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Clinical Infection & Immunity

Review

Volume 6, Number 3, September 2021, pages 71-74

Stroke Risk in COVID-19 Patients

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China at the end of 2019 resulted in a pandemic with a crisis in global health. Clinical presentation of patients infected with SARS-CoV-2 is variable, ranging from asymptomatic infection to serious complications including severe pneumonia, acute respiratory distress syndrome, cardiovascular complications, thromboembolism and death [1]. In addition to these complications, cerebrovascular accidents (CVAs) were described in some patients severely infected with SARS-CoV-2 [2-5]. CVA accident (stroke) remains a diagnostic and therapeutic emergency during the crisis of coronavirus disease 2019 (COVID-19). Recent studies in Wuhan have shown that 5% of patients admitted for COVID-19 infection presented with ischemic stroke which increased the risk of mortality by 38% [2]. In this report we try to discuss the pathophysiology, approach to diagnostic and therapeutic measures of stroke associated with infection by SARS-CoV-2.

Complications from the new coronavirus are being discovered as the pandemic progresses. While it was thought that COVID-19 only causes respiratory syndromes, today the varied presentation with inflammatory, cardiovascular and neurological complications is well known. Many neurological symptoms have also been identified in patients with COVID-19. However, not all of them result from direct damage to the nervous system [6].

Normally, stroke risk is high in people with risk factors such as smoking, obesity, high cholesterol and high blood pressure. But, with COVID-19 there is an increased prevalence of stroke in young adults. Worse yet, the death rate among them is reported to be high, approaching as high as 55%. In the event of COVID-19, most of these are reported secondary to hypercoagulability in this condition. Patients in their 30s to 40s and who did not necessarily have severe forms of the coronavirus have died of stroke [7].

Not all neurological symptoms indicate damage to the nervous system by the virus. Thus, headache, dizziness and myalgia described in the first studies are an integral part of the flu-like syndrome associated with the infection itself. These symptoms, which also exist during seasonal respiratory virus infections, do not generally indicate a damage to the nervous system. In addition, they usually ameliorate spontaneously within few days.

Stroke represents more than a quarter of the neurological manifestations associated with COVID-19. These are most often ischemic strokes. Often extensive, these strokes affect patients with additional vascular risk factors such as high blood pressure or diabetes. Despite the presence of these factors, the exact cause of these strokes remains unidentified in two-thirds of cases of COVID-19 [8]. During this infection hypercoagulability is reported, the result of the hyper-inflammatory state and infection of the vessel wall by the virus itself [9].

The association of ischemic stroke and SARS-CoV-2 infection is not trivial, since hospital mortality was particularly high in this subgroup, around 16%. A dedicated international study has further confirmed that patients with ischemic stroke and infection with the SARS-CoV-2 have a higher risk of disability and death compared to patients with stroke outside the context of COVID-19 [10].

Inflammation is increasingly recognized as a key contributing factor in the pathophysiology of neurovascular diseases and in acute vascular events triggered by arteriovenous occlusions [11, 12]. It has been shown that inflammatory blood factors (interleukin (IL) and C-reactive protein (CRP)) are responsible for the events triggered by abnormalities of coagulation [13, 14]. In their study [2], Li et al found that the CRP level was significantly more increased in patients infected with SARS-CoV-2 with neurovascular complications compared to COVID-19 patients without CNS involvement (51.1 vs. 12.1 mg/L, P < 0.01) [10]. They also demonstrated that the level of D-dimers was significantly higher in patients infected with SARS-CoV-2 with CNS involvement, compared to COVID-19 patients without CNS involvement (6.9 vs. 0.5 mg/L, P < 0.001) [10]. On the other hand, in their studies [5, 8] it was showed that increased rate of D-dimers is a factor predictive of mortality. In the study by Mao et al [3], the patients with severe COVID-19 disease presented with more nervous system involvement compared to patients with milder form of the disease (5.7% vs. 0.8%).

The authors found that these patients had plasma cytokine levels (IL-2, IL-7, IL-0, granulocyte colony-stimulating factor (G-CSF), interferon (IFN)-γ-inducible protein (IP-10), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF)-alpha) higher than those of patients with non-severe infections [15]. The importance of the inflammatory response explains the hypercoagulable states observed at an early stage disease which could be one of the main causes of the appearance of CNS symptoms. In addition, inflammation has been shown to impair the stability of the atherosclerotic plaque, which is a physiopathological mechanism of ischemic CVAs [16].

Another physiopathological hypothesis is that, the infection with SARS-CoV-2 leads to hypoxia of tissue which is responsible for CVAs. Amongst other advanced pathophysiological mechanisms is the concept of cerebral vasculitis. In fact, it has been shown in recent publications that antiphospholipid antibodies were positive in severely infected patients by SARS-CoV-2 with or without genetic predisposition and suffered stroke [17]. So the COVID-19 disease can trigger transient or permanent antiphospholipid antibody syndrome that should be evaluated, ideally, 12 weeks after the acute infectious episode according to current recommendations [18]. For hemorrhagic vascular accidents, structural analysis of the angiotensin-converting enzyme 2 (ACE2) receptor has been shown to have a BoaT1 receptor (slC6a19) for SARS-CoV-2 [19]. Secondary to this, some hypertensive patients who are infected by SARS-CoV-2 may present with abnormally high blood pressure, which increases the risk of intracerebral hemorrhage.

According to the European stroke organization (ESO), the number of hospitalizations with stroke is increased during the pandemic [20]. Currently, general population, general physicians and emergency services are focused on COVID-19 disease and consider the hospital as an unsafe place for elderly, hypertensive, diabetic, obese and heart disease patients because they have a higher mortality if they acquire SARS-CoV-2 infection. The rate of stroke in COVID-19 is reported with an increased incidence in younger people, and the strokes are often more serious compared to those occurring in people not infected with SARS-CoV-2 [3].

In a study carried out in New York during the period between March 15 and April 19, 2020, out of 3,556 hospitalized patients diagnosed with COVID-19 infection, 32 patients (0.9%) presented with CVA. The authors compared these 32 patients admitted for stroke and COVID-19 to those admitted with stroke but tested negative for SARS-CoV-2 (46 patients). They found that patients infected with SARS-CoV-2 were young people (63 years old vs. 70 years old), had more extensive stroke assessed by the National Institute of Health Stroke Scale (NIHSS) (19 vs. 8), had a rate of more increased D-dimers (10,000 vs. 525), needed anticoagulants (75% compared to 23.9%), and had a significantly higher death rate (63.6% vs. 9.3%) [21]. In a study recently published in China, comprising 221 patients with infection by SARS-CoV-2, 13 (5.9%) had CVAs, and among them 11 patients (84.6%) presented with one stroke, one patient (7.7%) presented with cerebral venous sinus thrombosis and another presented with hemorrhagic stroke (7.7%). Beyrouti et al in their study, described six cases of stroke secondary to severe infection with SARS-CoV-2, 50% of which had multiple strokes and two additionally had venous sinus thrombosis [17]. All patients had a rate of D-dimers ≥ 1,000 µg/L, 83.33% of patients had positive circulating anticoagulant antibodies with an occlusion of large vessels on brain imaging.

A survey carried out [22] indicates that from severely ill, 86 patients infected from the virus in China, six reported ischemic stroke whereas one patient suffered from cerebral hemorrhage. A considerably higher prevalence of antiphospholipid antibodies has been explained in the seven brain-infarct patients (83.3% vs. 26.9%, P < 0.05) [22]. In another cohort study comprising of 187 patients at Montefiore Medical Center in the Bronx, New York, there was seen an increased frequency of positive lupus anticoagulants (LA) amongst COVID-19 patients after they have been adjusted with CRP levels. Additionally, from 30 patients that were diagnosed with LA positive, 19 patients has documented thrombosis (arterial and venous) as well as two strokes which calculate the event rate to be 63% in comparison to the percentage of LA-negative patients which was 34% [23].

A multicenter international registry (the Global COVID-19 Stroke Registry) has undergone a 1:1 propensity score matching analysis, which intends to compare the severity of the stroke as well as its outcomes in almost 174 patients suffering from COVID-19 and ischemic stroke with that of non-COVID-19 and ischemic stroke that have been registered in Lausanne Registry [24]. The median NIHSS was higher in patients with COVID-19 (10) vs. 6 (interquartile range (IQR): 3 - 14), P = 0.03; (odds ratio: 1.69; 95% confidence interval (CI): 1.08 - 2.65). Those patients who were infected with the virus had a higher probability of developing severe disability (median modified RS: 4 (IQR: 2 - 6) vs. 2 (IQR: 1 - 4), P < 0.001), and death ratio (odds ratio: 4.3, 95% CI: 2.22 - 8.30) in comparison to patients that were tested negative for the virus [24].

The mean time between infection with SARS-CoV-2 and onset of stroke was approximately 12 days [4]. But in some cases the stroke can be the presenting symptom with the disease [23]. All patients had an inflammatory syndrome with hypercoagulable state.

There are many studies which indicate that the incidence of stroke amongst patients diagnosed with COVID-19 infection tends to range from 0.9% to 2.7%. Irrespective of the infection presence, patients arriving at the hospital in an appropriate time frame should be provided treatment with mechanical thrombectomy or systemic thrombolysis [21].

Since the outbreak of the COVID-19 pandemic, a triage protocol has been activated in many emergency rooms in order to assess each patient: either as a suspected SARS-CoV-2 infection or confirmed. The World Health Organization (WHO) recommends that all health workers in contact with patients suspected of or suffering from the disease COVID-19 must wear personal protective gear [25]. The development of aCOVID-19 circuit is mandatory in all hospital structures taking care of patients infected with SARS-CoV-2. It allows protecting these structures, as well as health personnel against infection while maintaining open access and continuous care to all patients. When the patient is already known to be COVID-19 positive, they should benefit from brain imaging. Patients deemed eligible for intravenous thrombolysis should follow the standard protocol of thrombolysis, then hospitalized in the COVID-19 unit. The patients who are candidates for an endovascular procedure should be transferred to the interventional neuroradiology unit. Health personnel working in catheterization room should be notified in order to adapt to the pandemic. At the end of the procedure, the patient would be transferred to, depending on his state of vigilance, either the COVID-19 unit or an intensive care unit (ICU) dedicated to patients infected with SARS-CoV-2. Non-candidate patients for mechanical thrombectomy should be taken to the COVID-19 unit with monitoring by the neurology team.

The SARS-CoV-2 virus results in various coagulation disorders in many patients which further leads to developing thromboembolism in both the venous circulation and arterial circulation. This is considered as one important factor for CVAs in patients infected with the virus. Along with CVA, deep vein thrombosis, pulmonary embolism risk increases as well. In case there is a causal relation, anticoagulation tends to lower down the associated risks of these thromboembolic events which can pave way for a better prognosis.

A retrospective evaluation was done amongst five hospitals in New York where the role of anticoagulation in COVID-19 patients is studied and published [26]. Patients have been enrolled between March 1 and April 30, 2020 and the endpoint of the research was based upon hospital mortality. Secondary endpoints were events of serious bleeding and needing intubation. In this study, almost 4,089 have matched the inclusion criteria. The median age of the participants was 65 years and from this 45% of the patients were female. From this, 900 patients received therapeutic anticoagulation whereas, 1,959 patients received prophylactic anticoagulation and only 1,530 patients did not receive anticoagulation. A total of 1,073 patients (20.4%) died in the process of this study. Therapeutic anticoagulation had an outcome of 47% reduction in in-hospital rate of mortality. Additionally, patients who received prophylactic anticoagulation experienced a 50% reduced mortality rate in comparison to those patients who did get receive anticoagulation.

In conclusion, amongst the patients that were hospitalized with COVID-19 infection both therapeutic and prophylactic anticoagulation has the potential to improve hospital mortality and prognosis.

The actual pathophysiological relationship between COVID-19 infection and the occurrence of stroke has not yet been completely understood. Additionally, it is also not known as to whether the standard treatment of infected patients with dexamethasone [27], remdesivir [28, 29] and methylprednisolone tends to reduce the risk of stroke, or they need antiplatelets or anticoagulants as part of standard therapy. More and more data and well designed case studies are needed to further understand all neurologic complications of COVID-19 in general and CVAs risk in particular.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Data Availability

The author declares that data supporting the findings of the study are available within the article.

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