Fulminant myocarditis with myositis after treatment with immune checkpoint inhibitors

González-Ferrero, Teba; Vargas-Osorio, Kelly; González-Juanatey, José Ramón

doi:10.1016/j.medcli.2021.04.014

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(A) Destruction of myocardial fibers by an inflammatory infiltrate mainly consisting of lymphocytes and histiocytes. Lymphocytes were predominantly T cells with CD3, CD4 and CD8 (inset) positivity. (B) Skeletal muscle fibers infiltrated by identical inflammatory population, including T lymphocytes and CD68 (inset) positive macrophages (inset). (A and B, haematoxylin and eosin stain; insets A and B, immunohistochemistry for CD8 and CD68 respectively; original magnification, 400×)." ] ] ] "textoCompleto" => "Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies such as lung cancer, melanoma and kidney cancer. However, despite their excellent therapeutic effect, these medications typically lead to a wide spectrum of toxicity reactions and immune-related adverse events. Cardiotoxicity is uncommon but has high mortality and has not been well recognized.<a class="elsevierStyleCrossRef" href="#bib0030">1</a>Case reportA 70-year-old man with arterial hypertension and dyslipidemia with was diagnosed with clear cell renal cell carcinoma, WHO/ISUP grade 3, pT3a, cN1, cM1.Treatment consisted of a right nephrectomy with adrenalectomy, followed by immune checkpoint inhibitors (ipilimumab/nivolumab). Two weeks after the first cycle of drugs, the patient was referred to our hospital due to severe asthenia and dyspnea. Initial ECG showed right bundle branch block with sinus tachycardia. At physical exploration, the patient did not have cardiac murmurs but presented tachypnea and signs of respiratory failure. Blood pressure was 130/76mmHg, and heart rate was 110 beats per minute. Initial laboratory testing revealed raised levels of CK at 9800 (normal range 38–174), troponin I at 35 (NR<0.017) and myoglobin at 20,000; acute kidney failure with creatinine of 2.2; and acute liver failure with INR of 1.5, TOG of 655; TGP of 301, probably related to muscle involvement, as rhabdomyolysis is often associated with a raise of aminotransferases.Due to these alterations, a TTE (transthoracic echocardiogram) was performed. Moderate left ventricle hypertrophy, preserved biventricular systolic function and no valvulopathies were found.The first suspected diagnosis was ICI-induced myocarditis and myositis, so a high dose of glucocorticoids was initiated (2mg/kg/day intravenous methylprednisolone). Within 24h, a new auriculoventricular (AV) conduction delay appeared, later followed by complete AV block, so a temporary pacemaker was placed. Progressive clinical deterioration followed, with multisystem organ failure. Serial echocardiography revealed severely depressed biventricular systolic function. He was treated with a higher dose of glucocorticoids (methylprednisolone 1g/kg), mycophenolate mofetil and even plasmapheresis. Thoracic computed tomography showed nothing relevant, as did bronchoscopy. Despite intensive support therapy—intubation, mechanical ventilation and hemodiafiltration—respiratory failure was impossible to manage, leading to the patient passing away.The post-mortem examination revealed a severe lymphohistiocytic inflammatory infiltrate, diffusely affecting the heart and skeletal muscle. This infiltrate consisted mainly of a necrotizing and inflammatory myopathy CD3-, CD4- and CD8-positive T lymphocytes, along with numerous CD68-positive macrophages.Very few CD20-positive lymphocytes were observed. Cardiac involvement was diffuse, with inflammatory aggregates destroying myocardial fibers distributed throughout the atrial and ventricular tissue (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>DiscussionICIs have changed the treatment and prognosis of several types of cancer. However, the majority of patients suffer side effects, which are occasionally severe. Myocarditis occurred more frequently early after treatment and was more recurrent with the combination of ICI than with single therapy.<a class="elsevierStyleCrossRef" href="#bib0035">2</a>First testing in a case of ICI-associated myocarditis should be ECG (usual changes are nonspecific) and echocardiogram to provide left ventricular ejection fraction. However, normal TTE does not rule out myocarditis. To accurately diagnose myocarditis, a CMR (cardiovascular magnetic resonance) should be performed. However, CMR might not be feasible in patients who require invasive management due to hemodynamic instability.<a class="elsevierStyleCrossRef" href="#bib0030">1</a>Endomyocardial biopsy (EMB) is considered the gold standard diagnostic test for inflammatory cardiomyopathy and it is a fundamental tool in ICI-related myocarditis. Nevertheless, it has its own limitations, specially in patchy or focal cases.<a class="elsevierStyleCrossRef" href="#bib0035">2</a>In most of the cases muscle biopsy showed a marked phenomenon of necrosis, macrophage and muscle regeneration with perivascular inflammatory infiltrates with a large component of macrophagic cells.<a class="elsevierStyleCrossRef" href="#bib0040">3</a>Depending on how severe the myocarditis is, its treatment varies. Usually, a high dose of glucocorticoids (methylprednisolone 1mg/kg) is the main treatment, but sometimes it is not enough.For those with poor response to steroids, other immunosuppressive drugs could be used, such as immunoglobulin, plasmapheresis, mycophenolate mofetil, tacrolimus and even infliximab.For early diagnosis of subclinical myocarditis, serial laboratory tests, ECG and TTE can be beneficial for patients treated with ICIs. Out of all the laboratory markers, troponin is generally the most sensitive marker for confirming or excluding the diagnosis of myocarditis.<a class="elsevierStyleCrossRef" href="#bib0045">4</a>However, multi-institutional efforts are needed to understand the pathophysiology of myocarditis, and a multipronged approach is needed to understand who is at risk of developing myocarditis.FundingNone.Conflict of interestThe authors declare that there is no conflict of interest regarding the publication of this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Case report" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Discussion" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Funding" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of interest" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 905 "Ancho" => 1305 "Tamanyo" => 353596 ] ] "descripcion" => array:1 [ "en" => "Histopathology. (A) Destruction of myocardial fibers by an inflammatory infiltrate mainly consisting of lymphocytes and histiocytes. Lymphocytes were predominantly T cells with CD3, CD4 and CD8 (inset) positivity. (B) Skeletal muscle fibers infiltrated by identical inflammatory population, including T lymphocytes and CD68 (inset) positive macrophages (inset). (A and B, haematoxylin and eosin stain; insets A and B, immunohistochemistry for CD8 and CD68 respectively; original magnification, 400×)." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:4 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune checkpoint inhibitor-associated cardiotoxicity: current understanding on its mechanism, diagnosis and management" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y.W. Zhou" 1 => "Y.J. Zhu" 2 => "M.N. Wang" 3 => "Y. Xie" 4 => "C.Y. Chen" 5 => "T. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fphar.2019.01350" "Revista" => array:4 [ "tituloSerie" => "Front Pharmacol" "fecha" => "2019" "volumen" => "10" "paginaInicial" => "1350" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myocarditis in patients treated with immune checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.S. Mahmood" 1 => "M.G. Fradley" 2 => "J.V. Cohen" 3 => "A. Nohria" 4 => "K.L. Reynolds" 5 => "L.M. Heinzerling" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2018.02.037" "Revista" => array:6 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2018" "volumen" => "71" "paginaInicial" => "1755" "paginaFinal" => "1764" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29567210" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0040" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Emerging PD-1 and PD-1L inhibitors-associated myopathy with a characteristic histopathological pattern" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Matas-García" 1 => "J.C. Milisenda" 2 => "A. Selva-O’Callaghan" 3 => "S. Prieto-González" 4 => "J. Padrosa" 5 => "C. Cabrera" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.autrev.2019.102455" "Revista" => array:5 [ "tituloSerie" => "Autoimmun Rev" "fecha" => "2020" "volumen" => "19" "paginaInicial" => "102455" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31838162" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute fatal myocarditis after a single dose of anti-PD-1 immunotherapy, autopsy findings: a case report" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Hardy" 1 => "M. Yin" 2 => "J.A. Chavez" 3 => "I. Ivanov" 4 => "W. Chen" 5 => "T. Nadasdy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.carpath.2020.107202" "Revista" => array:5 [ "tituloSerie" => "Cardiovasc Pathol" "fecha" => "2020" "volumen" => "46" "paginaInicial" => "107202" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32062109" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/00257753/0000015800000003/v1_202202020734/S0025775321002578/v1_202202020734/en/main.assets" "Apartado" => array:4 [ "identificador" => "66430" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Cartas al Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/00257753/0000015800000003/v1_202202020734/S0025775321002578/v1_202202020734/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775321002578?idApp=UINPBA00004N"]

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