key: cord-0960502-pl8357m9
authors: Patel, Urvish; Malik, Preeti; Mehta, Deep; Rajput, Priyanka; Shrivastava, Mashu; Naveed, Madiha; Urhoghide, Eseosa; Martin, Mehwish; Somi, Shamima; Jaiswal, Richa; Patel, Achint; Israni, Avantika; Singh, Jagmeet; Kichloo, Asim; Shah, Shamik; Lunagariya, Abhishek
title: Outcomes of COVID-19 complications and their possibilities as potential triggers of stroke
date: 2021-04-08
journal: J Stroke Cerebrovasc Dis
DOI: 10.1016/j.jstrokecerebrovasdis.2021.105805
sha: 88862f5b2b3576cb3d5df5b4fc52ba85ed0a446e
doc_id: 960502
cord_uid: pl8357m9

INTRODUCTION: There is limited literature on coronavirus disease 2019 (COVID -19) complications such as thromboembolism, cardiac complications etc. as possible trigger for stroke. Hence, we aim to evaluate the prevalence and outcomes of COVID-19 related cardiovascular complications and secondary infection and their possibility as potential triggers for the stroke. METHODS: Data from observational studies describing the complications [acute cardiac injury (ACI), cardiac arrhythmias (CA), disseminated intravascular coagulation (DIC), septic shock, secondary infection] and outcomes of COVID‐19 hospitalized patients from December 1, 2019 to June 30, 2020, were extracted following PRISMA guidelines. Adverse outcomes defined as intensive care units, oxygen saturation less than 90%, invasive mechanical ventilation, severe disease, and in‐hospital mortality. The odds ratio and 95% confidence interval were obtained, and forest plots were created using random‐effects models. A short review of these complications as triggers of stroke was conducted. RESULTS: 16 studies with 3480 confirmed COVID-19 patients, prevalence of ACI [38%vs5.9%], CA [26%vs5.3%], DIC [4%vs0.74%], septic shock [18%vs0.36%], and infection [30%vs12.5%] was higher among patients with poor outcomes. In meta-analysis, ACI [aOR:9.93(95%CI:3.95–25.00], CA [7.52(3.29–17.18)], DIC [7.36(1.24–43.73)], septic shock [30.12(7.56–120.10)], and infection [10.41(4.47–24.27)] had higher odds of adverse outcomes. Patients hospitalized with acute ischemic stroke and intracerebral hemorrhage, had complications like pulmonary embolism, venous thromboembolism, DIC, etc. and had poor outcomes CONCLUSION: The complications like acute cardiac injury, cardiac arrhythmias, DIC, septic shock, and secondary infection had poor outcomes. Patients with stroke were having history of these complications. Long term monitoring is required in such patients to prevent stroke and mitigate adverse outcomes.

The coronavirus disease 2019 (COVID -19) has been a pandemic like no other seen in our times. It has impacted the entire globe affecting more than 180 countries with 81.9 million cases and 1.7 million deaths as of December 29, 2020 (1) . Unlike other virus-related spread, COVID-19 since its early days is known to have a high infection rate as well as high mortality, which in turn has resulted in such a devastating impact across the world. The mortality rates among hospitalized patients with COVID-19 infection without stroke range from 22% to 45% (2,3), but the mortality was very high (38%) in stroke patients with COVID-19 infections (4) . It has inflicted significant personal, social as well as economic impact. SARS-CoV-2 is known to mainly affect the respiratory system. However, the emerging literature has reported its effect on multiple systems triggering cascades of conditions leading to hypercoagulable state, thromboembolism, septic shock, cardiac shock, multiorgan failure and even death (5) .

Cardiovascular disease (CVD) is the leading global cause of death, accounting for more than 17.3 million deaths in 2013, and the toll might reach 23.6 million by 2030 (6, 7) . Cerebrovascular disease (CeVD) remains one of the top causes of mortality and morbidity across the world (6) . Patients with CeVD and CVD usually have multiple deficits requiring prolonged hospitalizations and care. This in turn is likely to increase their exposure to COVID-19 in hospitals. COVID-19 patients are noted to have higher prevalence of comorbidities including CeVD and CVD, however pathophysiology contributing to such comorbidities and associated outcomes of such patients are unknown (8) (9) (10) .

Furthermore, the immune response, which is activated in response to viral infection, is believed to be causing widespread activation of coagulation cascades to variable extent, leading to disseminated intravascular coagulation (DIC). DIC is known to cause both thrombo-embolism as well as bleeding secondary to consumption of coagulation factors (11) . This can lead to CeVD (both ischemic as well as hemorrhagic) and CVD, along with affecting multiple organs. Such immunological and systemic cascades were noted in prior viral pandemics such as severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East respiratory syndrome-coronavirus (MERS-CoV) to various extent affecting different organ systems. Vigorous activation of coagulation cascades may explain COVID-19 related complications.

Moreover, CVD on its own remains one of the major contributors to cascades leading to embolic CeVD.

Multiple cardiovascular conditions such as cardiac shock, myocardial injury, cardiac arrhythmias; along with DIC lead to clot formation via various pathophysiology; and results in CeVD whenever that clot propagates to the brain.

A recent study by Li et al., reported 4.6% of their COVID-19 patients had acute ischemic stroke, and 1 patient had intracerebral hemorrhage (4) . Additionally, small single center studies have reported the cardiovascular complications and secondary infection in COVID-19 patients. These results cannot be generalized due to sample size and geographic location. This greatly necessitates identification of patients who are at higher risk of developing COVID-19 related complications. Identification of such patients would be of great value to emphasize prevention of such complications as well as appropriate allocation of resources to mitigate such complications, and therefore de-impacting COVID-19 burden. In this meta-analysis, we aim to evaluate the prevalence and outcomes of COVID-19 related cardiovascular complications and secondary infection. We have also evaluated whether these complications could be potential triggers for strokes (AIS-acute ischemic stroke; ICH-intracerebral hemorrhage) and their associated outcomes in COVID-19 patients.

The aim of the study is to evaluate the role of cardiovascular complications and secondary infection in predicting outcomes in COVID-19 hospitalized patients. COVID-19 confirmation in individual studies was evaluated by reverse transcription PCR, antibody testing, and symptoms.

COVID-19 related complications are defined as acute cardiac injury (with evident rise in cardiac enzyme), cardiac arrhythmia, disseminated intravascular coagulation (DIC), secondary infection, and septic shock. Poor outcomes were defined by intensive care unit (ICU) admission, oxygen saturation<90%, invasive mechanical ventilation (IMV) utilization, severe disease, and in-hospital mortality. Study-specific poor outcomes are mentioned in Table 1 (2,12-16). 

Abstracts were reviewed, and articles were retrieved and reviewed for availability of data on complications and outcomes of COVID-19 patients. Studies which gave details on outcomes were selected for quantitative analysis. Preeti Malik (PM) and Deep Mehta (DM) independently screened all identified studies and assessed full-texts to decide eligibility. Any disagreement was resolved through consensus with Urvish Patel (UP).

From the included studies, we extracted the following variables: cardiac complications, acute cardiac injury, cardiac arrhythmias, DIC, septic shock, secondary infection and outcomes. Additionally, details on binary outcomes (Defined in Table 1 ) like ICU vs. non-ICU admission, severe vs non-severe disease, IMV vs no-IMV use oxygen saturation <90% vs >90%, in-hospital mortality vs discharged alive and survivors were collected using prespecified data collection forms by two authors (PM and DM) with a consensus with UP. We have presented the study characteristics like the first author's last name, publication month and year, country of origin, sample size, mean or median age, males, outcomes and definition of outcomes assessed in that individual study Table 1 .

Data analysis was performed using Review Manager version 5.4 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). If the study has more than one outcome comparison, then we have used data from the most severe outcome in the analysis to minimize the overall selection bias of our study.

The Maentel-Haenszel formula was used to calculate dichotomous variables to obtain odds ratios (ORs) along with its 95% confidence intervals (95%CI) to describe the relationship of cardiac complications and outcomes of COVID-19 patients in each study. Random-effects models were used regardless of heterogeneity to estimate the combined effect and its precision, to give a more conservative estimate of the ORs and 95%CI. The I 2 statistic was used to assess statistical heterogeneity. The I 2 statistic of >50% was considered significant heterogeneity. p<0.05 was considered significant. Publication bias was assessed visually using funnel plots and the Newcastle-Ottawa Scale (NOS). Newcastle Ottawa Scale (NOS) was used to assess the quality and bias in the included studies, which rates selection, comparability, and outcome. All studies were assessed to be of moderate quality (Supplemental file).

The pooled OR and 95% CI are represented in the form of forest plots. Each square on the chart area represents individual study and the area of each square is equivalent to the weight of the study, which is the inverse of the study variance. The diamond represents the summary measures, and the width corresponds to the 95% CI.

Review (27) (28) (29) . Cardiac involvement was found in 58% of patients who have recovered from COVID-19 in a study (30) . Isolated studies have reported that myocardial injury has been associated with poor outcomes in hospitalized patients as well as other complications like acute kidney injury and coagulation disorders (31, 32) . Cardiac biomarkers like CK-MB and TnI were found to be higher in those who were critically ill/ admitted to the ICU in some studies (13, 14) . A study by Goyal et al. showed that 18.5% (24/130) patients who were on invasive mechanical ventilation developed some form of arrhythmia vs. only 1.9% (5/263) in patients who did not require invasive mechanical ventilation (19) . In another study by Wang et. al, 20% (13/65) patients who died developed some form of arrhythmia vs. 8% (22/274) in patients who survived (17) . This arrhythmogenic effect could be a direct effect of the virus, hypoxia, inflammatory stress or medications like hydroxychloroquine. Excessive inflammation, disseminated intravascular coagulation (DIC), immobilization or a combination of these could lead to venous thromboembolism (33) . Many studies have shown abnormalities in the coagulation pathway and elevated d-dimer levels (19, 34) . Table 2 are 'detected' strokes (as opposed to those that remain undiagnosed) and the location, size etc. is not reported. Despite these limitations, meta-analysis of 16 studies with 3480 confirmed COVID-19 patients, we found that complications such as DIC, acute cardiac injury, cardiac arrhythmias, septic shock and secondary infection were significantly associated with poor outcomes in COVID-19 patients.

The complications like acute cardiac injury, cardiac arrhythmias, DIC, septic shock, and secondary infection not only had higher prevalence but also had higher odds of poor outcomes in COVID-19 hospitalization. In review, COVID-19 patients hospitalized with AIS and ICH, had history of systemic inflammation, coagulation abnormalities or complications like cardiac arrhythmias, systemic thrombosis, DIC, etc. which may have caused stroke. Long term monitoring is suggested in these patients as they are at risk of developing or worsen arrythmias and may lead to complications triggered stroke. 

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