Virus-Negative Myopericarditis in Human Coronavirus Infection
2020; Lippincott Williams & Wilkins; Volume: 13; Issue: 11 Linguagem: Inglês
10.1161/circheartfailure.120.007636
ISSN1941-3297
AutoresFranca Del Nonno, Andrea Frustaci, Romina Verardo, Cristina Chimenti, Emanuele Nicastri, Andrea Antinori, Nicola Petrosillo, Eleonora Lalle, Chiara Agrati, Giuseppe Ippolito,
Tópico(s)Viral Infections and Immunology Research
ResumoHomeCirculation: Heart FailureVol. 13, No. 11Virus-Negative Myopericarditis in Human Coronavirus Infection Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessCase ReportPDF/EPUBVirus-Negative Myopericarditis in Human Coronavirus InfectionReport From an Autopsy Series Franca del Nonno, Andrea Frustaci, Romina Verardo, Cristina Chimenti, Emanuele Nicastri, Andrea Antinori, Nicola Petrosillo, Eleonora Lalle, Chiara Agrati, Giuseppe Ippolito and on behalf of the INMI COVID study group Franca del NonnoFranca del Nonno INMI L. Spallanzani, Rome, Italy (F.d.N., E.N., A.A., N.P., G.I.). , Andrea FrustaciAndrea Frustaci Correspondence to: Andrea Frustaci, MD, Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic, and Geriatric Sciences, La Sapienza University, Viale del Policlinico 155, 00161 Rome, Italy. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5748-0725 Department of Clinical, Internal, Anesthesiologist and Cardiovascular Sciences, La Sapienza University, Rome, Italy (A.F., C.C.). Cellular and Molecular Cardiology Lab (A.F., R.V., C.C.), IRCCS L. Spallanzani, Rome, Italy. , Romina VerardoRomina Verardo https://orcid.org/0000-0001-5542-567X Cellular and Molecular Cardiology Lab (A.F., R.V., C.C.), IRCCS L. Spallanzani, Rome, Italy. , Cristina ChimentiCristina Chimenti Department of Clinical, Internal, Anesthesiologist and Cardiovascular Sciences, La Sapienza University, Rome, Italy (A.F., C.C.). Cellular and Molecular Cardiology Lab (A.F., R.V., C.C.), IRCCS L. Spallanzani, Rome, Italy. , Emanuele NicastriEmanuele Nicastri https://orcid.org/0000-0002-5606-8712 INMI L. Spallanzani, Rome, Italy (F.d.N., E.N., A.A., N.P., G.I.). Laboratory of Virology (E.L.), IRCCS L. Spallanzani, Rome, Italy. , Andrea AntinoriAndrea Antinori INMI L. Spallanzani, Rome, Italy (F.d.N., E.N., A.A., N.P., G.I.). , Nicola PetrosilloNicola Petrosillo https://orcid.org/0000-0002-2585-7567 INMI L. Spallanzani, Rome, Italy (F.d.N., E.N., A.A., N.P., G.I.). , Eleonora LalleEleonora Lalle Laboratory of Virology (E.L.), IRCCS L. Spallanzani, Rome, Italy. , Chiara AgratiChiara Agrati Laboratory of Immunology (C.A.), IRCCS L. Spallanzani, Rome, Italy. , Giuseppe IppolitoGiuseppe Ippolito https://orcid.org/0000-0002-1076-2979 INMI L. Spallanzani, Rome, Italy (F.d.N., E.N., A.A., N.P., G.I.). and on behalf of the INMI COVID study group Originally published12 Nov 2020https://doi.org/10.1161/CIRCHEARTFAILURE.120.007636Circulation: Heart Failure. 2020;13:e007636Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 12, 2020: Ahead of Print The cause of death in patients with coronavirus disease 2019 (COVID-19) infection has not yet been completely clarified. In addition to lung failure, cardiac inflammation has also been suggested to occur. However, its source from a direct or indirect COVID-19 involvement, type of mechanism, that is, cytopathic versus immune-mediated, and compartments involved (vessels, nerves, and conduction tissue) are still undefined.We report cardiac autopsy findings in 9 patients (aged 92 [male], 82 [female], 64 [female], 58 [male], 93 [male], 81 [male], 35 [male], 54 [male], and 70 [male] years) with COVID-19 infection (diagnosed with polymerase chain reaction of nasal secretion) and pneumonitis who died because of cardiogenic shock or sudden death, during hospitalization. The patients were under treatment with antiviral and antibiotics. In addition, all patients were treated with anticoagulants (enoxaparine/clexane). No systemic arterial hypertension was recorded in our cohort. ECG demonstrated sinus rhythm with nonspecific abnormalities of ST-T segments and normal QT duration in all patients. Echocardiogram showed severe compromise of cardiac contractility in 6 patients (92 [male], 82 [female], 64 [female], 58 [male], 93 [male], and 81 [male] years; left ventricular ejection fraction, ≤30%) and mild left ventricular dysfunction (ejection fraction between 40% and 48%) with ventricular tachyarrhythmias and then sudden death in 3 (35 [male], 54 [male], and 70 [male] years; Table).Table. Clinical and Postmortem Data of 9 Patients With Coronavirus InfectionSexAge, yLength of Illness, dLown classEF, %ComorbiditiesCOVID-19 therapyCause of deathF6421128%Lobectomy for lung cancerL, R, CPneumonitis, pericarditis, myocarditis, coronary vasculitis.M5815325%NoneL, R, H, CPneumonitis associated to pulmonary thrombosis, and myocarditis, coronary vasculitis.M9324322%DementiaL, R, H, CPneumonitis associated to pulmonary thrombosis, pericarditis, myocarditis, and coronary vasculitis.OsteomyelitisF8219227%Chronic obstructive pulmonary diseaseL, R, CPneumonitis associated to pulmonary thrombosis, pericarditis, myocarditis, and coronary vasculitis.M8123330%Aortic aneurysmL, R, H, CPneumonitis associated to pulmonary thrombosis, pericarditis, myocarditis, and coronary vasculitis.M9231228%AtherosclerosisL, R, H, CPneumonitis associated to pulmonary thrombosis, pericarditis, myocarditis, and coronary vasculitis.M35184A45%NoneL, R, H, T, CPneumonitis associated to pulmonary thrombosis, pericarditis, myocarditis, inflammation of cardiac conduction tissue and of subepicardial ganglia.M70104B48%AtherosclerosisL, R, H, CPneumonitis associated to pulmonary thrombosis, pericarditis, myocarditis, inflammation of cardiac conduction tissue and of subepicardial ganglia.M54154A43%NoneL, R, H, CPneumonitis associated to pulmonary thrombosis, pericarditis, myocarditis, inflammation of cardiac conduction tissue and of subepicardial ganglia.C indicates clexane; COVID-19, coronavirus disease 2019; EF, ejection fraction; F, female; H, hydroxychloroquine; L, lopinavir; M, male; R, ritonavir; and T, tocilizumab.At macroscopic examination, the heart was always increased in weight (Figure 1A), pale and flabby (Figure 1B), and in 6, a pericardial effusion (Figure 1A) was also observed. No relevant (>70%) stenosis of epicardial coronary arteries was documented. At histology, lymphomononuclear infiltrates (CD68, CD45 Ro positive) were observed in the myocardium with focal necrosis of adjacent myocytes (Figure 1C and 1D), in all patients and in the pericardium (Figure 1E and 1F) and in intramural vessels with necrosis of vessels' wall (Figure 1G and 1H) in the 6 subjects who died because of heart failure. Inflammatory infiltrates were mostly registered in the adventitia and outer vessel layer. Vasculitis of pulmonary vessels (Figures I and II in the Data Supplement) was commonly observed in our cohort. In the 3 patients with ventricular arrhythmias, who suffered sudden death, subepicardial ganglia were also involved by inflammation with degradation of neuron fibers (Figure 1I). In the last cohort, several sections including peripheral segments of His-Purkinje system presented lymphocytic infiltration and necrosis of conduction tissue (Figure 1J). The extensive involvement of intramural coronary vessels in these patients suggests to have been, in addition to cardiomyocyte necrosis, a major determinant of heart failure and cardiogenic shock. Inflammation of cardiac conduction tissue and of subepicardial ganglia documented in 3 patients gives reason for the occurrence of severe electrical instability and sudden death.Download figureDownload PowerPointFigure 1. Cardiac postmortem findings in 9 patients affected by coronavirus disease 2019 (COVID-19) infection.A, Overweight heart (450 g) in a patient with coronavirus infection. Plaque-like fibrous whitish thickened pericardium denoting pericarditis. B, Grossly, the heart was dilated, and the ventricular myocardium was flabby and pale with thickened walls. C, Lymphocytic myocarditis (hematoxlin and eosin, 200×). D, Immunohistochemistry for cluster differentiation68 showing positive macrophages in the inflamed myocardium. E and F, Lymphocytic pericarditis (hematoxlin and eosin, 200×). G, Necrotizing vasculitis of an intramural coronary artery (hematoxlin and eosin, 200×). H, Immunohistochemistry for Cluster differentiation45Ro suggesting lymphocytic infiltration and necrosis of an intramural coronary artery (200×). I, Lymphocytic infiltration of a subepicardial ganglion (cluster differentiation45Ro, 400×). J, Severe infiltration with damage of a section of conduction tissue (hematoxlin and eosin, 200×).Real-time polymerase chain reaction has been obtained from several frozen myocardial samples for the most common cardiotropic viral genomes, including adenovirus, cytomegalovirus, parvovirus B19, Epstein-Barr virus, human herpes virus 6, and herpes simplex virus 1 and 2, enterovirus, influenza virus A and B, hepatitis C virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Molecular studies failed to find viral genomes, including SARS-CoV-2, in the myocardium of our cohort. Polymerase chain reaction for SARS-CoV-2 was always positive in the lung tissue.These findings strongly suggest myocardial inflammation in COVID-19 infection contributes significantly to patients' death. To this regard, all cardiac compartments may be involved including pericardium, myocardium, coronary vessels, conduction tissue, and neuron ganglia.Our autopsy series demonstrated myocardial inflammation in the absence of viral genomes most likely related to an abnormal immunologic response.1 Its severity is probably linked to the specificity of human leukocyte antigen (HLA) system and explains the different clinical response to SARS-CoV-2 infection: indeed, some patients have a mild or a moderate form of myocarditis and recover spontaneously, whereas others may have a severe manifestation and die.A recent report demonstrates that HLA variation affects the cellular immune response to peptides from human-infecting coronaviruses with HLA-B*46:01 causing increased and HLA-B*15:01 reduced vulnerability to viral infection.2Lack of detection of SARS-CoV-2 in the myocardium is at variance with another previously published case report3 showing ultrastructural evidence of viral particles in cardiac macrophages. This probably represents a hyperacute and highly viremic phase of the COVID-19 disease, with a direct viral damage, which is likely followed after some days, as in our cases, by an immune-mediated insult.Differently from recent observation of endothelitis4,5 caused by SARS-CoV-2, coronary vasculitis in our study proceeded from adventitia to internal vessel layers (Figure 1C and 1D) suggesting the immunologic damage coming from vasa vasorum. We can speculate that immunocytes and circulating immunocomplexes might participate in vessel inflammation as recently suggested.5 Pathological implication in this instance is the loss of pericytes leading to additional impairment of angiogenesis.6Clinical implications from these observations are that these patients may respond to immune-modulation therapy, including steroids, inhibitors of interleukin-1β, and inhibitors of receptors for interleukin-6, in addition to an antiviral therapy. The presence of extensive necrotizing vasculitis of intramural coronary vessels solicits the administration of high-dosage immune-modulating agents.Download figureDownload PowerPointFigure 2. Biomarker data of 9 patients (pts) with coronavirus infection. The levels of fibrinogen, CRP, d-dimer, lactate dehydrogenase (LDH), troponin I, and lymphocytes were evaluated by diagnostic tools in 9 pts with coronavirus infection. CRP indicates C-reactive protein; and na, not available.Sources of FundingThis work was supported by Line 1, Ricerca Corrente of the Italian Ministry of Health, on emerging and reemerging infections and by Progetto COVID 2020 12371675, 12371817 both funded by the Italian Ministry of Health and European Project-Transnational Research Projects on Cardiovascular Diseases ERA-CVD.DisclosuresNone.Supplemental MaterialsFigures I and IIFootnotes*Drs del Nonno and Frustaci contributed equally to this work.The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCHEARTFAILURE.120.007636.For Sources of Funding and Disclosures, see page 695.Correspondence to: Andrea Frustaci, MD, Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic, and Geriatric Sciences, La Sapienza University, Viale del Policlinico 155, 00161 Rome, Italy. Email biocard@inmi.itReferences1. Sala S, Peretto G, Gramegna M, Palmisano A, Villatore A, Vignale D, De Cobelli F, Tresoldi M, Cappelletti AM, Basso C, et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection.Eur Heart J. 2020; 41:1861–1862. doi: 10.1093/eurheartj/ehaa286CrossrefMedlineGoogle Scholar2. Nguyen A, David JK, Maden SK, Wood MA, Weeder BR, Nellore A, Thompson RF. Human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2.J Virol. 2020; 94:e00510–e00520. doi: 10.1128/JVI.00510-20CrossrefMedlineGoogle Scholar3. Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, Sepe PA, Resasco T, Camporotondo R, Bruno R, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock.Eur J Heart Fail. 2020; 22:911–915. doi: 10.1002/ejhf.1828CrossrefMedlineGoogle Scholar4. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395:1417–1418. doi: 10.1016/S0140-6736(20)30937-5CrossrefMedlineGoogle Scholar5. Magro CMulvey JJBerlin DNuovo GSalvatore SHarp JBaxter-Stoltzfus ALaurence J. Complement associated microvascular injury and thrombosis in the pathogenesis of severe Covid-19 infection: a report of five case.Transl Res. 2020; 220:1–13. doi: 10.1016/j.trsl.2020.04.007CrossrefMedlineGoogle Scholar6. Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance.Neuro Oncol. 2005; 7:452–464. doi: 10.1215/S1152851705000232CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Moreno M, Yee B, Haque L and Lei K Myopericarditis as a Delayed Complication of COVID-19 Infection: A Case Report, Cureus, 10.7759/cureus.46655 Nishiyama K, Morikawa K, Shinozaki Y, Ueno J, Tanaka S, Tsuruoka H, Azagami S, Ishida A, Yanagisawa N, Akashi Y and Mineshita M (2023) Case report: Electrocardiographic changes in pembrolizumab-induced fatal myocarditis, Frontiers in Immunology, 10.3389/fimmu.2023.1078838, 14 Ungureanu R, Cobilinschi C, Cotae A, Darie R, Tincu R, Constantinescu S, Avram O, Moldovan H, Grintescu I and Mirea L (2022) Hemorrhagic Cardiac Tamponade—An Unusual Threat in the COVID-19 Recovery Phase, Medicina, 10.3390/medicina59010003, 59:1, (3) Aleksova A, Fluca A, Gagno G, Pierri A, Padoan L, Derin A, Moretti R, Noveska E, Azzalini E, D'Errico S, Beltrami A, Zumla A, Ippolito G, Sinagra G and Janjusevic M (2022) Long-term effect of SARS-CoV-2 infection on cardiovascular outcomes and all-cause mortality, Life Sciences, 10.1016/j.lfs.2022.121018, 310, (121018), Online publication date: 1-Dec-2022. Almamlouk R, Kashour T, Obeidat S, Bois M, Maleszewski J, Omrani O, Tleyjeh R, Berbari E, Chakhachiro Z, Zein-Sabatto B, Gerberi D, Tleyjeh I, Paniz Mondolfi A, Finn A, Duarte-Neto A, Rapkiewicz A, Frustaci A, Keresztesi A, Hanley B, Märkl B, Lardi C, Bryce C, Lindner D, Aguiar D, Westermann D, Stroberg E, Duval E, Youd E, Bulfamante G, Salmon I, Auer J, Maleszewski J, Hirschbühl K, Absil L, Barton L, Ferraz da Silva L, Moore L, Dolhnikoff M, Lammens M, Bois M, Osborn M, Remmelink M, Nascimento Saldiva P, Jorens P, Craver R, Aparecida de Almeida Monteiro R, Scendoni R, Mukhopadhyay S, Suzuki T, Mauad T, Fracasso T and Grimes Z (2022) COVID-19–Associated cardiac pathology at the postmortem evaluation: a collaborative systematic review, Clinical Microbiology and Infection, 10.1016/j.cmi.2022.03.021, 28:8, (1066-1075), Online publication date: 1-Aug-2022. Guglin M, Ballut K, Ilonze O, Jones M and Rao R (2021) Clinical variants of myocardial involvement in COVID-19-positive patients: a cumulative experience of 2020, Heart Failure Reviews, 10.1007/s10741-021-10129-2, 27:4, (1341-1353), Online publication date: 1-Jul-2022. Chawla K, Hong S, Shields R, Ford A, Pacella G and Lurie F (2022) Multifactorial Effects of COVID-19: A Review of Published Autopsy Reports, COVID, 10.3390/covid2050041, 2:5, (553-568) Frustaci A, Verardo R, Galea N, Lavalle C, Bagnato G, Scialla R and Chimenti C (2022) Hypersensitivity Myocarditis after COVID-19 mRNA Vaccination, Journal of Clinical Medicine, 10.3390/jcm11061660, 11:6, (1660) Chimenti C, Magnocavallo M, Ballatore F, Bernardini F, Alfarano M, Della Rocca D, Severino P, Lavalle C, Francesco F and Frustaci A (2022) Prevalence and Clinical Implications of COVID-19 Myocarditis, Cardiac Electrophysiology Clinics, 10.1016/j.ccep.2021.11.001, 14:1, (53-62), Online publication date: 1-Mar-2022. Frustaci A (2022) New Insights in Human Myocarditis, Journal of Clinical Medicine, 10.3390/jcm11040924, 11:4, (924) Caforio A, Baritussio A, Basso C and Marcolongo R (2022) Clinically Suspected and Biopsy-Proven Myocarditis Temporally Associated with SARS-CoV-2 Infection, Annual Review of Medicine, 10.1146/annurev-med-042220-023859, 73:1, (149-166), Online publication date: 27-Jan-2022. Mallick U (2022) The Pathological Features of CoViD19 Cardiovascular Complications Cardiovascular Complications of COVID-19, 10.1007/978-3-030-90065-6_4, (47-62), . Ferrer-Gómez A, Pian-Arias H, Carretero-Barrio I, Navarro-Cantero A, Pestaña D, de Pablo R, Zamorano J, Galán J, Pérez-Mies B, Ruz-Caracuel I and Palacios J (2021) Late Cardiac Pathology in Severe Covid-19. A Postmortem Series of 30 Patients, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.748396, 8 Schultheiss H, Baumeier C, Pietsch H, Bock C, Poller W and Escher F (2021) Cardiovascular consequences of viral infections: from COVID to other viral diseases, Cardiovascular Research, 10.1093/cvr/cvab315 Maiese A, Frati P, Del Duca F, Santoro P, Manetti A, La Russa R, Di Paolo M, Turillazzi E and Fineschi V (2021) Myocardial Pathology in COVID-19-Associated Cardiac Injury: A Systematic Review, Diagnostics, 10.3390/diagnostics11091647, 11:9, (1647) Hanley B, Jensen M and Osborn M (2021) Emerging spectrum of COVID-19-related cardiopulmonary pathology in adults, Diagnostic Histopathology, 10.1016/j.mpdhp.2021.05.002, 27:8, (317-324), Online publication date: 1-Aug-2021. Peretto G, Villatore A, Rizzo S, Esposito A, De Luca G, Palmisano A, Vignale D, Cappelletti A, Tresoldi M, Campochiaro C, Sartorelli S, Ripa M, De Gaspari M, Busnardo E, Ferro P, Calabrò M, Fominskiy E, Monaco F, Cavalli G, Gianolli L, De Cobelli F, Margonato A, Dagna L, Scandroglio M, Camici P, Mazzone P, Della Bella P, Basso C and Sala S (2021) The Spectrum of COVID-19-Associated Myocarditis: A Patient-Tailored Multidisciplinary Approach, Journal of Clinical Medicine, 10.3390/jcm10091974, 10:9, (1974) Gauchotte G, Venard V, Segondy M, Cadoz C, Esposito-Fava A, Barraud D and Louis G (2021) SARS-Cov-2 fulminant myocarditis: an autopsy and histopathological case study, International Journal of Legal Medicine, 10.1007/s00414-020-02500-z, 135:2, (577-581), Online publication date: 1-Mar-2021. November 2020Vol 13, Issue 11 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.120.007636PMID: 33176456 Originally publishedNovember 12, 2020 Keywordsautopsycoronavirus infectionsheart failurehypertensionstroke volumePDF download Advertisement SubjectsHeart FailureInflammatory Heart DiseasePericardial Disease
Referência(s)