COVID‐19‐associated Brugada pattern electrocardiogram: Systematic review of case reports

Abstract Aims To summarize published case reports of patients diagnosed with coronavirus disease 2019 (COVID‐19) and Brugada pattern electrocardiogram (ECG). Methods The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses checklist were followed. A literature search was conducted using PubMed, EMBASE, and Scopus up until September 2021. The incidence, clinical characteristics, and management outcomes of COVID‐19 patients with a Brugada pattern ECG were identified. Results A total of 18 cases were collected. The mean age was 47.1 years and 11.1% were women. No patients had prior confirmed diagnosis of Brugada syndrome. The most common presenting clinical symptoms were fever (83.3%), chest pain (38.8%), shortness of breath (38.8%), and syncope (16.6%). All 18 patients presented with type 1 Brugada pattern ECG. Four patients (22.2%) underwent left heart catheterization, and none demonstrated the presence of obstructive coronary disease. The most common reported therapies included antipyretics (55.5%), hydroxychloroquine (27.7%), and antibiotics (16.6%). One patient (5.5%) died during hospitalization. Three patients (16.6%) who presented with syncope received either an implantable cardioverter defibrillator or wearable cardioverter defibrillator at discharge. At follow‐up, 13 patients (72.2%) had resolution of type 1 Brugada pattern ECG. Conclusion COVID‐19‐associated Brugada pattern ECG seems relatively rare. Most patients had resolution of the ECG pattern once their symptoms have improved. Increased awareness and timely use of antipyretics is warranted in this population.

distress syndrome (Johnson et al., 2020). However, emerging data in the early phases of the pandemic identified serious cardiovascular complications in COVID-19 patients (Bansal, 2020;Johnson et al., 2020), which include cardiac arrhythmias, myocarditis, pericarditis, acute coronary syndrome, heart failure, cardiogenic shock, and cardiac arrest (Bader et al., 2021;Dherange et al., 2020;Nishiga et al., 2020). Currently, there are two proposed mechanisms that explain the development of cardiac complications in COVID-19: First, SARS-CoV-2 has a binding affinity for the ACE-2 receptor in myocardial cells and thus has elevated risk for direct cellular toxicity by entry and replication (Centurión et al., 2021). The second proposed mechanism relates to the heightened release of pro-inflammatory cytokines through activation of the innate and adaptive immune system, often leading to a cytokine storm, which is a clinical entity, characterized by high and unrelenting fevers, often with temperatures >39.4°C (Centurión et al., 2021). Finally, the severity of these complications was further exacerbated in those patients with preexisting cardiovascular disease risk factors, such as hypertension, diabetes mellitus, and obesity (Sabatino et al., 2020).
Of the previously listed cardiac manifestations of COVID-19, several studies have identified arrhythmias as one of the more common presenting complications. One study found 17% of COVID patients presented with an arrhythmia while a systematic review showed that up to 20% of hospitalized COVID-19 patients developed an arrhythmia (Liao et al., 2020;Wang, Hu, et al., 2020).
Among the spectrum of cardiac arrhythmias and ECG changes, atrial tachyarrhythmias, atrioventricular conduction blocks, ST-T changes, and malignant arrhythmias have been highlighted as some of the more common manifestations Turagam et al., 2020;. More importantly, the development of arrhythmia during a hospitalization for COVID-19 confers an increased mortality risk (Mountantonakis et al., 2021;Turagam et al., 2020). The hypercytokinemic state of COVID-19's has been associated with deadly arrhythmias (Singh & Desai, 2020), though the exact mechanism is not fully understood. However, one such possible cause may be linked to underlying Brugada syndrome.
A current review of literature offers multiple case reports of the emergence of inducible type 1 Brugada ECG pattern in patients hospitalized with COVID-19; however, due to its rare incidence there are no studies dedicated to its appearance.

| Search strategy and selection criteria
The reporting of this systematic review followed the standards of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement (Page et al., 2021). Two researchers independently performed the literature search, extracted the data, and assessed for study quality. This study protocol was submitted to the PROSPERO registration as well.
We searched PubMed, Embase, and Scopus using "COVID", "Brugada", and "Coronavirus" as keywords. The following data were extracted from included studies: baseline demographics past medical history, clinical presentation, diagnostic studies performed, medications received and clinical outcome for the patient, including the insertion of a cardioverter defibrillator. All patients had Brugada pattern type 1 based on HRS expert consensus diagnostic criteria. A synopsis of the data is provided in Table 1 below.

| RE SULTS
Overall, 109 studies were captured in our initial search strategy and is illustrated in the recommended PRISMA flow diagram ( Figure 1).
After the screening process, 19 studies were identified. One study was excluded after full-text analysis as the patient had a known Brugada syndrome diagnosis.

| DISCUSS ION
The emergence and persistence of the COVID-19 pandemic demonstrates the importance of recognizing how this disease interacts with other medical conditions, and how this may change management.
However, in this systematic review, for those with only Brugada pattern on ECG, rather than Brugada Syndrome, the fever did not seem to have any proclivity toward an arrhythmic arrest and had a 72% resolution of ECG changes upon recovery. Additionally, for TA B L E 1 Summary of patients' clinical characteristics and course.  et al., 2013;Michowitz et al., 2018;Priori et al., 2013): increases in body temperature have been proven to cause sodium channel deactivation, and thus increased phase 2 re-entry ventricular arrhythmias and potentially sudden death in Brugada Syndrome (Antzelevitch & Brugada, 2002;Keller et al., 2005;Sorgente et al., 2020). At this point in time, there is no data regarding the direct effect of COVID-19 upon sodium channels that could lead to any physiologic effect upon those with Brugada Syndrome, nor medium-or long-term outcome data surrounding the two.

Study
COVID-19 has also been postulated to create ST elevation through microthrombi and myocarditis without obstructive coronary artery disease (Sorgente et al., 2020) in those who end up with an angiographically normal coronary angiography, as also demonstrated in our review of cases, though no studies have been dedicated to investigating this hypothesis yet. However, emerging data suggest the possibility of selective ion channel dysfunction in the setting of immunologic/inflammatory insult (Lazzerini et al., 2018), which may warrant further investigation specifically in the connection between the COVID-19 hypercytokinemic state and its effect on ion channels.
Despite data regarding the known effects of aggravating factors for Brugada-pattern ECG, the various forms and labels of Brugada classification may cause confusion with regards to management.
Thus, we propose the below algorithm to help guide management in patient's presenting with a new Brugada-ECG pattern to merge the Despite the limited data pool available, the baseline data do seem to reflect an approximate sample population based on current knowledge of Brugada Syndrome, with a known proclivity to male dominance (our measured 9:1 ratio) (Benito et al., 2008), and similar incident age of diagnosis (our measured 47 years, compared to average age of 41 years) (Priori et al., 2002).
F I G U R E 1 PRISMA flow diagram of included studies.

| CON CLUS ION
As the pandemic continues, there will be more patients with COVID-19-associated Brugada pattern, which will allow for further accuracy in characterization of such presentations.

AUTH O R CO NTR I B UTI O N S
All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.
Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in the Annals of Noninvasive Electrocardiology.

FU N D I N G I N FO R M ATI O N
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CO N FLI C T O F I NTE R E S T S TATE M E NT
All authors have no Conflict of Interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

E TH I C A L A PPROVA L
This research did not contain any studies involving animal or human participants, nor did it take place on any private or protected areas.
The declaration of Helsinki was adequately addressed and no specific permissions were required for corresponding locations.

R E FE R E N C E S
Adler, A., Topaz, G., Heller, K., Zeltser, D., Ohayon, T., Rozovski, U., Halkin, A., Rosso, R., Ben-Shachar, S., Antzelevitch, C., & Viskin, S. (2013). AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American college of cardiology/American heart association task force on clinical practice guidelines and the heart rhythm society: A report of the American college of cardiology/American heart association task force on clinical practice guidelines and the F I G U R E 2 A proposed treatment algorithm for patients presenting with Type 1 Brugada-pattern ECG. *Spontaneous Brugada pattern is described as a Type 1 Brugada ECG pattern that does not resolve with resolution of aggravating factors. ** Inducible Brugada pattern is described as a Type 1 Brugada ECG pattern that resolves with removal of aggravating factors.