perry D, et al. Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor-Induced Myocarditis. JACC CardioOncol. 2022;4:689–700. Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2019;7:306. Yoshikawa Y, Imamura M, Yamauchi M, Hayes CN, Aikata H, Okamoto W, et al. Prevalence of immune-related adverse events and anti-tumor efficacy following immune checkpoint inhibitor therapy in Japanese patients with various solid tumors. BMC Cancer. 2022;22:1232. Diehl A, Yarchoan M, Hopkins A, Jaffee E, Grossman SA, et al. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget. 2017;8:114268–80. Eun Y, Kim IY, Sun JM, Lee J, Cha HS, Koh EM, et al. Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab. Sci Rep. 2019;9:14039. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4515177","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":324737616,"identity":"782ef079-7021-4d3f-ad85-e61ab50fa549","order_by":0,"name":"Norio Kodaka","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Norio","middleName":"","lastName":"Kodaka","suffix":""},{"id":324737617,"identity":"cdb9cf85-6551-429f-9117-eb3c083ada54","order_by":1,"name":"Noriyuki Hayashi","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Noriyuki","middleName":"","lastName":"Hayashi","suffix":""},{"id":324737618,"identity":"27bf4882-12e2-4b63-8254-66437d038866","order_by":2,"name":"Nanae Asakawa","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Nanae","middleName":"","lastName":"Asakawa","suffix":""},{"id":324737619,"identity":"7e608e56-1501-47a6-8715-adfe5eece62d","order_by":3,"name":"Masahiro Yoshida","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Yoshida","suffix":""},{"id":324737620,"identity":"ac569d77-2fb3-41cc-97dc-23925b12baa9","order_by":4,"name":"Kayo Watanabe","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kayo","middleName":"","lastName":"Watanabe","suffix":""},{"id":324737621,"identity":"4300495b-0938-4fff-8798-7ef0727ac337","order_by":5,"name":"Hiroto Matsuse","email":"data:image/png;base64,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","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Hiroto","middleName":"","lastName":"Matsuse","suffix":""}],"badges":[],"createdAt":"2024-06-02 00:38:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4515177/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4515177/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60610922,"identity":"6a8d0eac-978f-4265-809a-801f43c94a96","added_by":"auto","created_at":"2024-07-18 18:31:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":186016,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChest CT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Lung cancer at diagnosis. A large tumor is seen bordering the heart.\u003c/p\u003e\n\u003cp\u003eB: After CCRT. The tumor has shrunk and only a small shadow remains.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4515177/v1/e515a72cfe53a3ba52c28d3b.png"},{"id":60609840,"identity":"4446e8eb-d6e8-4d7b-8063-5a3906f55d49","added_by":"auto","created_at":"2024-07-18 18:23:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":425213,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eElectrocardiogram\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA:\u003c/strong\u003e After CCRT. The electrocardiogram revealed sinus and within normal limits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB:\u003c/strong\u003e At the onset of myocarditis as irAE. The electrocardiogram revealed sinus tachycardia, low voltage of all limb and chest leads[A1] , T-wave inversion in anterior waves, and V1-V2 QS type.\u003c/p\u003e\n\u003cp\u003e[A1]Remark: I made this revision for improved clarity and readability.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4515177/v1/17c151fe0124b95ecf3e3b82.png"},{"id":60609842,"identity":"b9a9f8a2-8d6c-4b8f-9353-41acb7e47b2d","added_by":"auto","created_at":"2024-07-18 18:23:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":962012,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePathology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMyocardial biopsy demonstrating myocarditis (h[A1] ematoxylin-eosin, immunohistochemistry; IHC (CD68,CD20,CD3,CD4,CD8) 200×,\u003c/p\u003e\n\u003cp\u003e[A1]Remark: The brackets appear to be left open, please check and complete.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4515177/v1/ce1654ead3b647923a6b0fa2.png"},{"id":91610042,"identity":"3de0a7c6-88a0-45c7-a5b7-a131bf1cb17f","added_by":"auto","created_at":"2025-09-18 09:47:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2203851,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4515177/v1/33bd9085-b5d6-4dab-9807-86fe8f6aef5c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elderly patient with squamous cell carcinoma of the lung with irAE-associated hidden myocarditis: A case report","fulltext":[{"header":"Background","content":"\u003cp\u003eImmune checkpoint inhibitors (ICIs) hold a significant position in lung cancer pharmacotherapy per treatment guidelines. ICIs sustain T-cell activation and exert anti-tumor effects by blocking immunosuppressive signaling from antigen-presenting cells and tumor cells.\u003csup\u003e1)\u003c/sup\u003e Thus, unlike conventional cytotoxic anti-cancer agents, ICIs can give rise to a wide range of immune-related adverse events (irAEs). Among these, myocarditis, when identified, has a high mortality rate; thus, it requires prompt diagnosis and treatment initiation.\u003csup\u003e2)\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCurrently, seven ICIs are approved for the treatment of cancer; they are nivolumab, pembrolizumab as programmed cell death 1 (PD-1) inhibitors, atezolizumab, durvalumab, avelumab as PD-L1 inhibitors, and ipilimumab and tremelimumab as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors.\u003c/p\u003e \u003cp\u003eAmong the irAEs, myocarditis has a lower incidence than the others such as thyroid dysfunction or liver dysfunction. To our knowledge, there are fewer reports on PDL-1-related irAEs than on PD-1-related irAEs. To the best of our knowledge, there are only a few reported cases of myocarditis or similar side effects with the use of durvalumab in the PACIFIC regimen.\u003csup\u003e3)\u003c/sup\u003e\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 79-year-old female with a smoking history of at least 50 pack years and a medical history of hypertension had\u0026nbsp;no medical history of diabetes mellitus and dyslipidemia and no family history of coronary artery disease.\u003c/p\u003e\n\u003cp\u003eShe had stage Ⅲb (T3N2M0) lung squamous cell carcinoma. The tumor had no associated driver mutation detected, and she had a PD-L1 TPS of \u0026lt;1%. The patient\u0026rsquo;s performance status was 0, and CCRT + PDL-1 therapy was selected.\u003c/p\u003e\n\u003cp\u003eShe had completed two cycles of carboplatin and TS-1 and received 50 Gy of radiation. After five months of bi-weekly durvalumab treatment, periodic echocardiography was performed because the tumor was in contact with the heart on chest CT. (Figure 1A,B) After eleven courses, despite the absence of complaints, she experienced a significant cardiac function decline as observed via echocardiography performed during a regular examination. Echocardiography revealed that her ventricle size was within the normal range (left ventricle end-diastolic dimension 43 mm), atrial enlargement (left atrium dimension LA 43 mm), and a significantly reduced ventricular ejection fraction (left ventricular ejection fraction: 30%), pericardial effusion all-round the heart. The electrocardiogram (ECG) revealed sinus tachycardia, low voltage of all limb and chest leads, T-wave inversion in anterior waves, and the V1-V2 QS type. The new ECG\u0026rsquo;s findings differed significantly from those of the previous one (Figure 2A, B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eShe was urgently hospitalized. Upon hospitalization, she was afebrile with a blood pressure of 145/91mm Hg, heart rate of 107 beats/min, respiratory rate of 20 beats/min, and 97% oxygen saturation on room air. Markers of myocardial injury tests revealed elevated NT-proBNP (2064.0), hs-cTn (0.663), and creatine kinase-myocardial band (CK-MB; 18.9).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe suspected that the cause of the patient\u0026rsquo;s pericardial effusion was either lung cancer invasion of the pericardium or durvalumab-induced myocarditis.\u003c/p\u003e\n\u003cp\u003eMyocarditis as irAE diagnosis was confirmed through a myocardial biopsy. The myocardial biopsy enhanced features of iatrogenic myocarditis with inflammatory infiltrates of mononuclear lymphocytes and macrophages. Immunostaining of the tissue revealed an inflammatory cell infiltrate predominantly composed of CD68-positive macrophages and CD3,8-positive T cells, with a slight predominance of CD4-positive T cells in the myocardium with subendocardial and intermyocardial fibers and in the perivascular area.\u0026nbsp;CD20-positive B cell infiltration was poor\u0026nbsp;(Figure 3).\u003c/p\u003e\n\u003cp\u003eWe initiated daily methylprednisolone (1000 mg for three days)\u0026nbsp;and intravenous immunoglobulin (IVIg; 400 mg/kg for five days) immediately after the endocardial biopsy,\u0026nbsp;and also started on the beta blocker (carvediol) 2.5 mg and ACE (renibase) 2.5 mg as a diuretic and cardioprotective agent. After that, a glucocorticoid (prednisolone at a dose of 0.5 mg/kg) was administered and tapered off. After one week, Hs-cTn (0.327) and CK-MB (3.8) decreased on blood tests; however, NT-proBNP levels did not decrease. Her myocarditis improved with durvalumab treatment discontinuation and steroid administration.\u003c/p\u003e\n\u003cp\u003eAfter three weeks, echocardiography revealed that her cardiac ejection fraction (left ventricular ejection fraction: 50%) was improved，and her pericardial effusion had almost completely been resorbed. After discharge, she has not only remained free of cardiac deterioration for the past two years but has also been free of lung cancer flare-ups without using anti-cancer drugs.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion and conclusion","content":"\u003cp\u003eHerein, we report a rare case of an elderly patient with durvalumab-associated hidden myocarditis.\u003c/p\u003e \u003cp\u003eThe exact mechanism underlying ICI-induced myocarditis remains poorly understood. Although the incidence of cardiac irAE is relatively low, ranging from 0.27\u0026ndash;1.14%\u003csup\u003e4,5,6)\u003c/sup\u003e, its fatality rate (50%) is high\u003csup\u003e7)\u003c/sup\u003e. However, we were able to confirm that corticosteroids and IVIG are effective treatments for durvalumab-induced myocarditis.\u003c/p\u003e \u003cp\u003eHowever, to the best of our knowledge, evidence of the efficacy of both steroid therapy and IVIG in the treatment of irAE-associated myocarditis is still scarce. Nevertheless, there are reports of the efficacy of IVIGs in the treatment of myocarditis with low cardiac function\u003csup\u003e8)\u003c/sup\u003e, and considering the suppressive effects of T cells on IVIG inflammation\u003csup\u003e9)\u003c/sup\u003e, it may be effective in irAE-associated myocarditis.\u003c/p\u003e \u003cp\u003eElderly patients sometimes have no symptoms or complaints of dyspnea, which may be clinically atypical for each individual. Even in asymptomatic patients, regular echocardiography tests and ECGs can help to detect the disease at an early stage.\u003c/p\u003e \u003cp\u003ecasein this case, the condition occurred five months after the administration of an immune checkpoint inhibitor. Although the time between the administration of immune checkpoint inhibitors (ICIs) and the onset of myocarditis is generally considered to be within three months\u003csup\u003e6,7)\u003c/sup\u003e, there are only a few reports on the onset of myocarditis more than one year after the first administration of ICIs to the best of our knowledge.\u003csup\u003e10,11)\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMyocarditis is an inflammatory disease of the myocardium caused by cancer, viral infection, autoimmunity, drugs, and eosinophil count elevations.\u003csup\u003e12)\u003c/sup\u003e Myocarditis is classified as eosinophilic, lymphocytic, giant cell, granulomatous, or pleomorphic based on the type of cells infiltrating the myocardium. ICI-induced myocarditis occurs when ICIs maintain T lymphocyte activity, T lymphocytes infiltrate the myocardium, and the immune response is excessive. Histological analyses of endomyocardial biopsy specimens have revealed myocardial infiltration by CD8-positive lymphocytes and CD68-positive macrophages.\u003csup\u003e13)\u003c/sup\u003e The histopathological findings in this case were typical of irAE myocarditis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral biomarkers, such as troponin, electrocardiography, and CK, have been shown to be useful for cardiac irAE.\u003csup\u003e14,15)\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the present study, hs-cTn and CK-MB levels were also elevated, and they decreased as the patient\u0026rsquo;s myocarditis improved. However, NT-proBNP did not change significantly, suggesting that NT-proBNP is not a suitable biomarker for cardiac irAE follow-up.\u003c/p\u003e \u003cp\u003eThe recommended regimen after CCRT is one year of durvalumab maintenance therapy. However, in this case, the patient was treated with durvalumab for only six months; notwithstanding, her lung cancer has not worsened for more than two years.\u003c/p\u003e \u003cp\u003eAccording to several tissue sample analyses, lung cancer patients who experience strong side effects of ICI may also be responsive to ICIs.\u003csup\u003e16,17)\u003c/sup\u003e In addition, the patient had a TPS of \u0026lt;\u0026thinsp;1%; however, the ICI administered was effective because it was an immunostain and not a quantitative test; so, errors in the biopsy pathology specimen analysis may have been a factor.\u003c/p\u003e \u003cp\u003eAlthough there is still insufficient evidence of durvalumab-induced cardiotoxicity, its onset is thought to be dose-independent. Although studies are underway to determine the risk of onset, it is impossible to completely predict the outcome. \u003csup\u003e18,19)\u003c/sup\u003e As demonstrated in the present case, the possibility of avoiding death is increased by performing echocardiography regularly to ensure the early diagnosis of myocarditis.\u003c/p\u003e \u003cp\u003eIn patients on ICIs, especially elderly patients, it is important to pay attention to irAEs and perform periodic electrocardiograms and ECGs, even in asymptomatic persons, for early detection and prognosis improvement. Considering the paucity of clinical evidence of myocarditis related to PD-L1 treatment, we believe the present case report is of clinical value for the treatment and prognosis of PD-L1-relatedmyocarditis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCK: Creatine kinase-myocardial\u003c/p\u003e\n\u003cp\u003eCCRT:\u0026nbsp;Combined chemotherapy and radiotherapy\u003c/p\u003e\n\u003cp\u003eICIs: Immune checkpoint inhibitors\u003c/p\u003e\n\u003cp\u003eTPS: Tumor proportion score\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient gave written consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article.\u003c/p\u003e\n\u003cp\u003eFurther inquiries can be directed to the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNK initiated the study and wrote the manuscript. NK, NH, NA, and MY collected clinical data. KW and HM reviewed the manuscript. All authors have read and approved author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Enago (https://www.enago.jp) for reviewing and editing this manuscript for English language.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eThai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398:535\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWong SK, Nebhan CA, Johnson DB. Impact of patient age on clinical efficacy and toxicity of checkpoint inhibitor therapy. Front Immunol. 2021;12:786046.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAntonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377:1919\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu JR, Florido R, Lipson EJ, Naidoo J, Ardehali R, Tocchetti CG, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 2019;115:854\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71:1755\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19:1579\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoland S, Czer LS, Siegel RJ, Tabak S, Jordan S, Luthringer D, et al. Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature. Can J Cardiol. 2008;24:571\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHori A, Fujimura T, Murakami M, Park J, Kawamoto S. Intravenous immunoglobulin (IVIg) acts directly on conventional T cells to suppress T cell receptor signaling. Biochem Biophys Res Commun. 2020;522:792\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391:933.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEscudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, et al. Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity. Circulation. 2017;136:2085\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKodaka N, Nakano C, Oshio T, Hirouchi T, Satou M, Moroi M, et al. Successful treatment of an elderly patient with severe eosinophilic asthma and eosinophilic myocarditis using benralizumab. Geriatr Gerontol Int. 2022;22:175\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSobol I, Chen CL, Mahmood SS, Borczuk AC. Histopathologic characterization of myocarditis associated with immune checkpoint inhibitor therapy. Arch Pathol Lab Med. 2020;144:1392\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune checkpoint inhibitor myocarditis: pathophysiological cha teristics, diagnosis, and treatment. J Am Heart Assoc. 2020;9:e013757.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVasbinder A, Chen Y, Procureur A, Gradone A, Azam TU, Perry D, et al. Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor-Induced Myocarditis. JACC CardioOncol. 2022;4:689\u0026ndash;700.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDas S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2019;7:306.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshikawa Y, Imamura M, Yamauchi M, Hayes CN, Aikata H, Okamoto W, et al. Prevalence of immune-related adverse events and anti-tumor efficacy following immune checkpoint inhibitor therapy in Japanese patients with various solid tumors. BMC Cancer. 2022;22:1232.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDiehl A, Yarchoan M, Hopkins A, Jaffee E, Grossman SA, et al. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget. 2017;8:114268\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEun Y, Kim IY, Sun JM, Lee J, Cha HS, Koh EM, et al. Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab. Sci Rep. 2019;9:14039.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ICIs, irAEs, PD-L1, myocarditis","lastPublishedDoi":"10.21203/rs.3.rs-4515177/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4515177/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Immune checkpoint inhibitors (ICIs) are the standard therapy for various types of cancer. One of them, durvalumab, as a programmed cell death ligand 1 (PD-L1) inhibitor, is commonly used to treat pulmonary malignancies.\u003csup\u003e \u003c/sup\u003eIt has a wide range of known side effects, known as immune-related adverse events (irAEs). Myocarditis as an irAEs is rare but fatal. Currently, there is a paucity of reports on myocarditis as an irAE after durvalumab treatment in elderly patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e The patient was a 79-year-old female with stage Ⅲb squamous cell lung carcinoma and myocarditis as an irAE after durvalumab treatment.\u003c/p\u003e\n\u003cp\u003eShe had completed two cycles of carboplatin and TS-1 and received 50 Gy of radiation. After combined chemotherapy and radiotherapy (CCRT), she was administered 10 mg/kg of durvalumab every two weeks as maintenance therapy. After eleven courses over five months of durvalumab, despite the absence of complaints, she experienced a significant decline in cardiac function as observed via echocardiography. Blood tests revealed elevated levels of high-sensitivity cardiac troponin T(hs-cTn). The diagnosis of myocarditis was confirmed through a myocardial biopsy, indicating that it was an irAE following durvalumab therapy. Her myocarditis improved with the discontinuation of durvalumab treatment and the administration of steroid therapy.\u003c/p\u003e\n\u003cp\u003eShe has been successfully treated for lung cancer for more than two years without flare-up of myocarditis or lung cancer deterioration, although no treatment for lung cancer has been attempted since the occurrence of myocarditis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003eIn patients on ICIs, especially elderly patients, it is important to pay attention to irAEs and perform periodic electrocardiograms and ECGs, even in asymptomatic persons, for early detection and prognosis improvement.\u003c/p\u003e","manuscriptTitle":"Elderly patient with squamous cell carcinoma of the lung with irAE-associated hidden myocarditis: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 18:22:58","doi":"10.21203/rs.3.rs-4515177/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"522f442a-0db9-4496-8a96-2ee59254a04f","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-18T09:39:30+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-18 18:22:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4515177","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4515177","identity":"rs-4515177","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}