key: cord-0852873-6vz38e82 authors: Nakatani, Satoshi; Ohta-Ogo, Keiko; Nishio, Mayu; Amemiya, Kisaki; Sato, Shuho; Sawano, Hirotaka; Hatakeyama, Kinta; Katano, Harutaka; Suzuki, Tadaki; Hirooka, Keiji title: Microthrombosis as a Cause of Fulminant Myocarditis-like Presentation with COVID-19 Proven by Endomyocardial Biopsy. date: 2022-05-16 journal: Cardiovasc Pathol DOI: 10.1016/j.carpath.2022.107435 sha: 36771af61a930bccb33122d565a6e165c535d66f doc_id: 852873 cord_uid: 6vz38e82 Myocardial injury has been reported as a complication of COVID-19. Although several mechanisms have been proposed as its cause, they are mostly based on autopsy studies, We report a 49-year-old male with COVID-19-associated myocardial injury presented like fulminant myocarditis. We performed endomyocadial biopsy on day 2 and we confirmed the presence of microthrombosis histologically. He died on day 5 due to cardiogenic shock. Myocarditis has been reported as a complication of COVID-19 infection. Mostly, it has been diagnosed by cardiac magnetic resonance imaging and elevated cardiac enzymes (1, 2) . We report a case with COVID-19-associated myocardial injury presented like fulminant myocarditis in whom the presence of microthrombosis was histologically confirmed by endomyocardial biopsy. A 49-year-old male without prior medical history was admitted to an outside hospital in a shock-state. He had the first dose of COVID-19 vaccination 9 days before and had been suffered from sore throat, chill and fever for 4 days. Then, he was confirmed to be affected by COVID-19 with its antigen test on the nasopharyngeal swab one day before admission. Echocardiography showed a low left ventricular ejection fraction (<20%) and diffuse myocardial hypertrophy. Chest computed tomography revealed bilateral mild ground glass appearance, bilateral pleural effusion and pericardial effusion. He was intubated and cannulated for extracorporeal membrane oxygenation (ECMO), and was transferred to our hospital with inotropes infusion for further treatment. On admission to our hospital, blood tests showed elevated troponin T (1.010 ng/mL, normal range ≤0.014 ng/mL), NT-proBNP (27541.0 pg/mL, normal range ≤125.0 pg/mL), creatine kinase (929 IU/L, normal range 24-195 IU/L), C-reactive protein (1.685 mg/dL, normal range ≤0.180 mg/dL) and D-dimer (3.8 μg/mL, normal range <1.0μg/mL) while white blood cell count was 7100 (normal range 4000-8000 /μL) and platelet count was 53000 (normal range 150-360 /μL). Coronary angiography revealed no obstructive coronary artery disease. We administered methylprednisolone (1000mg daily for 3 days) and gamma globulin (80g daily for 2 days) in addition to catecholamine infusion and ECMO support. However, the hemodynamics did not improve. On day 2, we performed endomyocardial biopsy from the right ventricle. He died on day 5 due to intractable cardiogenic shock. Myocardial samples were processed for light microscopy. There was mild lymphocytic infiltration and moderate to severe perivascular fibrosis with wall thickening of intramural arterioles. There was no sign of severe myocardial injury compatible with typical active myocarditis. However, ischemic changes were found with a focal coagulative necrotic area at microvascular level (approximately 0.08mm 2 in area) with losing nuclei, accompanied by microthrombi with fibrin and platelets in small vessels, 5 which suggested microvascular thrombotic injury ( Figure 1A , B). Scattered megakaryocytes were also seen in the capillaries (inset in Figure 1A ). Microthrombi was seen throughout the specimens ( Figure 1C ) and myocytes in non-necrotic areas often showed diffuse cytoplasmic vacuolization ( Figure 1D We experienced a case with COVID-19 showing cardiogenic shock in whom microvascular thrombosis was demonstrated by endomyocardial biopsy. Pathological studies have demonstrated that myocardial injury has been common in patients with COVID-19. The mechanisms hypothesized include direct viral invasion of the heart, immune-mediated myocarditis, stress-induced cardiomyopathy, myocardial infarction, cytokine storm and microvascular thrombi (4, 5) . One report shows myocardial localization of coronavirus in a patient with COVID-19 myocarditis (6) . There may be multiple mechanisms that cause cardiac injury in patients with 6 COVID-19. The incidence of pathologically proven myocarditis ranges 2 -30% in autopsied patients with COVID-19 (4, 5, 7) . Although the present case showed a drastic clinical course compatible with severe fulminant acute myocarditis, the pathologic study demonstrated only mild myocardial inflammation without associated myocyte necrosis. Instead, we found microthrombosis in small vessels and ischemic necrotic changes. According to a recent study of systematic pathological analysis of 40 hearts from patients dying of COVID-19, 14 cases had myocardial necrosis and 9 of 14 (64%) had microthrombi in small vessels (8) . Interestingly, none had typical evidence of myocarditis as defined by the European Society of Cardiology (9) . Other recent investigations also reported the incidence of microthrombi in the autopsied hearts with COVID-19 to be high as 70% (48 out of 69 cases) (10) and 80% (12 out of 15 cases) (7). The present case adds further evidence to these observations by demonstrating the presence of microthrombosis associated with acute myocardial ischemic injury in acute phase of COVID-19 by endomyocardial biopsy prior to death. Of note, in our case, there were only fresh microthrombi, and no organizing/organized mural thrombi which coexisted in reported autopsy cases. Microthrombosis throughout the specimens, presumably in the setting of endothelial dysfunction, must have contributed to the global myocardial ischemia causing diffuse LV systolic dysfunction, as histologically shown by coagulation necrosis and diffuse cytoplasmic vacuolization of myocytes, both of which are characteristic of acute ischemia. Patients with COVID-19 are at a high risk for thromboembolic events probably resulting from cytokine storm. Although no data on inflammatory cytokine levels were available in the present case, there could be excessive cytokine release, endothelial dysfunction and coagulopathy, as is common in 7 COVID-19, which related to microthrombi formation in myocardial small vessels and myocardial injury (11) . Sampling errors should be born in mind in the analysis of endomyocardial biopsy specimens but failure to demonstrate viral genomes by PCR may support the above hypothesis. Moderate to severe perivascular fibrosis may suggest the presence of subclinical underlying heart disease such as hypertension but it was not apparent from his medical history. Catecholamine infusion can cause myocardial injury which is usually characterized by contraction band necrosis of single myocyte or groups of several myocytes. However, we infused catecholamine for only 1 day before endomyocardial biopsy and coagulative necrosis with losing nuclei, not contraction band necrosis, found in the present case suggested ischemic injury was the most likely explanation. Although a direct causal relationship may not be definitively established, no other causes were difficult to identify than COVID-19-associated myocardial injury. The vaccine-related associated myocarditis or myocardial injury has been reported mostly in young male recipients after the 2 nd dose with most being mild illness, which is different from the present case. Rare fatal cases have also been reported including two adolescent males resembling a catecholamine-induced injury but without microthrombosis microscopically (12) and two patients in forties (one woman and one man) with histologically-proven fulminant myocarditis (13) Myocarditis associated with COVID-19 has been mostly diagnosed by imaging studies and its mechanisms are only speculation. We showed microthrombosis as a cause of myocardial injury which mimicked fulminant myocarditis in acute phase of COVID-19 by endomyocardial biopsy. Unfortunately, our case died on day 5 but this report may give a clue to further treatment in a patient with COVID-19 with myocardial injury. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There are no relationships with industry. SARS-CoV-2 fulminant myocarditis Coronavirus disease 2019 (Covid-19) presenting as purulent fulminant myopericarditis and cardiac tamponade: a case report and literature review A novel real-time PCR system for simultaneous detection of human viruses in clinical samples from patients with uncertain diagnoses Pathological features of COVID-19-associated myocardial injury: a multicenter cardiovascular pathology study Myocarditis is rare in COVID-19 autopsies: cardiovascular findings across 277 postmortem examinations Myocardial localization of coronavirus in COVID-19 cardiogenic shock COVID-19-associated nonocclusive fibrin microthrombi in the heart Microthrombi as a major cause of cardiac injury in COVID-19. A pathologic 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 Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation Autopsy histopathologic cardiac findings in two adolescents following the second COVID-19 vaccine dose Myocarditis after Covid-19 mRNA We thank Manabu Kobayashi, BS and Motomu Tsuji, MD, PhD for their excellent help in preparing histological biopsy samples.