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COVID-19-associated myocarditis can be a lethal complication in previous variants, but it is not well understood in the Omicron variant. We present an unvaccinated case of COVID-19-associated fulminant myocarditis due to the Omicron BA.2 sub-lineage requiring mechanical circulatory support (MCS). A 66-year-old female without vaccination against SARS-CoV-2 was hospitalized due to COVID-19. On the next day, she was transferred to our hospital due to the development of fulminant myocarditis. After arrival, she was treated with Impella CP and venoarterial extracorporeal membrane oxygenation due to unstable hemodynamics. In addition to MCS, we treated her with inotropes, methylprednisolone, tocilizumab, and remdesivir. Left ventricular contraction gradually improved, and MCS was removed on day 8. Endomyocardial biopsy showed mild interstitial infiltration of CD3+-T lymphocytes and CD68+-macrophages with no remarkable necrosis or fibrosis. This case showed similar histological characteristics to COVID-19-associated myocarditis before the Omicron variant. The vaccination against the Omicron variant should be considered to prevent the development of severe illness, including fulminant myocarditis.
Learning objective
Although the Omicron variant is thought to be generally less severe, COVID-19-associated fulminant myocarditis, as in this case, can occur. The vaccination against the Omicron variant should be considered to prevent from developing severe illness.
Coronavirus disease 2019 (COVID-19) is still a pandemic worldwide. As of 2022, the dominant variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Japan was the Omicron variant, characterized by mild symptoms including upper respiratory infection, less common in pneumonia, but faster spreading than any previous variants [
Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study.
]. SARS-CoV-2 causes acute myocarditis called COVID-19-associated acute myocarditis. Unlike SARS-CoV viruses, SARS-CoV-2 has a unique affinity for angiotensin-converting enzyme 2 (ACE2), which is also expressed in human cardiomyocytes and is considered a causative pathway for myocarditis. It can be a lethal complication in previous variants, but it is not well understood about the clinical course of myocarditis or histological features in the Omicron variant. The Omicron variant has mutated residues in the receptor binding domain with ACE2. Even in the Omicron variants, sub-variants BA.2 and BA1.1 have the structural basis of higher binding affinity to human ACE2 than the Omicron sub-variant BA.1 [
], suggesting the concerns about predisposition to myocardial damage by those sub-variant infections. Here, we present an unvaccinated female case of COVID-19-associated fulminant myocarditis due to SARS-CoV-2 Omicron BA.2 sub-lineage requiring mechanical circulatory support (MCS) to recover.
Case report
A 66-year-old previously healthy female developed dyspnea and fever. She had not been vaccinated against SARS-CoV-2, and her husband was affected by COVID-19 five days ago. She was diagnosed with COVID-19 by polymerase chain reaction (PCR) for SARS-CoV-2. She was hospitalized due to general fatigue. Treatment for COVID-19 was started with 6.6 mg/day of dexamethasone and remdesivir 100 mg/day. On the next day, she presented with peripheral coldness and tachycardia, and a transthoracic echocardiogram showed diffuse left ventricular (LV) systolic dysfunction with 30 % of left ventricular ejection fraction (LVEF). Because of suspected acute myocarditis with cardiogenic shock, she was placed on a ventilator and transferred to our hospital.
On arrival, she presented hypotension (84/42 mmHg), tachycardia (105 beats/min), and tachypnea (24 breaths/min). Precise body temperature was not able to be measured due to massive cold sweat. Physical examination revealed no murmur and rales but marked peripheral coldness.
Chest X-ray showed mild enhancement of pulmonary vascular congestion, and an electrocardiogram demonstrated diffuse ST-segment elevation and mild QRS widening. Computed tomography showed pericardial effusion, but no evidence of ground glass opacity in lungs often seen in COVID-19. Laboratory data showed high levels of lactate (15.1 mmol/l), creatine kinase (933 U/l), cardiac troponin I (14.2 ng/ml), B-type natriuretic peptide (5720 pg/ml), and interleukin-6 (249 pg/ml). Coronary angiography showed no atherosclerotic stenosis. A right heart catheterization revealed a low cardiac index (1.32 l/min/m2). The patient presented cardiogenic shock, and mechanical circulatory supports (MCS) with Impella CP and venoarterial extracorporeal membrane oxygenation (VA-ECMO) were promptly inserted. Endomyocardial biopsy (EMB) showed mild interstitial inflammatory cell infiltration with no remarkable necrosis or fibrosis. Additional immunostaining revealed diffuse CD3+-T lymphocytes and interstitial CD68+-macrophages infiltration (CD3+-T lymphocytes 43 cells/mm2, CD68+-macrophages 33 cells/mm2), meeting the acute myocarditis definition by the European Society of Cardiology [
Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the european Society of Cardiology Working Group on myocardial and pericardial diseases.
]. In addition, CD4+-T lymphocytes were dominant compared with CD8+-T lymphocytes (Fig. 1). We used tocilizumab 400 mg twice daily, started methylprednisolone 120 mg/day, and remdesivir 100 mg/day. Because her hemodynamics gradually stabilized, VA-ECMO was discontinued on day 4, and Impella CP was explanted on day 8 (Fig. 2). Serological screening showed no significant increase in other viral antibody titers, such as coxsackie B virus and adenovirus. The PCR sample was sequenced, and Omicron BA.2 sub-lineage was confirmed. Based on these findings, we finally diagnosed COVID-19-associated fulminant myocarditis due to Omicron BA.2 sub-lineage. LVEF recovered to normal ranges on day 9. She was transferred back to the referring hospital for rehabilitation.
Fig. 1Histological findings of endomyocardial biopsy.
(a, b) Hematoxylin and eosin staining showed mild inflammatory cell infiltration, with no myocardial necrosis and destruction (a, H&E, ×200; b, H&E, ×400). (c) No remarkable fibrosis was observed (EM staining, ×200). (d-g) Mild infiltration of CD3+-T lymphocytes and interstitial infiltration of CD68+-macrophages were observed (d, CD3, ×200; e, CD3, ×400; f, CD68, ×200; g, ×400). (h) A few CD20+-B lymphocytes. (i, j) CD4+-T lymphocytes were dominant over CD8+-T lymphocytes.
This case is COVID-19-associated fulminant myocarditis due to the Omicron variants in an unvaccinated 66-year-old female who was successfully treated with Impella CP and VA-ECMO.
VA-ECMO improves disrupted hemodynamics promptly, but retrograde blood flow increases afterload and hinders LV function, leading to severe lung congestion, thrombosis formation in the LV cavity, and impairs myocardial tissue drainage [
]. On the other hand, the Impella device can pump blood flow out of the left ventricle into the aorta, restoring physiological hemodynamics. Therefore, using both devices is ideal for treating fulminant myocarditis [
Concomitant implantation of Impella((R)) on top of veno-arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock.
]. Consistent with that theory, we managed her hemodynamics using both VA-ECMO and Impella CP, and early recovery of cardiac function was obtained in the present case.
Non-COVID-19 acute myocarditis often demonstrates diffuse infiltration of inflammatory cells with myocardial necrosis and destruction [
]. Regarding to COVID-19-associated acute myocarditis, two reports summarized the myocardial histological findings of pre-Omicron COVID-19. Ammirati et al. have reported that inflammatory cells are present diffusely, but infiltration with myocardial injury is less observed compared to non-COVID-19 acute myocarditis (35.3 % versus 71.1 %, P = 0.018) [
]. Basso et al. have reported that myocardial interstitial macrophage infiltration was observed in 86 % of autopsy cases of consecutive COVID-19 patients [
]. In the present case, the EMB specimen showed interstitial infiltration of CD68+-macrophages and CD3+-T lymphocytes with CD4+-T lymphocytes predominating over CD8+-T lymphocytes. Myocardial injury, such as necrosis or destruction of cardiomyocyte with proximity effects of infiltrating inflammatory cells, was mild. Thus, these histological findings of this case are similar to the two reports in terms of inflammatory cell infiltration, suggesting that the Omicron variants may induce acute myocarditis with similar characteristics to the previous variants.
Although the effectiveness of vaccination against the development of Omicron-associated myocarditis is unclear, Price et al. reported that full vaccination by BNT162b2 reduced the risk of Omicron-associated hospitalization and prevented critical illness caused by either variant of the Omicron or the Delta [
]. In addition, the incidence of myocarditis due to the vaccination was reported to be 0.3–5.0 cases per 100,000 vaccinated persons, with a mortality rate of less than 1 % [
]. On the other hand, the incidence of COVID-19-associated myocarditis was reported to be 2.4–4.1 cases per 1000 COVID-19 admissions, with a rate of fulminant myocarditis of 38.9 % and a mortality rate of 5.5 % [
]. These results suggest that the benefits of vaccination outweigh the risks, and vaccination should be considered to prevent developing severe illnesses.
Patient consent statement
Informed consent was obtained from the patient for publication of the case and accompanying images.
Declaration of competing interest
The authors declare that there is no conflict of interest.
Acknowledgments
None.
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Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study.
Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the european Society of Cardiology Working Group on myocardial and pericardial diseases.
Concomitant implantation of Impella((R)) on top of veno-arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock.
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