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Delayed Acute Myocarditis and COVID 19 Relatedmultisystem in Ammatory Syndrome

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ESC HEART FAILURE CASE REPORT

ESC Heart Failure 2020; 7: 4371–4376


Published online 26 October 2020 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13047

Delayed acute myocarditis and COVID‐19‐related


multisystem inflammatory syndrome
Martin Nicol1††, Lea Cacoub1††, Mathilde Baudet1, Yoram Nahmani1, Patrice Cacoub2, Alain Cohen‐Solal1,4,
Patrick Henry1,4, Homa Adle‐Biassette3,4 and Damien Logeart1,4*
1
Cardiology Department, APHP, Lariboisiere Hospital, Paris, France; 2Internal Medicine Department, APHP, Pitie‐Salpetriere Hospital, Paris, France; 3Pathology Laboratory,
APHP, Lariboisiere Hospital, Paris, France; 4Université de Paris, Paris, France

Abstract
Precise descriptions of coronavirus disease 2019 (COVID‐19)‐related cardiac damage as well as underlying mechanisms are
scarce. We describe clinical presentation and diagnostic workup of acute myocarditis in a patient who had developed
COVID‐19 syndrome 1 month earlier. A healthy 40‐year‐old man suffered from typical COVID‐19 symptoms. Four weeks later,
he was admitted because of fever and tonsillitis. Blood tests showed major inflammation. Thoracic computed tomography was
normal, and RT–PCR for SARS‐CoV‐2 on nasopharyngeal swab was negative. Because of haemodynamic worsening with both
an increase in cardiac troponin and B‐type natriuretic peptide levels and normal electrocardiogram, acute myocarditis was
suspected. Cardiac echographic examination showed left ventricular ejection fraction at 45%. Exhaustive diagnostic workup
included RT–PCR and serologies for infectious agents and autoimmune blood tests as well as cardiac magnetic resonance im-
aging and endomyocardial biopsies. Cardiac magnetic resonance with T2 mapping sequences showed evidence of myocardial
inflammation and focal lateral subepicardial late gadolinium enhancement. Pathological analysis exhibited interstitial oedema,
small foci of necrosis, and infiltrates composed of plasmocytes, T‐lymphocytes, and mainly CD163+ macrophages. These find-
ings led to the diagnosis of acute lympho‐plasmo‐histiocytic myocarditis. There was no evidence of viral RNA within myocar-
dium. The only positive viral serology was for SARS‐CoV‐2. The patient and his cardiac function recovered in the next few days
without use of anti‐inflammatory or antiviral drugs. This case highlights that systemic inflammation associated with acute myo-
carditis can be delayed up to 1 month after initial SARS‐CoV‐2 infection and can be resolved spontaneously.

Keywords Myocarditis; COVID‐19; Pathological analysis


Received: 22 June 2020; Revised: 11 September 2020; Accepted: 16 September 2020
*Correspondence to: Prof. Damien Logeart, Cardiology Department, Hôpital Lariboisière, 2 rue Ambroise Pare, 75010, Paris, France. Email: damien.logeart@aphp.fr
†These authors contributed equally to the study.

Introduction The present report describes a case of biopsy‐proven myo-


carditis in the setting of SARS‐CoV‐2 infection and helps to
Since the start of the coronavirus disease 2019 (COVID‐19) discuss mechanisms of cardiac involvement. The patient pro-
outbreak, it has been considered that SARS‐CoV‐2‐related vided written informed consent, and the diagnostic proce-
heart damage was relatively frequent according to the rate dures were conducted in accordance with institutional
of increase in cardiac troponin levels and because of the pres- guidelines about the protection of human subjects.
ence of angiotensin‐converting enzyme 2 receptors—re-
quired to infect cells—within myocardium. In addition, the
increase in cardiac biomarkers is associated with worse out- Case report
come in infected patients.1,2 However, descriptions of such
cardiac involvement and underlying mechanisms are scarce A 40‐year‐old man, without past medical history or
and incomplete, and the existence and mechanisms of acute co‐morbidities except an obesity (body mass index = 34.8 kg/
myocarditis related to SARS‐CoV‐2 infection remain m2), described symptoms of COVID‐19 including fever, intense
questioned.3,4 fatigue, myalgia, and anosmia. He isolated himself at home

© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the 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.
4372 M. Nicol et al.

and took paracetamol without any diagnostic test. After a few worsening although ear–nose–throat infection symptoms im-
days, most symptoms resolved. Four weeks later, he pre- proved. The electrocardiogram showed sinus tachycardia
sented at the emergency unit of this hospital with fever, (110 b.p.m., PR duration = 150 ms, QRS duration = 80 ms,
odynophagia, and left neck pain. The initial examination re- and no repolarization abnormality). Blood levels of cardiac
vealed a body temperature at 39.9°C, blood pressure at troponin (high‐sensitivity troponin I) were increased at
110/60 mmHg, heart rate at 123 b.p.m., and tonsillitis with 485 ng/L (N < 34) and B‐type natriuretic peptide (BNP) at
cervical adenopathy. On biological test, leukocytes blood 2960 ng/L. Blood level of interleukin‐6 (Roche Diagnostics)
count was 25 × 109/L (neutrophils 22 × 109/L, eosinophils was highly increased at 75.6 μg/L (N < 7). A thoracic
0.04 × 109/L, and lymphocytes 0.90 × 109/L). All markers of se- contrast‐enhanced computed tomography displayed only a
rum inflammation were highly increased, that is, C‐reactive moderate bilateral pleural effusion without any sign of
protein 604 mg/L, fibrinogen 12.5 g/L, procalcitonin 14 μg/L, SARS‐CoV‐2 pneumonia or pulmonary embolism. Cardiac
and D‐dimer 5700 ng/L. Because of the outbreak of COVID‐ echography revealed a decrease in left ventricular ejection
19, a nasopharyngeal swab was performed on admission and fraction at 45%, low cardiac output (3 L/min), and both subtle
the RT–PCR assay returned negative for SARS‐CoV‐2. Blood hypertrophy and akinesia of posterolateral left ventricular
cultures were negative. Intravenous antibiotic therapy—ceftri- wall with small pericardial effusion opposite. At Day 3, a cor-
axone and metronidazole—was started in the event of celluli- onary angiogram overruled the hypothesis of obstructive cor-
tis. There was no purulent collection and dental granuloma nor onary disease. Cardiac magnetic resonance (CMR) at 1.5 T
tonsil phlegmon requiring surgery. (Figure 1) showed normal left ventricular size (left ventricular
The patient was referred at Day 2 of hospitalization in the end‐diastolic volume index: 75 mL/m2) and mild systolic dys-
intensive care unit because of respiratory and haemodynamic function (left ventricular ejection fraction: 45%) with global

Figure 1 (A) Initial T2 mapping sequence in short axis view showing intense interstitial myocardial oedema (native T2 = 62 ms). (B) One month later, T2
mapping sequence in short axis view showing normalization of native T2 = 44 ms, suggesting disappearing of myocardial oedema. (C) Initial
phase‐sensitive inversion recovery sequences in four‐chamber view showing pericardial effusion and focal lateral subepicardial late gadolinium en-
hancement (white narrow). (D) One month later, phase‐sensitive inversion recovery sequences in four‐chamber view showing no pericardial effusion
and no subepicardial late gadolinium enhancement.

ESC Heart Failure 2020; 7: 4371–4376


DOI: 10.1002/ehf2.13047
Delayed acute myocarditis and COVID‐19‐related multisystem inflammatory syndrome 4373

hypokinesia. The presence of myocardial inflammation was enterovirus, coronavirus 229E, HKU1, NL63, OC43 and MERS,
confirmed by T2 mapping (global T2 relaxation times: human herpes virus 6 and 8, cytomegalovirus, Epstein–Barr
62 ms; centre‐specific cut‐off value for acute myocarditis: virus, varicella‐zoster virus, HIV, and SARS‐CoV‐2. RT–PCR
≥55 ms). Late gadolinium enhancement imaging (inversion for herpes simplex virus 1 and 2, varicella‐zoster virus, adeno-
time by using the Look‐Locker technique: 280 ms) showed virus, enterovirus, human herpes virus 6A and B, and parvovi-
focal lateral subepicardial enhancement with prolonged T1 rus B19, as well as Elisa tests for HIV, CMV, and EBV, were
relaxation times (global T1 relaxation times: 1160 ms; also performed on blood and were negative. Only SARS‐
centre‐specific cut‐off value for acute myocarditis: CoV‐2 serology returned positive: IgG blood level was in-
≥1000 ms). Cardiac magnetic resonance imaging also showed creased with signal cut‐off ratio at 3.9 (positive threshold at
small pericardial effusion. Overall, revised 2018 Lake Louise 1.4, Abbott Diagnostics) whereas there was no IgM. The fol-
criteria for diagnosis of acute myocarditis were fulfilled. Be- lowing measurements were also performed to rule out auto-
cause of the clinical severity of the acute heart failure with immune disease: the blood research of antinuclear, anti‐DNA,
left ventricular dysfunction and pulmonary oedema requiring anti‐extractable nuclear antigen, and anti‐neutrophil cyto-
intensive oxygenotherapy and high doses of diuretics, plasm antibodies were negative, and the measurement of
endomyocardial biopsies of left ventricle (posterolateral wall) complement components C3 and C4 was normal.
were performed on Day 4. Pathological analysis found an in- Medical treatment of heart failure included
terstitial oedema, small foci of necrosis, interstitial and angiotensin‐converting enzyme inhibitors and beta‐blockers,
perivascular infiltrates composed of CD138+ CD79a+ CD20 no anti‐inflammatory drug because of ear–nose–throat
plasmocytes, CD3+ CD8+ T‐lymphocytes (7 cells/mm2), few infection requiring antibiotic treatment, and as transient
neutrophils, and a dense and diffuse infiltration by CD163+ atrial fibrillation occurred at Day 6, anticoagulant and
macrophages (Figure 2). Exhaustive research of viruses was anti‐arrhythmic therapy were added. The patient rapidly re-
performed by RT–PCR on frozen myocardial fragments and covered and was discharged at Day 9 while C‐reactive protein
was negative for the following: adenovirus, B19 parvovirus, was at 44 mg/L, cardiac troponin I 71 ng/L, and BNP 197 ng/L,
parainfluenza 1, 2, 3, and 4, influenza A and B, rhinovirus, and echocardiographic examination was normal. One month

Figure 2 (A–D) Endomyocardial biopsy showing multiple foci of lymphocytes (arrow and arrowhead) in a diffuse inflammatory and oedematous back-
ground. (B) A higher magnification of the interstitial and perivascular inflammatory foci shown by an arrow in (A). (C) A few neutrophils are shown by
+
arrowheads. (D) Myocyte necrosis, infiltrated by inflammatory cells (arrow). (E–H) The inflammatory cells were composed of numerous CD138
+ + +
plasmocytes, CD3 CD8 T cells, and numerous CD163 macrophages.

ESC Heart Failure 2020; 7: 4371–4376


DOI: 10.1002/ehf2.13047
4374

Table 1 Publishe`d case reports of patients with heart failure and suspicion of acute myocarditis related to SARS‐CoV‐2 infection

Time from onset


of COVID Diagnostic test Clinical
Authors symptoms for COVID manifestations Blood tests CMR Cardiac biopsy Treatments Outcome
5
Doyen et al. Day 7 PCR on nasal 65 years, cough, TnI 9000 ng/L Normal LVEF No Hydrocortisone
swab fever, dyspnoea Subepicardial
inferolateral LGE
6
Luetkens et al. Day 2 PCR on nasal 53 years, fever, CRP 13 mg/L No No Dobutamine
swab dry cough TnT 0.24 ng/mL Hydroxychloroquine,
NT‐pro‐BNP lopinavir/ritonavir,
5647 pg/mL methylprednisolone
7
Kim et al. Day 1 PCR on nasal 21 years TnI 1.26 ng/mL LVEF 40% No
swab NT‐pro‐BNP 929 pg/mL T1 = 1431 ms,
transmural LGE
8
Sala et al. Day 3 PCR on nasal 37 years, dyspnoea, TnT >10 000 ng/L No No Corticosteroids Full recovery
swab chest pain, NT‐pro‐BNP >21 000 ng/L Noradrenalin within 1 week
diarrhoea, Immunoglobulins
cardiogenic shock Diuretics
Milrinone
Tazocilline
9
Caforio et al. Day 7 PCR on nasal 53 years, cough, Increase in TnT LVEF 35% No Dobutamine, lopinavir/ Progressive
swab fever, fatigue and BNP Diffuse LGE, ritonavir, steroids, stabilization
pericardial effusion chloroquine
10
Ferreira et al. Day 3 PCR on nasal 37 years, chest TnT >10 000 ng/mL No No Diuretic, milrinone, Full recovery
swab pain, dyspnoea, Creatine Kinase Myocardite norepinephrine, within 3 weeks
diarrhoea Band (CPKMB) methylprednisolone,
112.9 ng/mL immunoglobulin,
NT‐pro‐BNP 21 025 ng/L piperacillin, sulbactam
3 +
Zhou Day 3 PCR on nasal 43 years, dyspnoea, CRP 18 mg/L LVEF 43% Diffuse CD3 Lopinavir/ritonavir, Full recovery of
swab chest pain TnT 135 ng/L Diffuse LGE T‐lymphocytic hydroxychloroquine LVEF at Day 7
NT‐pro‐BNP 521 ng/L inflammatory Persistence of a
infiltrates mild hypokinesia at
basal and mid‐left
ventricular
segments; at the
same sites
11
Tavazzi et al. Day 4 PCR on nasal 69 years, CRP 52 mg/dL No Low‐grade Noradrenaline, IABP,
swab respiratory distress TnI 4332 ng/L macrophagic ECMO
and cardiogenic interstitial and
shock endocardial cardiac
inflammation
12
Bonnet et al. Day 30 PCR on nasal 19 years, PCT 155 μg/L No No necrosis Diuretics, antibiotics,
swab respiratory distress TnI 4200 ng/L Inflammatory inotropic and
and cardiogenic NT‐pro‐BNP infiltrates (T‐lymphocytes vasopressive drugs
shock, LVEF 20% 17 377 pg/mL and neutrophils)

CMR, cardiac magnetic resonance; CRP, C‐reactive protein; ECMO, extracorporeal membrane oxygenation; IABP, intra‐aortic balloon pump; LGE, late gadolinium enhancement; LVEF, left
ventricular ejection fraction; NT‐pro‐BNP, N‐terminal pro‐brain natriuretic peptide; PCR, polymerase chain reaction; PCT, procalcitonin; Tn, cardiac troponin levels.

ESC Heart Failure 2020; 7: 4371–4376


M. Nicol et al.

DOI: 10.1002/ehf2.13047
Delayed acute myocarditis and COVID‐19‐related multisystem inflammatory syndrome 4375

after hospital discharge, clinical examination was completely ventricular dysfunction recovered spontaneously. Interest-
normal (no fever and no signs of heart failure). CMR and ingly, the authors observed viral particles within macro-
transthoracic echocardiogram showed disappearance of myo- phages but not within myocytes, suggesting the role of
cardial oedema (global T2 relaxation time = 44 ms, global T1 SARS‐CoV‐2‐mediated cardiac inflammation by either tran-
relaxation time = 1006 ms), recovering of left ventricular ejec- sient viraemia or infected macrophage migration. In our pa-
tion fraction (60%), absence of pericardial effusion, and myo- tient, myocardial infiltrates also consisted of macrophages
cardial late gadolinium enhancement. The hypersensitive as shown in Figure 2 but without evidence of virus according
troponin I and BNP levels were <14 and 21 ng/L, respec- to PCR analysis. Some similarities can be also found with a
tively. Biological markers of systemic inflammation returned study14 that reported Kawasaki‐like disease in children in
to normal values, that is, C‐reactive protein <4 mg/L, the setting of COVID‐19 pandemic. These young patients suf-
procalcitonin <0.02 mg/L, and D‐dimers <270 ng/L. fered from multisystem inflammatory syndrome and acute
heart failure with complete recovery in a few days, suggesting
that myocardial involvement could be due to myocardial
Discussion stunning/oedema more than to myocardial necrotic damage.
Most of them had negative nasopharyngeal RT–PCR, but
A few case reports of acute heart failure and/or left ven- SARS‐CoV‐2 serology testing was positive in 89% of patients.
tricular dysfunction with abnormalities in CMR suggesting This study shows also that 60% of patients had cervical
myocarditis have been published in the setting of acute lymphadenopathy. Very recently, Bonnet et al. reported a
SARS‐CoV‐2 infection (Table 1),4–7,13 but diagnosis of ac- short clinical case of biopsy‐proven severe myocarditis re-
tive myocarditis was proven by endomyocardial biopsy in lated to COVID‐19 in a young adult male.12 As in our case,
only one case.8 Our case report highlights the importance symptoms of fulminant myocarditis were delayed by 1 month
of exhaustive and careful workup to specify diagnosis and after the initial SARS‐CoV‐2 infection, and endomyocardial bi-
causes of acute myocarditis using both blood tests, echo, opsy failed to demonstrate the presence of virus within
CMR analysis, and also endomyocardial biopsies if myocardium.
necessary.9,10 After carefully ruling out usual aetiologies
of myocarditis such as common viruses, bacteria, autoim-
mune disease, giant cells, and hypereosinophilic syndrome, Conclusions
we hypothesized that SARS‐CoV‐2‐mediated systemic in-
flammation could be the cause of this acute cardiac inflam- We report an exhaustive description of acute lympho‐
matory response. The nearly 1‐month delay between acute plasmo‐histiocytic myocarditis related to severe systemic in-
heart failure and initial COVID‐related symptoms of our pa- flammation. Our case is unique by its delay after the initial
tient is unusual. All previously published cases occurred COVID‐19 infection. Myocarditis is a difficult diagnosis with
within the first week after initial symptoms of COVID. various underlying mechanisms and therapeutic issues. This
Our hypothesis is that prolonged systemic inflammation report underlines the importance of careful workup to con-
(‘cytokines storm’) led to both tonsillitis and dense myo- clude such diagnosis. Our patient recovered without use of
cardial inflammation. Sala et al. reported recently the first anti‐inflammatory drugs or antiviral drugs. Finally, it is impor-
evidence of acute myocarditis by endomyocardial biopsy in tant to remind that SARS‐CoV‐2 infection can lead to systemic
a patient with COVID‐19.8 As in our patient, they did find inflammatory response with organ involvement up to several
evidence of SASR‐CoV‐2 within myocardium using RT– weeks after initial infection that highlights the importance of
PCR. Similarities with Tako‐Tsubo syndrome were also clinical surveillance even after resolving of initial symptoms.
underlined in this case.
In another patient with severe pulmonary inflammation
and cardiogenic shock requiring extracorporeal membrane
oxygenation, endomyocardial biopsy showed a low‐grade Conflict of interest
macrophagic interstitial and endocardial cardiac inflamma-
tion, without evidence of acute myocarditis.11 The severe left None declared.

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ESC Heart Failure 2020; 7: 4371–4376


DOI: 10.1002/ehf2.13047

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