Archives of Academic Emergency Medicine. 2021; 9(1): e32 https://doi.org/10.22037/aaem.v9i1.1153 REV I EW ART I C L E Corticosteroid Therapy in Management of Myocarditis As- sociated with COVID-19; a Systematic Review of Current Evidence William Kamarullah1∗, Nurcahyani1, Claudia Mary Josephine1, Rachmatu Bill Multazam1, Aqila Ghaezany Nawing1 1. Indonesian Cardiovascular Research Center, National Cardiovascular Center Harapan Kita, Jakarta, Indonesia. Received: February 2021; Accepted: March 2021; Published online: 16 April 2021 Abstract: Introduction: Myocarditis in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) seems to be associated with a higher mortality rate. This study aims to summarize the latest evidence on whether the use of corticosteroids in patients with myocarditis associated with COVID-19 is necessary. Meth- ods: We performed an extensive search using a combination of search terms in PubMed, Europe PMC, ProQuest, EBSCOhost, and Google Scholar up to January 2021. Full-text articles that met the predefined inclusion criteria were included in the present study. Results: The full-texts of 18 articles have been reviewed. Thirteen out of the eighteen (72%) patients who got corticosteroid administration experienced major clinical improvements during follow-up while the other five (28%) were experiencing uneventful events. The mean age of the reported patients was 47.8±13.2 years. There was no gender predominance. Most of the reported cases were from USA (39%) fol- lowed by Spain, China, and UK (11% each), while Brazil, Colombia, France, Belgium, and Italy contributed one case each. Various corticosteroids were used but the most commonly applied were methylprednisolone (89%), hydrocortisone (5.5%), and prednisolone (5.5%). The most common route of administration among the studies was intravenous administration and the duration of treatment varied between one and fourteen days. Conclu- sion: A review of the currently available literature shows that with the use of corticosteroid agents in treating myocarditis associated with COVID-19, favorable outcomes are attainable. Well-established randomized clini- cal trials are needed to evaluate the efficacy and safety of using corticosteroids in this condition. Keywords: COVID-19; myocarditis; corticosteroid; treatment Cite this article as: Kamarullah W, Nurcahyani, Mary Josephine C, Bill Multazam A, Ghaezany Nawing A. Corticosteroid Therapy in Manage- ment of Myocarditis Associated with COVID-19; a Systematic Review of Current Evidence. Arch Acad Emerg Med. 2021; 9(1): e32. 1. Introduction Late in 2019, the world was staggered by the emergence of a new virus derived from Wuhan, China, which caused severe pneumonia and was later called the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The diease caused by the virus was named coronavirus disease 19 (COVID-19) (1). This disease has led to more than 20 million active cases in 218 countries with more than 1.5 million people losing their lives (2). In the midst of this pandemic, a lot is still yet to be discovered, including the true magnitude of the disease. ∗Corresponding Author: William Kamarullah; Jl S Parman Kav 87, Slipi, Jakarta Barat, Postal code: 11420, Jakarta, Indonesia. Mobile: +62811189696, Fax: +6221 5684220, Email: williamkamarullah@hotmail.com, ORCID: http://orcid.org/0000-0001-6623-3868. It was later discovered that since it binds with angiotensin converting enzyme (ACE) 2 receptors, which are also present in endothelial cells, it also affects the cardiovascular system and could manifest as myocarditis (3, 4). As many studies investigating the mechanism of multiple organ dysfunction syndrome (MODS) associated with COVID-19 indicated, sys- temic hyper inflammation syndrome has become a leading theory to explain the condition (5). Currently, there is no guideline that specifically addresses use of corticosteroids in treatment of myocarditis caused by COVID-19. Considering that uncertainty remains regarding this issue, we aimed to systematically review the use of corticosteroids in patients with myocarditis associated with COVID-19. We hypothe- sized that the addition of immunosuppressant therapy e.g. corticosteroids at this stage may reduce the severity of this hyperinflammatory condition. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem W. Kamarullah et al. 2 2. Methods 2.1. Protocol and Registration This systematic review was conducted in line with the Cochrane Handbook for Systematic Reviews of Interventions and reported based on the Preferred Reporting Items for Sys- tematic Reviews and Meta-Analysis (PRISMA) (6, 7). The pro- tocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO), under registration num- ber CRD42020223524. 2.2. Search Strategy Due to the lack of research articles, we performed a com- prehensive search on case reports/series that presents pa- tients with myocarditis associated with COVID-19 who were treated with corticosteroids using keywords ((COVID 19) OR (COVID-19) OR (Coronavirus) OR (Coronavirus disease) OR (Novel Coronavirus) OR (Novel human coronavirus) OR (SARS coronavirus) OR (SARS-CoV2) OR (SARS-CoV-2) OR (SARS CoV-2) OR (2019-nCoV )) AND ((Myocarditis) OR (Carditis) OR (Pericarditis) OR (Myopericarditis)) AND (Cor- ticosteroid)) from the time in which SARS-CoV-2 was identi- fied ( January 2020) up until January 2021 through PubMed, EuropePMC, ProQuest, EBSCOhost, and Google Scholar. To ensure the identification of all relevant articles and publica- tions, hand-searched articles from reference lists were also reviewed as an additional source of studies. We did not in- clude words related to the outcomes of interest in order to obtain the largest number of search results possible. Our search was in line with PRISMA guidelines and the flowchart in Figure 1 portrays the search and screening processes. 2.3. Eligibility Criteria In the present study, all cases using corticosteroids for pa- tients with myocarditis associated with COVID-19 were in- cluded to be reviewed. Exclusion criteria comprised ani- mal studies, expert opinions, literature review studies, news articles, letters, editorials, guidelines, and any studies that did not mention the outcomes and specify the corticosteroid used in the study. We also limited our search to articles writ- ten in English. The outcomes of interest were all-cause mor- tality, clinical improvement, and hospital discharge. 2.4. Study Selection and Data Collection Process Articles were sorted based on whether titles or abstracts met the inclusion criteria. Full-text articles were then read, any duplicate studies were deleted, and those that did not sat- isfy the inclusion criteria were excluded. Data from the ar- ticle were extracted and summarized using predesigned ta- bles that consisted of name of the first author, year of pub- lication, country in which the study was conducted, age and sex distribution of the patients, complete assessment of the patient, corticosteroid used, dose, route, and duration of ad- ministration, other medications, and outcomes. All steps of study selection and data collection process were conducted by all authors. Disagreements regarding study selection and data extraction were resolved through consensus-based dis- cussion. 2.5. Risk of Bias Assessment Two independent reviewers critically assessed the included studies using The Joanna Briggs Institute’s critical assess- ment tool for case reports (8). The presence of bias was de- termined for each article using the checklist of eight ques- tions included in Table 2. The articles received a score to indicate their degree of bias (low (included) and high (ex- cluded)). For the purpose of this study, if "yes" was answered for more than half of the eight questions on the checklist, the study was considered to have a low risk of bias. Otherwise, answering "no" or “unclear” to half or more of the eight ques- tions means the study was ascertained to have a high risk of bias and was excluded from this systematic review. Discrep- ancies in quality ratings were resolved through consensus- based discussion. 3. Results 3.1. Study Selection and Characteristics Five databases were used to find articles related to the use of corticosteroid in myocarditis associated with COVID-19. We found 3479 articles; out of which, eighteen case reports were then deemed eligible for inclusion in the present study (9- 26). A PRISMA flow diagram detailing the process of iden- tification, screening, inclusion, and exclusion of studies is shown in Figure 1. The mean age of the reported patients was 47.8±13.2 years (range 18–69 years). There was no gender predominance. Most of the reported cases were from USA (39%) followed by Spain, China, and UK (11% each), while Brazil, Colombia, France, Belgium, and Italy contributed one case each. Various corticosteroids were used but the most commonly applied were methylprednisolone (89%), hydro- cortisone (5.5%), and prednisolone (5.5%). The most com- mon route of administration among the studies was intra- venous administration and the duration of treatment varied between one and fourteen days. Other drugs were also used as combination therapy along with corticosteroids. Table 1 recounts the characteristics of the included studies. 3.2. Risk of Bias within Studies All articles were determined to have low risk of bias. Seven other studies were identified as having high risk of bias and were excluded from the final inclusion process. Overall, stud- ies did not report the adverse events resulting from the in- terventions. Moreover, low-level evidence from the included This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2021; 9(1): e32 studies could not explain the causal relationship between the interventions and the outcomes. A complete risk of bias as- sessment of the comprised studies is displayed in Table 2. 4. Discussion Eighteen case reports administering corticosteroids to sub- jects with myocarditis associated with COVID-19 were in- cluded in this systematic review. These case reports de- scribed several types of corticosteroids, doses, routes of ad- ministration, and various outcomes. For instance, in the Colombian study conducted by Bernal-Torres et al. (9), the authors described a 38-year-old woman without any comor- bid conditions presenting with palpitations as well as general malaise since 3 days prior to admission. The patient had pos- itive PCR examination on nasal swab for COVID-19. Further- more, the patient was diagnosed with fulminant myocarditis associated with COVID-19 and was treated with intravenous immunosuppressant in the form of methylprednisolone. As a result, the patient experienced clinical improvement and was discharged on day 16. Case reports with similar popula- tion, without comorbid conditions, and with similar steroid therapy regimen were also provided by Garau et al. (12), Hu et al. (13), and Naneishvili et al. (19). They showed progres- sive clinical improvements in various aspects. Higher dose of methylprednisolone was also found to provide good clin- ical improvements in studies performed by Salamanca et al. (22) and Sampaio et al. (23). Some patients with certain co- morbidities such as hypertension (11, 18), heart failure (15), and type 1 diabetes mellitus (21) showed clinical improve- ments as well. In addition, there were also various studies that did not specify the steroid dose used (14, 16). Besides, it was not uncommon to use other types of corticosteroids such as hydrocortisone (11) as well as oral prednisolone (24), which provided good clinical improvements as well. Each and every study used other therapeutic agents, such as antibiotics (67%), hydroxychloroquine (50%), immunoglob- ulin (38%), antiviral drugs (27%), immunomodulators (27%), colchicine (22%), and other agents in addition to corti- costeroid therapy to manage myocarditis associated with COVID-19 in patients. Regarding the outcomes, at the time of submission of those case reports, the majority of patients had survived (72%). Most of the patients who reportedly passed away were noted to have both acute respiratory distress syn- drome (ARDS) and multiple-organ failure (Table 1). Most of the cases in this study were reported in sufficient de- tail; however, four reports did not specify the dose of the cor- ticosteroid used and three of them did not report the dura- tion of the corticosteroid’s usage. The use of corticosteroids in myocarditis associated with COVID-19 seemed to have a better outcome in this small study. From the majority of those who got myocarditis from COVID-19 infection, good outcomes were reported more in those undergoing corticos- teroid therapy (thirteen out of eighteen patients) compared with those who did not take a corticosteroid (five out of eigh- teen patients). The plausible explanation for these is that according to current researches, higher concentration of proinflamma- tory cytokines and chemokines were detected in patients with multiple organ dysfunction syndrome associated with COVID-19 due to exaggerated immune response to the virus (27). Based on this mechanism, corticosteroids can be clin- ically utilized to prevent the immune system from attracting more inflammatory cells to the tissue e.g. cardiac, which re- duces inflammation (28). Recently, the European Society of Cardiology has issued a guidance in dealing with cardiovascular manifestations of COVID-19, yet there is no clear recommendation for the treatment of myocarditis associated with SARS-CoV-2 (29). Myocarditis is a potentially life-threatening disease. For this reason, from the current evidence that was drawn from this systematic review, the authors of this study proposed that corticosteroid must be considered as a last resort in terms of treating patients with myocarditis associated with COVID-19. This systematic review pooled case reports of patients with myocarditis caused by COVID-19 infection. Since this is a pooled case report, the evidence is weaker than controlled clinical trials. The number of cases was also small; there were only 18 cases from 18 studies. The findings of the pooled case reports might not apply to all patients, and the level of evidence is low. Secondly, the observed outcomes can- not be solely attributed to the corticosteroid therapy due to the combination of multiple drugs. This systematic review is a hypothesis-generating study. Further investigation needs to be done to obtain consecutive samples in a controlled study where the patients are blinded to corticosteroid ther- apy group and control group. However, the rarity of this event may impede such effort. In that case, the need for reviewing this matter in a systematic way was considered by the authors although good level of evidence were limitedly available. 5. Conclusion The current systematic review showed that the use of corti- costeroid agents is beneficial in improving the outcome of myocarditis associated with COVID-19. The present study showed that no randomized clinical trial has been performed with the aim of assessing the efficacy and safety of using cor- ticosteroids for treating myocarditis associated with COVID- 19, thus well-established randomized clinical trials should be pursued in order to confirm the findings of the present re- view. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem W. Kamarullah et al. 4 6. Declarations 6.1. Authors’ Contributions WK helped in the conception and design of the study. WK, N, CMJ, RBM, AGN, and SD were actively involved in literature search, study selection, data extraction, extensive review, and writing the manuscript. All authors read and approved the final submitted version. 6.2. Acknowledgements None. 6.3. Funding The authors declared that no specific grant was received for this research from any funding agency in the public, com- mercial or not-for-profit sectors. There was no external fund- ing to support this study and this study has no relationship with any industrial company. 6.4. Conflict of Interests The authors report no financial relationships or conflicts of interest regarding the content herein. References 1. WHO. Coronavirus disease (COVID- 19) pandemic 2020 [Available from: https://www.who.int/emergencies/diseases/novel- coronavirus-2019. 2. WHO. Situation Reports 2020 [Available from: https://www.who.int/indonesia/news/novel- coronavirus/situation-reports. 3. Mokhtari T, Hassani F, Ghaffari N, Ebrahimi B, Yarah- madi A, Hassanzadeh G. COVID-19 and multiorgan fail- ure: A narrative review on potential mechanisms. Journal of molecular histology. 2020;51(6):613-28. 4. Mai F, Del Pinto R, Ferri C. COVID-19 and cardiovascular diseases. J Cardiol. 2020;76(5):453-8. 5. 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Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020. 29. ESC. ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic 2020 [Available from: https://www.escardio.org/Education/COVID-19-and- Cardiology/ESC-COVID-19-Guidance. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem W. Kamarullah et al. 6 Table 1: Clinical studies that reported the use of corticosteroid in management of myocarditis associated with COVID-19 Authors ( Year) Age Gender Complete Assessment Corticosteroid Dose Route Duration Other Medication(s) Outcome(s) Bernal- Torres et al. (2020) Colombia 38 Female Fulminant myocarditis associated with COVID-19, cardiogenic shock, and COVID-19 pneumonia Methylprednisolone 200 mg/day IV 12 days Intravenous human immunoglobulin, hydroxychloroquine, azithromycin, lopinavir/ritonavir Norepinephrine, dobutamine, and levosimendan on first day of admission Clinical improvement, discharged on day-16 Coyle et al. (2020) USA 57 Male Myocarditis and severe acute respiratory distress syndrome related to COVID-2019 Methylprednisolone 500 mg/day IV 4 days Hydroxychloroquine, azithromycin, ceftriaxone, colchicine, tocilizumab, milrinone Clinical improvement, discharged on day-19 Doyen et al. (2020) France 69 Male Myocarditis associated with COVID-19, hypertension Hydrocortisone N/A IV 9 days Aspirin, fondaparinux Clinical improvement, discharged on day-21 Garau et al. (2020) Belgium 18 Female Fulminant myocarditis associated with COVID-19, cardiogenic shock, and COVID-19 pneumonia Methylprednisolone 200 mg/day IV 8 days Intravenous human immunoglobulin, hydroxychloroquine, antibiotics Dobutamine and other vasopressors on first day of admission Clinical improvement, discharged on day-45 Hu et al. (2020) China 37 Male Fulminant myocarditis associated with COVID-19, cardiogenic shock, and COVID-19 pneumonia Methylprednisolone 200 mg/day IV 4 days Intravenous human immunoglobulin, piperacillin-sulbactam, pantoprazole Norepinephrine, diuretic, Milrinone Clinical improvement, discharged on day-21 Hussain et al. (2020) USA 51 Male Fulminant myopericarditis associated with COVID-19, hypertension Methylprednisolone N/A IV N/A Dobutamine, indomethacin, azithromycin, hydroxychloroquine, remdesivir, colchicine Deteriorated after seventh day of admission Inciardi et al. (2020) Italy 53 Female Myocarditis associated with COVID-19, heart failure Methylprednisolone 1 mg/kgBW/day IV 3 days Intravenous aspirin, hydroxychloroquine, lopinavir/ritonavir Heart failure treatment: canrenone, furosemide, bisoprolol, and dobutamine in the first 48 hours Progressive clinical and hemodynamic improvement Khalid et al. (2020) USA 34 Female Myopericarditis associated with COVID-19, pericardial effusion, and cardiogenic shock Methylprednisolone Not specified (high dose) IV + Oral 3 days Colchine, dobutamine, norepinephrine Clinical improvement, discharged on day-9 Khatri et al. (2020) USA 50 Male Purulent myopericarditis associated with COVID-19, cardiogenic and distributive shock with multi-organ failure Methylprednisolone 200 mg/day IV 2 days Dobutamine, vasopressin, norepinephrine, hydroxychloroquine, vancomycin, azithromycin, cefepime, and intravenous human immunoglobulin Death due to multi-organ failure Li et al. (2020) USA 60 Male COVID-19-induced myopericarditis, cardiogenic shock, hypertension, hyperlipidemia Methylprednisolone 200 mg/day (50 mg/6h) IV 4 days Intravenous human immunoglobulin, hydroxychloroquine, azithromycin Epinephrine on the first day of admission Clinical improvement, discharged on day-52 Naneishvili et al. (2020) UK 44 Female Fulminant myocarditis associated with COVID-19 Methylprednisolone 1000 mg (1st day) 250 mg/day (2 days) IV 3 days Milrinone, norepinephrine Clinically improved, echocardiography result improved Ortiz et al. (2020) Spain 59 Female Fulminant myocarditis due to COVID-19, hypertension, cervical degenerative arthropathy, chronic lumbar radiculopathy, lymph node tuberculosis Methylprednisolone 500 mg/d at tapering dose IV 14 days Immunoglobulins, antiviral treatment consisting of IFNB, and ritonavir-lopinavir Deteriorated with rapid clinical progression to cardiogenic shock. Normal biventricular function was regained within a few days, with severe subsequent dyspnea that required continued ECMO Richard et al. (2020) USA 28 Female Fulminant myocarditis associated with COVID-19, diabetes mellitus type 1 with multiple previous episode of diabetic ketoacidosis, diabetic gastroparesis, asthma, anxiety, depression Methylprednisolone 1 g/day IV 3 days Dobutamine, norepinephrine, heparin, insulin, potassium, vancomycin, and piperacillin-tazobactam Clinically improved on the third day following corticosteroid administration Salamanca et al. (2020) Spain 44 Male Fulminant myocarditis associated with COVID-19, cardiogenic shock Methylprednisolone 1000 mg IV 1 day Tocilizumab, hydroxychloroquine, azithromycin, and lopinavir-ritonavir. Clinical status improved Sampaio et al. (2020) Brazil 45 Female Fulminant myopericarditis associated with COVID-19, cardiac tamponade, and refractory circulatory shock Methylprednisolone 750 mg and 250 mg (1st and 2nd day) followed by 40 mg twice a day) IV 2 days Tocilizumab, intravenous human immunoglobulin, convalescent plasma, azithromycin, piperacillin/tazobactam, and teicoplanin Noradrenaline, dobutamine, milrinone and vasopressin. Clinical improvement, discharged on day-65 Shabbir et al. (2020) UK 50 Female COVID-19-induced myopericarditis, myositis, hypertension, reactive arthritis Prednisolone 30 mg Oral 12 days Ibuprofen, codeine phosphate, colchicine Clinical improvement, discharged on day-13 Tavares et al. (2020) USA 61 Male Fulminant myocarditis associated with COVID-19 and cardiogenic shock Methylprednisolone Not specified (high dose) IV N/A Norepinephrine, furosemide, cefepime, doxycycline, hydroxychloroquine, enoxaparin Death Zeng et al. (2020) China 63 Male Fulminant myocarditis associated with COVID-19, severe pneumonia, ARDS, and multiple organ dysfunction syndrome (MODS) Methylprednisolone N/A N/A N/A Lopinavir–ritonavir, interferon α-1b, immunoglobulin, piperacillin–tazobactam The patient died on the 33rd day of hospitalization Abbreviations: kgBW: kilogram Body Weight; N/A: Not Available; ECMO: Extracorporeal Membrane Oxygenation; IV: intravenous; ARDS: acute respiratory distress syndrome. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2021; 9(1): e32 Table 2: Assessment of the risk of bias of the included studies Authors Were patient’s demographic characteristics clearly described? Was the patient’s history clearly described and presented as a timeline? Was the current clinical condition of the patient on presentation clearly described? Were diagnostic tests or assessment methods and the results clearly described? Was the intervention(s) or treatment procedure(s) clearly described? Was the post- intervention clinical condition clearly described? Were adverse events (harms) or unanticipated events identified and described? Does the case report provide takeaway lessons? Total Risk of bias Bernal-Torres et al. Yes Yes Yes Yes Yes Yes Unclear Yes 87.5% Low Coyle et al. Yes Yes Yes Yes Yes Yes Unclear Yes 87.5% Low Doyen et al. Yes Yes Yes Yes Unclear Yes No Yes 75% Low Garau et al. Yes Yes Yes Yes Yes Yes Unclear Yes 87.5% Low Hu et al. Yes Yes Yes Yes Yes Yes No Yes 87.5% Low Hussain et al. Yes No Yes Yes No Yes Unclear Yes 62.5% Low Inciardi et al. Yes Yes Yes Yes Yes Yes Yes Yes 100% Low Khalid et al. Yes Yes Yes Yes Unclear Yes Yes Yes 87.5% Low Khatri et al. Yes Yes Yes Yes Yes Yes Yes Yes 100% Low Li et al. Yes Yes Yes Yes Yes Yes Unclear Yes 87.5% Low Naneishvili et al. Yes Yes Yes Yes Yes Yes Unclear Yes 87.5% Low Ortiz et al. Yes Yes Yes Yes Yes Yes Yes Yes 100% Low Richard et al. Yes Yes Yes Yes Yes Yes Unclear Yes 87.5% Low Salamanca et al. Yes Yes Yes Yes Yes Yes Unclear Yes 87.5% Low Sampaio et al. Yes Yes Yes Yes Yes Yes Unclear Yes 87.5% Low Shabbir et al. Yes Yes Yes Yes Yes Yes No Yes 87.5% Low Tavares et al. Yes Yes Yes Yes Unclear Yes No Yes 75% Low Zeng et al. Yes Yes Yes Yes Unclear Yes Yes Yes 87.5% Low All articles were published in 2020. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem W. Kamarullah et al. 8 Figure 1: Flow chart of study selection. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Conclusion Declarations References