Post SARS-CoV-2 Myocarditis

Abstract

Background

Giant cell myocarditis (GCM) and multisystem inflammatory syndrome in adults (MIS-A) with myocarditis that appears after SARS-CoV-2 infection (COVID-19) may manifest similarly.

Case Summary

We describe a patient with GCM who presented with cardiogenic shock and received a misdiagnosis of MIS-A myocarditis because of a lack of giant cells identified on endomyocardial biopsy (EMB). Her cardiac function improved with combined immunosuppressive therapy, including cyclosporine, but subsequently worsened, with premature cessation of immunosuppression resulting from the misdiagnosis. The patient received a heart transplant. Pathologic examination of the explanted heart confirmed the diagnosis of necrotizing GCM.

Discussion

The diagnosis of GCM is challenging given the limited sensitivity of EMB. Treatment includes prolonged calcineurin-based combined immunosuppression, and early cessation of treatment can lead to fatal relapse.

Take-Home Message

COVID-19 may cause delayed myocarditis, and high clinical suspicion for GCM is crucial to inform appropriate management and increase the likelihood of survival.

Visual Summary

Visual Summary.

Clinical Course

ECMO = extracorporeal membrane oxygenation; IVIG = intravenous immunoglobulin; LVEF = left ventricular ejection fraction (as measured in transthoracic echocardiogram).

History of Presentation

A 46-year-old woman presented to the emergency department with 2 weeks of intermittent fevers and right upper quadrant abdominal pain. She denied chest pain, shortness of breath, or peripheral edema. One month earlier, she had experienced a SARS-CoV-2 infection (COVID-19) with mild upper respiratory symptoms and fevers for 4 days. In the emergency department, her vital signs were as follows: temperature, 97.1 °F; heart rate, 112 beats/min; blood pressure, 92/51 mm Hg; respiratory rate, 18 breaths/min; and oxygen saturation on room air, 97%. She appeared acutely ill, with right upper quadrant tenderness. Her cardiopulmonary examination was normal.

Take-Home Messages

• •COVID-19 may lead to delayed myocarditis through different mechanisms, thus warranting different treatment regimens and durations.
• •Clinical suspicion is crucial for the appropriate management of GCM with long term calcineurin inhibitor–based immunosuppression, given the limited sensitivity of EMB.

Her initial laboratory test results were notable for the following: white blood cell count, 17.87 × 10⁹/L; alanine aminotransferase, 307 IU/L; total bilirubin, 1.5 mg/dL; troponin I, 1.78 ng/mL; B-type natriuretic peptide, 757 pg/mL; and C-reactive protein, 197.9 mg/L. Lactate was 1.9 mmol/L. The initial echocardiogram showed a left ventricular ejection fraction (LVEF) of 69%. A computed tomography scan of her chest, abdomen, and pelvis suggested acute hepatitis but was otherwise unremarkable.

Past Medical History

The patient had mild asthma for which she rarely used inhalers, and she had never required hospitalization. This was her third episode of COVID-19. Her family history was significant for no premature coronary artery disease, cardiomyopathy, or sudden cardiac death. She had no recent travel and did not smoke cigarettes, drink alcohol, or use illicit drugs.

Clinical Course and Investigations

The patient was admitted to the medical floor. Extensive evaluation for infections was unrevealing, including the following: blood, urine, and stool cultures; polymerase chain reaction for influenza, respiratory syncytial virus, enterovirus, hepatitis A, hepatitis B, hepatitis C, human immunodeficiency virus, cytomegalovirus, Ebstein-Barr virus, COVID-19, adenovirus, and norovirus; serum antibody for Coxsackie A virus; and T-cell spot of tuberculosis assay.

Over the next 4 days, the patient developed progressive dyspnea and chest pain with sinus tachycardia and hypotension. Her troponin I levels were persistently elevated at 4.00 to ∼6.00 ng/mL, with no ischemic changes on serial 12-lead electrocardiograms. An echocardiogram 4 days after presentation showed an LVEF of 25%. A coronary angiogram showed normal coronary arteries. The patient developed cardiogenic shock requiring inotropic support and an intraaortic balloon pump.

Differential Diagnosis

Stress cardiomyopathy, COVID-19 myocarditis, inflammatory syndrome in adults (MIS-A) with cardiac involvement, giant cell myocarditis (GCM), and sarcoidosis were considered in the differential diagnosis of her new onset nonischemic cardiomyopathy with troponin elevation.

Management

An endomyocardial biopsy (EMB) was performed, with 2 samples showing fulminant necrotizing myocarditis without giant cells or eosinophils (Figure 1). The patient was empirically treated with methylprednisolone (1 mg/kg/d × 3 days, followed by 1 g/d × 3 days), intravenous immune globulin (IVIG) (0.5 g/kg/d × 2 days), and anakinra (300 mg/d × 7 days) for presumed post-COVID-19 MIS-A myocarditis.

Figure 1.

Pretransplantation Endomyocardial Biopsy: Necrotizing Myocarditis Without Giant Cells or Eosinophils

The patient’s condition deteriorated further over the next 3 days, and she developed ventricular fibrillation requiring venoarterial (VA) extracorporeal membrane oxygenation (ECMO) support for 2 weeks. Cyclosporine (3 mg/kg/d) was added for off-label usage with a goal level 150 to 300 ng/mL given its efficacy in treating refractory multisystem inflammatory syndrome in children (MIS-C), according to case reports.¹ She was weaned from ECMO 5 days later, and her LVEF improved to 40%. A cardiac magnetic resonance study showed diffuse late gadolinium enhancement consistent with diffuse myocarditis and, at most, minimal scarring with an LVEF of 39%. A cardiac positron emission tomography-computed tomography scan showed diffuse minimal myocardial hypermetabolism not suggestive of cardiac sarcoidosis. The decision was made to taper and discontinue all immunosuppression after a 1-month course, given the absence of giant cells on her EMB. She was discharged home after implantation of a cardioverter-defibrillator for secondary prevention.

Outcome and Follow-Up

A month after discharge, she returned to the emergency department with recurrent dyspnea, edema, anorexia, and somnolence. She was hypotensive, with a troponin I elevated at 4.44 ng/mL and an initial lactate level of 2.0 mmol/L. An echocardiogram showed an LVEF of 22%. She was admitted to the cardiac critical care unit for cardiogenic shock. Despite readministration of a pulse dose of methylprednisolone and IVIG, her hemodynamics rapidly deteriorated, requiring VA ECMO support. The patient was listed as status 1 for heart transplantation and underwent the transplantation procedure 2 days later. Pathologic examination of the explanted heart confirmed severe necrotizing GCM (Figure 2). Despite standard post-transplant immunosuppressant agents, including corticosteroids, tacrolimus, and mycophenolate mofeil, her post-transplant course was complicated by recurrent giant cells in her surveillance EMB 1 month after transplantation with normal graft function. She received IVIG for 2 days, with no further recurrence.

Figure 2.

Explanted Heart: Severe Necrotizing Myocarditis With Giant Cells

Tissue microdissected from the left ventricle. (A) Floridly inflamed necrotizing myocarditis with scattered giant cells accompanied by mature lymphocytes, histiocytes, and plasma cells. (B) Dense CD8⁺ T lymphocyte infiltration. (C) CD163⁺ macrophage aggregation and fusion into multinucleated giant cells (arrows). H&E = hematoxylin and eosin.

Discussion

COVID-19 may lead to myocarditis through multiple heterogeneous pathogenesis mechanisms, including direct virus-induced myocardial toxicity, exaggerated inflammatory responses causing cardiomyocyte injury, autoimmune responses ranging from vasculitis, endotheliitis, lymphocyte infiltration, and direct tissue injury.² The accurate diagnosis of post-–COVID-19 myocarditis is crucial to ensure timely and adequate treatment with the appropriate regimen and increased patient survival.³

GCM and MIS-A myocarditis manifest with similar symptoms. GCM is a T-lymphocyte–mediated autoimmune disease. Although there is no clear mechanistic link to COVID-19, it has been associated in patients with recent COVID-19.⁴ Similarly, MIS-A is characterized by a hyperinflammatory state of macrophage overactivation and cytokine storm with resultant impact on multiple organs, including the cardiovascular system with myocarditis. Both diseases may manifest as delayed symptoms after a COVID-19 infection, and they respond well to immunosuppressive therapy. However, the recommended duration of treatment for GCM is typically 1 to 2 years,⁵ in contrast to case reports indicating treatment for 8 weeks or less for MIS-A myocarditis.^6,7 The clinical impact of this differential duration of treatment is clear; this patient was misdiagnosed with COVID-19 MIS-A myocarditis given the absence of giant cells in her EMB, and therefore she received inadequate immunosuppressive treatment.

The diagnosis of GCM is challenging. Rapidly progressive heart failure not responding to usual treatment within 1 to 2 weeks warrants an EMB.⁵ However, because of the patchy involvement of GCM, 5 to ∼6 biopsy samples should be obtained from at least 1 region, including the right ventricular septum, and compared with the 2 tissue samples as in this patient. Although EMB is required for diagnosis, the sensitivity is only 80%.⁵ The mere absence of giant cells on histopathologic examination should not exclude the diagnosis of GCM, especially in the presence of fulminant necrosis. Repeat EMB of the right ventricle and/or left ventricle should be considered in patients with fulminant myocarditis but nondiagnostic pathologic findings. Imaging and electroanatomic mapping–guided biopsy may increase the diagnostic yield.⁵ Unfortunately, when our patient was weaned from VA ECMO, and stable enough to undergo cardiac magnetic resonance and positron emission tomography studies, her myocarditis had already improved with treatment. Therefore, both imaging studies showed mild, diffuse, nonspecific inflammation.

Without immunosuppressive treatment, GCM carries a mortality rate of 100% even with treatment with corticosteroids alone. The addition of calcineurin inhibitors (cyclosporine or tacrolimus) significantly improves transplant-free survival to 52% by 5 years.⁵ Similar to post–heart transplant management, current standard GCM treatment includes corticosteroids, a calcineurin inhibitor, and an antimetabolite (azathioprine or mycophenolate mofetil). For patients whose condition stabilizes on this regimen, the prednisone and antimetabolite are typically generally tapered after 1 year, whereas the calcineurin inhibitor is continued for 2 years or indefinitely. Premature cessation of immunosuppression has been associated with fatal disease relapse. In this case, continuation of immunosuppression after the initial presentation may have obviated the need for heart transplantation.

Antithymocyte globulin, muromonab, and alemtuzumab have been used in single cases;⁵ there are no reports of anakinra use in GCM. In this patient, a 7-day course of anakinra was ineffective in improving her cardiac function.

In contrast to GCM, MIS-A with cardiac involvement carries a mortality rate of 7%, and there is no good evidence-based treatment. Corticosteroids and/or IVIG, with the possible addition of anakinra or tocilizumab in refractory cases, have been associated with favorable outcomes in case reports.⁸ Cyclosporine has shown effectiveness in pediatric case reports, with no reports in adult patients with MIS-A. In retrospect, the fact that this patient’s condition deteriorated despite solumedrol, IVIG, and anakinra but later improved with the addition of cyclosporine could have been a sign that the patient had GCM rather than MIS-A myocarditis.

The post-transplant prognosis in GCM is similar to that in other types of nonischemic cardiomyopathy. Recurrent GCM after transplantation does occur in 20% to 25% patients, but it is mostly asymptomatic and detected on surveillance EMB, as in in this case.⁵ There is no standard treatment for post-transplant recurrent GCM, other than avoiding corticosteroid weaning. Our patient was successfully treated with IVIG, with the continuation of her post-transplant immunosuppressants.

Conclusions

This case study illustrates the challenges in GCM diagnosis and management. Given the limited sensitivity of EMB, GCM can be misdiagnosed as other types of myocarditis that do not warrant prolonged combined calcineurin-inhibitor–based immunosuppression and subsequently lead to inadequate treatment and fatal outcomes. Clinicians should maintain high suspicion, consider repeat EMB or imaging and electroanatomic mapping guided biopsy, and avoid premature cessation of immunosuppressive therapy, especially calcineurin inhibitors.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.