key: cord-0828639-yguqwc1l
authors: Fink, Ericka L.; Robertson, Courtney L.; Wainwright, Mark S.; Roa, Juan D.; Schober, Michelle E.
title: Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C
date: 2021-12-28
journal: Pediatr Neurol
DOI: 10.1016/j.pediatrneurol.2021.12.010
sha: 640fea391b3517d4f19a209e24f6562d33cff66d
doc_id: 828639
cord_uid: yguqwc1l

BACKGROUND: Our objective was to characterize the frequency, early impact, and risk factors for neurologic manifestations in hospitalized children with acute SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children (MIS-C). BASIC PROCEDURES: Multicenter, cross-sectional study of neurologic manifestations in children age < 18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020-April 2021. Multivariable logistic regression to identify risk factors for neurologic manifestations was performed. MAIN FINDINGS: Of 1,493 children, 1,278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurologic manifestation. The most common neurologic findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both p<0.05. Children with neurologic manifestations were more likely to require ICU care (51% vs. 22%), p<0·001. In multivariable logistic regression, children with neurologic manifestations were older (odds ratio [OR] 1·1 and 95% confidence interval [95% CI] 1·07-1·13), and more likely to have MIS-C vs. acute SARS-CoV-2 (OR 2·16, 95% CI 1·45, 3·24), pre-existing neurologic and metabolic conditions (OR 3·48, 95% CI 2·37-5·15; and OR 1·65, 95% CI 1·04-2·66, respectively), and pharyngeal (OR 1·74, 95% CI 1·16-2·64) or abdominal pain (OR 1·43, 95% CI 1·03-2·00); all p<0·05. PRINCIPAL CONCLUSIONS: In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurologic manifestations, which were associated with ICU admission and pre-existing neurologic condition. Post-hospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.

Globally, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic has led to an estimated 13·5 million cases and 10,600 deaths in children and young adults under 20 years of age as of May 2021 (https://data.unicef.org/resources/covid-19-confirmed-cases-and-deaths-dashboard/). Among hospitalized adults with COVID-19, the acute disease caused by SARS-CoV-2 infection, 36-82% experienced central and peripheral central nervous system manifestations associated with increased risk of mortality 1,2 . Reports show that neurologic signs and symptoms such as headache and altered mental status 3, 4 , and conditions such as Guillain Barre Syndrome 5 and encephalitis 6, 7 , occur in children with COVID-19 and the post-infectious Multisystem Inflammatory Syndrome in Children 

This is a preliminary analysis of a multinational, observational cohort study conducted between January 1, 2020 and April 30, 2021. Screening was performed at each center using locally-approved methods including chart review and hospital registries. Local regulatory approval was obtained at each study site. The University of Pittsburgh Institutional Review Board (STUDY20060012) approved the Data Coordinating Center at the University of Pittsburgh to receive and analyze the data.

Inclusion criteria. Children aged < 18 years who were admitted to the hospital with SARS-CoV-2-related condition. Acute SARS-CoV-2 patient cases were either confirmed (positive SARS-CoV-2 virus or antibody test) or presumed (clinical diagnosis), may or may not have been symptomatic, and did not receive a diagnosis of MIS-C.

Presumed acute SARS-CoV-2 infection was defined as a patient who was diagnosed clinically due to clinical suspicion and/or a close contact being positive for the virus; this situation occurred most often early in the pandemic when testing was restricted due to lack of testing availability. MIS-C diagnosis was determined by treating physicians with guidance from the Centers for Disease Control (https://www.cdc.gov/mis/hcp/index.html).

Exclusion criteria. Previous enrollment.

The GCS-NeuroCOVID Consortium studies hospitalized adult (18 years or older) and pediatric (< 18 years of age) patients with SARS-CoV-2-related conditions. The over-arching goals of this consortium include to 9 : 1) characterize neurologic manifestations; 2) identify predictors of neurologic manifestations; 3) determine the impact of neurologic manifestations on post-hospital outcomes; and 4) explore mechanisms and predict outcome of neurologic injuries.

Pediatric centers were recruited from pediatric critical care professional networks with endorsements from the Neurocritical Care Society (NCS) and the Pediatric Neurocritical Care Research Group (PNCRG) and registered on an NCS webpage 10 . Thirty centers submitted data for this preliminary analysis (eTable 1). Twenty-six (n=1,440 patients) centers J o u r n a l P r e -p r o o f were in North America. Nearly all centers were university-affiliated (99·8%) and 64% were free-standing children's hospitals.

A Case Report Form (CRF) 11 with common data elements, data dictionary, and guide to data collection was provided to centers. The following data types were extracted from the medical record and entered into the CRF: a) patient characteristics (e.g., pre-existing condition); b) disease details (e.g., neurological manifestations, initial Glasgow 12 , c) testing results (e.g., SARS-CoV-2 testing); d) acute SARS-CoV-2 and MIS-C-related treatments (e.g., steroids); e) patient outcomes at hospital discharge (e.g., mortality); f) center characteristics (e.g., number of hospital beds); and rehabilitation consultations (e.g., physical therapy). Testing for SARS-CoV-2 related conditions was determined by individual center clinicians and availability of resources. The definitions of neurologic manifestations studied here were previously published by the consortium 11 . Conditions such as stroke, which included both ischemic and hemorrhagic stroke, and seizure were diagnosed by local clinicians without specific study criteria. Encephalopathy was defined as new onset altered mental status, lethargy, or drowsiness not otherwise diagnosed as delirium. Delirium was diagnosed clinically or through a delirium scoring tool used at the center. Body mass index (BMI) was calculated as follows: weight (kg) / [height (m)]2. Obesity was defined as BMI ≥ 30 13 .

The primary outcome was frequency and type of neurologic manifestations, overall and by acute SARS-CoV-2 and MIS-C groups. Secondary outcomes included risk factors for neurologic manifestations, overall and by acute SARS-CoV-2 and MIS-C groups.

J o u r n a l P r e -p r o o f Each site was assigned a study identification code and entered data into a custom Microsoft Excel (2019) CRF. Data entry was performed by faculty, trainees, and/or research coordinators. Webinars and email served to provide regular study updates and training for study start-up and execution.

The Data Coordinating Center (DCC) primary investigator and coordinator team worked with the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center at the University of Pittsburgh to manage central data collection, quality, security, and analysis. Centers with a data use agreement in place with the University of Pittsburgh submitted patient data to the DCC using encrypted email or via upload to a secure cloud (https://www.globus.org/). Data were stored on a password-protected network at the DCC, with additional periodic secure offsite backups to the database. Data were screened for missing or implausible information and queries were issued for clarification and adjusted.

Statistical analysis. Most data were non-parametric and presented as median (interquartile range [IQR]).

Comparisons were made between children 1) with and without neurologic manifestations, and 2) acute SARS-CoV-2 versus MIS-C groups. Kruskal-Wallis, Mann-Whitney, Fisher's exact, and chi-square tests were used as appropriate.

Multivariable logistic regression modeling was performed to identify patient and disease characteristics associated with neurologic manifestation in the overall cohort and by acute SARS-CoV-2 and MIS-C groups. Spearman correlations for neurologic conditions (e.g., stroke) and symptoms (e.g., headache) were performed to explore common patient presentations. No adjustment was made for multiple comparisons except for correlations; secondary outcomes results should be interpreted as hypothesis-generating. Statistical analysis by region was not performed due to the small number of centers and subjects in some regions. The majority of variables had less than 10% missing data, and missing data were not imputed (thus sample sizes for variables and denominators varied slightly). All p-values were two-sided, 

The median age of the 1,493 children analyzed in the overall cohort was 8 (IQR 1·1-14·0) years and 47% were female (Table 1) . Forty-two per cent and 28% identified as White or Black race, respectively, and 37% as Hispanic or Latino. Most patients were admitted during the July-December 2020 epoch (55%) versus January-June 2020 (34%) and January-April 2021 (10%), p<0·001. Of 863 (58%) children with a pre-existing condition, the most common were respiratory and neurologic (20% each). The most common acute, constitutional, non-neurologic symptoms reported were fever (64%), cough (36%), and anorexia (29%). Six per cent of children had a GCS score ≤ 12 on hospital admission.

Thirty-five per cent of children required ICU care, with PELOD score 7 (1-11). Ninety-five per cent of children were discharged to home, 2% were discharged to inpatient rehabilitation, and 1% died.

Eighty-six per cent of children were diagnosed with acute SARS-CoV-2 versus 14% with MIS-C. Children with acute SARS-CoV-2 were more often admitted in earlier epochs, were younger, and of Hispanic ethnicity than children with MIS-C, all p<0·05. SARS-CoV-2 polymerase chain reaction (PCR) or antigen tests were positive in 96% and 64% of children with acute SARS-CoV-2 and MIS-C, respectively, while antibody tests were positive in 14% and 86% of these populations. Pre-existing conditions were more common in children with acute SARS-CoV-2 (61%) than those with MIS-C (37%), p<0·001. Initial GCS scores were similar between acute SARS-CoV-2 and MIS-C groups. Children with MIS-C were more frequently admitted to the ICU (69% vs. 29%) and had longer lengths of ICU and hospital stay than children with acute SARS-CoV-2, all p<0·05. Eleven (1%) children with acute SARS-CoV-2 and 4 (2%) children with MIS-C died by hospital discharge, p=0·174. Children with MIS-C had increased frequency of all non-neurologic symptoms compared with children with acute SARS-CoV-2; the most common non-neurologic symptoms for both groups was fever (59% vs. 96%, acute SARS-CoV-2 versus MIS-C, respectively, p<0·001).

Forty-four per cent of children presented with at least one neurologic sign or symptom and 12% of children had two or more (Table 2, Figure 1 ). Headache (20%) and encephalopathy (16%) were the most common neurologic manifestations in children overall, followed by seizures (8%). Anosmia (4%), ageusia (3·6%), meningitis/encephalitis J o u r n a l P r e -p r o o f (1·3%), and stroke (0·9%) were less common. Non-neurologic symptoms were generally more common in children with neurologic manifestations (Table 1) . More children with neurologic manifestations had moderate (GCS 8-12, 8% vs. 1%) or severe (GCS<8, 5% vs. 0·4%) impairment of consciousness on admission compared to children without neurologic manifestation, p<0·05. More children with neurologic manifestations required ICU care compared to children without neurologic manifestations (51% vs. 22%, p<0·05). Hospital (5 [2] [3] [4] [5] [6] [7] [8] [9] vs. 3 [2] [3] [4] [5] [6] days) and ICU (5 [3] [4] [5] [6] [7] [8] vs. 3 [2] [3] [4] [5] days) lengths of stay were longer for children with neurologic manifestations compared to children without neurologic manifestations, both p<0·05.

Forty per cent of children with acute SARS-CoV-2 and 66% with MIS-C presented with at least one neurologic sign or symptom. The most common neurologic manifestations in children with acute SARS-CoV-2 were headache (16%), acute encephalopathy (15%), and seizures (8%) whereas children with MIS-C most commonly had headache (47%), acute encephalopathy (22%), and dizziness (12%). Anosmia and vision impairment had similar prevalence between acute SARS-CoV-2 and MIS-C populations. Stroke was reported in 12 (0·9%) and 1 (0·5%) children with acute SARS-CoV-2 and MIS-C, respectively. Other neurologic manifestations reported by participating centers as write-ins included co-acute neurologic conditions such as traumatic brain injury (n=13, all in the acute SARS-CoV-2 group) and acute psychosis (n=7; acute SARS-CoV-2 n=4 and MIS-C n=3). More children with MIS-C vs. acute SARS-CoV-2 had 2 or more neurologic manifestations (66% vs. 40%), p<0·001.

Median days to onset of neurologic and non-neurologic symptom(s) and neurologic condition(s) in the overall cohort and acute SARS-CoV-2 and MIS-C sub-cohorts are presented in Figures 2 and 3 , with day 0 corresponding to the day of hospitalization. In the overall and acute SARS-CoV-2 groups, the earliest pre-hospitalization neurologic symptoms included headache, ageusia, and anosmia, all occurring at median 3 days prior to hospitalization except headache in the acute SARS-CoV-2 group occurring at median 2 days prior to hospitalization. In the MIS-C group, the earliest pre-hospital neurologic symptoms included syncope (median 7·5 days prior to hospitalization), ataxia (6 days), headache (4 days), and dizziness (3 days). All non-neurologic manifestations occurred prior to hospitalization (Figure 3 ). Correlations between symptoms and conditions are in Supplemental Table 4 . Weak correlations were found, with unique patterns of neurologic symptoms for each neurologic condition.

Twenty-eight percent of children received ICU care. Children who were older (10 [4·9-15·0] vs. 7 [0·8-14·0] years), male (58% vs. 50%), and those with pre-existing conditions (66% vs. 53%) were more likely to be admitted to an ICU, all p<0·05 (eTables 1 and 2). Critically ill children generally had more neurologic manifestations reported compared with children admitted to the ward, all p<0·05.

In a multivariable logistic regression in the overall cohort, older age (adjusted odds ratio [OR] 1·10, 95% confidence interval [95% CI] 1·07-1·13), MIS-C vs. acute SARS-CoV-2 diagnosis (OR 2·16, 95% CI 1·45, 3·24), neurologic (OR 3·48, 95% CI 2·37-5·15) and metabolic pre-existing condition (OR 1·65, 95% CI 1·04-2·66), and throat (OR 1·74, 95% CI 1·16-2·64) and abdominal pain (OR 1·43, 95% CI 1·03-2·00) were associated with neurologic manifestations, all p<0·05 (Table 4a ).

In the acute SARS-CoV-2 group, older age (OR 1·10, 95% CI 1·07-1·13) and pre-existing neurologic (OR 3·64, 95% CI 2·45-5·48) or metabolic (OR 1·78, 95% CI 1·09-2·96) condition, anorexia (OR 1·56, 95% CI 1·10-2·22) and throat pain (OR 1·85, 95% CI 1·15-3·00), were associated with neurologic manifestations, all p<0.05. Black race (OR 0·63, 95% CI 0·42-0·94) and pre-existing cardiovascular condition (OR 0·52, 95% CI 0·30-0·89) were protective factors, both p<0·05 (Table 4b ).

In the MIS-C group, older age (OR 1·16, 95% CI 1·06-1·27), pre-existing respiratory condition (OR 4·98, 95% CI 1·21-27·88) and abdominal pain (OR 5·36, 95% CI 2·39-12·63), were associated with neurologic manifestations, all p<0·05. Pre-existing gastrointestinal (OR 0·03, 95% CI 0·001-0·27) condition was protective, p<0·05.

In this preliminary report of neurologic manifestations in children hospitalized with acute SARS-CoV-2 and MIS-C: 1) neurologic manifestations were common (44%); 2) the frequency of severe neurologic conditions including stroke were uncommon, but children with neurologic manifestations were more likely to present with abnormal GCS and require ICU care; and 3) older children and those with specific pre-existing conditions and constitutional symptoms were at increased risk of neurologic manifestations, although this risk differs by acute SARS-CoV-2 vs. MIS-C diagnosis.

The frequency of neurologic manifestations in this prospective cohort of hospitalized children is lower than that reported by the GCS-NeuroCOVID Consortium -Adult study (All COVID-19 cohort, 80%) 2 . Our cohort had higher prevalence of neurologic manifestations than reported in a secondary analysis of the Overcoming COVID-19 study (n=1,695 children in US hospitals) 6 . In the latter cohort, only 22% of children hospitalized with SARS-CoV-2 infection (not reported by acute SARS-CoV-2 or MIS-C separately) had neurologic manifestations. In that cohort, fatigue/weakness were most common, followed by altered awareness or confusion, and then headache. One explanation for the difference in neurologic manifestation type and frequency is that our study collected more granular data collection on neurologic manifestations than the Overcoming COVID-19 study, and our study did not assess fatigue/weakness 11 .

Finally, a meta-analysis of neurologic manifestations in SARS-CoV-2 infection in children found that fatigue/myalgia was most prevalent (14%) followed by acute encephalopathy (13%), with a lower headache and seizure prevalence than we observed at 4% and 3%, respectively 15 . Differences in our study population, such as including children with pre-existing neurologic conditions and a substantial number of children with MIS-C, may account for some of the differences in reported frequency of neurologic manifestations. Many excellent reviews exist regarding potential mechanisms of neurologic manifestations with SARS-CoV-2 in children; detailed discussion of this is outside the scope of this report 16 .

Headache and acute encephalopathy were the predominant neurologic manifestations, especially in children with MIS-C. This differs from adults, in whom acute encephalopathy was the most commonly reported neurologic manifestation (50%), which was also associated with mortality 2 . An International Pediatric Stroke Study Group multinational study reported that of children with strokes occurring during the pandemic, fewer than half were tested for acute SARS-CoV-2 infection and that most children with stroke had underlying risk factors for stroke 17 . In our study, stroke was less prevalent in children than in the adult GCS-NeuroCOVID consortium study (1% vs. 3%), but seizure/status J o u r n a l P r e -p r o o f epilepticus was more prevalent in children than adults (8% vs. 1%). Further, seizure/status epilepticus was more than twice as frequent in children with acute SARS-CoV-2 than MIS-C. In the Overcoming COVID-19 study, seizures were more common in younger versus older children 6 . Other more severe conditions occurred rarely, similar to a cohort in the United Kingdom, which prospectively studied children with SARS-CoV-2-related illness who were hospitalized and received a neurology consultation 7 . They found more encephalopathy and neuropsychiatric manifestations occurred in the children with MIS-C versus acute SARS-CoV-2 infection.

Children with pre-existing conditions were at increased risk of more severe SARS-CoV-2-related illness and neurologic manifestation 6 . This finding is similar to newly reported data in children with pre-existing neurologic disease with influenza 18 . In our study, children with SARS-CoV-2-related illness and pre-existing neurologic conditions had 3·48 higher odds for neurologic manifestation compared to children without pre-existing neurologic condition. It is possible that children with pre-existing neurologic conditions have decreased cognitive and functional reserves and hence less tolerance to systemic insults common to hospitalized patients such as oxygen desaturation, hypotension, and fever.

Children with MIS-C had more than 2 times higher odds of neurologic manifestation compared with the acute SARS-CoV-2 cohort. This may be due in part to hyperinflammation; more research is needed 19 . Metabolic disease, which includes type I diabetes mellitus, was also associated with neurologic manifestations in children with acute SARS-CoV-2, with SARS-CoV-2 having mechanistic plausibility for "diabetogenic effect", similar to other viruses 20 . 25, 26 , exposure to maltreatment 27 , developmentally important experiences 28 , and parental loss 29, 30 .

Neurologic manifestations were only recorded if present in the medical record; thus, younger age and developmental status as well as inconsistent documentation contribute to lower reporting due to ascertainment bias.

Some manifestations, such as encephalopathy, may present differently by age or developmental stage unaccounted for in our data definitions. It is thus possible that encephalopathy was over or underreported if a child's baseline developmental status was not known by the documenting clinicians. Hospital presentation GCS scores were recorded but baseline GCS scores were not. Pre-existing conditions were determined by site research investigators using data available in chart review. Despite the goal of diverse geographical inclusion, centers participating in this preliminary report are largely from North America. Some acute SARS-CoV-2 group patients were admitted for other primary diagnoses (e.g., trauma) and were found to be positive for SARS-CoV-2 due to center testing policies; we are unable to accurately report the number of these patients. Otherwise asymptomatic children with neurologic conditions such as stroke may not have been tested for SARS-CoV-2 due to low clinical suspicion and thus some neurologic manifestations may be underreported 17 . In children presenting with comorbid acute neurologic disease, we were not able to determine whether neurologic manifestations were due to SARS-CoV-2 related condition or the comorbid disease. Some patients in our consortium were included in other published US cohort studies. Last, impact of the SARS-CoV-2 delta variant is largely absent from this analysis.

The strengths of our study include prospective data collection using a case report form with defined data elements in a multicenter, multinational consortium. Future consortium reports will focus on relationships between neurologic manifestations, physiologic and laboratory data, acute SARS-CoV-2 and MIS-C specific treatments, and outcomes at hospital discharge. Additionally, the consortium has launched a post-hospital discharge outcome in a subset of patients. Results of these studies will inform future hypothesis-driven proposals to uncover pathophysiology of neurologic manifestations of SARS-CoV-2 conditions in the developing brain and therapeutic opportunities. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

Roa had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design

Acquisition, analysis, and interpretation of data

Critical revision of the manuscript for important intellectual content

Children's Hospital of Philadelphia)

Children's Healthcare of Atlanta)

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