Authors: Raquel Falcão de Freitas 1, Sofia Cardoso Torres 2, Francisco Javier Martín-Sánchez 3, Adrián Valls Carbó 3, Giuseppe Lauria 4, José Pedro L Nunes
. 2021 Nov;235:102872. doi: 10.1016/j.autneu.2021.102872. Epub 2021 Aug 27.
Abstract
Background
Syncope is not a common manifestation of COVID-19, but it may occur in this context and it can be the presenting symptom in some cases. Different mechanisms may explain the pathophysiology behind COVID-19 related syncope. In this report, we aimed to examine the current frequency and etiology of syncope in COVID-19.
Methods
A systematic review across PubMed, ISI Web of Knowledge and SCOPUS was performed, according to PRISMA guidelines, in order to identify all relevant articles regarding both COVID-19 and syncope.
Results
We identified 136 publications, of which 99 were excluded. The frequency of syncope and pre-syncope across the selected studies was 4.2% (604/14,437). Unexplained syncope was the most common type (87.9% of the episodes), followed by reflex syncope (7.8% of the cases). Orthostatic hypotension was responsible for 2.2% of the cases and syncope of presumable cardiac cause also accounted for 2.2% of cases. Arterial hypertension was present in 52.0% of syncope patients. The use of angiotensin receptor blockers or angiotensin converting enzyme inhibitors were not associated with an increased incidence of syncope (chi-square test 1.07, p 0.30), unlike the use of beta-blockers (chi-square test 12.48, p < 0.01).
Conclusion
Syncope, although not considered a typical symptom of COVID-19, can be associated with it, particularly in early stages. Different causes of syncope were seen in this context. A reevaluation of blood pressure in patients with COVID-19 is suggested, including reassessment of antihypertensive therapy, especially in the case of beta-blockers rterial hypertension
1. Introduction
The ongoing Coronavirus pandemic has proved to be a challenging setback to the health of the world population ever since its first cases were announced in the city of Wuhan, China, around December 2019. As of the 1st of July 2021, there have been a total of approximately 181 million confirmed cases of COVID-19 (Coronavirus disease 2019) worldwide and 3.9 million deaths, translating to a fatality rate of 2% (
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel betacoronavirus and COVID-19 is the infectious disease caused by this novel virus. Its spike protein (glycoprotein S) determines the specificity of the virus for epithelial cells of the respiratory tract (. It is composed of a receptor binding domain that recognizes the ACE-2 (type 2 angiotensin converting enzyme) receptor specifically, allowing the entrance of the virus into its target cells (
). The ACE-2 receptor can be found on the surface of epithelial cells in the lungs, intestines, kidneys and blood vest is currently known that, although the novel SARS-CoV-2 virus can lead to significant disease in the respiratory system, it can also negatively affect several other vital organ systems. Significant damage, namely, to the cardiovascular, nervous and hematopoietic systems has been outlined and an impact in hemostasis has also been thoroughly discussed as blood hypercoagulability is common among hospitalized COVID-19 patient). Regarding the cardiovascular manifestations, heart failure, thromboembolism, myocarditis, arrhythmias, pericarditis and acute coronary syndromes have been described in this contex). On the other hand, the most common neurological symptoms reported in COVID-19 patients have been smell and taste disturbances, headache, myalgia, and altered mental status (yncope is largely defined as a transient loss of consciousness due to cerebral hypoperfusion
). It is characterized by a rapid onset, short duration and spontaneous, complete rec
). Presyncope, on the other hand, is the state that resembles the prodrome of syncope (with all its signs and symptoms such as pallor, sweating, nausea, palpitations) without being followed by a loss of consciousness (In the light of a severe systemic disease, non-traumatic transient loss of consciousness can have distinct etiologies, varying from the benign reflex syncope and syncope due to orthostatic hypotension to the increasingly serious cardiac). Apart from unexplained syncope, these three main groups stem from different mechanisms and, therefore, may require specialized treatment. Consequently, an accurate diagnosis becomes imperative.
Recently, some case reports and case-series have emerged reporting syncope as a possible symptom of COVID-19, whether it had developed at the onset or during the course of the d). It is important to mention that some of these reports outline its occurrence days before the main respiratory symptoms, or even as an isolated p). If a valid relationship between COVID-19 and syncope is established, a number of patients could be isolated in a timely manner, minimizing the contagious phase.
In the present report, we aimed to systematically review the recent published literature that describes syncope or presyncope as a symptom of COVID-19, having it been observed in the days before or after the diagnosis. We aimed to calculate its frequency and divide it into each different type of syncope observed.
As a secondary aim of the review, the investigation of the relationship between syncope and use of angiotensin receptor inhibitor drugs (ACEi), angiotensin receptor blockers (ARBs) and/or beta-blockers in the context of COVID-19 was carried out. This seemed to be important to investigate since arterial hypertension is a common comorbidity among COVID-19 patien, and the use of standard anti-hypertensive agents could influence the incidence of this symptom.
2. Methods
2.1 Eligibility criteria
Regarding our population of interest, we were in the search for studies that simultaneously described COVID-19 and syncope or presyncope presented as a possible symptom of the acute infection or occuring in a post-acute COVID-19 setting. Articles were excluded if they described falls in the context of COVID-19 that were not stated to be of syncopal origin; episodes of syncope not temporally related with SARS-CoV-2 infection (for example, occurring throughout the year prior to the infection) and episodes of syncope with another possible underlying cause mentioned in the study as relevant apart from COVID-19. We included case-series, case-reports, cross-sectional studies with prospective data collection, retrospective analyses and letters published in 2020 or 2021 for which it was possible to extract an exact number of patients with COVID-19 exhibiting syncope/presyncope.
We did not restrict articles to witnessed syncope nor exclude articles that did not describe the specific comorbidities, clinical characteristics or evolution exhibited by the pre/syncope cohort. This was because our primary outcome measure was to quantify the number of COVID-19 related pre/syncopal episodes published in the literature thus far.
We considered articles written in English, Spanish, French, Italian, or Portuguese. Articles written in German, Hungarian or Mandarin were excluded (since the authors are not familiar with these languages).
2.2 Search strategy
A comprehensive literature search was carried out with the purpose of identifying all reported articles relating syncope to COVID-19, according to the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analys. This search was conducted on the databases Medline (PUBMED), ISI Web of Knowledge and SCOPUS.
The search query, which took place on the 9th of March 2021, included the following MeSH terms and keywords: “(“COVID-19” OR “COVID 19” OR “SARS-COV-2” OR “coronavirus” OR “2019 novel coronavirus”) AND (“syncope” OR “presyncope” OR “syncopal”). Additionally, we scanned the list of references from the included studies in this analysis and of systematic reviews pertaining to neurological symptoms in the context of COVID-19.
2.3 Selection process
Two investigators independently assessed whether the studies addressed the topic in question and if all the inclusion/exclusion criteria were met. Initially, this was done according to the “screening phase”, where only the title and the abstract were analyzed. After this process, 52 articles were considered eligible. This was followed by the “inclusion phase”, where the integral text was fully evaluated. Any doubtful situation was solved by consensus between the authors, after which, concerning study eligibility, 100% agreement between authors was seen in each step of the study assessment.
2.4 Data collection process and data items
From the selected articles, two authors worked independently to retrieve the following data: location, number of patients (with and without pre/syncope), age, sex and ethnicity when available, comorbidities (from patients with and without pre/syncope), chronic medications the patients were on regarding treatment of arterial hypertension and the description of the clinical course, including relevant laboratory findings and any auxiliary exams performed, such as computerized tomography scans and cardiac magnetic resonances. Any doubtful situation was solved by consensus between the authors.
2.5 Study quality assessment
Quality of the observational cohorts and cross-sectional studies and case-series was evaluated using the National Heart, Lung and Blood Institute study quality assessment t
) and is presented in Table 1, Table 2. Any disagreements between the two main reviewers were discussed with a third evaluator.
Table 1Quality assessment tool for observational cohort and cross-sectional studies. Y – Yes; NR – Not Reported; NA – Not Applicable.
| Oates et al. | Chen et al. | Canetta et al. | Radmanesh et al. | Chachkhiani et al. | García-Moncó et al. | Xiong et al. | Romero-Sánchez et al. | Chuang et al. | Mizrahi et al | Martin-Sanchez et al. | Travi et al. | Chou et al. | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Was the research question or OBJECTIVE in this paper clearly stated? | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Was the study population clearly specified and defined? | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Was the participation rate of eligible persons at least 50%? | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Was a sample size justification, power description, or variance and effect estimates provided? | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Was the exposure(s) assessed more than once over time? | NR | NR | NR | NR | NR | NR | NR | NR | NR | Y | Y | NR | NR |
| Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Were the outcome assessors blinded to the exposure status of participants? | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Was loss to follow-up after baseline 20% or less? | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? | NR | NR | NR | NR | Y | NR | NR | NR | NR | Y | Y | Y | Y |
| Quality rating | Good | Fair | Good | Good | Good | Fair | Fair | Fair | Fair | Good | Good | Good | Good |
Table 2Quality assessment tool for case-series studies. Y – Yes; NR – Not reported; NA – Not applicable.
| Ebrille et al. | Birlutiu et al. | Argenziano et al. | Espinoza et al. | Gonfiotti et al. | |
|---|---|---|---|---|---|
| Was the study question or objective clearly stated? | Y | Y | Y | Y | Y |
| Was the study population clearly and fully described, including a case definition? | Y | Y | Y | Y | Y |
| Were the cases consecutive? | NR | NR | Y | NR | NR |
| Were the subjects comparable? | Y | Y | Y | Y | Y |
| Was the intervention clearly described? | Y | Y | Y | Y | Y |
| Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants? | Y | Y | Y | Y | Y |
| Was the length of follow-up adequate? | NR | Y | Y | NR | Y |
| Were the statistical methods well-described? | NA | NA | Y | NA | NA |
| Were the results well-described? | Y | Y | Y | Y | Y |
| Quality Rating | Fair | Good | Good | Fair | Good |
2.6 Outcome measures
The primary outcome measures assessed were the occurrence of syncope or presyncope either in the days prior or subsequent to a COVID-19 diagnosis and its relative frequency, divided into each type of syncope experienced.
We also assessed the association between the usage of ARBs or ACEi and beta blockers with the occurence of syncope as well as the association of syncope with mortality.
2.7 Effect measures
Concerning these latter data, a chi-square test was used, with a level of significance of 0.05. Statistical analysis was done using Stata, version 17.0, StataCorp, Texas, USA.
3. Results
3.1 Study selection
With the use of our keywords, we obtained 51 results from Medline (PUBMED), 28 from ISI Web of Knowledge, 50 from SCOPUS and 7 from scanning the references of the selected articles and adequate systematic reviews (Fig. 1) – with a total number of 37 articles selected for the purpose of the present study (Fig. 1). The complete set of selected studies is presented in Table 3. SARS-CoV-2 infection was diagnosed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) or a chest X-ray or CT scan showing the characteristic bilateral interstitial pneumonia of COVID-19 in all cases, except in the report by Romero-Sánchez et al., in which a minority of patients were diagnosed by means of serological testing
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Table 3Summary of included articles. Pts – patients; ARBs – angiotensin receptor blockers; PPM – permanent pacemaker implantation; ECG – electrocardiogram; ICD – implantable cardioverter-defibrillator; AV – atrioventricular; ACE-I – angiotensin-converting-enzyme inhibitors; CMR – cardiac magnetic resonance; CSF – cerebrospinal fluid; CT -computed tomography; MRI – magnetic resonance imaging; RT-PCR – real time polymerase chain reaction; CRP – C-Reactive Protein, NT-proBNP – N-terminal type B natriuretic peptide; POTS – Postural Orthostatic Tachycardia Syndrome; BP – blood pressure.