key: cord-0890977-ucfbqwx2
authors: Pranata, Raymond; Huang, Ian; Lim, Michael Anthonius; Wahjoepramono, Prof. Eka Julianta; July, Julius
title: Impact of Cerebrovascular and Cardiovascular Diseases on Mortality and Severity of COVID-19 – Systematic Review, Meta-analysis, and Meta-regression
date: 2020-05-14
journal: J Stroke Cerebrovasc Dis
DOI: 10.1016/j.jstrokecerebrovasdis.2020.104949
sha: 100f1780bc3a35d6a6c9a43de480eebe13ae533b
doc_id: 890977
cord_uid: ucfbqwx2

Background We conducted this systematic review and meta-analysis to evaluate the latest evidence on the association between cerebrovascular, cardiovascular disease, and poor outcome in patients with Coronavirus Disease 2019 (COVID-19) pneumonia. Methods A comprehensive systematic literature search was performed using PubMed, SCOPUS, EuropePMC, and Cochrane Central Database. The outcome of interest was composite poor outcome that comprised of mortality and severe COVID-19. Results A total of 4448 patients were obtained from 16 studies. Cerebrovascular disease was associated with increased poor composite outcome (RR 2.04 [1.43, 2.91], p<0.001; I(2): 77%). Subgroup analysis revealed that cerebrovascular disease was associated with mortality (RR 2.38 [1.92, 2.96], p<0.001; I(2): 0%) and was borderline significant for severe COVID-19 (RR 1.88 [1.00, 3.51], p=0.05; I(2): 87%). Cardiovascular disease was associated with increased composite poor outcome (RR 2.23 [1.71, 2.91], p<0.001; I(2): 60%), and its mortality (RR 2.25 [1.53, 3.29], p<0.001; I(2): 33%) and severe COVID-19 (RR 2.25 [1.51, 3.36], p<0.001; I(2): 76%) subgroup. Meta-regression demonstrate that the association was not influenced by gender, age, hypertension, diabetes, and respiratory comorbidities. The association between cerebrovascular disease and poor outcome was not affected by cardiovascular diseases and vice versa. Conclusion Cerebrovascular and cardiovascular diseases were associated with increased risk for poor outcome in COVID-19.

At the time of writing this paper, Coronavirus Disease 2019 (COVID-19) was announced as a global pandemic which has infected over 3.3 million people and cause more than 238.000 deaths, 1 these numbers are likely to increase by the time of publication. Even though most of the infected individuals have mild or no symptoms, some of them exhibit more serious complications, including severe pneumonia, acute respiratory distress syndrome, and multiorgan failure. Clinical markers can be valuable for efficient allocation of resources during a pandemic.

Initial report of COVID-19 cases in China had identified that cerebrovascular and cardiovascular disease were prevalent comorbidities among COVID-19 patients. 2 Further study had shown that both cerebrovascular and cardiovascular were associated with a higher incidence of severe COVID-19, which needs to be monitored in the intensive care unit (ICU) care. 3 However, due to the sample size, the report did not reach adequate statistical power for definite conclusion. Nevertheless, these findings lead us to postulate that cerebrovascular and cardiovascular comorbidities might independently be associated with severity of COVID-19. In this systematic review and meta-analysis, we aimed to evaluate the latest evidence on the association between cerebrovascular, cardiovascular disease, and poor outcome in patients with COVID-19 pneumonia.

We carried out a comprehensive systematic literature search from PubMed, SCOPUS, EuropePMC, and Cochrane Central Database with search terms being 1) "COVID-19" OR "SARS-CoV-2" AND "characteristics", 2) "COVID-19" OR "SARS-CoV-2" AND "cerebrovascular", 3) "COVID-19" OR "SARS-CoV-2" AND "cardiovascular". Two authors independently performed initial search and screening for relevant articles through title/abstract. Discrepancies were then resolved by discussion and discretion of the third author. After removal of duplicates, the potential full-texts were then evaluated by applying inclusion and exclusion criteria. The literature search was finalized on April 10 th , 2020.

We included every studies reporting adult patients with COVID-19 that provide information on cerebrovascular or cardiovascular diseases and mortality or clinically validated definition of severe COVID-19. 4 We excluded review articles, editorials, correspondence, case reports, case series, pediatric population, articles in non-English language.

Two independent authors carried out data extraction from the studies. We used standardized forms which include author, year, study design, age, gender, cerebrovascular diseases, cardiovascular diseases, hypertension, diabetes mellitus, mortality, and severe COVID-19 were used.

The definition of cerebrovascular disease used in this meta-analysis was history (comorbidity) of cerebrovascular disease and its synonyms such as stroke and brain infarction. The definition of cardiovascular disease in this meta-analysis was history (comorbidity) of cardiovascular or cardiac disease. Hypertension/coronary heart disease/cardiomyopathy in specific terms was excluded because the diseases often overlap and potentially result in overestimation of case.

The outcome of interest was composite poor outcome that consisted of mortality and severe COVID-19. Severe COVID-19 was defined as patients who had any of the following features at the time of, or after, admission: (1) respiratory distress (≥30 breaths per min); (2) oxygen saturation at rest ≤93%; (3) ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (fiO2) ≤300 mmHg; or (4) critical complication (respiratory failure, septic shock, and or multiple organ dysfunction/failure). 4

The meta-analysis of studies was performed using Review Manager 5.3 (Cochrane Collaboration) and Stata version 16. We used Mantel-Haenszel formula for calculating dichotomous variables to find risk ratios (RRs) which are reported along with its 95% confidence intervals (CIs). Random-effects model was used for the calculation regardless of heterogeneity. All P-values in this study were two-tailed, and the statistical significance was set at <0.05. A restricted-maximum likelihood random effects meta-regression was performed for age, gender, cardiovascular disease/cerebrovascular disease, hypertension, and diabetes mellitus. Regression-based Harbord's test was implemented to evaluate the small-study effect. Inverted funnel-plot analysis was done to evaluate risk of publication bias.

We had a total of 1082 records, and 537 remained following the omission of duplicates.

After screening the title/abstracts, 490 records were excluded. After evaluating 47 full-text for eligibility, we decided to exclude 31 full-text articles because 1) no outcome for cardiovascular disease/cardiac disease or cerebrovascular disease (n=25), 2) specific groups (i.e., myocarditis, cardiac injury) (n=6). 16 studies were included in the qualitative synthesis and meta-analysis. [ Figure 1 ]. In total, there were 4448 patients from 16 studies. 5, 6, [15] [16] [17] [18] [19] [20] [7] [8] [9] [10] [11] [12] [13] [14] The characteristics of the included studies are displayed in Table 1 . The data for the table was presented in grouping of poor outcome (+) vs poor outcome (-). The forest plot was presented in grouping of cerebrovascular disease (+) vs cerebrovascular disease (-) and cardiovascular disease (+) vs cardiovascular disease (-). 

Meta-regression indicated that the association between cerebrovascular disease and composite poor outcome was not influenced by gender (p=0.714), age (p=0.872), hypertension (p=0.575), cardiovascular diseases (p=0.607), diabetes (p=0.356) and respiratory comorbidities (p=0.981).

Meta-regression indicated that the association between cardiovascular disease and composite poor outcome was not influenced by gender (p=0.722), age (p=0.910), hypertension (p=0.218), cerebrovascular diseases (p=0.502), diabetes (p=0.062), and respiratory comorbidities (p=0.703).

Inverted funnel-plot demonstrate a qualitatively asymmetrical shape for both cerebrovascular disease and cardiovascular disease on composite poor outcome.

Regression-based Harbord's test was demonstrate no indication of small-study effects for cerebrovascular disease (p=0.579) and cardiovascular disease (p=0.116) on composite poor outcome.

Cerebrovascular and cardiovascular diseases were associated with increased poor outcome in COVID-19. The association was not influenced by gender, age, hypertension, diabetes, and respiratory comorbidities. The association between cerebrovascular disease and poor outcome in COVID-19 was not affected by cardiovascular diseases and vice versa.

The presence of underlying diseases such as cardiac and cerebrovascular pathologies may increase the incidence and severity of infectious diseases, this also applies to COVID-19 due to its pathomechanism. 21, 22 Acute respiratory infections, including viral and bacterial etiologies, are well-recognized triggers of cardiovascular events; hence it is plausible that COVID-19 disease may either induce new cardiac pathologies and/or aggravate existing cardiovascular diseases. 21, 23, 24 Angiotensin-converting enzyme 2 (ACE2) is a type 1 transmembrane metalloenzyme and carboxypeptidase that abundantly presented in cardiac epithelial cells as well as respiratory, kidney and intestinal tissue. The aforementioned enzyme plays an important role on the interaction between cardiovascular diseases and COVID-19. ACE2 cleaves angiotensin II into angiotensin 1-7, thus exerting more anti-inflammatory and antioxidant actions than inflammatory roles. 25, 26 This enzyme might be embraced by the virus after the activation of viral surface spike (S) protein by the transmembrane protease serine 2 (TMPRSS2). 27 One of the possible mechanisms that mediates cardiovascular disease and higher severity of COVID-19 is through ACE2 pathway. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are commonly used in individuals with cardiovascular diseases. These drugs upregulate ACE2 expression which consequently facilitates COVID entry into pneumocytes and further cause exarcebation/decompensation of the underlying disease. 28 The virus downregulates ACE2 expression, limiting its organoprotective effects, and consequently causes renin-angiotensin-aldosterone system (RAAS) dysfunction. 25, 29 Unfortunately, the included studies did not provide information regarding the use of ACEI/ARB, thus the relationship remains inconclusive. Nevertheless, recent evidences demonstrated that cardiac damage might be due to combination of direct damage and indirect damage through cytokine storm; additionally, elevation of troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been associated with increased mortality. 30, 31 The underlying mechanism of increased severity of COVID-19 in patients with cerebrovascular disease remains unclear. This topic is a matter of interest. One of the plausible explanation is that both cerebrovascular and cardiovascular diseases share the same risk factors and often overlapped, hypertension, atrial fibrillation, chronic kidney diseases, and diabetes may increase the risk for various cardio-cerebrovascular diseases.

Factors such as diabetes itself has also been shown to increase mortality and severity of COVID-19. 22 ACEI/ARB is often used for patients with hypertension and prior stroke, hence, interplay between these mechanisms may partially explain the association. 32 Nevertheless, the presence of the hypertension, cardiovascular diseases, and diabetes did not affect the association between cerebrovascular diseases and poor outcome. However, it should be noted that meta-regression itself has limitation for exploring the association between variables and larger cohorts might be needed. Aside from the indirect association, theoretically, presence of brain medullary cardiorespiratory or autonomic nervous system dysfunction potentially cause blood pressure and respiratory dysfunction which promotes the risk of contracting opportunistic infections (viral and bacterial). 33 Cholinergic Pathway was shown to suppresses pulmonary innate immunity, increasing the risk for bacterial pneumonia in post-stroke patients. 34 Another possible hypothesis for underlying cerebrovascular disease in increasing the risk for poor outcome in COVID-19 may be due to the relatively immobile in post-stroke patients which will increase the risk for hypercoagulable state that culminates in thrombus formation. Severe SARS-CoV-2 infection itself could induce dysfunctional haemostatic system leading to a hypercoagulable state, a condition which we commonly encounter in sepsis. 35, 36 Furthermore, a recent evidence of lung pathology in critically-ill COVID-19 patients has shown occlusion and micro-thrombosis formation in pulmonary blood vessels which would suggest pulmonary embolism might have a role in increasing the risk for poor outcome. 37 Unfortunately, all the included studies did not specify any functional and motoric status among patients with cerebrovascular disease, thus any conclusion regarding this hypothesis could not be proven nor be refuted.

Furthermore, emerging evidence demonstrate extra-pulmonary invasion including central nervous system, causing substantial neuronal damage. 38 Neuroinvasion is one of the possible traits of COVID-19 because of the similarities between SARS-CoV and SARS-CoV-2.

The potential for neuroinvasion have been shown in human coronaviruses (OC-43, 229E, MERS, and SARS) and in several animal coronaviruses. 39 However, central nervous system normally expressed very low concentrations of ACE2 or dipeptidyl peptidase 4 (DPP4), which is the receptor for SARS-CoV and MERS-CoV entrance. 40 Possible routes for nervous system involvement after COVID-19 infection are direct invasion through blood circulation or neuronal pathway, hypoxic injury, immune system damage, ACE2 and other routes such as the lack of major histocompatibility complex (MHC) antigens in nerve cells. It is currently thought that SARS-CoV-2, together with host immune mechanisms, can turn these infections into persistent diseases with neurological complications, like viral encephalitis, infectious toxic encephalopathy and acute cerebrovascular disease. 41 A single-center observation showed that in 221 COVID-19 patients, 5% developed acute ischemic stroke, 0.5%, developed cerebral venous sinus thrombosis, and 0.5% cerebral hemorrhage; the incident was higher in older patients with risk factors. 42 The authors also stated that an increased inflammatory response and hypercoagulable state was found in patients that developed cerebrovascular events. It has been demonstrated that the risk for poor outcome was higher in patients with prolonged prothrombin time, international normalized ratio, thrombin time, and d-dimer which indicates coagulopathy that predispose patients to thrombotic events. 43 Previously, influenza has been shown to increase the risk of stroke. 46 These complications can be more severe in the presence of compromised cerebral vasculature. Cerebrovascular diseases often coexist with cardiovascular diseases and their association with poor outcome might be influenced by the latter. Nevertheless, meta-regression demonstrated that the association was not affected by the presence of cardiovascular disease.

This meta-analysis showed that cerebrovascular and cardiovascular diseases were important risk factors for mortality and severity of COVID-19. Physicians should also be alerted that the risks of opportunistic and bacterial infections are higher in patients with cerebrovascular diseases. We encourage prognostic research to include cerebrovascular and cardiovascular as a component of prognostic models.

Limitation of this systematic review and meta-analysis is that a considerable amount of included articles were preprints. Most of the studies originated from China and were retrospective in design. Whether the association is causal cannot be established, further prospective cohort studies dedicated to analyze this matter with adjustment to confounders are needed. The risk of publication bias is high, as shown by the asymmetrical inverted funnel plot. Information regarding the use of chronic medications such as ACEI/ARB were lacking. The included studies only investigate cerebrovascular disease as comorbidity; recent evidences showed that it may be precipitated by COVID-19, we encouraged future studies to investigate this matter. The broad category of cerebrovascular disease did not differentiate between intracranial hemorrhage, ischemic stroke, and SAH. The location of the insult was not differentiated, as certain locations of cerebrovascular damage have greater associations with autonomic dysfunction which possibly link increase mortality and COVID.

Cerebrovascular and cardiovascular diseases were associated with increased risk for poor outcome in COVID-19. We encouraged future studies to investigate this matter with a more detailed cerebrovascular disease classification and adjust the analysis to confounders. 

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