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Abstract Vaccine-associated myocarditis is an extremely rare, yet potentially lethal disease, which requires early diagnosis and prompt treatment. However, its pathogenesis remains elusive. We report the first case of biopsy-proven eosinophilic myocarditis related to tetanus toxoid immunization, with unique histopathologic findings, characterized by perivascular eosinophilic infiltrates with myocyte necrosis and abundant interstitial lymphocytic infiltrates with myocyte necrosis, separately. A systemic high-dose corticosteroid treatment had a dramatic beneficial effect on hemodynamic instability and resulted in complete recovery. This case highlights the value of endomyocardial biopsy in establishing a definite diagnosis and understanding the pathogenesis of vaccine-associated myocarditis. Highlights • Acute eosinophilic myocarditis may be induced by tetanus toxoid immunization. • An endomyocardial biopsy is critical for early diagnosis and prompt treatment. • The clinical significance of vaccine-associated myocarditis should be recognized. [ABSTRACT FROM AUTHOR]

• Pathologists worldwide report various biopsy practice of myocarditis diagnosis. • There are regional differences in adopting diagnostic criteria and ancillary testing. • Non-uniformity in current criteria hinders comparative and multicenter studies. Dallas criteria (DC) and European Society of Cardiology criteria (ESCC) have provided valuable frameworks for the histologic diagnosis and classification of myocarditis in endomyocardial biopsy (EMB) specimens. However, the adaptation and the usage of these criteria are variable and depend on local practice settings and regions/countries. Moreover, several ancillary tests that are not included in the current criteria, such as immunohistochemistry (IHC) or viral polymerase chain reaction (PCR), have proven useful for the diagnosis of myocarditis. As a joint effort from the Association for European Cardiovascular Pathology (AECVP) and the Society for Cardiovascular Pathology (SCVP), we conducted an online survey to understand the current practice of diagnosing myocarditis. A total of 100 pathologists from 23 countries responded to the survey with the majority practicing in North America (45%) and Europe (45%). Most of the pathologists reported to examine less than 200 native heart biopsies per year (85%), and to routinely receive 3-5 fragments of tissue per case (90%). The number of hematoxylin-eosin-stained levels for each case varies from 1 to more than 9 levels, with 20% of pathologists routinely asking for more than 9 levels per case. Among the 100 pathologists, 52 reported to use the DC alone, 12 the ESCC alone, 28 both DC and ESCC and 8 reported to use neither the DC nor the ESCC. Overall, 80 pathologists reported to use the DC and 40 the ESCC. Use of DC alone is more common among North American pathologists compared to European ones (80% vs 32.6%) while use of ESCC alone is more common in Europe (20.9% vs 2.5%). IHC is utilized in either every case or selected cases by 79% of participants, and viral PCR is performed by 35% of participants. Variable terminologies are used in reporting, including both histological and clinical terms. The diagnosis of myocarditis is rendered even in the absence of myocyte injury (e.g., in cases of borderline or inactive/chronic myocarditis) by 46% respondents. The majority of the participants think it is time to update the current criteria (83%). The survey data demonstrated that pathologists who render a myocarditis diagnosis practice with variable tissue preparation methods, use of ancillary studies, guideline usage, and reporting. This result highlights the clinically unmet need to update and standardize the current diagnostic criteria for myocarditis on EMB. Additional studies are warranted to establish standard of practice. [ABSTRACT FROM AUTHOR]

• One hundred digital cases were evaluated by cardiovascular pathologists • Consensus was achieved on 90 cases • Subtle forms of myocarditis are challenging to diagnose The two histopathology benchmarks used to diagnose myocarditis are the Dallas Criteria, developed in 1984 and the European Society of Cardiology criteria, developed in 2013, which added immunohistochemistry for the detection of CD3+ T cells (lymphocytes) and CD68+ macrophages. Despite their near universal acceptance, the extent to which pathologists use these criteria or their own criteria to consistently render the diagnosis of myocarditis on endomyocardial biopsy (EMB) is unknown. We digitally scanned slides from 100 heart biopsies, including a trichrome stain and immunostaining, that were chosen as representative of myocarditis, non-myocarditis, and borderline myocarditis, as diagnosed per one institution's use of the Dallas Criteria. Eight blinded international cardiovascular experts were asked to render diagnoses and offer a confidence score on each case. No clinical histories were shared. There was full initial agreement across all experts on 37 cases (16 myocarditis and 21 non-myocarditis) and moderate consensus on 35 cases. After individual inquiries and group discussion, consensus was reached on 90 cases. Diagnostic confidence was highest among the myocarditis diagnoses, lowest for borderline cases, and significantly different between the three diagnostic categories (myocarditis, borderline myocarditis, non-myocarditis; P -value=8.49 × 10−57; ANOVA). Diagnosing myocarditis, particularly in cases with limited inflammation and injury, remains a challenge even for experts in the field. Intermediate cases, termed "borderline" in the Dallas Criteria, represent those for which consensus is particularly hard to achieve. To increase consistency for the histopathologic diagnosis of myocarditis, we will need more specifically defined criteria, more granular descriptions of positive and negative features, clarity on how to incorporate immunohistochemistry findings, and improved nomenclature. [ABSTRACT FROM AUTHOR]

• Endomyocardial biopsy results are integral for diagnosis and management of myocarditis. Current diagnostic classifications of myocarditis are based on the microscopic and immunochemical characterization of inflammation do not include monocyte/macrophage-predominant (i.e. "histiocytic") myocarditis as a histologic subtype. We describe 6 cases of patients with acute heart failure whose endomyocardial biopsies showed predominant inflammation with macrophages and monocytes identified by immunopositivity for CD68. • Our cases were both cardiac limited (i.e. primary) and associated with systemic disease, including autoimmune disease. Some biopsies showed coagulative necrosis, and some showed features resembling antibody mediated rejection of cardiac allografts. Clinical outcomes ranged from spontaneous resolution to persistent heart failure. • Histiocytic myocarditis appears to be a distinct histopathological subtype associated with heterogeneous clinical contexts and outcomes, and its presence may reflect antibody mediated myocardial injury. Endomyocardial biopsy results are integral for diagnosis and management of myocarditis. Current diagnostic classifications of myocarditis are based on the microscopic and immunochemical characterization of inflammation do not include monocyte/macrophage-predominant (i.e. "histiocytic") myocarditis as a histologic subtype. Endomyocardial biopsies from 6 patients with sudden heart failure were reviewed by 3 cardiac pathologists. Routine stains and immunostains to identify T cells and monocytes/macrophages, complement C4d, and endothelium were applied. Electron microscopy was performed in 2 cases. The 6 patients included 2 with diagnoses of systemic lupus erythematosus (SLE) and 4 without known disease. Microscopy showed space-occupying inflammation in 2 cases and interstitial inflammation in 4. No giant cell myocarditis or eosinophilic myocarditis was found. Immunostains showed infiltration predominantly by macrophages and/or monocytes with markedly fewer T cells. In 4 of 6 cases necrotic cells were immunopositive for complement C4d. Monocytes we identified immunochemically within the microvasculature in 5 cases and by electron microscopy in 2. Patients with SLE had microvascular C4d positivity or interstitial/sarcolemmal staining. Clinical outcomes ranged from spontaneous resolution to persistent heart failure requiring an internal cardioverter/defibrillator. (1) Heart failure with CD68 predominant inflammation ("histiocytic" myocardial inflammatory disease, HMID) occurs with variable clinical presentation and outcome; (2) HMID may be primary or secondary; (3) some cases of HMID show features suggestive of antibody and/or complement mediated myocardial injury, and (4) HMID is a diagnosis distinct from those in classification systems currently in use. [ABSTRACT FROM AUTHOR]

Abstract: Background: The long-term prognosis of biopsy-proven myocarditis is not well known. We hypothesized that a detailed pathological examination of an endomyocardial biopsy (EMB) would reveal prognostic information in patients with acute myocarditis. Methods: Fifty-four patients were diagnosed with acute myocarditis based on an EMB. Pathological diagnosis was categorized into lymphocytic dominant (29.6%), eosinophilic dominant (22.2%), and borderline myocarditis (48.1%). Masson’s trichrome staining and further immunohistochemical staining for CD3, CD20, CD68, HLA-DR, TLR4, TLR8, enteroviral VP1, and caspase-3 expression were performed. The clinical outcomes were defined as all-cause and cardiovascular (CV) death. Results: During the median 10.4 years of follow up (9.7±5.7 years), the overall all-cause mortality was 20.4% and the CV mortality was 14.8% in patients with acute myocarditis. Lymphocytic dominant myocarditis patients showed a poor clinical outcome when compared with eosinophilic dominant myocarditis patients for both all-cause (37.5% vs. 0%, p=0.015) and CV (31.2% vs. 0%, p=0.029) mortality. Among borderline myocarditis patients, the presence of fibrosis was linked with poor clinical outcomes in both all-cause (75.0% vs. 21.4%, p=0.045) and CV (100.0% vs. 25.0%, p=0.034) mortality. No significant associations between clinical outcome and all other immunohistochemical staining targets were observed. Conclusions: Detailed pathological evaluation on an EMB provides prognostic information in patients with acute myocarditis. EMB evaluation should be considered in patients with suspected myocarditis. [Copyright &y& Elsevier]

• Endomyocardial biopsy remains a valuable diagnostic tool in patients with suspected myocarditis. • Seventy-five percent of our patients with a diagnostic biopsy for myocarditis had a Class I or IIa indication for biopsy. • ↑ age and ventricular arrhythmias associated with ↑ mortality in diagnostic biopsy myocarditis. • Twenty-five percent of diagnostic biopsy myocarditis patients did not have a 2007 guideline indication for biopsy. • Diagnostic biopsy myocarditis patients more frequently required inotropes + advanced therapies. Diagnostic endomyocardial biopsy (EMB) in patients with suspected myocarditis helps to direct therapy and guide prognosis. This study aimed to investigate the correlation between the 2007 clinical guideline indications for EMB and the presence of a diagnostic biopsy result and associated outcomes in patients with suspected myocarditis in a national quaternary referral center in a contemporary cohort. All cases of suspected myocarditis referred to the National Cardiac Transplant Centre who underwent EMB between 2009 and 2019 were identified retrospectively through pathology records. Outcomes including subsequent need for inotrope and/or mechanical circulatory support (MCS), heart transplantation and in-hospital mortality were recorded. In total, 25 (68% male, mean age of 45 ± 15 years) EMBs were performed for this indication across this time period, 64% (n = 16) of which demonstrated diagnostic results, the majority (75%, n = 12) identifying acute lymphocytic myocarditis, 13% (n = 2) giant cell, one patient (6.3%) eosinophilic and one (6.3%) an immune checkpoint inhibitor myocarditis. The majority of those with histologically confirmed myocarditis had a Class I or IIa guideline indication for EMB (n = 12, 75%). The remaining 4 patients (25%), either met Class IIb criteria (n = 2) or would not have been accounted for in this guideline. The majority of patients requiring inotropes and/or MCS (n = 9/11), and/or heart transplant (n = 3/4), or who later died (n = 4/5) were in the diagnostic biopsy group. In this 10-year National referral sample, 75% of patients with histologically confirmed myocarditis had a Class I or IIa indication for EMB, reinforcing the usefulness of traditional guidelines in this contemporary era. However, 25% of patients with a subsequent confirmed histological diagnosis had either none or a less well-established indication for EMB, highlighting the need for clinical suspicion outside of accepted clinical scenarios. [ABSTRACT FROM AUTHOR]

• The histological activity did not differ depending on the presence of the virus in the myocarditis. • The immune activity in virus-positive patients was as high as that of virus-negative patients. • Immunosupressive therapy is effective both in virus-negative and virus-positive patients. • The virus-positive patients in the absence of IST had no clinical improvement. to study the effect of immunosupressive therapy (IST) in the virus-negative and virus-positive patients with immune-mediated myocarditis. in 60 patients (45 male, 46.7 ± 11.8 years, mean LV EDD, 6.7 ± 0.7 cm, EF 26.2 ± 9.1%) active/borderline myocarditis was verified by endomyocardial biopsy (n = 38), intraoperative biopsy (n = 10), examination of explanted heart (n = 3) and autopsy (n = 9). Indications for IST determined based on histological, immune activity. The follow-up was 19.0 [7.25; 40.25] months. The viral genome in the myocardium was detected in 32 patients (V + group), incl. parvovirus B19 in 23. The anti-heart antibody level was equally high in the V + and V- patients. Antiviral therapy was administered in 24 patients. IST (in 22 V + and 24 V- patients) include steroids (n = 40), hydroxychloroquine (n = 20), azathioprine (n = 21). The significant decrease of LV EDD (6.7 ± 0.7 to 6.4 ± 0.8), PAP (48.9 ± 15.5 to 39.4 ± 11.5 mm Hg, р<0,01), increase of EF (26.5 ± 0.9 to 36.0 ± 10.8), and lower lethality (23.9% and 64.3%; RR 0.37, 95% CI 0.19–0.71), p <0.01, were found only in IST group. Significant improvement due to IST were achieved not only in V-, but also in V + patients. IST in patients with immune-mediated lymphocytic myocarditis is effective and is associated with lower lethality both in virus-negative and virus-positive patients. [ABSTRACT FROM AUTHOR]

Myocarditis continues to present challenges in diagnosis and management. The goal of this study is to determine the occurrence and manifestations of myocarditis in a heart failure (HF) population. The analyzed patients had acute or persistent HF and were referred over a 6-year period to a quaternary HF center for advanced HF therapies including mechanical circulatory support, left ventricular assist device (LVAD) implantation, and/or heart transplantation. The histopathological diagnosis of myocarditis was made based on the presence of an inflammatory infiltrate of the myocardium, typically with associated cardiomyocyte (CMC) damage, combined as indicated with immunohistochemical and molecular biology characterization. The pathological findings were correlated with a panel of clinical parameters and clinical course of the patients. Myocarditis was identified in 36 patients, with initial diagnoses made in 10 (40%) of 25 by endomyocardial biopsy (EMB), 1 by atrial biopsy (maze procedure), 7 (2.1%) of 331 at LVAD implantation, and 18 (7.8%) of 229 in the explanted heart. There were 20 cases of lymphocytic myocarditis, 4 cases of giant cell myocarditis, 3 cases of eosinophilic myocarditis, and 9 cases of lymphohistocytic with granulomas myocarditis - cardiac sarcoidosis. EMB was performed in 25 patients and was positive in 10 (40%) of cases. Myocarditis was found in 23 explanted hearts including 18 cases de novo and 5 cases with a previously positive specimen. Of the 23 explanted hearts, 21 were nonischemic cardiomyopathy and 2 were ischemic cardiomyopathy. Our findings show that, in patients presenting to a quaternary medical center, myocarditis can be manifest as acute HF as well as a complicating factor in chronic HF. • Myocarditis continues to present challenges in diagnosis and management. • Myocarditis was found in 36 patients in an advanced heart failure (HF) population over 6 years. • Myocarditis was detected in EMB (10 of 25), atrial biopsy (1case), LV plugs (7 cases) and explanted hearts (18 cases). • Myocarditis types were lymphocytic (20 cases), giant cell (4 cases), eosinophilic (3 cases) and sarcoidosis (9 cases). • Myocarditis can be manifest as acute HF as well as a complicating factor in chronic HF. [ABSTRACT FROM AUTHOR]

Abstract: Giant cell myocarditis (GCM) is a serious condition that warrants immediate diagnosis and treatment. It often presents as rapidly progressive heart failure and/or malignant ventricular arrhythmias. Here, we describe a 34-year-old patient with myasthenia gravis who presented with GCM 2 weeks after resection of a thymoma. A cardiac biopsy confirming the diagnosis was done within 3 days after admission. After institution of an aggressive immunosuppressive drug regimen, implantation of an implantable cardioverter defibrillator, and intensive cardiac rehabilitation, the patient recovered dramatically. In control biopsies after 4 weeks and 6 months, no more giant cells were found. We conclude that, in the case of nonischemic acute heart failure in young patients, a biopsy should be performed as soon as possible to prevent an unfavourable outcome of this often fatal disease. [Copyright &y& Elsevier]