COVID-19 Related Myocarditis in Adults: A Systematic Review of Case Reports

Despite the progress of its management, COVID-19 maintains an ominous condition which constitutes a threat, especially for the susceptible population. The cardiac injury occurs in approximately 30% of COVID-19 infections and is associated with a worse prognosis. The clinical presentation of cardiac involvement can be COVID-19-related myocarditis. Our review aims to summarise current evidence about that complication. The research was registered at PROSPERO (CRD42022338397). We performed a systematic analysis using five different databases, including i.a. MEDLINE. Further, the backward snowballing technique was applied to identify additional papers. Inclusion criteria were: full-text articles in English presenting cases of COVID-19-related myocarditis diagnosed by the ESC criteria and patients over 18 years old. The myocarditis had to occur after the COVID-19 infection, not vaccination. Initially, 1588 papers were screened from the database search, and 1037 papers were revealed in the backward snowballing process. Eventually, 59 articles were included. Data about patients’ sex, age, ethnicity, COVID-19 confirmation technique and vaccination status, reported symptoms, physical condition, laboratory and radiological findings, applied treatment and patient outcome were investigated and summarised. COVID-19-related myocarditis is associated with the risk of sudden worsening of patients’ clinical status, thus, knowledge about its clinical presentation is essential for healthcare workers.


Introduction
The pandemic of COVID-19 had an immense impact on nearly every aspect of the modern world. Until August 2022 585 million people have been infected, and 6.4 million died [1]. Initially, it was considered a respiratory disease, but it soon occurred to be a multidimensional condition, dangerous for several systems, including cardiovascular [2][3][4]. Cardiac manifestations of COVID are varied and include i.a., arrhythmias, acute coronary syndrome, heart failure decompensation and myocarditis [5]. Myocarditis is an inflammatory disease of the myocardium with vast symptomatology and not entirely ascertained pathogenesis [6]. Since myocarditis can lead to life-threatening conditions and its incidence is interwound with the current most crucial epidemiological problem-COVID-19-w decided to perform a systematic review of the available literature. The aim of our study was to show the up-to-date evidence of epidemiology, clinical course, diagnostics, treatment and prognosis of COVID-related myocarditis.

Eligibility Criteria
Inclusion criteria were: full-text peer-reviewed articles in English, case-report formula, age of patient ≥18 years, myocarditis after the COVID infection, laboratory-confirmed COVID infection (including COVID in medical history), diagnosis of myocarditis by ESC criteria [6]. Exclusion criteria were: incident of myocarditis after the vaccination, unsure relation of myocarditis with COVID (e.g., positive serological results of different viruses), and unfulfilling ESC criteria.

Data Extraction and Studies Quality Assessment
Similarly to the study selection, data were extracted independently by two researchers (GI and MJ) and discrepancies were solved by the third (SU). Data regarding demographics and medical history, COVID presentation, applied diagnostics, treatment methods and outcome were collected (Tables 1 and 2). We have analyzed exclusively case-report studies, which are per se associated with a high risk of bias, given that we have not applied a standardized tool for the quality assessment.

Nakatani et al. NR
Mild lymphocytic infiltration and moderate to severe perivascular fibrosis with wall thickening of intramural arterioles, no sign of severe myocardial injury compatible with typical active myocarditis, ischemic changes were found with a focal coagulative necrotic area at microvascular level (approximately 0.08 mm 2 in area) with losing nuclei, accompanied by microthrombi with fibrin and platelets in small vessels, scattered megakaryocytes were also seen in the capillaries, microthrombi were seen throughout the specimens and myocytes in non-necrotic areas often showed diffuse cytoplasmic vacuolization, presence of platelets in obstructive and non-obstructive microthrombi within the lumens of microvessels was confirmed by immunohistochemical expression of CD61, fibrin-rich microthrombi were also present as confirmed by phosphotungstic acid-hematoxylin stain, microvessels including intramural arterioles often showed swollen endothelial cells Cardiogenic shock death on day 5 due to intractable cardiogenic shock  short tau inversion recovery sequence showed a subepicardial high-intensity signal in the mid posterolateral wall of LV which suggests myocardial wall oedema, subepicardial late gadolinium enhancement of the posterolateral wall in the mid-ventricle suggestive of myocarditis at 5 and 10 min after contrast administration, respectively no no recovery

Results
After the full-text assessment, 59 studies and 70 patients were included in the analysis. All the counted percentages were calculated from the number of patients who had reported specific parameters.

Demographics
Men constituted 50 out of 69 (73%) cases which reported sex. Age was reported in every case; the mean age was 44 (SD 15.67). Only in 1 reported case patient was vaccinated; however, the vaccination scheme was not fulfilled-the patient received one dose of an unspecified vaccine 9 days before admission. Prior medical history and comorbidity status were reported in 46 cases-15 patients (33%) had no previous significant medical history. The most frequent comorbidities were hypertension (n = 16, 35%), obesity (n = 5, 11%), dyslipidaemia (n = 4, 9%) and asthma (n = 3, 7%).
Fever status was reported in 43 cases, and the exact value of temperature was reported in 39 cases, mean reported temperature was 38 C (SD 1.42) and 18 patients (42%) were febrile (over 38 C). Heart rate (HR) was reported in 46 cases, and the exact value was shown in 44 cases. The mean HR value was 112 beats per minute (SD 26.5), and tachycardia (over 100) was reported in 33 patients (75%). Blood pressure was described in 44 patients, and the exact value was shown in 40 cases. Mean systolic blood pressure was 105 mmHg (SD 26.17), and diastolic was 66 mmHg (SD 16.83). Hypotension (mean arterial pressure below 65 mmHg) occurred in 15 patients (34%). Oxygen saturation without oxygen supply was reported in 37 cases; the mean value was 90% (SD 8.06), and 21 (57%) patients were considered to have low saturation (below 95%).

Time of COVID-Related Myocarditis
The time relationship between COVID and myocarditis, i.e., myocarditis concurrent with the infection or after a specific period, was reported in 69 cases. In 46 patients (67%), myocarditis occurred during the infection. In the remaining 23 patients (33%), myocarditis followed infection. The time between infection and myocarditis was reported in 20 cases (87% of cases of myocarditis after COVID), and the mean time was 52 days (SD 49.13).

Laboratory Markers
Method of confirmation of COVID infection was declared in 56 patients. Polymerase chain reaction (PCR) showed the virus presence in 45 cases (80%), COVID was diagnosed based on serology results in 5 patients (9%), biopsy analysis revealed infection in 4 patients (7%), antigen test was performed in 2 cases (4%).
All the values are from the earliest assessment during patients a hospital stay. We decided not to provide mean or median values of the reported markers due to different normal range values and laboratory assessment methods.
3.6. Imaging Diagnostics 3.6.1. X-ray Chest X-ray findings have been reported in 30 cases (43%). The radiograph description of the heart has been mentioned in 3 cases, out of which 3 demonstrated cardiomegaly as a cardiac abnormality. Changes in lungs, however, have been reported in 19 case reports (27%), primarily multifocal opacities suggestive of viral pneumonia.

CA
The result of coronary angiography (CA) has been reported in 23 cases (33%). None of them revealed any relevant coronary artery stenosis.

CT
Computed Tomography (CT) has been performed in 42 cases (60%). Changes in heart have been stated in 11 patients (26%), out of which pericardial effusion was described in 6 cases and cardiomegaly in 4 patients. The changes in lungs have been observed in 31 cases (74%), mostly bilateral ground-glass opacities and pleural effusion characteristic of viral pneumonia. 1 case report mentioned evidence of pulmonary embolism in CT findings.

ECHO
The echocardiography results have been mentioned in 66 out of 70 cases (94%). Systolic dysfunction has been described in 55 patients (83%), among which 13 (24%) cases reported on biventricular. The Left ventricular ejection fraction (LVEF) has been measured in 46 cases, and the average LVEF turned out to be 28%. Heart wall hypokinesia or akinesia was reported in 24 cases (36%). The observation of pericardial effusion has been described in 19 cases (29%), heart hypertrophy in 13 cases (20%) and mitral or tricuspidal regurgitations in 6 cases (9%).

Biopsy
Myocardial biopsy has been performed in 23 out of 70 cases (33%). The Dallas Criteria for myocarditis have been fulfilled in 21 (91%). The most commonly reported changes were diffuse lymphocytes infiltration which was found in 21 cases (91%), myocyte necrosis, mentioned in 5 cases (21%) and oedema in 4 described cases (17%).

ESC Criteria
The sufficient information for establishing fulfilment of criteria of clinically suspected myocarditis, according to the European Society of Cardiology (ESC) guidelines [6], has been provided in 68 out of 70 cases (97%). The cases fulfilling only one criterium constituted 3 out of 68 cases (4%). The fulfilment of two criteria has been observed in 29 out of 68 cases (43%), three of them in 25 out of 68 cases (37%) and four of them were met in 11 out of 68 cases (16%). The mean number of fulfilled criteria was 3.
The first criterium, I. ECG/Holter/stress test features was fulfilled in 34 out of 68 cases (50%), the second criterium, II. Myocardiocytolysis markers was fulfilled in 64 out of 68 cases (94%), the third criterium, III. Functional and structural abnormalities on imaging (echo/angiography/CMR) was fulfilled in 58 out of 68 cases (85%) and the fourth one, IV. Tissue characterization by CMR was met in 24 out of 68 cases 35%).
3.9. Treatment 3.9.1. Pharmacotherapy The analysis of treatment implemented in the care of described patients revealed the applied pharmacotherapy in 65 out of 70 cases (92%). Antibiotics were used in 43 out 65 cases (66%), among which azithromycin in 14, piperacillin/tazobactam in 10, meropenem in 8, vancomycin in 7, doxycycline in 7, colchicine in 7 and ceftriaxone in 6 cases. Steroids have been used in 42 cases (65%), with methylprednisone being most often prescribed-in 24 cases. Vasopressors were used in 24 out of 65 cases (37%). Anti-viral drugs were applied in 18 out of 65 cases (28%), among which remdesivir in 9 and Lopinavir + Ritonavir in 5 cases. Inotropics were used in 16 out of 65 cases (25%), among which dobutamine was prescribed in 10 cases. Furtherly, anti-hypertensive drugs in 14 cases, hydroxychloroquine in 14 cases, IVIG in 14 cases, diuretics in 11 cases, anticoagulants in 11 cases, antiplatelet therapy in 10 cases, tocilizumab in 5 cases, NSAIDs in 4 cases and PPIs in 4 cases.

Procedures
The information about medical procedures performed in the care of described patients was mentioned in 34 out of 70 cases (49%). Mechanical ventilation has been applied in 14 patients (41%), and breathing support, meaning CPAP, high-flow or just oxygen, in 8 cases (24%). Extracorporeal membrane oxygenation (ECMO) was used in 16 patients (47%), and Continuous Renal Replacement Therapy (CRRT) in 7 patients (21%). Cardiac devices (ex. Impella CP) have been implemented in 10 cases (29%). The performance of pericardiocentesis or pericardiotomy has been mentioned in 6 cases (18%). Resuscitation was performed in 3 out of 34 cases (9%) and heart transplant in 1 out of 34 patients (3%).

Outcome
The final outcome has been reported in 63 out of 70 cases (90%). In 53 cases (84%), recovery has been achieved. The number of days till the patient's discharge was stated in 22 out of 53 cases (42%), with the average number of 16 days and the range from 3 to 52 days. Death was the outcome in 11 out of 63 cases (17%). The number of days from admission to the hospital till death has been given in 7 out of 11 cases (64%), with the average number of 9 days with the range from <1 day to 33 days. Most important features are shown in Figure 2. Clinical features by outcome groups are summarized in the harvest plot ( Figure 3).
A summary of the most important findings is shown in Tables 1 and 2 and displayed in Figure 1. The full report of reviewed cases is in Supplementary Materials (Supplementary Table S1).

Clinical Characteristics of Patients
Reported patients were predominantly men (73%). Myocarditis occurred in relatively young patients (mean age 44 years). Notably, 33% of patients had no previous medical history. Given that, the phenotype of the myocarditis patient-a mid-aged man with no or a few comorbidities, does not suggest severe illness and can be falsely comforting for a physician. In 33% of cases, myocarditis occurred sometime after the COVID infection. Center for Disease Control and Prevention reports that myocarditis can be diagnosed several months after the infection. In the observed cohort of 36,005,294 patients, 89.6% were diagnosed with myocarditis in the same month as COVID infection, 6.6% 1 month after, and 3.9% ≥ 2 months after [69]. In our case, the mean time between infection and myocardium affection was 52 days. However, one case occurred after 6 months after the initial disease. This highlights the necessity of watchful surveillance of susceptible patients after the COVID, even up to half a year. Most of the published case reports describe patients who experienced myocarditis when the vaccines were not yet available. Only one patient was vaccinated, however, he did not finish the complete vaccination scheme. Further, some studies showed an increased incidence of myocarditis after COVID vaccines [70,71]. A recent analysis performed by the Center for Disease Control and Prevention, which included 40 health care systems, revealed that the risk of myocarditis after vaccination is lower than the risk of myocarditis after COVID infection regardless of sex and age group [72]. The impact of the vaccination on the incidence and severity of myocarditis after COVID infection-despite prior immunization-needs further cohort studies.

Clinical Presentation
Some of the most reported symptoms were dyspnoea, cough, chest pain and reported weakness. These are the typical myocarditis manifestations, and as they overlap the symptomatology of the COVID infection, making an appropriate diagnosis can be challenging [73]. Noteworthy, we observed a relatively high occurrence of diarrhoea (16%). In every, except one, cases diarrhoea accompanied myocarditis at the time of COVID. Given that, it can be associated rather with the infection than the myocarditis [74].
Inflammatory markers, including white blood count, CRP, procalcitonin, ferritin, and interleukin-6, were typically elevated. The precise pathophysiology of COVID-related myocarditis remains unsolved, and a cytokine storm remains one of the hypotheses [75]. Significant elevation of inflammatory markers (CRP, ferritin, DDimer) were also associated with a more aggressive course [8,76].
Noteworthy, cytokine storm as a reflection of the hyperactive immune response is not the only proposed hypothesis for explaining myocardial injury by COVID-19. COVID molecules invade i.a. heart cells via the protein receptor angiotensin-converting enzyme 2 (ACE2). ACE2 is also associated with the modulation of the myocardial inflammatory response. The affected heart cells were noted to have a higher expression of the ACE2 receptors [77,78]. Given that, the role of the ACE2 receptors in COVID-related myocarditis pathophysiology seems to be significant.
Cardiac markers, such as troponin or NT-proBNP, were elevated in most cases. The rise of both biomarkers in COVID infection was associated with a poor prognosis. Notably, the prognosis of the patients with preceding cardiovascular disease remained favorable [79]. The high troponin level was also associated with the arrhythmia prevelance [80]. Cardiac biomarkers, especially troponin, should be analyzed in the context of other laboratory results. While the isolated rise of troponin reflects the isolated cardiac involvement, the rise of troponin with the surrounding intensive rise of inflammatory biomarkers reflects the hyperinflammatory state with possible multiorgan dysfunciton [8]. This distinction has important clinical implications, as physicians should always recognize which therapeutical pathway would be more rewarding, i.e., targeting inflammation by using steroids, immunoglobulins, biological treatment (e.g., anakinra, tocilizumab, sarilumab, canakinumab, JAK inhibition) or focusing on the cardioprotective treatment [81][82][83][84][85].
Described electrocardiographic findings present a wide range of changes and are not characteristic of myocarditis. On the other hand, physiological ECG was reported only in 5% of cases, suggesting that the ECG can successfully serve as a screening tool for myocarditis.

Imaging Diagnostics
Although endomyocardial biopsy (EMB) has lost its popularity [86], it remains the gold standard in diagnosing myocarditis. As it is an invasive procedure, it requires professional training and has complications, but when done correctly, it has invaluable diagnostic and prognostic value [87,88]. The EMB was performed in 33% of all reviewed cases.
Lymphocytic infiltrates associated with myocyte necrosis, which stands for Dallas Criteria, were present in 91% of cases (n = 21). With the evolution of immunohistochemistry technics, more detailed analysis allows detecting more myocarditis cases and overcoming the limitations present in the traditional sample examination [89].
The deterioration of left ventricular systolic function was present in 83% of the described patients. This finding remains consistent with other systematic reviews: Jaisiwal et al.-74% [73], Ho et al.-66% [9]. Similarly to what has been shown in previous systematic review performed by Castiello T. et al. [8], one of the most common echocardiographic findings was global and regional wall hypokinesia 36.4% (n = 24), suggestive of myocardial oedema. Even though there are no echocardiographic changes unique to myocarditis, the assessment of echocardiographic parameters is recommended prior to the EMB procedure. It allows excluding pericardial effusion or intracavitary thrombus, as well as it could help to exclude other causes of heart failure and may have a prognostic value [89]. Moreover, the initial ECHO diagnostic is also an excellent parameter to be controlled in follow-up [90].
Cardiac magnetic resonance is considered a noninvasive gold standard for diagnosing myocarditis [91]. Late gadolinum enhancement, indicating the most inflamed areas, was present in 66,7% (n = 22) of patients. It is also a prognostic marker for the increased risk of adverse cardiac outcomes in patients with myocarditis [92]. Myocardial oedema, which was present in 51% (n = 17) of reviewed cases, may affect myocardial function. It can be an expression of diffuse inflammation due to systematic response, vascular leakage induced by endothelial barrier dysfunction or direct myocardial damage caused by SARS-CoV-2 [93,94].
The most often quoted abnormal finding in X-Ray was cardiomegaly (25%, n = 9) which can be a non-specific manifestation of various primary or acquired cardiomiopathies [95]. The most common X-Ray findings were opacities suggesting COVID-19 pneumonia (61% n = 19). Normal X-Ray findings were described in 12% (n = 4). The 22 patients (31%) who underwent CA were predominantly men (n = 16), and their age ranged from 19 to 69, with a median of 42.5 years. Although CA is not a standard procedure in the diagnostics of myocarditis, the patients presenting acute retrosternal pain and dyspnoea at a relatively young age raise the alarm for myocardial infarct procedures [96].

Treatment
The pharmacotherapy strategies varied among the described patients, depending on comorbidities and centre-specific procedures. It is impossible to enucleate specific myocarditis treatment, as the strategy should focus first on the disease source and unique patient's symptomatic [89].
One of the main targets for the pharmacotherapy of COVID-19 myocarditis was cytokine storm. Incorporating the steroids (65% of our cases) into the COVID treatment was an attempt to address this pathological pathway. Indeed, the RECOVERY platform trial has proven that steroids play an important role in reducing COVID-19 mortality [97]. Dexamethasone was also found to diminish myocardial oedema and improve systolic function [93]. Another drug considered to dump patients' immune response was tocilizumab (5 reviewed cases), which was shown to reduce mortality even in the group already treated with steroids [84,85,98]. Intravenous immunoglobulins were used in 14 patients, yet their use to modulate inflammation in COVID is still under debate [99,100]. Other conceptions for the immunomodulatory treatment in COVID tested interleukin-1β inhibitor-canakinumab; and colchicine. These conceptions did not show clinical or prognostic benefit in COVID setting [83,101].
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in myopericarditis is another unsolved problem. There are studies supporting the hypothesis that it can be potentially harmful and should be avoided in myocarditis [102], as well as studies where NSAIDs neither affected all-cause mortality rate nor left ventricle function [103]. Nevertheless, none of the studies showed the benefit of NSAIDs in myocarditis treatment, and generally, they should not be widely implemented [6].
As ARDS was the most common complication, antibiotics were used, i.a., to prevent bacterial superinfection. The most willingly used antibiotic was azithromycin [9,73,104]. It seems that using antibiotics in standard COVID care is unjustified [105]. The antiviral treatment was applied in 27% of the reviewed cases. None of the tested antiviral agents has proven its efficacy in improving COVID survival [106][107][108]. Further, there is a lack of evidence about antiviral treatment for myocarditis in general [89,109]. Thus, the symptomatic treatment according to NYHA functional class (with beta-blockers, diuretics, angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers) should be applied [6,89].
Surgical procedures like mechanical circulatory support or heart transplant are warranted particularly for patients with cardiogenic shock in the course of fulminant myocarditis, whose clinical state is deteriorating despite optimal medical treatment. Similarly, cardiac devices implementation should be considered in patients with myocarditis-related atrioventricular blocks or after a myocardial infarct. These technics should be considered early, when the highest possible pharmaceutics doses are insufficient to facilitate recovery [6,89].

Prognosis and Outcome
The overall incidence of combined in-hospital mortality and heart transplantations associated with myocarditis, presented in 2018 in the study from Multicenter Lombardy Registry, was 3.2% [110], much lower than in our work (17% of deaths). Higher mortality was also reported in the corresponding systematic reviews [8,9,73,104], ranging from 15.2% to 31.8%. It can be explained by the specific course of COVID-related myocarditis, which is overlapped by the aggressive, infectious disease. Noteworthy, case reports are the low-quality evidence and reported cases are usually severe and complicated, which may artificially increase the reported mortality. Given that, forthcoming registries are warranted to establish reliable COVID-related myocarditis mortality.

Limitations
Our study is not free from limitations. The most important one is that the data for our analysis come from the case-report papers, which provide poor quality evidence. Further, most of the reported cases demonstrate very dramatic situations-patients with severe and sophisticated course and complications-which is attractive for the publication reasons but does not reflect the typical clinical situation. Given that, the generalizability of our conclusions is limited, especially in epidemiology. Conversely, presented descriptions give a detailed, patient-level evaluation of each case. Submitted data was frequently incomplete-not every parameter was regularly described. We tried to choose and analyze only the most repetitive factors. Laboratory parameters were unsuitable for statistical analysis, as laboratories use different evaluation techniques and normal range values. Considering it all, quality or bias assessments could not be performed. Our study provides a current, interim summary of the data, while the results of more extensive, well-designed studies are unavailable.

Conclusions
This systematic review provides the most recent summary of the reported COVIDrelated myocarditis. We present the complex summary of COVID-related myocarditis, which can serve as a reliable source of knowledge on that topic. Importantly, in approximately one-third of patients, myocarditis occurs a few weeks after infection, even up to 6 months. The necessity of considering COVID as a cause of myocarditis in relatively young and healthy populations should be strongly highlighted. Susceptible patients should be carefully observed after the COVID infection, even the poorly symptomatic one.