COVID-19 & Stroke

Epidemiology

Despite data suggesting coronavirus disease 2019 (COVID-19) may contribute to stroke risk, stroke-related hospitalizations during the COVID-19 pandemic appear to be lower during the pandemic’s first peak. Reported decreases in the volume of patients with stroke range from 30% to 60%,^1-3 similar to reductions seen in other acute conditions (eg, gastrointestinal hemorrhages and myocardial infarctions).⁴ Although the cause of the decreases is uncertain, it seems unlikely to be caused by a decrease in the incidence of these conditions; it may, instead, be a result of social distancing decreasing early identification of stroke, or patients fears about coming to the hospital in the midst of a pandemic.⁵

COVID-19 seems to be associated with increased stroke risk, particularly ischemic stroke. A recent meta-analysis calculated an overall stroke incidence of 1.1% among 6,368 people with COVID-19,⁶ which is 2 to 3 times higher than the general hospital population. This risk may be increased among individuals with advanced age, male sex, or “classic” stroke risk factors. Although respiratory infections have been associated with increased stroke risk,^6-8 especially among adults under age 45,⁷ at least 1 study has shown significantly higher risks among people with COVID-19 vs those with influenza (1.6% vs 0.2%).⁹

Although several early studies from locations severely affected in the first surge of the pandemic suggested COVID-19 may increase stroke risk at an earlier age, overall data are mixed. A report from 1 hospital described the treatment of 5 patients less than age 50 with mild COVID-19 respiratory symptoms and large vessel stroke in a 2-week period, compared with an average of 0.7 patients every 2 weeks over the previous year.¹⁰ In 5 and 10 consecutively treated individuals with COVID-19 who underwent thrombectomy in New York¹¹ and Paris,¹² median age was 52.8 and 59.6, respectively. In a larger study in a New York health care system, 0.9% of 3,556 people hospitalized with COVID-19 and stroke were median age 63, lower than contemporary (age 70) and historical (age 68) median ages for people with stroke not associated with COVID-19. The mild decrease in median age and vascular risk factor burden has been reported for some other cohorts,¹³ but other cohort studies,^14,15 some with larger cohorts, have not identified an increased risk of stroke in COVID-19. The overall stroke risk among individuals with COVID-19, including different age groups and individuals without vascular risk factors, remains to be determined in larger studies.

Pathophysiology

Intense research to understand COVID-19-related coagulopathy is ongoing with rapidly emerging data, but knowledge is still limited. Several processes appear to play roles in the prothrombotic state associated with COVID-19 including hypercoagulability, cytokine storm, endothelial cell and platelet activation, complement activation, and the renin-angiotensin system (RAS) alternative axis.^16,17 In addition, COVID-19 and associated critical illness may contribute to stroke risk secondary to myocarditis, heart failure, and dysrhythmias. Intracranial hemorrhage (ICH) in COVID-19 has been less frequently reported with less-well understood pathophysiology.

Retrospective analysis provides evidence of a coagulopathic state associated with severe COVID-19 pulmonary infections of some of the earliest cases in Wuhan, China.¹⁸ Further studies have demonstrated associations between COVID-19, thrombotic events, and altered coagulopathic markers, including elevations in fibrinogen, von Willebrand factor (VWF), factor VIII, D-dimer, prolongation of partial thromboplastin time (PTT), and others.¹⁹ Additional studies suggest endothelial cell and platelet activation may also contribute.²⁰ Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been shown to elicit a cytokine storm, in which an excess of proinflammatory cytokines are released and cause systemic tissue damage and endothelial activation, in some individuals later in the disease. A host of cytokines have been found elevated in individuals with COVID-19 including both those receiving critical care and on noncritical-care wards.^21,22 Data regarding the influence of specific cytokines, such as interleukin-6 (IL-6), have been more mixed but may suggest clinical targets for intervention.^23,24 Cytokines and chemokines can recruit and activate neutrophils, leading to the release of neutrophil extracellular traps (NETs) and immunothrombosis.²⁵ Active tissue factor expression on macrophages and endothelial cells, in conjunction with hypoxia induced by acute respiratory distress syndrome (ARDS), may increase cytokine production and a procoagulant state. The complement pathway has also been implicated in at least some severe COVID-19 pulmonary infections.²⁶ Activated endothelial cells express P-selectin, VWF, and fibrinogen, which all contribute to microvascular thrombosis. In a cohort of people with COVID-19, elevated VWF antigen, VWF activity, and factor VIII activity highlighted an endotheliopathy in critically ill individuals with COVID-19.²⁰ Platelet activation and platelet-monocyte aggregation have been demonstrated in COVID-19.^27,28

SARS-CoV-2 enters the body when the viral spike protein binds to angiotensin-converting enzyme 2 (ACE2) receptors, which may also contribute to thrombosis. ACE2 receptors are found on the surface of the cerebrovascular endothelium and elsewhere. Shear stress on endothelial cells increases cellular expression of ACE2, facilitating spike protein binding.²⁹ ACE2 generates angiotensin (Ang)1-7, which counterbalances the prothrombotic effects of ACE-generated Ang II.³⁰ SARS-COV-2 bound to the ACE2 receptor is internalized to the cell and downregulates this regulatory mechanism, resulting in an imbalance between the RAS and RAS alternative axis in favor of the prothrombotic RAS.^16,31,32 ACE2 may also inhibit platelet adhesion and thrombus formation.^33,34

COVID-19 appears to be associated with an increased risk of thrombotic events, particularly in those who are critically ill. This risk is related to multiple distinct pathways and may be most significant in severe disease leading to multiorgan complications affecting the lung, heart, and kidney, as well as increasing the risk of stroke.

Systems of Care

Pathways and Practical Considerations

Acute stroke care requires the integration of multiple teams including local emergency medical services (EMS), emergency department (ED) and stroke teams, radiology, pharmacy, nursing, anesthesia, and endovascular and neurocritical care teams. During the pandemic, any of these may be struggling with staffing reallocations, delays caused by safety or cleaning requirements, and capacity and limitations (Figure 1). Stroke programs must be flexible and closely integrated with larger health system partners in order to provide ongoing care.

Prehospital to ED Changes. There have been significant effects on stroke triage, with challenges including the need for additional screening, adequate use of personal protective equipment (PPE), respiratory status management, staff shortages, and the potential for additional time delays. Algorithms have been proposed to limit infectious spread and facilitate timely and enhanced communication between EMS, hospitals, and local coordinating authorities.³⁵ Factors guiding the triage decisions include the likelihood of large vessel occlusion (LVO), additional delays caused by interhospital transfer, the need for advanced critical care resources, and the available resources at hospitals (eg, staff, beds, or PPE). Clear and frequent communication between local and community health resources and hospital and stroke program leadership is needed to ensure preservation of stroke care.

ED Care and Acute Stroke Therapy. Hyperacute stroke assessment and management are high-stakes and time-sensitive, leading to proposals for a protected stroke code for rapid and effective stroke care.³⁶ The 2 key aspects include screening and operation of the protected stroke code. Screening includes prenotification and evaluation of infection symptoms, travel history, or other red flags.³⁷ Because acute stroke team members are frontline health care workers for patients who are often unable to give an adequate history and have unknown COVID-19 status, appropriate use of PPE by all team members is critical and should follow local and institutional guidelines. Placement of a surgical mask on a nonintubated patient is recommended after securing PPE for all team members who should receive training for safely putting on and taking off PPE to prevent potential breaches in the barrier PPE affords. Simulation training, especially in-situ, can alleviate the anxiety of the situation and reduce safety threats.³⁸ When appropriate, the number of team members in direct patient contact should be minimized to reduce exposure risks and conserve PPE. In some cases, telemedicine infrastructure can be deployed within hospitals to facilitate safe and timely evaluations.

Clinical evaluation and radiographic studies including head CT and CT angiogram (CTA) or CT perfusion (CTP) studies are the cornerstones to guide reperfusion therapy in acute ischemic stroke. For patients undergoing acute stroke evaluation, whose COVID-19 status is likely unknown, there may be delays in obtaining appropriate imaging, especially in the setting of limited resources. Advanced planning with established workflows can help streamline expedited imaging for evaluation of acute reperfusion therapy.

Standard evaluation of the risks vs benefits guides the decision for intravenous (IV) thrombolysis in the acute setting, even when COVID-19 is suspected.³⁹ Because of transportation or visitor restrictions, collateral information may not be readily available at the bedside; clinical teams may need to spend additional time contacting patients’ families or other witnesses. Although the potential for COVID-19–associated coagulopathy may indicate the benefit of detailed coagulation labs, the results are not typically required before considering IV thrombolysis. Changes to typical postthrombolysis and thrombectomy monitoring may be considered, including how often neurologic evaluations are conducted to limit exposure and preserve PPE, although the effects of these changes on patient outcomes are uncertain.^40,41

Current guidelines recommend mechanical thrombectomy in those presenting with acute ischemic stroke symptoms caused by occlusion of the intracranial internal carotid artery or proximal middle cerebral artery up to 24 hours after a person’s last known normal status, based on appropriate imaging.⁴² Some institutions consider elective intubation using appropriate PPE in a negative pressure room before arrival in the angiographic suite for mechanical thrombectomy.^41,43 When there is concern for SARS-CoV-2 infection, risks and benefits of intubation should be considered, as well as logistic factors regarding transportation and intraprocedural needs (eg, suctioning, oxygenation, and the potential for emergent intubation). Standardized protocols for intubation criteria and workflow can help minimize delays. Additional considerations include coordination for interfacility transfers for mechanical thrombectomy and established protocols for cleaning and disinfection of angiography suites, postprocedure monitoring, and repeat imaging.

Stroke Management and Secondary Prevention. Beyond the acute treatment phase, laboratory and radiographic studies help identify stroke etiology and guide stroke prevention. In addition to assessing traditional vascular risk factors (eg, hypertension, diabetes, and hyperlipidemia), a more detailed assessment of coagulation profile to identify underlying hypercoagulable states may be warranted in those found to have active COVID-19. Laboratory evaluation including D-dimer, C-reactive protein, serum ferritin, lactic acid dehydrogenase, soluble IL-2 receptor, IL-6, antiphospholipid antibodies (ie, cardiolipin immunoglobulin (Ig) A, β-2 glycoprotein IgA and IgM), VWF activity, VWF antigen, and factor VIII may be considered.²⁰ Management of vascular risk factors and antithrombotic therapy remain the cornerstone of secondary stroke prevention in people with COVID-19 who experienced a stroke. As much as possible, given the resources available, a complete and timely stroke evaluation, including telemetry, echocardiogram, and vascular imaging should be done to identify appropriate targets for secondary stroke prevention.

Those with COVID-19 are at heightened risk for medical complications (eg, cardiac arrhythmias, myocardial infarction, heart failure, myocarditis, and venous thrombosis), which require additional monitoring and evaluation. Considering the risk of a COVID-19–associated prothrombotic state, a prophylactic dose of anticoagulation with low molecular weight or unfractionated heparin is typically indicated within 24 to 48 hours of presentation,⁴⁴ and treatment algorithms may include the use of therapeutic anticoagulation based on inflammatory and other markers.⁴⁵ In these cases, as well as in individuals with extracerebral thromboses, the benefits of anticoagulation must be balanced against the risk of hemorrhagic transformation of stroke. Antiplatelet therapy for stroke treatment remains indicated in people with COVID-19 in the absence of a contraindication.

The ongoing COVID-19 pandemic presents logistic challenges for disposition and rehabilitation after stroke in both those who were and were not infected with SARS-COV-2. The availability of evaluations (eg, transesophageal echocardiograms and fiberoptic endoscopic evaluation of swallowing may be limited, because of the potential for aerosolization and the need for PPE. Systems may strive to minimize hospital stays and increase telemedicine use to maximize rehabilitation potential and limit viral transmission. Home exercise programs with video guidance using telerehabilitation services may be considered as an alternative to traditional rehabilitation services.⁴⁶ People recovering from stroke may have more than usual challenges to recovery related to limitations in the availability of family and community support.

As stroke programs navigate the pandemic, hospital capabilities, resources both within and outside of the hospital change rapidly, and protocols evolve frequently. The use of data and research teams to quantify case volumes, time metrics, and clinical outcomes and provide feedback to stroke and hospital leadership may help ensure stroke quality of care is upheld during these changes. Debriefings with team members, open communication, and attention to provider stress and mental well-being are tenets of team performance and should not be overlooked.

Outcomes

The COVID-19 pandemic has led to significant changes in stroke presentations, systems of care, and resource availability (Figure 2). Since the start of the pandemic, population-level increases in cardiovascular and cerebrovascular death have been identified.⁴⁷ Studies have demonstrated that people with COVID-19 who experience stroke have higher than expected rates of disability and death. Increased mortality from stroke among people with COVID-19 compared to historical controls has been reported (odds ratio [OR], 2.90; 95% CI, 1.77-7.17).⁴⁸ Others have shown low rates of ischemic stroke in those with COVID-19 but increased mortality when comparing these cases with contemporary stroke controls.^15,49 A retrospective analysis showed individuals with COVID-19 and stroke who underwent thrombectomy had higher mortality (29.8% vs 12.4%, P=.001) and a lower likelihood of discharge to home or acute rehabilitation (47.1% vs 61.8%, P=0.002) than those without COVID-19.⁵⁰ Meta-analysis found a 44.2% case fatality rate for those with stroke and COVID-19 %, higher than both typical stroke mortality (up to 23%) and the reported mortality of COVID-19 without stroke (4%-28%).⁶

In a regional cohort of people with stroke, COVID-19 was independently associated with higher odds of disability at hospital discharge (OR 3.82, CI 1.02-14.3);⁵¹ similar findings have been described in international registries (median modified Rankin scale 4; [intraquartile range (IQR), 2-6] vs 2 [IQR, 1-4]).⁵² COVID-19 has been shown to be an independent predictor of in-hospital mortality for people with ischemic stroke.⁵³ Although less commonly identified, ICH in the setting of COVID-19 may have a mortality rate approaching 50%.⁵⁴ Notably, many patients included in this and other studies had ICH in the setting of anticoagulation use.^55,56

Disparities in outcomes for people with COVID-19 who experience stroke have been observed and warrant further exploration. Male sex has been associated with higher mortality of comorbid stroke and COVID-19 in both single institution (adjusted OR 1.48 [1.07-2.04])⁵⁷ and multinational observational studies (OR 2.16 [1.04-4.48]).⁵⁸ Higher age has been associated with increased mortality risk,⁵⁹ especially for those with LVOs.⁶⁰ Among hospitalized individuals with COVID-19, those who had previous stroke history also had higher in-hospital mortality.⁶¹

In addition to direct effects on stroke risk, morbidity, and mortality, the COVID-19 pandemic has influenced stroke outcomes even for those not infected with SARS-COV-2. Health care systems around the world have been overwhelmed,⁶² resulting in decreased ability to accommodate patients with nonCOVID-19 diseases such as stroke.^62-64 Increasing evidence suggests people with stroke are delaying or eschewing care during the COVID-19 pandemic.^3,65,66 This “collateral damage,” combined with limitations in access to rehabilitation and preventive care, may worsen poststroke functional status and mortality whether or not individuals had COVID-19.

Future research and public health initiatives will be critically important for understanding the influence of COVID-19 on stroke, mitigating downstream effects on stroke care, and improving patient outcomes.