A Systematic Review of COVID-19 and Pericarditis

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan, China in December 2019. Since then, the disease has spread globally, leading to the ongoing pandemic. It can cause severe respiratory illness; however, many cases of pericarditis have also been reported. This systematic review aims to recognize the clinical features of pericarditis and myopericarditis in COVID-19 patients. Google Scholar, Medline/PubMed, CINAHL, Cochrane Central, and Web of Science databases were searched for studies reporting “Coronavirus” or “COVID” and “Peri-myocarditis,” “heart,” or “retrospective.” Case reports and retrospective studies published from May 2020 to February 2021 were reviewed. In total, 33 studies on pericarditis, myopericarditis, and pericardial infusion were included in this review. COVID-19 pericarditis affected adult patients at any age. The incidence is more common in males, with a male-to-female ratio of 2:1. Chest pain (60%), fever (51%), and shortness of breath (51%) were the most reported symptoms, followed by cough (39%), fatigue (15%), myalgia (12%), and diarrhea (12%). Laboratory tests revealed leukocytosis with neutrophil predominance, elevated D-dimer, erythrocyte rate, and C-reactive protein. Cardiac markers including troponin-1, troponin-T, and brain natriuretic peptide were elevated in most cases. Radiographic imaging of the chest were mostly normal, and only 31% of chest X-rays showed cardiomegaly and or bilateral infiltration. Electrocardiography (ECG) demonstrated normal sinus rhythm with around 59% ST elevation and rarely PR depression or T wave inversion, while the predominant echocardiographic feature was pericardial effusion. Management with colchicine was favored in most cases, followed by non-steroidal anti-inflammatory drugs (NSAIDs), and interventional therapy was only needed when patient developed cardiac tamponade. The majority of the reviewed studies reported either recovery or no continued clinical deterioration. The prevalence of COVID-19-related cardiac diseases is high, and pericarditis is a known extrapulmonary manifestation. However, pericardial effusion and cardiac tamponade are less prevalent and may require urgent intervention to prevent mortality. Pericarditis should be considered in patients with chest pain, ST elevation on ECG, a normal coronary angiogram, and COVID-19. We emphasize the importance of clinical examination, ECG, and echocardiogram for decision-making, and NSAIDs, colchicine, and corticosteroids are considered to be safe in the treatment of pericarditis/myopericarditis associated with COVID-19.


Introduction And Background
The novel coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. The pandemic began in Wuhan, China in December 2019. While affecting dominantly the respiratory system, COVID-19 can also cause acute and chronic damage to the cardiovascular system. The cardiovascular manifestations of COVID-19 are diverse and include arrhythmia, acute coronary syndrome, left ventricular heart failure, myocarditis, and acute and subacute pericarditis with or without pericardial effusion [2][3][4].
Pericarditis refers to the inflammation of the pericardium, the thin fibrous sac surrounding the heart, that can present as an isolated disease or as a manifestation of a systemic disorder, diagnosed in approximately 0.1% of patients hospitalized for chest pain. Although acute pericarditis has many causes, it is most often

Data Collection Process and Data Items
Data extracted from articles included the name of the first author, year of publication, country, and study design. Variables for which data were sought from all studies included patient age and sex and presenting complaints at the time of admission. Laboratory tests, diagnostic studies, management of pericarditis, and patient outcomes including complications were extrapolated from case studies.

Analysis of Results and Summary of Measures
Information was reviewed if it was reported by two or more articles. Subsequently, the data were tabulated, evaluated, and summarized.

Risk of Bias Across Studies
Potential bias across studies was analyzed within study characteristics. Two independent reviewers evaluated the methodological quality of the eligible studies. A third reviewer evaluated papers when there was no agreement. The Joanna Briggs Institute critical appraisal tool for case reports was used in this systematic review [8]. Bias was evaluated using a checklist of eight questions. Each question is specified in the Appendix concerning the risk of bias whereby an overall appraisal was made of each article: low risk of bias (included), high risk of bias (excluded), or uncertain risk of bias (more information is required). For this study, an answer of "yes" equal to or greater than 50% of the questions was considered to be low risk of bias. Similarly, an answer of "no" equal to or greater than 50% of questions was determined to be high risk of bias, whereas "unclear" answers were equal to or greater than a 50% response.

Study Selection
From the five databases, 12,310 articles were selected concerning COVID-19 and myocarditis. In total, 34 articles were selected once assessed for eligibility . The study by Rauch et al. [42] was removed from this list as it did not meet the minimum criteria required when assessed for bias. A PRISMA flow diagram detailing the process of identification, inclusion, and exclusion of studies is shown in Figure 1.

Risk of Bias Within Studies
In comparison to case reports, the majority of articles were rated to have a low risk of bias . As mentioned previously, only one study was characterized as high risk of bias [42] and was removed from the systematic review.

Patient Profile
COVID-19 patients selected for the systematic review were 49.3 ± 18.5 years of age, with more males affected than females at a ratio of 2:1 . The eldest was 82 years old [31], while the youngest was seven years old [32].

Risk of Bias Across Studies
Due to the nature of descriptive studies, the results being presented are liable to the investigator, procedure, and selection bias.

Limitation of the Study
Statistical analyses were not performed as there were no control/comparison groups in the included studies.

Discussion
Pathophysiology SARS-CoV-2 is thought to lead to myocardial damage and inflammation through the following processes: (1) direct invasion, (2) ischemic injury, and (3) cytokine storm. SARS-CoV-2 typically invades the respiratory epithelium through direct invasion via binding to angiotensin-converting enzyme-2 (ACE2) receptors on the host cells. These receptors are predominantly found on the respiratory epithelium and are also expressed on cardiac cells, facilitating a pathway and allowing for direct invasion and damage to cardiomyocytes [43]. Hypoxemia, which can result from pulmonary compromise from SARS-CoV-2 infection, can also lead to impaired myocardial oxygen supply resulting in a supply and demand mismatch, which then leads to ischemic injury to cardiomyocytes [43]. Cytokine storm is a known physiologic mechanism associated with SARS-CoV-2 infection, leading to the widespread production of high levels of pro-inflammatory cytokines. Large-scale production of these pro-inflammatory cytokines has also been linked to myocardial damage through recorded elevations in troponin levels during these states [43]. Autopsy reports on patients who died of COVID-19 infection have also shown findings within cardiac tissue consistent with inflammatory cellular infiltrate and multi-nucleated giant cells. Additionally, findings of pericardial effusions have also been seen in autopsy examinations [43].

Clinical Presentation
The clinical manifestations of COVID-19 in order of prevalence are fever, cough, and fatigue [2]. A common clinical manifestation of pericarditis is typically sharp and pleuritic chest pain that radiates posteriorly to the bilateral trapezius ridges, which improves on sitting up or leaning forward [44]. The presence of fever, subacute course, large effusion, or tamponade are indicators of poor prognosis [45]. Auscultation of the left sternal border typically indicates a triphasic pericardial friction rub. Here, we identified that patients with COVID-19 pericarditis commonly presented with chest pain, in addition to fever and shortness of breath.

Laboratory Findings
It has been shown that thrombo-inflammatory biomarkers are associated with COVID-19 infection severity [46]. Our systematic review showed that COVID-19 patients with pericarditis exhibited leukocytosis with neutrophil predominance, elevated inflammatory markers (ESR and CRP), and elevated D-dimer levers as well. These case studies also exhibited elevated cardiac markers (troponin-I, troponin-T, CK-MB, and BNP) as well. Typically, 32-50% of cases of viral and idiopathic acute pericarditis as evidence of inflammatory myocardial damage and possible evidence of myopericarditis [47]. Patients with pericarditis and concomitant myocarditis have a potential for higher risk of complications, including left ventricular dysfunction and possible heart failure [48]. Similarly, our review showed that the deaths were from COVID-19 patients diagnosed with myopericarditis. Similarly, of the 10 studies to report COVID-19-related complications, eight of which were present in COVID-19 patients diagnosed with myopericarditis [20][21][22]24,25,34,36,39]. Furthermore, the only two deaths that were reported were from patients diagnosed with myopericarditis [20,22].

Imaging
The typical ECG presentation of a COVID-19 patient with pericarditis is sinus rhythm with ST-segment elevation, while a minority of individuals exhibit PR-segment depression or tachycardia. ECG presentation of widespread ST-segment elevation and PR depression, although this finding is considered characteristic for pericarditis, es only found in slightly more than half of the patients with acute pericarditis, particularly among younger males [44]. Disease progression may evolve to include T waves [44].
Echocardiographic patterns of the brightness of the pericardial layers, which are associated with fibrinous pericarditis, and pericardial effusion have been described in pericarditis [44]. Approximately 60% of patients with acute pericarditis were found to have developed a pericardial effusion, although its absence does not exclude pericarditis. Our systematic review found that the predominant feature found in the majority of patients with pericarditis is pleural effusion, while a minority of patients have hypokinesis or depressed ejection fraction.
Chest radiograph findings in patients with acute pericarditis are usually normal except in the setting of very large pericardial effusion, which would convey the characteristic water bottle-shaped cardiac silhouette [44]. CT and cardiac MRI with gadolinium contrast are recommended as secondary imaging techniques after echocardiography and chest radiographs to detect and confirm pericardial inflammation, assess pericardial thickening or late gadolinium enhancement, and identify the presence of effusion or constrictive physiology [44,49]. Likewise, the case resorts in our systematic reported predominantly COVID-19 disease of the lungs with bilateral infiltrates or ground-glass opacities, with characteristic pericarditis features of pericardial effusion or cardiomegaly demonstrated in a minority of patients. In diagnostic CT scans, findings of pericardial effusions were also studied and reported to be present in a small number of patients as well, and the degree of pericardial effusion was also seen to correlate to the severity of infection. Evidence of myocarditis was also reported on CT scans, with increases in cardiac wall thickness, myocardial edema, and wall hypokinesia. In cardiac MRIs, these studies are limited; however, there have been reports of myocardial edema and significant findings of wall motion abnormalities in patients already clinically diagnosed with acute myocarditis. The use of positron emission tomography scan in detailing diagnostic findings of pericardial effusions and cardiomegaly only highlighted small studies which did not reveal any evidence of cardiac involvement [50].

Treatment
There was no prevailing strategy regarding the medical management to treat pericarditis in patients with COVID-19. We found that colchicine, aspirin, NSAIDs, and/or corticosteroids were used in the majority of studies. NSAIDs, most commonly ibuprofen (600 to 800 mg every six to eight hours), indomethacin (25 to 50 mg every eight hours), and aspirin (2 to 4 g daily in divided doses) have long been the mainstay of medical therapy for both acute and recurrent pericarditis whether or not it is of idiopathic or viral causes [41,[51][52][53]. Corticosteroid therapy (0.2 to 0.5 mg of prednisone per kg of body weight daily) used to be the initial choice in treating pericarditis with pericardial effusions or recurrent episodes unresponsive to aspirin or NSAIDs; however, it has been shown to be associated with an increased risk in adverse effects and higher recurrence risk in non-randomized studies [44,52]. There is considerable evidence highlighting that the use of colchicine is efficacious and safe for the treatment and prevention of both acute and recurrent pericarditis, as well as for reducing rehospitalizations and symptom duration in the process [54][55][56][57][58]. In the cases that were reviewed in our study, the majority utilized colchicine (17/33), and 13 cases utilized NSAIDs either in the form of aspirin, ibuprofen, or indomethacin, all of which were usually used in conjunction with colchicine, with the exception of 5/13 of the cases. Among 10/39 of the cases, there was no use of NSAID or colchicine therapy. Additionally, one case reported the use of Anakinra [19] after noting poor results with NSAID and colchicine therapy. All patients received some form of standardized COVID-19 therapy as well, including intravenous corticosteroids. All of the doses reported in the treatment of myopericarditis and pericarditis were within the appropriate dosages discussed in the standard therapies above.

Conclusions
Our systematic review provides a comprehensive characterization of the clinical features among COVID-19 patients with pericarditis. Currently, as data are limited, more research is needed to improve our understanding of COVID-19 pericarditis.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.