European Heart Journal - Case Reports (2020) 4, 1–6 CASE REPORT doi:10.1093/ehjcr/ytaa214 Other A different type of acute myocarditis: a case report of acute autoimmune myocarditis mediated by anti-PD-1 T lymphocyte receptor (pembrolizumab) Downloaded from https://academic.oup.com/ehjcr/article/4/5/1/5917792 by guest on 30 October 2023 Mario Salido Iniesta1,2,*, Laura López López1,3, Francesc Carreras Costa 1,4 , and Alessandro Sionis 1,5 1 Hospital de la Santa Creu i Sant Pau IIB Sant Pau, Carrer de Sant Quintı́, 89, 08041 Barcelona, Spain; 2Calle Castillejos 361, Barcelona, Spain; 3Carrer d’Urgell 50, Cornellà de Llobregat, Spain; 4Dr. Trueta 44, Barcelona, Spain; and 5Carrer Sicilia 33, Barcelona, Spain Received 28 November 2019; first decision 30 December 2019; accepted 17 June 2020; online publish-ahead-of-print 4 October 2020 Background Pembrolizumab is an immune check-point inhibitor (ICI), which acts by blocking the T lymphocyte PD-1 inhibitor receptor. It has been increasingly used in advanced or non-responsive tumours with promising results. However, acute myocarditis is an infrequent but potentially life-threatening autoimmune adverse effect related to ICIs. ................................................................................................................................................................................................... Case summary This case deals with a 69-year-old gentleman on second-line therapy with pembrolizumab for advanced non-small cell lung cancer. Three weeks after first dose, the patient was diagnosed with an autoimmune hepatitis, treated with decreasing corticoid dosage, followed by acute heart failure. On admission, his electrocardiogram (ECG) showed diffuse repolarization changes and a transthoracic echocardiography revealed severe left ventricle impair- ment (left ventricular ejection fraction 32%). High-sensitivity cardiac troponin was elevated and a coronary angio- gram was performed showing non-significant obstructive disease. An autoimmune myocarditis was suspected, and high-dose intravenous corticoid, intravenous vasodilators, and loop diuretics were started with favourable re- sponse. Cardiac magnetic resonance (CMR) imaging, performed 2 weeks after clinical onset, revealed extracellular oedema in the anteroseptal-apical left ventricle segments. A new transthoracic echocardiography, performed after 3 months, showed preserved left ventricle ejection fraction. Finally, the patient was readmitted due to an auto- immune myasthenia-like syndrome. ................................................................................................................................................................................................... Discussion Acute autoimmune myocarditis related to ICIs is a challenging diagnosis and its incidence has been underestimated in early studies. Endomyocardial biopsy (EMB) is the gold standard test for its diagnosis. Nevertheless, a definite myocarditis diagnosis is possible without EMB when characteristic clinical syndrome, elevated myonecrosis markers, and electrocardiographic, echocardiographic, and CMR changes are present together. 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 Keywords Acute myocarditis • Immune check-point inhibitor • Anti-PD-1 • Pembrolizumab • Case report *Corresponding author. Tel: 93 556 59 45, Fax: 93 556 56 03, Email: msalido@santpau.cat; salido.mario@gmail.com Handling Editor: Domenico D’Amario Peer-reviewers: Albert Galyavich and Hajnalka Vágó Compliance Editor: Mark Philip Cassar Supplementary Material Editor: Peysh A Patel C The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 2 M. Salido Iniesta et al. Learning points • Immune-mediated acute myocarditis is an infrequent pembrolizumab side effect that can potentially evolve to fulminant myocarditis which has a mortality up to 50% in published series. • The diagnosis is challenging due to both low event rate and the lack of well-established diagnostic criteria. • Definite myocarditis diagnosis is possible when characteristic clinical syndrome, elevated myonecrosis markers, electrocardiographic, echo- cardiographic, and CMR changes present together. .. Introduction .. .. Case presentation .. Immunotherapy is an emerging treatment in oncology, widely spread .. A 69-year-old gentleman, with a history of urothelial bladder cancer .. under complete remission 2 years previously, was diagnosed with Downloaded from https://academic.oup.com/ehjcr/article/4/5/1/5917792 by guest on 30 October 2023 in current clinical practice, which treats advanced or non-responsive .. tumours to improve their prognosis and survival. Pembrolizumab is a .. metastatic advanced non-small cell lung cancer. He was started on monoclonal antibody that works as an immune check-point inhibitor .. first-line therapy without response. He was subsequently treated .. (ICI). It acts both binding and blocking the T lymphocyte PD-1 inhibi- .. with pembrolizumab as second-line therapy completing his first cycle .. of treatment. Approximately 3 weeks after, the patient was hospital- tor receptor, providing T cytotoxic lymphocyte activation to attack .. the malignant cells. However, activating the immune system is not in- .. ized due to drug-related autoimmune hepatitis which was treated .. with a slow tapering off corticosteroid regimen with favourable clinic- nocuous and it has been related with autoimmune reactions against .. non-malignant cells, also well known as immune-related adverse .. al and laboratory markers response. .. effects. Among them, myocarditis is the most frequent and potentially .. Five days later, the patient presented a sudden episode of short- life-threatening cardiovascular side effect, which is potentially life- .. ness of breath. On physical examination, he was tachypnoeic at 35 .. threatening; therefore, it has become an emergent problem for clini- .. breath per minute with intercostal retraction, had a raised jugular .. venous pulse and bilateral lung crackles. His SpO2 was 95% on cians in their daily routines. .. .. room air, blood pressure was 165/90 mmHg and pulse was regular .. at 110 b.p.m. His chest X-ray was normal. Electrocardiogram .. .. (ECG) (Figure 1) showed 1 mm anterolateral ST-segment elevation .. Timeline .. . and anterolateral and inferior negative T waves. Transthoracic echo- cardiography showed a non-dilated left ventricle, with moderately .................................................................................................................................................................................................................... June 2016 Diagnosed with urothelial bladder cancer.Complete remission after treat- ment with transurethral resection of the prostate and Bacillus Calmette-Guérin therapy for a year. March 2018 Diagnosed with advanced non-small cell lung cancer. Started on first-line treatment (cisplatin and pemetrexed). August 2018 No response to treatment. Second-line treatment started with pembrolizumab. Admission 20 days after first pembrolizumab Autoimmune hepatitis treated with corticoid therapy, and favourable clin- doses ical response. Clinical presentation within 5 days after Switched from intravenous to oral admission corticoid therapy.Sudden tachypnoea, tachycardia, dyspnoea, and dif- fuse repolarization ECG changes.Transthoracic echocardiogram showed apical severe left ventricle dysfunction.Coronary angiography did not show significant coronary artery disease.Intravenous corticoid therapy restarted at high doses. Three days after clinical presentation Clinical resolution, ECG changes retrogradation and left ventricle ejection fraction recovery. Fifteen days after clinical presentation Interstitial oedema in cardiovascular magnetic resonance imaging (CRM). Three weeks after clinical presentation Discharge from hospital. Readmission 4 weeks after clinical presentation Diagnosed with autoimmune myasthenia-like syndrome. Pembrolizumab mediated autoimmune myocarditis 3 Downloaded from https://academic.oup.com/ehjcr/article/4/5/1/5917792 by guest on 30 October 2023 Figure 1 Initial ECG during acute heart failure onset, showing sinus tachycardia and diffuse alteration of repolarization (1 mm anterolateral ST-seg- ment elevation, and anterolateral and inferior negative T waves). Figure 2 Left coronary circulation. Non-significant obstructive disease shown by coronary angiography. Figure 3 It is shown diastolic left ventricular end-diastolic area in green and left ventricular end-systolic area in yellow by ventriculography. reduced left ventricular ejection fraction (LVEF) and anterior-septal- inferior apical hypokinaesia (previously normal). Biochemical analyses revealed elevated myocardial injury markers [high-sensitivity cardiac .. Oxygen therapy (FiO2 26%) and intermittent intravenous fur- .. troponin T 1563 ng/L (URL <13 ng/L) and creatine-kinase 1176 UI .. osemide were started. An urgent coronary angiography was per- (nL < 36 UI)]. .. formed showing normal coronary arteries (Figure 2); a left 4 M. Salido Iniesta et al. Downloaded from https://academic.oup.com/ehjcr/article/4/5/1/5917792 by guest on 30 October 2023 Figure 4 (A) Basal, mid, and apical left ventricle cross-sectional images in T2 mapping CMR. Quantitative T2 signal values in milliseconds (ms) with normal values in blue. Apical sector shows increased normal values (>56 ms), mainly in the anteroseptal apical segment consistent with myocardial oe- dema. (B) T2 STIR RMC images. Semiquantitative evaluation signal, showing a higher signal intensity in the apical segment, concordant with oedema at this level. .. ventriculography was performed confirming severe left ventricular .. System Best, The Netherlands). An LVEF improvement (48%) was function impairment with a left ventricular ejection fraction of 32% .. confirmed, although slightly reduced due to the overall dyssynchrony .. (Figure 3). Due to clinical instability, a myocardial biopsy was not .. of the LV. T1 and extracellular volume values were normal (1044 ms performed and the patient was transferred to the Intensive .. and 26%, respectively) at the mid-septal area and no myocardial late .. Cardiac Care Unit where high-dose boluses of methylpredniso- .. gadolinium enhancement was depicted in the myocardium, but an in- lone (1 g/day during 72 h), systemic vasodilators and loop diuretics .. crease of the myocardial intensity signal in the T2-STIR sequences .. (continuous infusions of furosemide and sodium nitroprusside) .. and T2 values (74 ms, nL <56 ms) in the parametric images were were administered under suspicion of acute pharmacological myo- .. .. found at the apical LV segments, suggesting the presence of residual carditis. Oxygen face mask was also needed (FiO2 30%) without .. myocardial oedema in this region (Figure 4). These findings supported the need for neither ventilatory support nor inotropic treatment. .. .. the previous clinical diagnosis of acute myocarditis, with no signs of He presented with favourable clinical course, restoring the .. permanent myocardial injury. Three weeks later, the patient was dis- .. haemodynamic stability. Corticosteroid dosage (methylpredniso- .. charged showing regression of the altered repolarization (Figure 5) lone 1 mg/kg/day), therapy was reduced progressively within 2 .. and of the LV regional contractility abnormalities (LVEF 53%). .. weeks without further incidents and enalapril, bisoprolol, and spir- .. Four weeks after clinical presentation, the patient was readmitted onolactone were initiated at low doses. An improvement of left .. due to new-onset pharmacological myasthenia-like syndrome. .. ventricular ejection fraction (45%) was evidenced in a control .. echocardiography before hospital discharge. .. Discussion .. Cardiac magnetic resonance with gadolinium contrast, including .. T1 and T2 mapping and T2-STIR sequences, was performed after 2 .. In the last decade, ICIs have shown encouraging outcomes in .. weeks of treatment with a 1.5 scanner (Interna CV, Philips Medical . advanced or metastatic malignancies, where previous prognosis was Pembrolizumab mediated autoimmune myocarditis 5 Downloaded from https://academic.oup.com/ehjcr/article/4/5/1/5917792 by guest on 30 October 2023 Figure 5 ECG control after 3 weeks of treatment showing regression of the abnormal repolarization pattern. ominous. Acute myocarditis is the most frequent PD-1 receptor in- .. establishment of treatment is only possible when there is a strong .. hibitor (pembrolizumab) induced cardiac toxicity.1,2 .. clinical suspicion.11,12 Cardiomyocytes express PD-L1 at low levels, binding to PD-1 T .. .. A confirmatory endomyocardial biopsy (EMB) is generally indi- cell receptor. The interaction leads into suppression of T-cell activa- .. cated. Unfortunately, in our case, an EMB could not be performed tion, maintaining self-tolerance and promoting resolution of inflam- .. .. due to the severe haemodynamic instability. However, in this case, mation. The deletion of gene encoding PD-1 and PD-L1 in mice has .. been demonstrated to cause dilated cardiomyopathy and lethal auto- .. there was a high clinical suspicion with a compatible clinical syn- .. immune myocarditis, respectively.3,4 .. drome, elevated myocardial injury biomarkers, together with electro- Although immune-related cardiotoxicity has been underestimated .. cardiographic and echocardiographic reversible changes consistent .. in initial studies, many cases of myocarditis and fulminant heart failure .. with definite myocarditis according to the diagnostic criteria pro- .. have been increasingly reported, so the real incidence still remains .. posed by Bonaca et al.13,14 This was further substantiated by the unknown.5,6 .. .. results of CRM imaging. Myocarditis frequently presents together with progressive and se- .. Other autoimmune side effects can frequently present concomi- vere ventricular dysfunction with a high mortality rate up to 50%, al- .. .. tantly. This is the first case report in literature where the patient was though a selection bias may contribute by magnifying its severity.7 Of .. note, early diagnosis followed by withdrawal of treatment and early .. first diagnosed with an autoimmune hepatitis, followed by an acute .. initiation of immunosuppression therapy are the main prognosis and .. myocarditis and a latter myasthenia-like syndrome. In fact, it has al- recovery modifiable factors. However, current evidence and clinical .. ready been described in some case series, where 23–25% of myocar- .. recommendations are based on case reports and case series, translat- .. ditis associate with myositis; and 10% with myasthenia-like ing the lack of scientific evidence available concerning this emerging .. .. syndrome.11,15 problem.8–10 .. Moreover, myocarditis related to ICIs is a challenging diagnosis as .. Finally, more studies are needed to provide further evidence and .. to understand underlying mechanisms of ICIs related to cardiac tox- it is a rare event without a specific definition in clinical trials. The low .. sensitivity and specificity of clinical manifestations, laboratory markers .. icity, as they are not fully understood to date. Also, clinical trials are .. and imaging testing may affect the final diagnosis. Nevertheless, rapid . required to standardize cardiotoxicity treatment. 6 M. Salido Iniesta et al. .. Lead author biography .. 2. Hurst JH. Cancer immunotherapy innovator James Allison receives the 2015 .. LaskerDeBakey Clinical Medical Research Award. J Clin Invest 2015;125: .. 3732–3736. Mario Salido Iniesta is a cardiology .. 3. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A et al. resident at Sant Pau University .. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science .. 2001;291:319–322. Hospital. At present, his work .. focuses on clinical cardiology. He .. 4. Lucas JA, Menke J, Rabacal WA, Schoen FJ, Sharpe AH, Kelley VR. Programmed .. death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and was graduated in Medicine at .. pneumonitis in MRL mice. J Immunol 2008;181:2513–2521. Pompeu Fabra University. His fa- .. 5. O’Kane GM, Labbé C, Doherty MK, Young K, Albaba H, Leighl NB. Monitoring .. and management of immune-related adverse events associated with programmed vourite place to work and do re- .. cell death protein-1 axis inhibitors in lung cancer. Oncologist 2017;22:70–80. search is Barcelona where there are .. 6. Costa R, Carneiro BA, Agulnik M, Rademaker AW, Pai SG, Villaflor VM et al. .. both: sea for surfing and mountain .. Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a for mountain-biking to practice in .. systematic review and meta-analysis of randomized clinical trials. Oncotarget .. 2017;8:8910–8920. his spare time. .. 7. Lyon AR, Yousaf N, Battisti NML, Moslehi J, Larkin J. Immune checkpoint inhibi- .. tors and cardiovascular toxicity. Lancet Oncol 2018;19:e447–e458. .. Downloaded from https://academic.oup.com/ehjcr/article/4/5/1/5917792 by guest on 30 October 2023 8. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J et al. .. Supplementary material .. Management of toxicities from immunotherapy: ESMO Clinical Practice .. Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 119–142. .. 9. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y et al. Fulminant Supplementary material is available at European Heart Journal - Case .. myocarditis with combination immune checkpoint blockade. N Engl J Med 2016; Reports online. .. 375:1749–1755. .. 10. 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 .. Funding .. Cardiol 2018;71:1755–1764. The authors received no financial support for the research, authorship, .. 11. Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J et al. Clinical .. features, management, and outcomes of immune checkpoint inhibitor-related and/or publication of this article. .. cardiotoxicity. Circulation 2017;136:2085–2087. .. 12. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM Slide sets: A fully edited slide set detailing this case and suitable for local .. et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll presentation is available online as Supplementary data. .. .. Cardiol 2018;71:1755–1764. .. 13. Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A et al. Consent: The authors confirm that written consent for submission and .. Myocarditis in the setting of cancer therapeutics: proposed case definitions publication of this case report including image(s) and associated text has .. for emerging clinical syndromes in cardio-oncology. Circulation 2019;140: been obtained from the patient in line with COPE guidance. .. 80–91. .. 14. Biesbroek PS, Hirsch A, Zweerink A, van de Ven PM, Beek AM, Groenink M .. Conflict of interest: none declared. .. et al. Additional diagnostic value of CMR to the European Society of .. Cardiology (ESC) position statement criteria in a large clinical population of .. patients with suspected myocarditis. Eur Heart J Cardiovasc Imaging 2018;19: References .. 1397–1407. 1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF .. 15. Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. .. reporting of fatal immune checkpoint inhibitor-associated myocarditis. 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