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SARS-CoV-2 Infection and Increased Risk for Pediatric Stroke

      Abstract

      Background

      There is an increased risk of stroke in adults with severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) infection, but whether there is a similar association with stroke in children is unclear. Our objective was to determine whether there is a correlation between COVID-19 infection, multisystem inflammatory syndrome in children (MIS-C), and pediatric ischemic stroke.

      Methods

      This was a retrospective, population-based cohort analysis between March 1, 2020, and June 30, 2021, conducted at a children's hospital. Pediatric patients with a diagnosis of ischemic stroke were identified using ICD-10 diagnoses of ischemic stroke, cerebrovascular accident, or cerebral infarction.

      Results

      We identified 16 patients, seven male and nine female, with ischemic stroke. Ages were 8 months to 17 years (median 11.5 years). More Asian (6%) and black (13%) patients had strokes compared with population prevalence (2% each, respectively). No patients had active COVID-19 infection. COVID-19 antibodies were identified in five of 11 patients tested (45%), of whom three were diagnosed with MIS-C. 82% of the strokes occurred between February and May 2021. The peak incidence was in February 2021, which was two months after peak incidence of pediatric cases of COVID-19 and one month after the peak of MIS-C cases.

      Conclusions

      Our study suggests that prior COVID-19 infection, but not acute infection, is correlated with a risk for stroke in the pediatric population. The risk for stroke appears to be distinct from the risk for MIS-C.

      Keywords

      Introduction

      Coronavirus disease 2019 (COVID-19) infection has been associated with stroke in adults, including up to 5% of hospitalized patients with COVID-19,
      • Li Y.C.
      • Bai W.Z.
      • Hashikawa T.
      The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.
      ,
      • Maury A.
      • Lyoubi A.
      • Peiffer-Smadja N.
      • de Broucker T.
      • Meppiel E.
      Neurological manifestations associated with SARS-CoV-2 and other coronaviruses: a narrative review for clinicians.
      and with large-vessel stroke in patients younger than 50 years.
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • et al.
      Large-vessel stroke as a presenting feature of Covid-19 in the young.
      Proposed mechanisms in adults include immune-mediated thrombosis and hypercoagulability, alternative renin-angiotensin pathway activation, cardioembolism and COVID-19 cardiopathy, and direct COVID-19-mediated damage of the neurovascular unit.
      • Sagris D.
      • Papanikolaou A.
      • Kvernland A.
      • et al.
      COVID-19 and ischemic stroke.
      ,
      • Gu S.X.
      • Tyagi T.
      • Jain K.
      • et al.
      Thrombocytopathy and endotheliopathy: crucial contributors to Covid-19 thromboinflammation.
      Furthermore, the neuroinvasive propensity of coronaviruses is well-documented, potentially through trans-synaptic transfer.
      • Li Y.C.
      • Bai W.Z.
      • Hirano N.
      • et al.
      Neurotropic virus tracing suggests a membranous-coating-mediated mechanism for transsynaptic communication.
      Biochemical properties of COVID-19, including its ability to enter cells via angiotensin-converting enzyme-2 receptors, may further contribute to its neurotropism and multiorgan effects.
      • Baig A.M.
      • Khaleeq A.
      • Ali U.
      • Syeda H.
      Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms.
      However, whether COVID-19 is associated with stroke in the pediatric population remains largely unclear. In two large reports on pediatric patients (<18 years) with COVID-19,
      • Dong Y.
      • Mo X.
      • Hu Y.
      • et al.
      Epidemiology of COVID-19 among children in China.
      ,
      • Parri N.
      • Magistà A.M.
      • Marchetti F.
      • et al.
      Characteristic of COVID-19 infection in pediatric patients: early findings from two Italian Pediatric Research Networks.
      there were no reports of stroke, cerebral vasospasm, or other focal neurological features. An international cohort study reported pediatric stroke as an uncommon (<5%) association with COVID-19 and did not find an increase in the rate of pediatric ischemic stroke in the early pandemic compared with the months preceding its onset.
      • Beslow L.A.
      • Linds A.B.
      • Fox C.K.
      • et al.
      Pediatric ischemic stroke: an infrequent complication of sars-cov-2.
      Further, the correlation between multisystem inflammatory syndrome in children (MIS-C) related to COVID-19 infection and pediatric stroke is also poorly understood. Neurological manifestations have been described in approximately one quarter of patients with MIS-C,
      • LaRovere K.L.
      • Riggs B.J.
      • Poussaint T.Y.
      • et al.
      Neurologic involvement in children and adolescents hospitalized in the United States for Covid-19 or multisystem inflammatory syndrome.
      as has a Kawasaki-like cardiac vasculopathy.
      • Akca U.K.
      • Kesici S.
      • Ozsurekci Y.
      • et al.
      Kawasaki-like disease in children with COVID-19.
      Stroke and thromboembolism in MIS-C has been described as a rare complication,
      • Menon N.M.
      • Srivaths L.V.
      Thromboembolism in children with multisystem inflammatory syndrome: a literature review.
      ,
      • Chang J.
      • Bulwa Z.
      • Breit H.
      • et al.
      Acute large vessel ischemic stroke in patients with COVID-19–related multisystem inflammatory syndrome.
      but the extent and whether there is a causal relationship remains unclear. Our goal was to understand whether COVID-19 infection was associated with pediatric ischemic stroke, and to characterize the relationship to MIS-C and other risk factors.

      Methods

      Standard protocol approvals, registrations, and patient consents

      The study was approved by the Institutional Review Board of the University of Utah and the Privacy Board of Intermountain Healthcare (IH).

      Setting

      This retrospective study was performed at Primary Children's Hospital (PCH) in Salt Lake City, Utah, which is the sole tertiary pediatric center for an estimated pediatric population of >1.7 million children in the Intermountain West region. PCH is also the primary hospital for the majority of pediatric hospitalizations along the Wasatch Front, an urban region centered on Salt Lake City with a total population (adult and pediatric) of >2 million. PCH is a freestanding, 289-bed tertiary care children's hospital operated by IH, a regional, not-for-profit integrated health care delivery system, with 22 hospitals and 160 clinics and urgent care facilities located in Utah and southeastern Idaho, serving about 60% of Utah's 3.5 million residents and 85% of Utah's children.
      About: Primary Childrens. Intermountain Healthcare.

      Study design

      The study was a retrospective population-based cohort analysis of all children younger than 18 years with an ICD-10 diagnosis of ischemic stroke, intracranial hemorrhage, cerebrovascular accident, or cerebral infarction, between March 1, 2020, and June 30, 2021, compared with patients with stroke hospitalized at PCH between March 1, 2015, and February 29, 2020.

      Cohort development

      Patients in both the pandemic and historical cohorts were identified electronically through the IH Enterprise Data Warehouse (EDW), which records administrative, financial, clinical, pharmacy, laboratory, and radiological data associated with patients seen at any IH facility. Strokes outside of the perinatal period and strokes of uncertain etiology were included. For example, strokes secondary to traumatic brain injury, cardiac arrest, extracorporeal membrane oxygenation therapy or surgical complications for conditions not related to COVID-19 were excluded from the study.

      Data collection

      Patient demographic information and other covariates were collected from the EDW, including age, gender, race/ethnicity, insurance, and socioeconomic status. Race/ethnicity status stored in the EDW is self-reported at the time of clinical presentation. Race and ethnicity data were recorded at patient registration at each hospital and clinic visit. Insurance type was categorized into two groups: “private” commercial insurance (∼89% of the cohort) and “public” insurance if patients were enrolled in either Medicaid or Children's Health Insurance Program. If the patient had different insurance coverages, the insurance coverage type (public or private) that was most frequently listed for their visits was used. If the patient had double coverage, their primary insurance type was used.
      Patients identified through the EDW who met inclusion criteria were then further reviewed for past medical history, admission information (length of admission, time in critical care unit), COVID-19 status (polymerase chain reaction [PCR] result, antibody result, vaccination status, and time from COVID-19 positivity to onset of stroke), presenting symptoms, National Institute of Health Stroke Scale (NIHSS) on presentation, stroke characteristics (type/location/vascular territory), acute treatment (tissue plasminogen activator [tPA] and/or thrombectomy), inpatient diagnostic evaluation, secondary stroke prevention, and stroke outcomes.
      We obtained state COVID-19 data, including timing of positivity, race/ethnicity, and age, from the Utah Department of Health to approximate the incidence of pediatric COVID-19 infection in Utah.
      Utah Department of Health
      Bureau of epidemiology. Disease response, evaluation, analysis, and monitoring program.
      The University of Utah Division of Pediatric Rheumatology manually tabulated all MIS-C admissions at PCH over the same time frame. Utah state race/ethnicity information was obtained through US Census Bureau data for 2020.

      Results

      We identified 101 patients with an ICD-10 diagnosis of stroke who were hospitalized between March 1, 2020, and June 30, 2021. Of these, 85 were excluded from our pandemic cohort (strokes in the prenatal period or of uncertain etiology, or patients with stroke before March 1, 2020, who presented for follow-up in an outpatient clinic appointment during the study time frame). Of the 16 patients who were included, there were seven male (44%) and nine female (56%) patients whose ages ranged from 8 months to 17 years, with a median age of 11.5 years. Race/ethnicity data showed higher proportions of Asian (6%) and black (13%) patients, compared with Utah state race/ethnicity data for the same period (Asian [2%], black [1%]) (Tables 1 and 2).
      TABLE 1.Clinical and Demographic Characteristics of the Early Pandemic (March 1, 2020, to June 30, 2021) Pediatric Ischemic Stroke Cases (n = 16) versus the Historical (March 1, 2015, to February 29, 2020) Pediatric Ischemic Stroke Cases (n = 25) at PCH
      CharacteristicPandemic Stroke Cases Number (%)Historical Stroke Cases Number (%)
      Age, years
       <11 (6)1 (4)
       1-41 (6)10 (40)
       5-104 (25)6 (24)
       11-155 (31)5 (20)
       16-184 (25)3 (12)
      Sex
       Female9 (56)10 (40)
       Male7 (44)15 (60)
      Race/ethnicity
       Hispanic3 (19)4 (16)
       Asian or Pacific Islander1 (6)1 (4)
       Black or African American2 (13)1 (4)
       White Non-Hispanic10 (63)19 (76)
      COVID-19 PCR status
       Positive2 (13)
       Negative14 (88)
      COVID-19 IgG status11 (69)
       Positive5 (31)
       Negative6 (38)
       Not tested5 (31)
      History of known or presumed COVID-19 infection2 (13)
      Diagnosis of MIS-C3 (19)
      NIHSS
       0-51 (6)0 (0)
       6-102 (13)1 (4)
       11-151 (6)0 (0)
       16-202 (13)0 (0)
       >200 (0)0 (0)
       Not tested/result not found10 (63)24 (96)
      Type of stroke
       Large-vessel occlusive9 (56)12 (48)
       CNS vasculitis/primary angiitis3 (19)0 (0)
       Spontaneous dissection2 (13)1 (4)
       Watershed infarct1 (6)2 (8)
       Lacunar, embolic0 (0)4 (16)
       Focal cerebral arteriopathy1 (6)6 (24)
      Location
       Anterior cortical region0 (0)2 (8)
       Lateral (MCA territory)9 (56)10 (40)
       Posterior cortical region3 (19)3 (12)
       Basal ganglia/thalamus3 (19)5 (20)
       Brainstem0 (0)3 (12)
       Spinal cord1 (6)0 (0)
       Multifocal0 (0)2 (8)
      Presenting symptoms
       Hemiparesis13 (81)20 (80)
       Gaze deviation5 (31)1 (4)
       Aphasia5 (31)3 (12)
       Dysarthria4 (25)5 (20)
       Altered mental status3 (19)6 (24)
       Fever3 (19)3 (12)
       Seizure2 (13)1 (4)
       Headache2 (13)4 (16)
       Neglect1 (6)0 (0)
       Ataxia1 (6)3 (12)
       Numbness1 (6)4 (16)
      Acute management
       tPA alone1 (6)0 (0)
       Thrombectomy alone1 (6)0 (0)
       tPA thrombectomy2 (13)2 (8)
       None12 (75)23 (92)
      Secondary prevention
       Aspirin alone9 (56)14 (56)
       Aspirin clopidogrel1 (6)1 (4)
       Warfarin1 (6)2 (8)
       Apixaban1 (6)0 (0)
       Enoxaparin1 (6)3 (12)
       None3 (19)5 (20)
      Abbreviations:COVID-19 = Coronavirus disease 2019CNS = Central nervous systemIQR = Interquartile rangeMCA = Middle cerebral arteryMIS-C = Multisystem inflammatory syndrome in childrenNIHSS = National Institute of Health Stroke ScalePCH = Primary Children's HospitalPCR = Polymerase chain reactiontPA = Tissue plasminogen activator
      TABLE 2.Case Descriptions of Early Pandemic (March 1, 2020, to June 30, 2021) Pediatric Ischemic Stroke Cases at PCH
      Patient NumberDemographicsCOVID-19 Result/MIS-C StatusStroke TypeTreatment/Length of StayOutcomes
      1<1-year-old previously healthy, white, presented with right hemiparesisPCR negativeWatershed stroke in left MCA distribution secondary to compressive effects from subdural hematomaNone/2 days PICU, 7 total days admittedNo residual deficits
      23-year-old previously healthy, black, presented with encephalopathy, right hemiparesis, left gaze preferencePCR negative, IgG positive/MIS-C diagnosisLeft M2 embolic strokeHeparin drip/19 days PICU, 31 total days admittedMild persistent right hemiparesis
      36-year-old previously healthy, white, presented with right hemiparesis and receptive aphasiaPCR and IgG negativeLeft anterior choroidal and distal M3 territory stroke secondary to primary angiitis of the CNSPrednisone, ASA/8 total days admittedMild persistent right hemiparesis
      49-year-old with trisomy 21, white, presented with seizure, encephalopathy, left hemiparesis, right gaze preferencePCR negativeLeft MCA embolic strokeASA/12 days PICU, 65 total days admittedResidual aphasia and left hemiparesis
      510-year-old previously healthy, black, presented with right hemiparesisPCR and IgG negativeLeft M1 embolic strokeASA + clopidogrel/2 days PICU, 8 total days admittedMild persistent left upper extremity weakness
      610-year-old previously healthy, Asian M presented with headache and left hemiplegiaPCR negativeRight MCA embolic stroke secondary to CNS vasculitisPrednisone, ASA/2 days PICU, 30 total days admittedMild persistent left hemiparesis
      710-year-old previously healthy, white F presented with right hemiparesis, left gaze preference, and right neglectPCR negative, IgG positive/MIS-C diagnosisLeft M1 embolic stroketPA and thrombectomy, ASA/2 days PICU, 8 total days admittedNo residual deficits
      811-year-old, previously healthy, presented with right hemiparesis, headache, dysarthriaPCR negative, IgG positiveLeft basal ganglia infarction secondary to bilateral ICA dissectionASA/5 total days admittedMild right spasticity and hemiparesis
      912-year-old, previously healthy, presented with fevers and abdominal painPCR positive, IgG positive/MIS-C diagnosisBilateral PCA territory ischemia from focal cerebral arteriopathyPrednisone, ASA/4 days PICU, 8 total days admittedPersistent bilateral superior hemianopia and episodic memory impairment
      1014-year-old with hypoplastic left heart syndrome, presented with aphasia and right hemiplegia 1 week after first dose of Pfizer COVID-10 vaccinePCR negative, IgG negativeLeft M1 embolic stroketPA and thrombectomy, ASA, warfarin/3 days PICU, 7 total days admittedNo residual deficits
      1114-year-old with remote history of thoracic spine compression fracture, presented with back pain and bilateral lower extremity weakness and numbnessPCR negativeAnterior spinal artery thrombotic strokeNone/31 total days admittedPersistent bilateral lower extremity weakness and numbness
      1215-year-old, previously healthy, presented with ataxia, encephalopathy, nystagmusPCR negative, IgG negativeLeft vertebral artery thrombus versus dissectionEnoxaparin/2 days PICU, 5 total days admittedNo residual deficits
      1316-year-old, previously healthy, presented with right hemiparesis and dysarthriaPCR positive 2 months before admissionLeft medial lenticulostriate artery stroke secondary to primary angiitis of CNSPrednisone, ASA/2 total days admittedMild right lower extremity weakness and spasticity
      1416-year-old, previously healthy, presented with left hemiparesis and dysarthriaPCR positive, IgG positiveRight MCA embolic stroketPA, ASA/1 day PICU, 3 total days admittedMild left lower extremity weakness
      1516-year-old with bicuspid aortic valve, presented with right hemiparesis and aphasiaPCR negative, IgG negativeLeft M2 embolic strokeThrombectomy/10 days PICU, 10 total days admittedDecreased
      1617-year-old with epilepsy, presented with left hemiparesis, dysarthria, seizurePCR negative, IgG negativeRight M1 embolic strokeASA, apixaban/10 days PICU, 31 total days admittedMild left hemiparesis
      Abbreviations:ASA = AspirinCNS = Central nervous systemCOVID-19 = Coronavirus disease 2019F = FemaleICA = Internal carotid arteryM = MaleMCA =Middle cerebral arteryMIS-C = Multisystem inflammatory syndrome in childrenPCA = Posterior cerebral arteryPCH = Primary Children's HospitalPCR = Polymerase chain reactionPICU = Pediatric intensive care unittPA = Tissue plasminogen activator
      All patients in the pandemic cohort had COVID-19 reverse transcription PCR testing performed at time of hospitalization; two were positive, although they were both also found to be COVID-19 IgG antibody positive. COVID-19 antibodies were tested in 11 patients and were positive in five (45%) patients. Co-occurring MIS-C diagnosis was present in three patients. One of the patients had received the first dose of the Pfizer COVID-19 vaccine one week before presentation with stroke. No other patients had been vaccinated against COVID-19. The majority (n = 13, 81%) of patients were previously healthy, without significant comorbidities (Tables 1 and 2).
      In the pandemic cohort, large-vessel occlusive (LVO) stroke was the most common stroke type (n = 9, 56%). Other stroke types included central nervous system vasculitis/primary angiitis (n = 3, 19%), spontaneous dissection (n = 2, 13%), watershed infarct (n = 1, 6%), and focal cerebral arteriopathy (n = 1, 6%). Nine (56%) of the strokes involved the middle cerebral artery territory, three (19%) were occipital, three (19%) involved the basal ganglia, and one (6%) involved the spinal cord. The most common presenting symptom was hemiparesis (n = 13, 81%), followed by aphasia (n = 5, 31%) and gaze deviation (n = 5, 31%). Fever was present in the three patients (19%) who were concomitantly diagnosed with MIS-C. NIHSS scoring was completed on six patients (38%), which ranged from scores of 0 to 5 (n = 1, 6%), 6 to 10 (n = 2, 13%), 11 to 15 (n = 1, 6%), and 16 to 20 (n = 2, 13%), and none scored greater than 20 (Tables 1 and 2).
      The majority of patients (12, 75%) presented outside of the timing to be eligible for intravenous tPA treatment in the pandemic cohort. Four patients (25%) underwent acute stroke management in the form of tPA, thrombectomy, or both tPA and thrombectomy. For secondary prevention, nine patients (56%) were treated with aspirin, and one patient each (6%) with aspirin and clopidogrel, warfarin, enoxaparin, or apixaban. Three patients (19%) were not started on a form of secondary prevention (Tables 1 and 2).
      Thirteen (81%) of the strokes occurred between February and May 2021, with a peak of seven strokes in February. During the study time frame at the study hospital (PCH), MIS-C cases peaked in January 2021 with a total of 17 cases. The initial pediatric COVID-19 surge reached its highest numbers in Utah in November and December 2020. The MIS-C cases at PCH reached their maximum one to two months after the pediatric COVID-19 surge, whereas stroke cases peaked two to three months after the pediatric COVID-19 surge in Utah (Fig. 1).
      Figure thumbnail gr1
      FIGURE 1Timing of pediatric coronavirus disease 2019 (COVID-19) cases in Utah, and pediatric stroke and multisystem inflammatory syndrome in children (MIS-C) cases at Primary Children's Hospital between March 1, 2020, and June 30, 2021. The color version of this figure is available in the online edition.
      When compared with strokes of uncertain etiology from the previous six years at PCH (2015: n = 1; 2016: n = 0; 2017: n = 5; 2018: n = 6; 2019: n = 9; 2020: n = 4), there were significantly more strokes in the pandemic timeframe (paired Sign test p-value of 0.031). The first six months of 2021 had more than triple (n = 13) the average yearly stroke rate (n = 4) (Fig. 2). Most of the historical strokes (10, 40%) were in the one- to four-year age range compared with most (13, 81%) over the age of five in the pandemic cohort. Like the pandemic cohort, the majority of historical strokes (12, 48%) were LVOs, but there were more lacunar strokes (four, 16%) and cases of focal cerebral arteriopathy (six, 24%) than in the pandemic cohort (one, 6%). Only one patient (4%) in the historical cohort had NIHSS scoring documented, and only two patients (8%) underwent acute intervention in the form of tPA and thrombectomy (Table 1).
      Figure thumbnail gr2
      FIGURE 2Ischemic pediatric stroke cases of uncertain etiology at Primary Children's Hospital between January 1, 2015, and June 30, 2021. The color version of this figure is available in the online edition.

      Discussion

      Our study found a correlation between an increase in pediatric ischemic strokes and a peak in pediatric COVID-19 cases that was distinct from timing of MIS-C cases. We found an increased number in pediatric strokes at PCH from March 2020 to June 2021, with a peak in incidence of cases in February 2021. Of these patients, over one-third had a history of prior COVID infection, were unvaccinated and had COVID-19 antibodies at the time of stroke, and/or had active diagnosis of MIS-C. This peak had a temporal relationship with the pediatric COVID-19 case rate in Utah, which peaked in December 2020. Our data suggest that prior COVID-19 infection, but not acute infection, may be related to the development of stroke in the pediatric population. Viral infection has been described as a potential trigger of pediatric ischemic stroke.
      • Fullerton HJ
      • Hills NK
      • Elkind MS
      • et al.
      Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study.
      Our study suggests that COVID-19 infection specifically could be a trigger, as rates of other pediatric viral infections were relatively low during our timeframe.
      • Olsen S.J.
      • Winn A.K.
      • Budd A.P.
      • et al.
      Changes in influenza and other respiratory virus activity during the COVID-19 pandemic — United States, 2020–2021.
      LVO strokes of the middle cerebral artery territories were the most common stroke type in both our pandemic and historical cohorts, which differs from other recent studies on pediatric stroke and COVID-19 infection, wherein focal cerebral arteriopathy was more implicated.
      • Beslow L.A.
      • Linds A.B.
      • Fox C.K.
      • et al.
      Pediatric ischemic stroke: an infrequent complication of sars-cov-2.
      However, acute intervention in the form of tPA and/or thrombectomy was only performed in one-quarter of patients in the pandemic cohort, with the majority of patients presenting with delayed diagnoses of stroke in both the pandemic and historical cohorts. These data have important clinical and public health implications and could broaden our understanding of long-term health consequences of COVID-19 infection in pediatrics and potentially provide guidance for stroke prevention moving forward.
      MIS-C and hyperinflammatory syndrome following COVID-19 infection, and its distinction from acute COVID-19 infection in children, is increasingly understood.
      • Feldstein L.R.
      • Tenforde M.W.
      • Friedman K.G.
      • et al.
      Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19.
      In a few patients of the pandemic cohort (n = 3), there was temporal overlap between MIS-C and diagnosis of stroke. The same number of patients (n = 3) had prior mild or asymptomatic COVID-19 infection, did not develop MIS-C, but did present with stroke. In terms of timing, there was a one- to two-month lag in MIS-C cases, but a two- to three-month time lag of stroke cases at PCH, following the peak pediatric COVID-19 rates in Utah in December 2020.
      We did not see a relationship between acute COVID-19 infection (PCR positivity) and stroke in our pandemic cohort, as the patients who were PCR positive at time of admission were also found to be COVID-19 antibody positive, suggesting that stroke could be a delayed complication of COVID-19 infection, similar to, and perhaps related to, the hyperinflammatory state that has been described two to six weeks following acute infection.
      • Rubens J.H.
      • Akindele N.P.
      • Tschudy M.M.
      • Sick-Samuels A.C.
      Acute Covid-19 and multisystem inflammatory syndrome in children.
      Likewise, hypercoagulability has been broadly recognized in the setting of COVID-19,
      • Connors J.M.
      • Levy J.H.
      Thromboinflammation and the hypercoagulability of COVID-19.
      to the extent that many pediatric inpatients meet NIH COVID-19 Treatment Guidelines criteria for therapeutic anticoagulation.
      Information on covid-19 treatment, prevention and research. National Institutes of Health.
      A proposed mechanism for this hyperinflammatory and prothrombotic state is from viral activation of the clotting cascade and simultaneous endothelial disruption.
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with COVID-19.
      Despite our setting at a major pediatric referral center, with a large pediatric catchment (>1.7 million), and with essentially near-complete ascertainment as all pediatric stroke patients are referred or transferred to PCH in this region, pediatric stroke remains relatively rare, and thus sample size was a limitation of our study. Within our pandemic cohort, the specific timing of COVID-19 infection in relation to stroke onset was difficult to delineate because many of our patients were asymptomatic and subsequently found to be antibody positive at the time of admission. Furthermore, antibody testing for COVID-19 was not performed in a third of our stroke cohort, so it is unknown whether they had prior COVID-19 infection. As such, our assumption about timing to stroke is based on population data in our region. Follow-up to this study could be bolstered by continued review for pediatric strokes with new surges in COVID-19 infection rates associated with the Delta and Omicron variants. We did note higher rates of black or Asian children who had stroke in our cohort, relative to population prevalence of these racial/ethnicity groups. However, we do not have data on relative rates of COVID-19 infection in different racial/ethnic groups of pediatric populations in Utah, so we cannot determine whether the higher stroke incidence reflects a higher risk of stroke, or reflects a higher incidence of COVID-19 infections.
      There is mounting evidence that COVID-19 infection can lead to a delayed hyperinflammatory response, and our study suggests that stroke, particularly LVO stroke, with or without co-occurring diagnosis of MIS-C, could be a presentation of this prothrombotic state. Based on epidemiologic data, we hypothesize that there is likely a delay of at least one month from the timing of initial COVID-19 infection to the development of stroke.
      We did find a correlation of increased risk of stroke after COVID-19 infection in children; this is in contrast to initial reports of no increased risk, but which only had data on the first three months of the pandemic.
      • Beslow L.A.
      • Linds A.B.
      • Fox C.K.
      • et al.
      Pediatric ischemic stroke: an infrequent complication of sars-cov-2.
      Furthermore, our finding is matched by a more recent multicenter study reporting an increased stroke risk.
      • Beslow L.A.
      • Agner S.C.
      • Santoro J.D.
      • et al.
      International pediatric stroke study group. International prevalence and mechanisms of SARS-CoV-2 in childhood arterial ischemic stroke during the COVID-19 pandemic.
      Our study also highlights the delay in pediatric stroke diagnosis, as the majority of patients in our study presented outside of the window for acute intervention; this underscores the need for greater education surrounding early stroke detection in children. Stroke in the pediatric population is often diagnosed late or misdiagnosed altogether, likely because it is relatively rare and often presents with vague symptoms. Understanding stroke risk factors and association with other disease states such as COVID-19 is imperative in guiding early diagnosis and potential prevention strategies of stroke in children.

      Declaration of interests

      M.J.V.: No competing interests.
      S.S.: No competing interest.
      D.N.: No competing interests.
      K.E.J.: No competing interests.
      B.B.: No competing interests.
      J.L.B.: Consultant: Bluebird Bio, Calico, Enzyvant, Denali Therapeutics, Neurogene, Passage Bio; Board of Directors: wFluidx; writing: Up-to-Date; stock: Orchard Therapeutics; royalties: Manson Publishing, BioMerieux (spouse); research support: NIH, European Leukodystrophy Foundation, Vanishing White Matter Foundation.

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