Patients infected with SARS-CoV-2 have varying manifestations of cardiac involvement. We report four patients presenting with symptomatic cardiac sarcoidosis (CS) or giant cell myocarditis (GCM) 1-8 months after mild COVID-19. All patients received immunosuppressive therapy and improved gradually within the following months. The possible temporal association between the CS/GCM and COVID-19 infection might suggest that COVID-19 could be a trigger for granulomatous myocarditis.Peer reviewe

Bergh, Niklas

Bollano, Entela

Kandolin, Riina

Lehtonen, Jukka

Mäyränpää, Mikko I.

Oldfors, Anders

Polte, Christian Lars

English

PubMed

Helsingin yliopiston digitaalinen arkisto

https://helda.helsinki.fiCardiac sarcoidosis and giant cell myocarditis after COVID-19 infectionBollano, Entela2022-08-22Bollano , E , Polte , C L , Mäyränpää , M I , Oldfors , A , Bergh , N , Lehtonen , J & Kandolin ,R 2022 , ' Cardiac sarcoidosis and giant cell myocarditis after COVID-19 infection ' , ESCHeart Failure . https://doi.org/10.1002/ehf2.14088http://hdl.handle.net/10138/352114https://doi.org/10.1002/ehf2.14088cc_by_ncpublishedVersionDownloaded from Helda, University of Helsinki institutional repository.This is an electronic reprint of the original article.This reprint may differ from the original in pagination and typographic detail.Please cite the original version.Cardiac sarcoidosis and giant cell myocarditis afterCOVID-19 infectionEntela Bollano1,2* , Christian Lars Polte2,3 , Mikko I. Mäyränpää4, Anders Oldfors5 , Niklas Bergh1,2 ,Jukka Lehtonen6 and Riina Kandolin61Department of Cardiology, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden; 2Institute of Medicine at Sahlgrenska Academy, University of Gothenburg,Gothenburg, Sweden; 3Department of Clinical Physiology and Radiology, Sahlgrenska University Hospital, Gothenburg, Sweden; 4Department of Pathology, HelsinkiUniversity Hospital, Helsinki, Finland; 5Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden; and 6Department of Cardiology, Heart andLung Center, Helsinki University Hospital, Helsinki, FinlandAbstractPatients infected with SARS-CoV-2 have varying manifestations of cardiac involvement. We report four patients presentingwith symptomatic cardiac sarcoidosis (CS) or giant cell myocarditis (GCM) 1–8 months after mild COVID-19. All patientsreceived immunosuppressive therapy and improved gradually within the following months. The possible temporalassociation between the CS/GCM and COVID-19 infection might suggest that COVID-19 could be a trigger for granulomatousmyocarditis.Keywords Cardiac sarcoidosis; Giant cell myocarditis; COVID-19; Heart failureReceived: 27 January 2022; Revised: 28 June 2022; Accepted: 18 July 2022*Correspondence to: Entela Bollano, Department of Cardiology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden. Tel: +46 31 3421000. Email: entela.bollano@vgregion.seIntroductionPatients infected with SARS-CoV-2 have varying manifesta-tions of cardiac involvement. Here, we describe the clinicalpresentation and management of four cases with granuloma-tous myocarditis [sarcoidosis or giant cell myocarditis (GCM)],1–8 months after mild COVID-19 infection (Supporting Infor-mation, Table S1).Case reportPatient 1A 35-year-old previously healthy male suffered from COVID-19 infection in December 2020. Initial symptoms were feverand myalgia, but later, he developed worsening dyspnoea.He was admitted in January 2021 and diagnosed with severeheart failure and non-sustained ventricular tachycardia(NSVT). Troponin I (TnI) and N-terminal pro-BNP (NT-proBNP)were significantly elevated, and COVID-19 PCR test at thispoint was negative. Cardiac magnetic resonance imaging(cMRI) showed severe biventricular dysfunction and acutemyocardial inflammation (Figure 1). 18F-Fluorodeoxyglucosepositron emission tomography/computed tomography(18F-FDG PET/CT) confirmed the presence of widespreadmyocardial inflammation as well as uptake in the mediastinaland abdominal lymph nodes, suggesting systemic sarcoidosiswith cardiac involvement.The final diagnosis of cardiac sarcoidosis (CS) was based onendomyocardial biopsy (EMB), which showed well-formednon-necrotizing granulomas and solitary giant cells (Figure 2).Pulse-dose steroids were administered for 3 days followed byoral prednisolone tapered down slowly over a year, and acardiac resynchronization therapy defibrillator (CRT-D) wasimplanted.A follow-up 18F-FDG PET in April 2021 showed decreasedextent and intensity of fluorodeoxyglucose (FDG) uptakeconsistent with attenuated inflammatory activity (Figure 3).On the latest follow-up in August 2021, left ventricularejection fraction (LVEF) had stabilized at 35%, symptomshad improved to New York Heart Association (NYHA) II, andTnI was effectively decreased. According to our protocol,the patient was continued on 10 mg oral prednisolone daily.CASE REPORT© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any me-dium, provided the original work is properly cited and is not used for commercial purposes.ESC HEART FAILUREESC Heart Failure (2022)Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.14088 20555822, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14088 by University Of Helsinki, Wiley Online Library on [21/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicensePatient 2A 53-year-old, previously healthy female had COVID-19 infec-tion in April 2020 with mild symptoms. However, she devel-oped progressive dyspnoea on exertion in the followingmonths. In December 2020, she was urgently admitted tothe hospital due to new-onset chest pain. Interestingly, elec-trocardiogram (ECG) showed arrhythmogenic right ventricu-lar dysplasia (ARVD)-type ECG features (Figure 4). Coronaryangiography showed atheromatous coronaries but no steno-ses. cMRI showed mild left ventricular (LV) dysfunction,marked right ventricular (RV) dysfunction, and RV dilationwith extensive late gadolinium enhancement (LGE) of the leftventricle (Figure 5). The finding did not fulfil minor nor majorcriteria for ARVD.The diagnosis of GCM was based on EMB results, showingsigns of extensive myocyte destruction, necrosis, abundantgiant cells, and eosinophils (Figure 6). In one of the biopsies,Figure 1 Cardiac magnetic resonance imaging images. T2 short tau inversion recovery (STIR) image showing signs of myocardial oedema (left) and lategadolinium enhancement (LGE) image showing widespread, midwall, non-ischaemic-type LGE on both ventricles (right).Figure 2 Endomyocardial biopsy demonstrating a small granuloma. Hae-matoxylin and eosin (H&E) staining.Figure 3 Cardiac 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images showing patchy fluorodeoxy-glucose (FDG) uptake in the left ventricle.2 E. Bollano et al.ESC Heart Failure (2022)DOI: 10.1002/ehf2.14088 20555822, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14088 by University Of Helsinki, Wiley Online Library on [21/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensethere was a loose granuloma formation. Given the abysmalprognosis of untreated GCM, treatment included steroids, ta-crolimus, and mycophenolate mofetil, and an implantablecardioverter defibrillator (ICD) was implanted. A controlEMB after 1 month showed fibrosis without inflammation.Follow-ups revealed robust treatment response with no ven-tricular arrhythmias.Patient 3A 47-year-old female with hypothyroidism had COVID-19 inDecember 2020. Symptoms were mild with fever and palpita-tions. After 3 months, the patient sought help at her generalpractitioners due to worsening palpitations and progressivedyspnoea. The initial ECG showed NSVT, which resulted inan immediate hospitalization. Coronary CT angiogram wasnormal. cMRI revealed signs of extensive myocardialinflammation.The first EMB revealed no signs of inflammation. However,a second magnetic resonance imaging (MRI)-guided EMB ofthe inferior part of the septum showed signs consistent withGCM (Figure 7). She was treated with a similar regimen as Pa-tient 2 including an ICD. During the first month, the ICD de-tected frequent NSVTs, and amiodarone was added to theFigure 4 (A) Electrocardiogram (ECG) limb leads showing first-degree atrioventricular (AV) block, low QRS amplitude, and T-wave inversions in inferiorleads. (B) ECG precordial leads showing first-degree AV block, T-wave inversions in right precordial leads V1–3, and epsilon wave. Recording speed was50 mm/s.Cardiac sarcoidosis and giant cell myocarditis after COVID-19 infection 3ESC Heart Failure (2022)DOI: 10.1002/ehf2.14088 20555822, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14088 by University Of Helsinki, Wiley Online Library on [21/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensedrug regimen. Patient is doing well, with only minor symp-toms with NYHA I–II with no arrythmias.Patient 4A 40-year-old, previously healthy male had COVID-19 in earlyMarch 2022 with mild symptoms. He initially recovered butwas admitted in mid-April for sustained ventricular tachycar-dias (VTs). cMRI demonstrated severe LV dysfunction andmyocardial oedema. EMB confirmed the diagnosis of GCM.He quickly developed cardiogenic shock and was placed onvenoarterial extracorporeal membrane oxygenation (VA-ECMO). He was started on triple immunosuppressive therapyand was weaned of extracorporeal membrane oxygenation(ECMO) after 8 days. ICD was implanted for secondary pre-vention. The tendency to VTs was decreased by the use ofamiodarone–mexiletine–bisoprolol combination, and he wasdischarged in stable condition in late May 2022.DiscussionWe describe four patients with granulomatous myocarditis asa sequela of a mild COVID-19 infection. Cardiac manifesta-tions of heart failure and/or ventricular tachycardia occurred1, 3, and 8 months after COVID-19 infection. All patients hada characteristic late gadolinium enhancement pattern oncMRI, as well as consistent 18F-FDG PET/CT findings in thecase of CS. EMB of the RV septum showed well-formed gran-ulomas in one patient and giant cells and eosinophils in threeother patients. Tests for SARS-CoV-2 in the myocardium werenegative. After the biopsy results, immunosuppressive ther-apy was started with a favourable response. As granuloma-tous myocarditis is an exceedingly rare disease, we speculateFigure 5 Cardiac magnetic resonance imaging (MRI) images. (A) Steady-state free precession (SSFP) sagittal functional image showing a thickenedright ventricular myocardium, (B) 2D phase-sensitive inversion recovery (PSIR) sagittal image showing extensive biventricular delayed enhancementinvolving mainly the septum and adjacent right ventricle (RV), and (C) 2D PSIR projection of the inflow and outflow tract of the RV showing extensivedelayed enhancement involving the RV.Figure 6 Endomyocardial biopsy demonstrating loss of myocytes, diffuseinfiltration of macrophages, lymphocytes, a few eosinophilic leucocytes,and some giant cells. Haematoxylin and eosin staining; bar correspondsto 50 μm.Figure 7 Endomyocardial biopsy demonstrating myocyte destruction anddiffuse infiltration of macrophages, lymphocytes, a few eosinophilicleucocytes, and some giant cells. Haematoxylin and eosin staining; barcorresponds to 50 μm.4 E. Bollano et al.ESC Heart Failure (2022)DOI: 10.1002/ehf2.14088 20555822, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14088 by University Of Helsinki, Wiley Online Library on [21/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensethat rather than being just a random event, CS/GCM devel-oped due to previous SARS-CoV-2 infection in these fourcases.In Patient 1, CS might have been smouldering even beforethe COVID-19 onset.Patients infected with SARS-CoV-2 have varying manifesta-tions of cardiac involvement. Myocardial injury is very com-mon as measured by elevated troponin levels but does notdistinguish among the causes of injury such as myocarditis,microvascular dysfunction, small vessel cardiac vasculitis,and right heart strain due to pulmonary embolism. Myocardi-tis is often suspected but rarely if ever histologically con-firmed even in autopsy studies.1 In clinical and autopsy series,only a few cases found histological evidence for lymphocyticinfiltrates or SARS-CoV-2 genome in the heart,2 which is inline with our own unpublished results. Based on the currentavailable evidence, acute myocarditis is rare in patients withCOVID-19 infection, on the order of ~1–2%.3Little is known regarding the long-term implications ofCOVID-19 on the heart.4 Pericarditis has been seen late afteran acute infection,5 whereas the findings of late gadoliniumenhancement of the myocardium on cMRI have unknownlong-term consequences. Taken together, a variety of labora-tory and imaging abnormalities are seen in post-acute COVID-19, although many of the cMRI findings are not detected at asignificantly higher rate than among healthy controls in somestudies.6Granulomatous inflammation has been described after aSARS-CoV infection in the heart,7 skin,8,9 lymph nodes,10and Löfgren’s syndrome, which is an acute form ofsarcoidosis.11 A delayed immunological response triggeredby viral infection might give rise to granulomatous lesions.Other data suggest that together with innate immune re-sponse factors, deficient clearance of bacterial and/or viraland/or inorganic particles might be associated with granulo-matous myocarditis.12 The presence of viruses in the myocar-dium can potentially trigger a hypersensitivity-type reaction,which can initiate CS and GCM. Based on possible temporalrelationship between COVID-19 and the development ofsymptomatic CS/GCM in our four cases, we speculate thatthe viral infection acted only as initiating factor. For Patient2, we do believe that longer time between the COVID-19 in-fection and diagnosis of GCM is due to diagnostic delay. Themechanism of granulomatous inflammation in these cases isunclear, but inflammation and a dysregulated immune re-sponse following SARS-CoV-2 infection might prompt otherenvironmental triggers to cause the observed pathologies inpredisposed individuals. Future studies will be needed to de-termine how common granulomatous inflammation in theheart is following a COVID-19 infection.AcknowledgementsWe express our gratitude to the patients for participating inthis study. We thank Kristiina Nokelainen for skilled technicalassistance with immunostainings.Conflict of interestNone declared.Supporting informationAdditional supporting information may be found online in theSupporting Information section at the end of the article.Table S1. Overview of disease manifestation and clinical find-ings for patient 1–4.References1. Escher F, Pietsch H, Aleshcheva G, BockT, Baumeier C, Elsaesser A, Wenzel P,Hamm C, Westenfeld R, Schultheiss M,Gross U, Morawietz L, Schultheiss HP.Detection of viral SARS-CoV-2 genomesand histopathological changes inendomyocardial biopsies. ESC Heart Fail.2020; 7: 2440–2447.2. Basso C, Leone O, Rizzo S, de Gaspari M,van der Wal AC, Aubry MC, Bois MC, LinPT, Maleszewski JJ, Stone JR. Patholog-ical features of COVID-19-associatedmyocardial injury: a multicentre cardio-vascular pathology study. Eur Heart J.2020; 41: 3827–3835.3. Kawakami R, Sakamoto A, Kawai K,Gianatti A, Pellegrini D, Nasr A, KutysB, Guo L, Cornelissen A, Mori M, SatoY, Pescetelli I, Brivio M, Romero M,Guagliumi G, Virmani R, Finn AV. Patho-logical evidence for SARS-CoV-2 as acause of myocarditis: JACC review topicof the week. J Am Coll Cardiol. 2021;77: 314–325.4. Satterfield BA, Bhatt DL, Gersh BJ. Car-diac involvement in the long-term impli-cations of COVID-19. Nat Rev Cardiol.2021; 19: 332–341.5. Carubbi F, Alunno A, Leone S, diGregorio N, Mancini B, Viscido A, delPinto R, Cicogna S, Grassi D, Ferri C.Pericarditis after SARS-CoV-2 infection:another pebble in the mosaic of longCOVID? Viruses. 2021; 13.6. Joy G, Artico J, Kurdi H, Seraphim A,Lau C, Thornton GD, Oliveira MF, AdamRD, Aziminia N, Menacho K, Chacko L,Brown JT, Patel RK, Shiwani H, BhuvaA, Augusto JB, Andiapen M, McKnightA, Noursadeghi M, Pierce I, Evain T,Captur G, Davies RH, Greenwood JP,Fontana M, Kellman P, Schelbert EB,Treibel TA, Manisty C, Moon JC,COVIDsortium Investigators. Prospec-tive case-control study of cardiovascularCardiac sarcoidosis and giant cell myocarditis after COVID-19 infection 5ESC Heart Failure (2022)DOI: 10.1002/ehf2.14088 20555822, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14088 by University Of Helsinki, Wiley Online Library on [21/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseabnormalities 6 months following mildCOVID-19 in healthcare workers. J AmColl Cardiol Img. 2021; 14: 2155–2166.7. Bearse M, Hung YP, Krauson AJ,Bonanno L, Boyraz B, Harris CK, HellandTL, Hilburn CF, Hutchison B, Jobbagy S,Marshall MS, Shepherd DJ, Villalba JA,Delfino I, Mendez-Pena J, Chebib I,Newton-Cheh C, Stone JR. Factorsassociated with myocardial SARS-CoV-2infection, myocarditis, and cardiac in-flammation in patients with COVID-19.Mod Pathol. 2021; 34: 1345–1357.8. Polat Ekinci A, Buyukbabani N, Mese S,Pehlivan G, Okumuş NG, Ağaçfidan A,Özkaya E. COVID-19-triggered sarcoidalgranulomas mimicking scar sarcoidosis.J Eur Acad Dermatol Venereol. 2021;35: e477–e480.9. Behbahani S, Baltz JO, Droms R, DengAC, Amano SU, Levin NA, O’Brien MC,Wiss K. Sarcoid-like reaction in a patientrecovering from coronavirus disease 19pneumonia. JAAD Case Rep. 2020; 6:915–917.10. Sekulic M, Harper H, Nezami BG, ShenDL, Sekulic SP, Koeth AT, Harding CV,Gilmore H, Sadri N. Molecular detectionof SARS-CoV-2 infection in FFPE sam-ples and histopathologic findings in fatalSARS-CoV-2 cases. Am J Clin Pathol.2020; 154: 190–200.11. Mihalov P, Krajcovicova E, Kacerova H,Sabaka P. Lofgren syndrome in closetemporal association with mild COVID-19—case report. IDCases. 2021; 26:e01291.12. Calender A, Israel-Biet D, Valeyre D,Pacheco Y. Modeling potential autoph-agy pathways in COVID-19 and sarcoid-osis. Trends Immunol. 2020; 41:856–859.6 E. Bollano et al.ESC Heart Failure (2022)DOI: 10.1002/ehf2.14088 20555822, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14088 by University Of Helsinki, Wiley Online Library on [21/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Cardiac sarcoidosis and giant cell myocarditis after COVID-19 infection

Patients infected with SARS‐CoV‐2 have varying manifestations of cardiac involvement. We report four patients presenting with symptomatic cardiac sarcoidosis (CS) or giant cell myocarditis (GCM) 1–8 months after mild COVID‐19. All patients received immunosuppressive therapy and improved gradually within the following months. The possible temporal association between the CS/GCM and COVID‐19 infection might suggest that COVID‐19 could be a trigger for granulomatous myocarditis

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Cardiac sarcoidosis and giant cell myocarditis after COVID‐19 infection

Cardiac sarcoidosis and giant cell myocarditis after COVID-19 infection

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