There is limited evidence available regarding the efficacy of immunosuppressive therapy for post Coronavirus disease 2019 (COVID-19) chronic active myocarditis. We present a case of a 28-year-old woman with post COVID-19 virus-negative chronic active myocarditis. Immunosuppressive therapy improved the left ventricular ejection fraction from 21% to 42%, and ameliorated inflammatory activity as assessed by cardiac magnetic resonance imaging (CMR) and endomyocardial biopsy (EMB). This is the first report to evaluate inflammatory activity before and after immunosuppressive therapy in post COVID-19 virus-negative chronic active myocarditis using both EMB and CMR. There is limited evidence available regarding the efficacy of immunosuppressive therapy for post Coronavirus disease 2019 (COVID-19) chronic active myocarditis. We present a case of a 28-year-old woman with post COVID-19 virus-negative chronic active myocarditis. Immunosuppressive therapy improved the left ventricular ejection fraction from 21% to 42%, and ameliorated inflammatory activity as assessed by cardiac magnetic resonance imaging (CMR) and endomyocardial biopsy (EMB). This is the first report to evaluate inflammatory activity before and after immunosuppressive therapy in post COVID-19 virus-negative chronic active myocarditis using both EMB and CMR. A 28-year-old female patient without notable medical history presented with a chief complaint of chest pain, three months after a mild case of Coronavirus disease 2019 (COVID-19) infection. After admission, she developed pulseless ventricular tachycardia, but responded well to conservative treatment. Acute lymphocytic myocarditis was diagnosed based on endomyocardial biopsy (EMB) findings. Cardiac magnetic resonance (CMR) was not performed because the diagnosis of lymphocytic myocarditis was unequivocally established by myocardial biopsy. There was an absence of any newly initiated medications, and blood sample analyses revealed no abnormalities indicative of systemic inflammatory disorders. She was discharged 24 days after admission, with a troponin I level of 0.004 ng/mL and a left ventricular ejection fraction (LVEF) of 42% on transthoracic echocardiography (TTE). One year later, she was readmitted due to the dyspnoea. TTE revealed a LVEF of 42% (Video 1), and blood tests showed an elevated troponin T level of 102 ng/mL (normal; below 16 ng/mL), an angiotensin converting enzyme level of 5.2 U/L (normal; 8.3 to 21.4 ng/mL) and a soluble interleukin-2 receptor level of 290 U/mL (normal; below 613 ng/mL). CMR revealed late gadolinium enhancement (LGE) in the subendocardial lesion of the entire left ventricle (Figures 1 A). CMR also revealed native T1 of approximately 1425 ms (normal; below 1300 ms), a native T2 ranging from 59 to 62 ms (normal; below 49 ms), and an extracellular volume (ECV) of approximately 40% (normal; below 35.2%), indicating myocardial oedema and non-ischemic myocardial injury (Figures 1 B and C). 18F-fluorideoxyglucose in positron emission tomography / computed tomography (FDG-PET CT) showed no substantial FDG uptake. EMB findings showed lymphocytic infiltration, myocardial damage, substantial infiltration of CD3-positive T cells, absence of eosinophils, and positive tenascin-C immunostaining in myocardial tissue. Based on these findings, we diagnosed chronic active myocarditis (Figures 1 D-G). Cardiotropic virus testing using quantitative real-time polymerase chain reaction with the Quick-DNA/RNA FFPE Miniprep Kit (ZYMO RESEARCH, CA) did not detect any significant pathogenic viruses, including Severe Acute Respiratory Syndrome Coronavirus 2, in the myocardial specimens. She was administered carvedilol at a dosage of 2.5 mg and enalapril at 1.25 mg. Titrating the dose of carvedilol and enalapril, along with the initiation of mineralocorticoid receptor antagonist and sodium-glucose cotransporter 2 inhibitor, proved challenging due to the emergence of symptomatic hypotension and anorexia. Immunotherapy was not initiated as the patient declined treatment due to concerns about potential side effects. Three months later, her shortness of breath was worsened, blood tests showed troponin T level of 86 ng/ml and LVEF further decreased to 21% (Video 2). Finally, she agreed to initiate immunosuppressive therapy and began oral treatment with prednisolone at a dose of 30 mg/day. One month after initiation of prednisolone, blood tests showed a decreased troponin T level of 7 ng/ml, TTE revealed an improved LVEF of 45% (Video 3). Furthermore, the findings on CMR had improved (native T1 of 1290-1320 ms, native T2 ranging from 46-52 ms, and ECV of approximately 35%), although the area of LGE unchanged (Figures 2 A-C). EMB showed decreased inflammatory cell infiltration, CD3-positive T cells, and the absence of myocardial injury (Figure 2 D-G). Based on these findings, we have decided to extend the duration of steroid treatment and proceed with a tapering approach, given the persistence of minimal residual myocardial oedema. Ammirati et al. defined chronic myocarditis in an expert consensus document as representing an intermediate stage between acute myocarditis and chronic inflammatory cardiomyopathy in patients with persistent myocardial inflammation.1Ammirati E. Frigerio M. Adler E.D. et al.Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.Circ Heart Fail. 2020; 13e007405Crossref PubMed Scopus (321) Google Scholar Recently, the Japanese Circulation Society guideline defined chronic active myocarditis as myocardial inflammation lasting for at least 30 days, accompanied by cardiomyocyte injury, including myocardial necrosis or degeneration. 2Nagai T. Inomata T. Kohno T. et al.JCS 2023 Guideline on the Diagnosis and Treatment of Myocarditis.Circ J. 2023; 87: 674-754Crossref PubMed Scopus (10) Google Scholar Limited evidence exists on the effectiveness of immunosuppressive therapy for chronic active myocarditis. However, the TIMIC trial demonstrated that immunosuppressive therapy improved LVEF and may reduce the risk of cardiac death in patients with chronic myocarditis.3Chimenti C. Russo M.A. Frustaci A. Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial.Eur Heart J. 2022; 43: 3463-3473Crossref PubMed Scopus (26) Google Scholar Additionally, several studies have reported that immunosuppressive therapy may be beneficial for COVID-19-associated myocarditis.4Blagova O. Lutokhina Y. Kogan E. et al.Chronic biopsy proven post-COVID myoendocarditis with SARS-Cov-2 persistence and high level of antiheart antibodies.Clin Cardiol. 2022; 45: 952-959Crossref PubMed Scopus (12) Google Scholar In this particular case, virus-negative, chronic lymphocytic myocarditis developed 3 months post COVID-19 infection. The immunosuppressive therapy led to decreased troponin levels, improved LVEF and yielded positive findings on CMR and histopathology. This suggests that immunosuppressive therapy might be beneficial for virus-negative, chronic lymphocytic myocarditis precipitated 3 months post-COVID-19 infection. CMR is a useful diagnostic tool for myocarditis, with T1/T2 mapping and ECV being particularly emphasised for assessing myocardial injury and oedema.5Eichhorn C. Greulich S. Bucciarelli-Ducci C. Sznitman R. Kwong R.Y. Gräni C. Multiparametric Cardiovascular Magnetic Resonance Approach in Diagnosing, Monitoring, and Prognostication of Myocarditis.JACC Cardiovasc Imaging. 2022; 15: 1325-1338Crossref PubMed Scopus (40) Google Scholar Native T1 and ECV increase as a reflection of myocardial oedema, necrosis, and fibrosis. Native T2 is specifically elevated in the presence of myocardial edema. However, it is poorly documented whether CMR is available for monitoring inflammatory activity before and after immunosuppressive therapy for chronic active myocarditis. Moreover, limited data exist on the potential usefulness of CMR in post-COVID-19 myocarditis.4Blagova O. Lutokhina Y. Kogan E. et al.Chronic biopsy proven post-COVID myoendocarditis with SARS-Cov-2 persistence and high level of antiheart antibodies.Clin Cardiol. 2022; 45: 952-959Crossref PubMed Scopus (12) Google Scholar In our case, CMR showed significant reduction in native T1, native T2, and ECV following the initiation of immunosuppressive therapy. These changes on CMR could reflect the disappearance of myocardial injury and improvement of myocardial oedema, consistent with the histopathological findings. To the best of our knowledge, this is the first report to evaluate inflammatory activity before and after immunosuppressive therapy in post COVID-19 virus-negative chronic active myocarditis using both EMB and CMR. While it is challenging to ascertain whether COVID-19 was causative for myocarditis in the present case, due to the absence of PCR testing on the initial myocardial specimen, there are documented instances of myocarditis manifesting up to 18 months following COVID-19 infection. Consequently, it remains plausible that chronic active myocarditis might develop subsequent to COVID-19 infection. Assessing inflammatory activity by CMR, using T1/T2 mapping and ECV, might be useful in post COVID-19 virus-negative chronic active myocarditis. Further studies are warranted to investigate the applicability of CMR for assessing inflammatory activity in post COVID-19 virus-negative chronic active myocarditis. ●CMR might be useful for assessing inflammatory activity in post-COVID-19 virus-negative chronic active myocarditis.●Immunosuppressive therapy might be a viable treatment option for post-COVID-19 virus-negative chronic active myocarditis. None.
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