key: cord-0820468-jr4zzyof authors: Jaiswal, V.; Nagpal, S.; Labitag, C. A. E.; Tayo, J.; Patel, A.; Lo, K. B.; Vijayan, R.; Wanessa F Matos, W. F.; Yaqoob, S.; Panday, P.; Savani, S.; Alnahas, Z.; Bhatnagar, A.; Diaz, Y.; Dylewski, J. R. title: A Systematic Review of COVID - 19 Induced Myocarditis - Symptomatology, Prognosis, and Clinical Findings date: 2021-06-02 journal: nan DOI: 10.1101/2021.05.29.21258059 sha: 96eff88eebc45d099d0e2f2d6642b8ffd96c84ef doc_id: 820468 cord_uid: jr4zzyof Objective: With the advent of a novel coronavirus in December 2019, several case studies have reported its adversity on cardiac cells. We conducted a systematic review that describes the symptomatology, prognosis, and clinical findings of patients with COVID-19-related myocarditis. Methods: Search engines including PubMed, Google Scholar, Cochrane Central, and Web of Science were queried for SARS-CoV-2 or COVID 19 and myocarditis. PRISMA guidelines were employed, and peer-reviewed journals in English related to COVID-19 were included. Results: This systematic review included 22 studies and 37 patients. Eight patients (36%) were confirmed myocarditis, while the rest were possible myocarditis. Most patients had elevated cardiac biomarkers, including troponin, CRP, CK, CK-MB, and NT-pro BNP. Electrocardiogram results noted tachycardia (47%), left ventricular hypertrophy (50%), ST-segment alterations (41%), and T wave inversion (18%). Echocardiography presented reduced LVEF (77%), left ventricle abnormalities (34%), right ventricle aberrations (12%), and pericardial effusion (71%). Further, CMR showed reduced myocardial edema (75%), non-ischemic patterns (50%), and hypokinesis (26%). The mortality was significant at 25%. Conclusions: Mortality associated with COVID-19 myocarditis appears significant but underestimated. Further studies are warranted to evaluate and quantify patients actual prognosis and outcomes with COVID-19 myocarditis. each study. The score ranged from zero to nine. Those with scores of zero to three were considered low quality, scores of four to six were moderate quality, and seven to nine were considered high quality. (Supplementary Table 1 and 2) 3. Results: The electronic search identified 974 potential studies. No additional studies were obtained using other sources. Most of the articles were duplicates; hence, only 624 articles were screened initially. The title and abstracts were reviewed against the inclusion criteria, and 492 articles were excluded on primary screening. Around 110 articles were not on COVID-19-related myocarditis, did not provide an English translation, were review articles, pregnant female and involved participants <50 years old and with known heart problems were excluded. A review of the full-text manuscript of the 22 articles revealed that all of them met the eligibility criteria. Hence, all 22 articles 9-30 were included in the systematic review illustrated according to PRISMA guidelines ( Figure 2 ). Twenty-two studies were selected for this systematic review, out of which twenty-one were case reports, and one was a retrospective study. All articles were published in the year 2020, and 41% were done within the US. The reports included a total sample of 37 patients with COVID-19-related myocarditis. Cases were reported by patients aged between 50 to 81 years with male predominance (62%). The patients were primarily seen in the intensive care unit (41%) and emergency department (32%). In six studies (27%), the participants had no existing illness. In contrast, among those with existing morbidities, the most common diseases were hypertension (55%) and ischemic stroke (9%) ( Table 1) The 'Research and Quality Scoring Method' by Sackett and Haynes, the Jadad scale, and the items published by Cho and Bero were employed to appraise the quality of each study (Han et al., 2011) 8 . Out of 22 studies, 21 studies (96%) were All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. ; https://doi.org/10.1101/2021.05.29.21258059 doi: medRxiv preprint deemed moderate, and one study (4%) has poor quality. The study design is a potential source of bias. The majority were case studies (96%), and there was one retrospective study (4%). Given the inherent limitations of case studies, the sample size was small, and there were no inclusion or exclusion criteria. Similarly, the sample size for the retrospective study was small at 16 (Supplementary Tables 1 and 2 presents the findings and the description of each criterion). Out of 22 studies, 17 articles reported the typical systemic symptoms of COVID-19 myocarditis, which included fever (77%), fatigue (41%), and myalgia (18%). Only 12 studies noted the cardiovascular complaints of the patients, such as chest pain (50%), tachycardia (25%), and hypotension (17%). Meanwhile, 21 studies discussed respiratory signs and symptoms, including shortness of breath (67%), cough (62%), acute respiratory distress syndrome (24%), hypoxia (19%), and tachypnea (14%). Out of 22 studies, only three reports examined the neurological presentation of COVID-19 myocarditis. All studies noted syncope (100%). Then, three studies documented the gastrointestinal complaints of the patients, wherein diarrhea (67%) was the most common presentation (Table 2 ). Out of 22 studies, only 16 articles (73%) reported mortality, while six studies (27%) did not mention any consequent prognosis. Variable outcomes were reported on COVID-19-related myocarditis with a mortality of 25% (n = 4). Out of 16 patients, 12 of them (75%) recovered (Table 2) . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Tachycardia was noted in eight studies (47%). In terms of rhythm, normal sinus rhythm was noted in nine studies (75%) and atrial fibrillation in one study (8%). The ECG reports also revealed left ventricular hypertrophy (50%). The findings also noted alterations in the ST segments (41%) and T wave inversion (18%) ( Table 4) . All in all, these electrocardiogram findings vary pretty broadly. The majority of studies (77%) observed a reduced left ventricular ejection fraction (LVEF). The mean LVEF was 33% (SD = 8.35). Out of the 17 studies, there were also significant abnormalities in the left ventricle in six studies (34%) and right ventricle in two studies (12%). Pericardial effusion was noted in 5 studies, but most studies had no mention of this (Table 5) . In terms of the coronary angiography results, only 1 study found a significant coronary artery disease, while of the ten studies, 8 (80%) had a chest CT noted with ground-glass changes, and 2 (20%) was noted with bilateral opacities. Similarly, in 14 studies with chest x-ray findings, 6 (43%) were noted with bilateral interstitial opacities, 2 (14%) with bilateral basal opacities, and 2 (14%) with bilateral pleural effusion (Table 6 ). The CMR and myocardial biopsy results were used to identify possible and confirmed cases of COVID-19-related myocarditis. Out of 22 studies, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. ; https://doi.org/10.1101/2021.05.29.21258059 doi: medRxiv preprint eight studies performed CMR, and only two were able to provide histopathological findings through EMB. Eight were confirmed cases (36%), and the rest were suspected cases (Table 7) . Generally, myocarditis can be suspected with clinical presentations suggestive of acute coronary syndrome on ECG, laboratory testing (e.g., increase troponin levels), and/or wall motion abnormalities with no obstruction of coronary arteries on coronary From the two studies that performed EMB, 1 study showed an increased number of This systematic review aimed to describe the symptomatology, prognosis, and clinical findings of patients with probable and confirmed COVID-19-related myocarditis. Frequent clinical findings of COVID-19 constitute fever, cough, shortness of breath, and fatigue 31 . WHO (World Health Organization) has also cited fever and cough as striking features of COVID-19 32 . Fever, dyspnea, and/or chest All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. pain are the typical manifestations of myocarditis that overlap with the symptoms of COVID-19, thus making diagnosis challenging 33 . However, laboratory investigations such as raised cardiac biomarkers and electrocardiogram may assist in diagnosing COVID-19 induced myocarditis. Our study's mortality rate from COVID-19-related myocarditis was high as 25%, which is comparable with the previous meta-summary, which noted 27% fatalities in patients with COVID-19 related myocarditis 34 . Our results align with a prior case report which proposes that myocardial injury is a cardinal predictor of mortality in COVID-19 35 . Even though the majority of the patients in our review survived COVID-19-related myocarditis, the actual mortality rate may be higher as many of the included studies did not report a fatality. COVID-19 symptoms can be minimal to severe 36 Furthermore, the echocardiogram findings were positive for a reduced left ventricular ejection fraction (LVEF) varying between 20% to 47% and pericardial effusion. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. BNP, and CK-MB might aid in the diagnosis but are non-specific because their levels can also rise in other conditions such as acute heart failure and demand ischemia. COVID-19 related mortality from myocarditis appears significant and underestimated. Many cases of COVID-19 myocarditis have not been subjected to definitive diagnostic approaches, including endomyocardial biopsy and MRI. In addition, rates of poor outcomes such as mortality and the presence of myocarditis itself might be underreported. Further studies are needed to outline the trends of All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. The authors have no conflicts of interest to disclose. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The reports included a total sample of 37 patients with COVID-19-related myocarditis. Cases were reported by patients aged between 50 to 81 years with male predominance (62%). The patients were primarily seen in the intensive care unit (41%) and emergency department (32%). In six studies (27%), the participants had no existing illness. In contrast, among those with existing morbidities, the most common diseases were hypertension (55%) and ischemic stroke (9%) (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. ; Most of the studies noted an increase in troponin (86%), NT-pro BNP (91%), ferritin (80%), WBC (80%), and D-dimer (67%) levels. The median troponin level was 290 (IQR = 3,543) ng/L, median NT-pro BNP was 4,639 (IQR = 4,678) pg/mL, median ferritin level was 948 (IQR = 244) ng/ml, mean WBC count was 17,500 (SD = 5,710.08) per μ L, and median D-dimer level was 949 (IQR = 742) ng/mL. Meanwhile, in the studies that examined creatine, 50% noted risen levels with a mean creatinine level of 1.31 (SD = 0.48) mg/dL. On the other hand, all studies that evaluated CRP, CK level, CK-MB, ESR and procalcitonin noted elevated laboratory findings. The median CRP level was 18.01 (IQR = 14.09) mg/dL, median CK level was 1130 (IQR = 1005) U/L, median CK-MB level was 20.1 (IQR = 11.94) ng/ml, mean ESR was 80 (SD = 2.83) mm/hr, and median procalcitonin level was 7.69 (IQR = 7.51) ng/ml. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. ; https://doi.org/10.1101/2021.05.29.21258059 doi: medRxiv preprint Tachycardia was noted in eight studies (47%). In terms of rhythm, normal sinus rhythm was noted in nine studies (75%) and atrial fibrillation in one study (8%). The ECG reports also revealed left ventricular hypertrophy (50%). The findings also noted alterations in the ST segments (41%) and T wave inversion (18%) ( Figure 6 ). All in all, these electrocardiogram findings vary pretty broadly. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. ; https://doi.org/10.1101/2021.05.29.21258059 doi: medRxiv preprint The majority of studies (77%) observed a reduced left ventricular ejection fraction (LVEF). The mean LVEF was 33% (SD = 8.35). Out of the 17 studies, there were also significant abnormalities in the left ventricle in six studies (34%) and right ventricle in two studies (12%). Pericardial effusion was noted in 5 studies, but most studies had no mention of this. Table 6 : Imaging findings of COVID-19 related myocarditis All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 2, 2021. ; https://doi.org/10.1101/2021.05. 29.21258059 doi: medRxiv preprint In terms of the coronary angiography results, only 1 study found a significant coronary artery disease, while of the ten studies, 8 (80%) had a chest CT noted with groundglass changes, and 2 (20%) was noted with bilateral opacities. Similarly, in 14 studies with chest x-ray findings, 6 (43%) were noted with bilateral interstitial opacities, 2 (14%) with bilateral basal opacities, and 2 (14%) with bilateral pleural effusion. 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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity Only 12 studies noted the cardiovascular complaints of the patients, such as chest pain (50%), tachycardia (25%), and hypotension (17%). Meanwhile, 21 studies discussed respiratory signs and symptoms, including shortness of breath (67%), cough (62%), acute respiratory distress syndrome (24%), hypoxia (19%), and tachypnea (14%) All studies noted syncope (100%). Then, three studies documented the gastrointestinal complaints of the patients