COVID-19 and myocarditisProf. Alida LP Caforio, MD, PhD, FESC

Chair ESC LT cardiomyopathy and myocarditis EORP registryCardiology

Dept of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, Padova, Italy

5th Webinar: ‘COVID-19, Cardiomyopathiesand Myocarditis - ERN GUARD HEART’

May 7th, 2020

ESC REPORT

Current stateofknowledgeonaetiology,diagnosis,management, and therapy of myocardit is:a posit ion statement of the European Societyof CardiologyWorkingGroup on Myocardialand Pericardial DiseasesAlida L. P. Cafor io1†*, Sabine Pankuweit 2†, Eloisa Arbust ini3, Cr ist ina Basso4,JuanGimeno-Blanes5, StephanB. Felix6,Michael Fu7, TiinaHelio8, StephaneHeymans9,Roland Jahns10, Kar in Klingel11, AlesLinhart 12, Bernhard Maisch2, W illiam McKenna13,JensMogensen14, Yigal M. Pinto15, Arsen Rist ic16, Heinz-Peter Schultheiss17,Hubert Seggewiss18, Luigi Tavazzi19, Gaetano Thiene4, Ali Yilmaz20,PhilippeCharron21, and Perry M. Elliot t 131Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 2UniversitatsklinikumGießen undMarburgGmbH, StandortMarburg,Klinik fur Kardiologie,Marburg, Germany;3AcademicHospital IRCCSFoundationPoliclinico, SanMatteo,Pavia, Italy;4Cardiovascular Pathology,Department ofCardiologicalThoracic and Vascular Sciences, University of Padua, Padova, Italy; 5Servicio deCardiologia,Hospital U.Virgen deArrixacaCtra.Murcia-Cartagena s/n, El Palmar, Spain; 6MedizinischeKlinik B,University of Greifswald,Greifswald, Germany; 7Department of Medicine, Heart FailureUnit, SahlgrenskaHospital,University of Goteborg, Goteborg, Sweden; 8Division ofCardiology, Helsinki University Central Hospital, Heart & LungCentre,Helsinki, Finland; 9Center for Heart FailureResearch, Cardiovascular Research Institute, University Hospital ofMaastricht, Maastricht, TheNetherlands; 10Department of Internal Medicine,Medizinische Klinik und Poliklinik I,Cardiology, Wuerzburg, Germany; 11Department of MolecularPathology,UniversityHospital Tubingen,Tubingen,Germany; 122ndDepartment of Internal Medicine, 1st School ofMedicine,CharlesUniversity,Prague2,CzechRepublic;13TheHeartHospital,University College, London,UK;14Department ofCardiology,OdenseUniversity Hospital,Odense,Denmark; 15Department of Cardiology (Heart FailureResearch Center),AcademicMedical Center, Amsterdam, TheNetherlands; 16Department of Cardiology, Clinical Center of Serbiaand Belgrade University School of Medicine, Belgrade, Serbia;17Department of Cardiology and Pneumology, Charite Centrum 11 (Cardiovascular Medicine), Charite–Universitatsmedizin Berlin, CampusBenjamin Franklin, Berlin, Germany;18Medizinische Klinik 1, LeopoldinaKrankenhausSchweinfurt, Schweinfurt, Germany; 19GVMCareand Research, MariaCeciliaHospital, Cotignola, RA, Italy; 20Robert-Bosch-Krankenhaus, Stuttgart,Germany; and 21UPMC Univ Paris6,AP-HP,Hopital Pitie-Salpetriere,CentredeReferenceMaladiescardiaques hereditaires, Paris, France

Received 14 December 2012; revised 19 April 2013;accepted 23May2013; onlinepublish-ahead-of-print 3 July2013

In thisposition statement of theESCWorkingGroup onMyocardial and Pericardial Diseasesan expert consensusgroup reviewsthe currentknowledge onclinical presentation, diagnosisand treatment of myocarditis, and proposesnew diagnostic criteria for clinically suspected myo-carditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, toimprovemanagement and provide acommon reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Myocarditis † Cardiomyopathy † Diagnosis † Therapy

Int roduct ionMyocarditisisachallengingdiagnosisduetotheheterogeneityofclinicalpresentations.1–3Theactual incidenceofmyocarditisisalsodifficult todetermineasendomyocardial biopsy(EMB),thediagnosticgoldstand-ard,1–3 isused infrequently.2,3Studiesaddressing the issue of suddencardiac death in young people report a highly variable autopsy

prevalenceofmyocarditis, rangingfrom2 to 42%of cases.4,5Similarly,biopsy-provenmyocarditisisreported in9–16%ofadult patientswithunexplained non-ischaemic dilated cardiomyopathy (DCM)6,7 and in46%ofchildrenwithanidentifiedcauseofDCM.8Inpatientspresentingwithmild symptomsandminimal ventricular dysfunction,myocarditisoften resolves spontaneously without specific treatment.9However,in up to 30%of cases, biopsy-proven myocarditis can progress to

†A.L.P.C. and S.P. contributed equally to thedocument.* Correspondingauthor.DivisionofCardiology,Department ofCardiological ThoracicandVascular Sciences,PaduaUniversityMedical School,PoliclinicoUniversitario,ViaNGiustinani,2, 35128Padova, Italy. Tel: + 39 (0)498212348, Fax: + 39 (0)498211802, Email: alida.caforio@unipd.itPublished on behalf of theEuropean Society of Cardiology. All rights reserved.& TheAuthor 2013.For permissionspleaseemail: journals.permissions@oup.com

EuropeanHeart Journal (2013) 34,2636–2648doi:10.1093/eurheartj/eht210

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Caforio A et al., Eur Heart J 2013;34:2636-2648

Myocarditis – different aetiologies

Acute myocarditisresolves in about 50%

of the patients in the first 2-4 weeks25% will develop persistent cardiac dysfunction

and 12– 25% may acutely deteriorateand either die or progress to end-stage DCM

with a need for heart transplantation

Myocarditis – ESC 2013 Task Force diagnostic criteria

Caforio A et al., Eur Heart J 2013;34:2636-2648

Myocarditis – ESC 2013 Task Force diagnostic criteria

Caforio A et al., Eur Heart J 2013;34:2636-2648

Clinically suspected Myocarditis in the presence of:

1 or more of the clinical presentations

and

1 or more of the diagnostic criteria from different categories *

in asymptomatic patients at least 2 diagnostic criteria should be met

*after exclusion of coronary heart disease, cardiac defect/ vitium, congenital cardiac anomaly etc.

-Accuracy of CMR is low in biopsy-proven myocarditis withCHF/DCM or arrhythmiapresentation

-CMR does not provideetiological diagnosis in myocarditis

Myocarditis - ESC 2013 Task Force diagnostic criteria: IV-role of CMR

What is myocarditis?• Definition (Circulation, 1995 WHO/ISFC classification; Eur Heart J, 1999;

AHA statements 2006, 2016; ESC 2008, Eur Heart J 2013)

– Myocarditis is an inflammatory disease of the myocardium and is

diagnosed by established histological, immunological and

immunohistochemical criteria

• Histological features (Dallas criteria on EMB)

• Myocarditis forms

– idiopathic,

– Infectious (mainly viral) and/or autoimmune

Myocarditis - Dallas-Criteria

Inflammatory infiltate withMyocyte necrosis

Inflammatory infiltratewithout myocyte necrosis

with/without fibrosis

No inflammatory infiltrate,No myocyte necrosis

± Fibrosis

Acute Myocarditis Borderline Myocarditis Healed Myocarditis

Only histological investigation of myocardial biopsies according to the Dallas-criteriais obsolete!

Myocarditis - AetiologyINFECTIOUS IMMUNE-MEDIATED TOXIC Bacterial Allergens: e.g. penicillin Drugs: e.g

catecholamine cocaine

SpirochetalFungal Alloantigens: e.g. heart-transplant

rejectionHeavy metals

ProtozoalParasitic Immune check-inhibitor (ICI)

associatedPhysical agents

RickettsialViral: coxsackievirus, cytomegalovirus, dengue virus, echovirus, encephalomyocarditis, Epstein–Barr virus, hepatitis A, hepatitis C virus, herpes simplex virus, herpes zoster, HIV, influenza A and B, Junin virus, lymphocytic choriomeningitis, measles, mumps, parvovirus, poliovirus, rabies, respiratory syncytial, rubella, rubeola, vaccinia, varicella–zoster, variola, and yellow fever virus

Autoantigens: e.g. myosin in giant-cell myocarditis and in virus-negative myocarditis , myocarditis associated to organ and non-organ-specific autoimmune diseases

VariousAgents, e.g stingbites

Caforio A et al., Eur Heart J 2013;34:2636-2648

Etiological forms of biopsy-proven myocarditis

Caforio et al. Eur Heart J

2013; 34:2636-48

In situ-Hybridisation

Calabrese et al, Cardiovascular Research 2003; 60: 11-25

Pankuweit & Klingel , Heart Fail Rev 2013;18(6):683-702

Polymerase chainreaction (PCR)

Myocarditis – Molecular biology

AV+

control

EMB

AV-

PCR +

DNA

Marker

negative

control

house-

keeping

gene

NON-COVID 19 myocarditis: current knowledge

• Myocarditis may be suspected by noninvasive cardiac imaging, but diagnosis of certainty is based upon EMB.

• Aetiologic diagnosis of infectious/viral vs immune-mediated/autoimmune myocarditis is based on EMB.

• Immunosuppression is indicated, safe and efficacious in infectious-negative immune-mediated/autoimmune myocarditis.

Caforio A et al., Eur Heart J 2013;34:2636-2648

What are the potential mechanisms for high troponin in COVID-19 ?• Rise and/or fall of troponin is common among patients with

acute respiratory infections and related with diseaseseverity.

• Given presence of ACE2 – the binding site for the SARS-CoV-2 – in cardiomyocytes, some postulated thatmyocarditis might explain rise of hs-cTn in some cases.

• Acute myocardial infarction (MI) – Type 1 MI based plaquerupture triggered by the infection, or Type 2 MI based on supply-demand inequity – is possible. A rise and/or fall of hs-cTn is not sufficient for the diagnosis of acute MI, whichshould be based on clinical symptoms/signs, and ECG.

• High troponin is NOT equivalent of myocarditis or acute MI.

High IL1-beta,IL-6,IFN gammaIL1-inhibitors

IL6-inhibitorsJAK-inhibitors

Myocarditis in COVID-19 infection? Epidemiological data

• More than 3.500.000 subjects have developed COVID-19, a pneumonia, which may be complicated in a proportion (about10%) of patients, by need of ICU stay, mechanical ventilation, ARDS and in few cases ECMO.

• Negative predictors for death in COVID-19 infection include old age (>60-70yrs), comorbidities (COPD, CAD, HTN, DM, cerebrovascular disease, cardiac injury defined as increasedTnI and natriuretic peptides).

• Biopsy-proven myocarditis is common in the young and in children, may occur in middle age, is rare in the elderly, isoften associated with heart failure, arrhythmia, with or withouttroponin increase.

Myocarditis in COVID-19 ? Interim analysis from autopsy series

• So far autopsy series found no histological myocarditis (i.e. inflammatory infiltrate and cardiomyocyte necrosis not typicalof myocardial infarction)

• 2 autopsy cases of COVID-19 genome or viral particles in endothelial cells and in macrophages, NOT in cardiacmyocytes.

• NO autopsy proof of viral myocarditis caused by COVID-19

• First biopsy-proven case of acute myocarditis according to ESC2013 and WHO criteria in a COVID-19 infected patient

• No evidence of viral genome for knowncardiotropic viruses(enterov.,rhinovirus,influenzaA/B,CMV, adenov., EBV,HSV,HHV6,PVB19) on EMB by PCR/RT-PCR)

• No evidence of COVID-19 genome by PCR on EMB

assessed at Cardiac Pathology and Microbiology dept, Padova

Myocarditis in COVID-19 ? Interim analysis from EMB series

• No case of biopsy-proven myocarditis caused by COVID-19 according to ESC criteria after 3.500.000 infected patients.

• One biopsy-proven virus-negative and COVID negative case

• No proof that COVID-19 enters cardiomyocytes and is a novelcardiotropic virus, replicating inside the myocyte and causingdirect cardiomyocyte necrosis, i.e.viral myocarditis.

• The clinically suspected cases during COVID-19 infectionmight be due to other viruses or non viral causes (immune-mediated, toxic).

• NO EMB proof of viral myocarditis caused by COVID-19

Diagnosis of Myocarditis in COVID19 infection: interim take-home messages

• In selected COVID-19 positive patients undergoingcoronary angiography for suspected STEMI/NSTEMI with concomitant heart dysfunction or for cardiogenic shock and with normal coro’s or in those undergoing ECMO positioning consider to perform endomyocardial biopsy ifmyocarditis is clinically suspected.

• Autopsy data, particularly in young COVID-19 victims withoutcomorbidities will be very valuable.

• Use the term «myocarditis» only for biopsy or autopsyproven cases.

Is any treatment that is being given for COVID-19 evidence-based?

Is any treatment that is being given for COVID-19 and evidence-based?

Is any treatment that is being given for COVID-19 evidence-based?

Management of Myocarditis in COVID19: interim take-home messages

• Steroids, mainly in combination with other immunosuppressivedrugs, are only used in biopsy-proven virus-negative NON-COVID-19 myocarditis in keeping with ESC reco’s.

• Biopsy-proven myocarditis during COVID-19 should be treatedwith standard cardiological treatment of heart failure and arrhythmia including inotropic support or mechanicalcirculatory assist devices as clinically indicated.

• No evidence based treatment for COVID-19 (includingclinically suspected myocarditis), work in progress, need for controlled studies, basic and translational research.

“Hic est locus ubi mors gaudet succurrere vitae”“This is the place where death delights to help the living ”

COVID19 and Myocarditis? Definitive proof is warranted

Anatomical theatre,Palazzo del Bo’ University of Padova, Italy

Galileo Galilei’s Chair, Palazzo del Bo’, University of Padova, Italy

“The experimental method: observation-hypothesis-experiment-conclusion-verification”