key: cord-0755236-cg20ikgl authors: Haussner, William; DeRosa, Antonio P.; Haussner, Danielle; Tran, Jacqueline; Torres-Lavoro, Jane; Kamler, Jonathan; Shah, Kaushal title: COVID-19 associated myocarditis: A systematic review date: 2021-10-22 journal: Am J Emerg Med DOI: 10.1016/j.ajem.2021.10.001 sha: c051d658390f70ae8306455fafb3dfb137092203 doc_id: 755236 cord_uid: cg20ikgl BACKGROUND: Most COVID-19 infections result in a viral syndrome characterized by fever, cough, shortness of breath, and myalgias. A small but significant proportion of patients develop severe COVID-19 resulting in respiratory failure. Many of these patients also develop multi-organ dysfunction as a byproduct of their critical illness. Although heart failure can be a part of this, there also appears to be a subset of patients who have primary cardiac collapse from COVID-19. OBJECTIVE: Conduct a systematic review of COVID-19-associated myocarditis, including clinical presentation, risk factors, and prognosis. DISCUSSION: Our review demonstrates two distinct etiologies of primary acute heart failure in surprisingly equal incidence in patients with COVID-19: viral myocarditis and Takotsubo cardiomyopathy. COVID myocarditis, Takotsubo cardiomyopathy, and severe COVID-19 can be clinically indistinguishable. All can present with dyspnea and evidence of cardiac injury, although in myocarditis and Takotsubo this is due to primary cardiac dysfunction as compared to respiratory failure in severe COVID-19. CONCLUSION: COVID-19-associated myocarditis differs from COVID-19 respiratory failure by an early shock state. However, not all heart failure from COVID-19 is from direct viral infection; some patient's develop takotsubo cardiomyopathy. Regardless of etiology, steroids may be a beneficial treatment, similar to other critically ill COVID-19 patients. Evidence of cardiac injury in the form of ECG changes or elevated troponin in patients with COVID-19 should prompt providers to consider concurrent myocarditis. The spread of COVID-19 began in late 2019, and by March of 2020 it was officially declared a pandemic by the World Health Organization (WHO). COVID-19 is the viral syndrome caused by SARS-CoV-2, a novel zoonotic RNA coronavirus. 1 The most common symptoms of COVID-19 are those of most viral syndromes and include fever, cough, shortness of breath, fatigue, and myalgia. Severe cases of COVID-19 manifest as multifocal pneumonia and acute respiratory distress syndrome (ARDS), with cardiovascular complications developing in many. 1, 2 The cardiovascular complications of COVID-19 include myocardial injury, thrombotic events, and heart failure. 2 These are believed to be secondary to severe pulmonary disease, the result of inflammatory cytokines, or due to thrombotic occlusion of the cardiopulmonary vasculature, including pulmonary embolism and myocardial infarction. 2 Emerging in the literature, however, is a subset of patients with COVID-19 who appear to have primary cardiac dysfunction consistent with myocarditis. In order to better understand COVID-19-associated myocarditis, including clinical presentation, risk factors, and prognosis, we performed a systematic review of the medical literature. Here we discuss the details of the reported cases of COVID-19-associated myocarditis. This systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. 3 Search terms were designed by a medical librarian after discussion of study aims with the authors. The search was run on the following databases: MEDLINE (via PubMed), Embase, The Cochrane Library, and Web of Science. The initial search was run on June 3, 2020 and repeated on November 13, 2020 to ensure that no relevant studies were missed in the intervening time frame. Controlled vocabularies and text words were used in the development of the search strategies in PubMed, Embase, and Cochrane. Web of Science does not employ a controlled vocabulary, so it was searched using only keywords. Search results were combined in a bibliographic management tool (EndNote), and duplicates were eliminated both electronically and through manual review. Search results were then imported into the systematic review support tool, Covidence, for further reference management and screening. The search terminology included two major components; both concepts were linked together with the AND operator: 1) COVID-19, including SARS-CoV-2, novel coronavirus, and variations of the disease name; 2) myocarditis, including cardiomyopathy, inflammation of the heart, and variations of cardiac inflammation terms. For a complete list of MeSH and keyword terms used, please refer to the MEDLINE search strategy accompanying this paper. To investigate the grey literature perspective of this systematic review topic, publication types from Embase and Web There was 90% agreement among the reviewers for the selected studies in the systematic review. The remaining 10% required a third reviewer to resolve the discrepancy. A total of 43 articles were included in the final analysis, and 51 patients were identified with COVID-19associated myocarditis based on clinical diagnosis, some with confirmatory testing. Cases were reported from 19 countries with the vast majority from the United States. Details of the included articles are described in Table A- 1. An assessment of the quality of the individual articles is detailed in Table A Among the 51 cases of COVID-19-associated myocarditis in the literature as of November 13, 2020, the average age was 56.3 years (median 58.5). The most common reported clinical signs and symptoms were tachycardia (76.4%), dyspnea (74.5%), shock (52.9%), and fever (37.3%). The patients' comorbidities included hypertension (41.1%), diabetes (17.6%), obesity (9.8%), and asthma/COPD (4%), with no comorbidities reported in 42%. All patients had signs of cardiac damage determined by ECG changes or elevation of troponin. Confirmatory diagnoses were performed by echocardiography alone (47.1%), MRI (23.5%), cardiac catheterization (15.7%), and myocardial biopsy (9.8%). The average length of stay was 14.9 days (median 14) . Nearly half of the patients (43.1%) were ultimately diagnosed with Takotsubo cardiomyopathy. Among the 22 patients with Takotsubo cardiomyopathy, the average age was 58.9 years. The average age was 53.8 years in the remaining 29 patients. No comorbidities were reported in only 29.2% of the patients with Takotsubo cardiomyopathy. Whereas 66.7% of patients without Takotsubo cardiomyopathy had no medical problems. One patient with Takotsubo cardiomyopathy, though clinically was diagnosed with COVID-19, was COVID negative on PCR swab and myocardial biopsy. Selected treatments for COVID-19-associated myocarditis were variable, but the most common approach was supportive treatment alone (43.1%). Supportive therapy included intravenous/oral hydration, beta-blockers, or diuretics. Additional interventions were vasopressor or inotropic support (31.3%), steroids (19.6%), and antivirals (7.8%). The overall mortality rate was 13.7, with a mortality rate of 27.3 in the Takotsubo group and 3.4 in the remaining patients without Takotsubo cardiomyopathy. Of the seven patients who died, three (42.9%) were treated with vasopressors only, two (28.6%) were treated with antivirals, one (14.3%) received steroids and vasopressors, and one (14.3%) received supportive care only. In the patients with Takotsubo cardiomyopathy, 64% presented with shock, compared to 41% of the remaining patients presenting with shock. The symptomatology of viral myocarditis and severe COVID-19 are almost indistinguishable. Both present with dyspnea and fever though the underlying pathophysiology is quite different. Myocarditis produces acute cardiac dysfunction, sometimes with reduced ejection fraction and infrequently, cardiogenic shock. The dyspnea associated with severe COVID-19, however, is usually secondary to a multifocal pneumonia and ARDS. Here we discuss from the current literature, a subset of patients diagnosed with COVID-19-associated myocarditis. The incidence of critical illness in patients with COVID-19 has been estimated at 5% overall and 22% in those requiring hospitalization. 4 All reported patients with COVID-19-associated myocarditis required hospitalization, and 54% were critically ill, making it a morbid disease entity. The mortality of all patients with COVID-19 has been estimated to be between 0.8% to 3.0%, with a significant rise in mortality in those with severe COVID-19 to an estimated 17.4%. 5,6 COVID-19-associated myocarditis appears to carry a similarly high mortality rate: among the reported cases in this review, the mortality rate was 14.0%. Patients with COVID-19-associated myocarditis had similar risk factors to those with severe COVID-19. Critical illness and mortality in patients with COVID-19 have been associated with older age and comorbidities, including diabetes, cardiovascular disease and respiratory disease. 6 About 50% of patients with severe COVID-19 had at least one of these risk factors. 4 Similarly, 58% of patients with COVID-19-associated myocarditis had at least one of the following comorbidities: hypertension, diabetes, obesity, and asthma/COPD. Patient-reported or measured fever is present in approximately 85% of all COVID-19 cases. 7 While only 36% of patients in this cohort had fever at presentation, a large predominance reported fever prior to hospital admission. Therefore, fever is not a distinguishing factor. Dyspnea was present in 76.9% of patients in this case series, compared to only 16.4% in all patients with COVID-19 and 53.7% of patients with severe COVID-19 (those necessitating intensive care). 6 COVID-19-associated myocarditis is more likely to cause respiratory distress compared to other forms of COVID-19. This falls in line with prior data on myocarditis, where mild dyspnea is frequently seen due to acute heart failure. 8, 9 COVID-19-associated myocarditis may be differentiated from other forms of severe COVID-19 by an early shock state. The true incidence of shock in severe COVID-19 is unclear, with studies reporting vastly different rates, ranging from 35-94%. 10 In patients with severe COVID-19, shock tends to develop secondary to respiratory failure and occurs days to weeks after the initial presentation to the hospital. 10 This is in contrast to the 52% of patients with COVID-19 myocarditis who were in shock on presentation, hence, an early shock state. The diagnosis of myocarditis was made most commonly by echocardiogram (48%). Findings suggestive of myocarditis were decreased ejection fraction or dilated cardiomyopathy. 11 In some cases, MRI was used adjunctively (24%) to determine a presence of enhancement within the myocardium. This finding indicates cardiac hyperemia and increased capillary permeability, which suggest an acute inflammatory pathology. 12 In 8 cases (16%), clinicians felt inclined to utilize cardiac catheterization to exclude occlusive myocardial infarct as a cause of symptoms. Only rarely was a myocardial biopsy performed (10%) to determine that SARS-CoV-2 had directly infected the myocardium. 11, 12 Curiously, this review has uncovered two distinct etiologies of acute heart failure in patients with COVID-19: viral myocarditis and Takotsubo cardiomyopathy. Takotsubo cardiomyopathy was diagnosed in 48.0% of patients in this series. Takotsubo cardiomyopathy (also called stress cardiomyopathy) is characterized by a reversible cardiomyopathy with pathognomonic ballooning of the apical left ventricle. 13 Sympathetic response is cited as the primary driver of its pathophysiology. 13 In our patients, Takotsubo cardiomyopathy was diagnosed by echocardiography showing apical left ventricular ballooning and MRI demonstrating lack of enhancement of the myocardium (thus excluding viral myocarditis). It is notable that the mortality of patients with Taktosubo was higher than those with viral myocarditis (27.3 vs 3.4%); however the signifance of this is unclear in this small sample. Notable within this data set is a low utilization of specific treatment for COVID-19 (44% received supportive treatment only). Only seven patients (14%) received steroids, an established therapy for patients with COVID-19 requiring supplemental oxygen. 14 Of the seven patients who received steroids, six survived (85.7%), demonstrating a potential utility of corticosteroids in the treatment of COVID-19-associated myocarditis. The success of supportive treatment (survival) may be attributed to a reduction in sympathetic drive, especially in patients with Takotsubo cardiomyopathy. However, more research is needed in this realm to make conclusive statements. COVID-19-associated myocarditis is a relatively new diagnostic entity for clinicians. Our knowledge is limited by the number of cases reported in the literature to date, and thus the conclusions we can extrapolate from this review are also limited. Hopefully there will be observational studies and randomized trials reported in the future. COVID-19-associated myocarditis is a distinct clinical entity that differs from COVID-19 respiratory failure by an early shock state. The risk factors and presenting signs and symptoms are similar to those of patients with severe COVID-19, with dyspnea being more prevalent in those with COVID-19-associated myocarditis. Steroids seem to be beneficial in this subset as well, similar to critically ill COVID-19 patients. Evidence of cardiac injury in the form of ECG changes or elevated troponin in patients with COVID-19 should urge providers to consider concurrent myocarditis. Echocardiography is usually sufficient for diagnosis, but more advanced methods can be used if available. Finally, Takotsubo cardiomyopathy produces a clinical picture similar to viral myocarditis and should be simultaneously considered in COVID-19 patients with acute cardiac dysfunction. 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