Review Cerebrovascular disease is associated with an increased disease severity in patients with Coronavirus Disease 2019 (COVID-19): A pooled analysis of published literature International Journal of Stroke 0(0) 1–5 ! 2020 World Stroke Organization Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1747493020921664 journals.sagepub.com/home/wso Gaurav Aggarwal1 , Giuseppe Lippi2,* and Brandon Michael Henry3,* Abstract Introduction: There is an urgent need to identify patients at high risk during the ongoing coronavirus disease (COVID19) pandemic. Whether a history of stroke is associated with increased severity of disease or mortality is unknown. Method: We pooled studies from published literature to assess the association of a history of stroke with outcomes in patients with COVID-19. Results: A pooled analysis of 4 studies showed a 2.5-fold increase in odds of severe COVID-19. While a trend was observed, there was no statistically significant association of stroke with mortality in patients with COVID-19 infection. Discussion: Our findings are limited by a small number of studies and sample size. Conclusion: There is a 2.5-fold increase in odds of severe COVID-19 illness with a history of cerebrovascular disease. Keywords Cerebrovascular disease, COVID-19, Coronavirus Received: 29 March 2020; accepted: 5 April 2020 Introduction Coronavirus Disease 2019 (COVID-19) infection is an ongoing pandemic, characterized by high morbidity and mortality. There is an urgent need to identify clinical and biological predictors of severity and mortality associated with COVID-19 infection for judicious use of limited resources. Data are scant about the risk factors and therapies for COVID-19, and most of the predictions are currently based on prior experience with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). A history of cerebrovascular disease in patients with SARS and MERS was shown to be associated with worse outcomes and increased healthcare resource utilization.1,2 Moreover, cerebrovascular disease was found to be associated with increased 90-day mortality in community acquired pneumonia.3 Whether cerebrovascular disease predicts outcomes in patients with COVID-19 is unknown. Few studies have been published with varying results, further limited by the small sample size number of patients with cerebrovascular disease. As such, in this article, we aim to carry out a pooled analysis of current studies. Methods We conducted PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials searches, using 1 Department of Medicine, Jersey City Medical Center, Jersey City, USA Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy 3 Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA 2 *These authors share senior authorship in this work. Corresponding author: Brandon Michael Henry, Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Email: Brandon.henry@cchmc.org International Journal of Stroke, 0(0) International Journal of Stroke, 0(0) 1 (1.2%) 54% 52 (26–78) a Age data presented as median (IQR) or mean (SD). MV: mechanical ventilation; ICU: intensive care unit; NR: not reported. 82 (58.6%) 2 (3.4%) 43% 64 (25–87) 58 (41.4%) 140 Zhang et al.10 Respiratory distress/ insufficiency 0 (0%) 30% 51.9 (12.9) 20 (38.5%) 7 (22%) 34% 64.6 (11.2) 32 (61.5%) 52 Yang et al.9 Death 1 (1%) 48% 51 (37–62) 102 (73.9%) 6 (16.7%) 39% 66 (57–78) 36 (26.1%) 138 Wang et al.8 Clinical variables, MV, death 5 (6%) 35% 50 (44–81) 82 (54.6%) 7 (10%) 28% 67 (15–81) 68 (45.3%) 150 Ruan et al.7 Death 51.8% 53 (41.25–62) 166 (36.7%) 8 (2.8%) 45.8% 61 (51–69) 286 (63.3%) 452 Qin et al.6 Respiratory distress/ insufficiency 42% 45 (34–57) 926 (84.3%) 4 (2.3%) 42% 52 (40–65) 173 (15.7%) 1099 Guan et al.5 Admission to ICU, MV, Death Age (yrs)a n (%) Age (yrs)a n (%) Outcomes Sample size An initial search included as many as 1683 publications. After removing duplicated or overlapping publications and excluding reviews and editorials, a total number of 21 documents could be initially identified (Supplementary Table 1). Fifteen studies were excluded because they did not provide the rate of cerebrovascular disease. One additional study was identified from the reference list of included articles. A total of seven articles were hence selected. The article by Mo et al. was excluded as a majority of patients in both groups had severe disease on admission.4 Thus, the final pooled analysis included six studies.5–10 Four studies compared cerebrovascular disease in severe vs. non-severe cases, with a sample of 1829 confirmed COVID-19 patients (553, 30.2% being severe cases). A total number of 49 patients (2.6%) were classified as having a history of cerebrovascular disease or stroke.5,6,8,10 Two studies with 202 patients (100, 49.5% being non-survivors) Table 1. Characteristics of included studies Results Study Severe patients/non-survivors Women (%) Cerebrovascular disease n (%) Non-severe patients/survivors Women (%) Cerebrovascular disease n (%) the terms ‘‘Coronavirus’’ OR ‘‘COVID-19’’ AND ‘‘stroke’’, OR ‘‘cerebrovascular disease’’ and their various combinations, until 31 March 2020. We then searched major journals reporting articles about COVID-19 infection for additional studies. We also hand-searched the bibliography of original studies and review articles to find other potentially eligible studies. Studies that fulfilled the following criteria were included: (1) studies reporting history of cerebrovascular disease in patients with COVID-19 and (2) reporting outcomes of interest. Studies were independently assessed for eligibility and bias risk by two authors (GA and BMH). Data were then extracted by the same authors. Disagreements were resolved by consensus. A clinically validated definition of ‘‘severe disease’’ (i.e. patients requiring mechanical ventilation, vital life support, intensive care unit admission, death) was required. As the number of studies was limited, no evaluation of bias or publication bias was performed. A pooled analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of cerebrovascular disease in COVID-19 patients with or without severe disease and in non-survivors versus survivors. The statistical analysis was carried out using MetaXL, software Version 5.3 (EpiGear International Pty Ltd, Sunrise Beach, Australia), with inverse variance model. A leave-one-out sensitivity analysis was performed to probe sources of heterogeneity. Moreover, to evaluate the impact of mean age among severe patients on the association of cerebrovascular disease with severity of COVID-19, a random effects meta-regression using log OR was employed. The study was performed in compliance with the Declaration of Helsinki and local legislation. 3 (1.8%) International Journal of Stroke 0(0) 11 (1.2%) 2 Aggarwal et al. 3 Figure 1. Results of meta-analysis showing association of cerebrovascular disease with severity of disease and mortality in patients with COVID-1. Figure 2. Meta-regression plot for impact of age on association of cerebrovascular disease on disease severity in COVID-19. compared the rate of cerebrovascular disease in COVID-19 patients who did not survive vs. survived, with 19 (9.4%) classified as non-survivors.7,9 Essential characteristics of the included studies are listed in Table 1. The results of pooled analysis are presented in Figure 1. In the four studies on severity, only one study by Wang et al. individually had a significant OR for cerebrovascular disease and COVID-19 severity.8 However, in pooled analysis, cerebrovascular International Journal of Stroke, 0(0) 4 disease was found to be associated with a statistically significant increased risk of a severe form of COVID-19 (OR: 2.55 (95% CI: 1.18 to 5.51), I2 ¼ 29%, Cochran’s Q, p ¼ 0.24). Although heterogeneity was low, a leaveone-out sensitivity analysis was still performed. Only excluding the study by Wang et al. significantly altered the results of the analysis and appeared to be the source of heterogeneity (OR: 1.88 (95% CI: 0.828 to 4.29), I2 ¼ 0%, Cochran’s Q, p ¼ 0.90).8 In the limited pooled analysis of mortality studies, a non-significant trend was found when evaluating association of cerebrovascular disease and enhanced risk of mortality in COVID-19 patients (OR: 2.33 (95% CI: 0.77 to 7.04), I2 ¼ 30%, Cochran’s Q, p ¼ 0.23). In the meta-regression analysis, a non-significant trend was observed between mean age of patients with severe COVID-19 and log odds of cerebrovascular disease and COVID-19 severity (correlation coefficient 0.1582, 95% CI: 0.0575 to 0.3740, p ¼ 0.15) (Figure 2). Limited studies prevented a meta-regression for mortality. Discussion In our pooled analysis of published studies to date, cerebrovascular disease was found to be associated with a 2.5-fold increased odds of severe disease in patients with COVID-19 infection. There was also a non-significant trend with cerebrovascular disease and odds of mortality in COVID-19 patients. Studies in patients with SARS have previously found higher risk of critical illness and multiorgan dysfunction in patients with cerebrovascular disease.11 Cerebrovascular disease is associated with high morbidity, mortality, and financial burden in the United States.12 In the current COVID-19 pandemic situation, healthcare resources are a limitation, so that predicting which patients are at higher risk could be helpful in optimizing allocation of human and technical resources.13 The main limitation of this pooled analysis is the limited number of studies with small sample size. However, at this stage with the ongoing pandemic, our findings may provide early insights into building models for risk stratification and help in judicious use of limited healthcare resources. Due to the small number of studies, we did not use any exclusion criteria and we also did not perform analysis for risk of bias. Sensitivity analysis was performed which showed the results for disease severity were mainly driven by the study by Wang et al. Age may be a confounding variable in our analysis. We did perform a meta-regression to assess the impact of mean age of severe patients on association of cerebrovascular disease with severity of International Journal of Stroke, 0(0) International Journal of Stroke 0(0) COVID-19, which suggested the association is more pronounced in older individuals. However, there were not enough studies to perform a meta-regression on the mortality endpoint. Hence, studies with larger sample size and number of events are needed to confirm our findings. Nonetheless, we encourage physicians to advise patients with a history of cerebrovascular disorders to take enhanced precautions during the ongoing pandemic. Conclusion In our pooled analysis, cerebrovascular disease was found to be associated with a 2.5-fold increased disease severity in patients with COVID-19. However, larger studies are needed to confirm these findings. Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD Gaurav Aggarwal https://orcid.org/0000-0002-8180-9287 Supplemental material Supplemental material for this article is available online. References 1. Chen CY, Lee CH, Liu CY, Wang JH, Wang LM and Perng RP. Clinical features and outcomes of severe acute respiratory syndrome and predictive factors for acute respiratory distress syndrome. J Chin Med Assoc 2005; 68: 4–10. 2. Lee SY, Khang YH and Lim HK. Impact of the 2015 Middle East respiratory syndrome outbreak on emergency care utilization and mortality in South Korea. Yonsei Med J 2019; 60: 796–803. 3. Mandal P, Chalmers JD, Choudhury G, Akram AR and Hill AT. Vascular complications are associated with poor outcome in community-acquired pneumonia. QJM 2011; 104: 489–495. 4. Mo P, Xing Y, Xiao Y, et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin Infect Dis 2020. Epub ahead of print. 16 March 2020. DOI: 10.1093/cid/ciaa270. 5. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020. Aggarwal et al. 6. 7. 8. 9. Epub ahead of print 28 February 2020. DOI: 10.1056/ NEJMoa2002032. Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020. Epub ahead of print. 12 March 2020. DOI: 10.1093/cid/ciaa248. Ruan Q, Yang K, Wang W, Jiang L and Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020. Epub ahead of print. 3 March 2020. DOI: 10.1007/s00134-020-05991-x. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan, China. JAMA 2020. Epub ahead of print. 7 February 2020. DOI: 10.1001/ jama.2020.1585. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 5 10. 11. 12. 13. observational study. Lancet Respir Med 2020. Epub ahead of print. 24 February 2020. DOI: 10.1016/S22132600(20)30079-5. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy 2020. Epub ahead of print. 19 February 2020. DOI: 10.1111/all.14238. Hu SS, Yang YJ, Zhu ML, et al. Effects of underlying cerebrocardiovascular diseases on the incidence of critical conditions and multiple organs dysfunction syndrome in severe acute respiratory syndrome cases. Zhonghua Yi Xue Za Zhi 2004; 84: 1257–1259. Virani SS, Alonso A, Benjamin EJ, et al. 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