key: cord-0902319-n6iogrgz
authors: Alcamo, Alicia M.; McGuire, Jennifer L.; Kanthimathinathan, Hari Krishnan; Roa, Juan David; Fink, Ericka L.
title: Worldwide epidemiology of neuro-coronavirus disease in children: lessons for the next pandemic
date: 2021-10-13
journal: Curr Opin Pediatr
DOI: 10.1097/mop.0000000000001069
sha: 442992d61afacca7763d60be5a0b0d394396451a
doc_id: 902319
cord_uid: n6iogrgz

PURPOSE OF REVIEW: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has overwhelmed the global community, negatively impacting patient health and research efforts; associated neurological manifestations are a significant cause of morbidity. This review outlines the worldwide epidemiology of neurologic manifestations of different SARS-CoV-2 clinical pediatric phenotypes, including acute coronavirus disease 2019 (COVID-19), multisystem inflammatory syndrome in children (MIS-C) and postacute sequelae of COVID-19 (PASC). We discuss strategies to develop adaptive global research platforms for future investigation into emerging pediatric neurologic conditions. RECENT FINDINGS: Multicenter, multinational studies show that neurological manifestations of acute COVID-19, such as smell/taste disorders, headache, and stroke, are common in hospitalized adults (82%) and children (22%), associated with increased mortality in adults. Neurological manifestations of MIS-C are reported in up to 20% of children, including headache, irritability, and encephalopathy. Data on PASC are emerging and include fatigue, cognitive changes, and headache. Reports of neurological manifestations in each phenotype are limited by lack of pediatric-informed case definitions, common data elements, and resources. SUMMARY: Coordinated, well resourced, multinational investigation into SARS-CoV-2-related neurological manifestations in children is critical to rapid identification of global and region-specific risk factors, and developing treatment and mitigation strategies for the current pandemic and future health neurologic emergencies.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes acute coronavirus disease 2019 (COVID-19) and the postinfectious hyperinflammatory shock syndrome, multisystem inflammatory syndrome in children (MIS-C), was declared the source of a global pandemic on March 11, 2020 by the World Health Organization (WHO) [1] . [2] (Fig. 1) . Neurological manifestations of SARS-CoV-2 infection were recognized early as a significant cause of mortality and morbidity, similar to influenza, Zika, and other emerging virus outbreaks [3, 4] . This review will outline the worldwide epidemiology and clinical manifestations of acute COVID-19, MIS-C, and postacute sequelae of SARS-CoV-2 (PASC) and their respective neurological manifestations in children. In addition to case counts and mortality rates, the SARS-CoV-2 pandemic has had other significant impacts on overall child health. Modeling estimates from LMICs suggest there has been an increase in child mortality from causes other than SARS-CoV-2 infection due to widespread disruption of healthcare systems [8] . Projections from UNICEF estimate that as a result of the pandemic, 140 million children are living in poverty in developing countries [9 && ], 463 million children have not had access to remote learning during school closures, 80 million children under the age of 1 have not received routine vaccinations [10], and 1.8 billion children are at risk for violence, exploitation and abuse due to disruption of violence prevention and response services [11] .

Severe acute respiratory syndrome coronavirus-2 variants As of July 2, 2021, the WHO has designated four notable SARS-CoV-2 variants of concern (VOC) in widespread global circulation, including: Alpha

Acute COVID-19, MIS-C, and PASC are different clinical phenotypes of SARS-CoV-2 infection in children with differing neurologic manifestation epidemiology.

The full range of neurological manifestations of acute COVID-19, MIS-C, and PASC and their impact on overall pediatric SARS-CoV-2 morbidity and mortality has yet to be determined.

Most existing pediatric epidemiological studies of viral illnesses such as SARS-CoV-2 report associated neurologic manifestations as secondary outcomes, using inconsistent terminology for neurologic signs and symptoms in cohorts of varying epidemiology, making comparisons across studies challenging.

The current SARS-CoV-2 pandemic is an urgent call to action to create an equitable, global neurology-focused platform for future emergent deployment to capture high-quality data and specimens from around the world with the goal of improving the health of all children and families worldwide. (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). Although there are many more variants in circulation, the VOCs listed above have each been associated with a change in public health significance, such as increased transmissibility, increased virulence, change in clinical presentation, decreased effectiveness of public health and social measures or available diagnostics, vaccines, and therapeutics [12] .

Severe acute respiratory syndrome coronavirus-2 clinical phenotypes in children Acute coronavirus disease 2019 Clinical signs and symptoms of acute COVID-19 range in severity. Up to 33% of infected individuals may be asymptomatic [13] . The remainder of children, similar to adults, have symptoms ranging from mild upper respiratory symptoms (fever, chills, cough) to more severe symptoms of hypoxemia, acute respiratory distress syndrome, and shock. Ten percent of children experience more severe illness with acute COVID-19 [14, 15] , particularly among Black children [16 & ], and those with reported underlying medical conditions [17, 18] .

Multisystem inflammatory syndrome in children First described in April 2020, MIS-C is a postinfectious hyperinflammatory syndrome that occurs in <1% of children [19] following confirmed SARS-CoV-2 infection [20] . Previously referred to as atypical Kawasaki disease, pediatric MIS (PMIS), and pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), MIS-C is a distinct clinical and immunologic entity from COVID-19 [21 & ]. MIS-C manifests primarily with gastrointestinal, mucocutaneous, and cardiovascular symptoms including myocardial dysfunction and shock; respiratory symptoms are less common. About 60% of children with MIS-C require intensive care unit admission. In addition, while children with acute COVID-19 have evidence of active SARS-CoV-2 infection by polymerase chain reaction (PCR), children with MIS-C more often have negative PCR but evidence of past infection by serology [22,23 && ]. As of June 28, 2021, the Centers for Disease Control and Prevention (CDC) reported a total of 4,196 cases of MIS-C in the US, including 37 deaths [24] . Affected children are more likely to be older school age or adolescent (compared to younger age), Black or Hispanic (compared to White) [25, 26 && ], and unlike acute COVID-19, children with MIS-C are most often previously healthy [26 && ]. Similar epidemiology has been described in the United Kingdom (UK) [27] , Europe [28, 29] , Canada, and South Africa [30] . Notably, there have been disproportionately fewer MIS-C reports in Asian countries; reasons for this difference are not yet clear [31] .

Multiple human coronaviruses (HCoV) have previously been associated with neurological manifestations [32] . Encephalitis [33] and acute disseminated encephalomyelitis (ADEM) [34] have been reported in association with HCoV-OC43. Headache, seizures, and cerebrovascular disease have been reported in association with SARS [35, 36] . Finally, ADEM, Guillain-Barré syndrome (GBS), Bickerstaff encephalitis, intracerebral hemorrhage, vasculopathy, encephalopathy, and seizures have been reported in association with Middle Eastern Respiratory Syndrome (MERS) [35, [37] [38] [39] .

Neurological manifestations in acute COVID-19 are reported globally in up to 82% of hospitalized adults [40 ,41,42] . The most commonly reported neurological manifestations are acute encephalopathy (up to 49%) and headache (37%); hospitalized adults with a neurological manifestation have been reported to have 6-fold higher odds of mortality [40 & ]. Smell/ taste disorders (anosmia, dysgeusia) have also been reported in 48-80% of all adults with acute COVID-19 [43, 44] , and ischemic stroke has been reported in 0.4-2.7% adults hospitalized or presenting to an ED [42, [45] [46] [47] [48] . There have been case reports of peripheral neurologic disorders (including GBS) [49] [50] [51] [52] , meningoencephalitis [53, 54] , ADEM and acute hemorrhagic necrotizing encephalopathy [49, 55] , seizures [56] [57] [58] , and posterior reversible encephalopathy syndrome [52] .

In children, there are fewer data regarding the prevalence of neurological manifestations of acute COVID-19 or MIS-C. Clinical neurologic, neurophysiologic, and neuroimaging data have not been routinely reported in large published epidemiologic cohorts, and cohorts often do not differentiate between acute COVID-19 and MIS-C. One potential reason for this lack of neurologic data is that some of the more subtle neurologic symptoms such as smell/taste disorders, headache, altered mental status, weakness, or paresthesia, may be difficult to identify in young children, and children may not recognize or volunteer these symptoms unless specifically asked. This ascertainment bias limits the ability of retrospective studies to adequately estimate the burden of neurologic manifestations among children.

The largest epidemiological study to date to examine neurological manifestations in hospitalized children included 1695 children with acute COVID-19 and MIS-C from 61 US hospitals. They found neurological manifestations in 22% of children with acute COVID-19 and 20% of children with MIS-C [59 && ]. Children with underlying neurological conditions had a higher prevalence of neurological manifestations (42% vs 22% previously healthy children) in the overall mixed cohort. The clinical spectrum of neurological manifestations reported was similar to that seen in adults. About a quarter of children with neurological manifestations presented with altered mental status or confusion, and seizures were more commonly a presenting symptom in younger children ($38% in children <5 years). Among a subset of 43 children with 'lifethreatening' neurologic manifestations in the mixed cohort, 26% died and 40% of survivors had new neurologic deficits at discharge [59 && ].

In the broader published pediatric literature, neurological manifestations such as smell/taste disorders, headache, seizures, and stroke appear to predominate in acute COVID-19, whereas headache, encephalopathy, and MRI changes suggesting neuroinflammation predominate in MIS-C. Examples of neurological manifestations in children reported to date are summarized by clinical phenotype in Table 1 As these studies represent different pediatric cohorts (e.g. critically ill vs hospitalized patients), caution should be taken in extrapolating this data.

There are several significant knowledge gaps in the epidemiology of pediatric SARS-CoV-2 neurological manifestations. First, cases of acute COVID-19 and MIS-C are not always clearly differentiated. Second, lack of common data elements and definitions for neurologic signs and symptoms make prevalence estimates difficult to interpret and evaluate in meta-analyses. For example, the term 'encephalopathy' is nonspecific; it may include altered mental status, irritability, lethargy, or some combination of the three. Several upcoming studies, including the pediatric arm of the GCS-NeuroCOVID (NCT04379089) may help address this limitation [81] (Table 2) . Third, despite limits placed on the conduct of research during the pandemic, increased research resources and preexisting research networks in HIC compared to LMIC led to publication biases, limiting our understanding of the scope of neurological manifestations and outcomes in less resourced regions. Finally, there are limited data regarding the impact of variants, vaccination, and disparities in access to vaccination, on the prevalence of neurological manifestations.

Postacute sequelae of SARS-CoV-2 infection among survivors are increasingly recognized, and sometimes referred to as Long COVID or PASC. In a systematic review of English-language cohort studies that included 9,751 adults following acute COVID-19 hospitalization, over 70% reported the persistence of one or more new symptoms such as fatigue (median: 40%), dyspnea (median: 36%), anxiety (median: 22%), anosmia and/or dysgeusia (median: 16%), depression (median: 15%), and cognitive deficits (median: 18%), including memory loss (median: 28%) and concentrating difficulties (median: 22%) [82] . Similar symptoms have been reported six months after acute infection in about 50% of adults with milder disease that did not require acute hospitalization [83] .

Children who have had either acute COVID-19 infection and/or MIS-C treated as outpatients or inpatients may also have postacute sequelae of infection [84, 85, 86 & ,87 & ], though estimates of prevalence vary. In a study of 129 children with prior SARS-CoV-2 infection in Italy, 58% had persistent symptoms at a mean of 163 (AE114) days follow-up. Risk factors included symptomatic infection and hospitalization. The most commonly reported symptoms were insomnia (18%), respiratory symptoms (15%), nasal congestion (12%), fatigue (11%) and concentration issues (10%) [84] . However, in the UK, <1% of children <17 years old self-reported symptoms of long COVID [88] . Hospitalized children and their families are also at risk of postintensive care/hospital syndrome (PICS) [89] , compounding the virus's effects on functional health domains, health-related quality of life, future development, and participation. Ongoing multicenter studies will provide further information about the long-term sequelae and outcomes associated with acute COVID-19 and MIS-C in pediatrics ( Table 2) .

In the US and the UK, the first vaccine approved for emergency use in people !16 years in December 2020, was Pfizer-BioNTech's mRNA vaccine [90, 91] . This approval was extended to US adolescents 12-15 years of age in May 2021 [92] with ongoing trials for younger children to determine dosing, safety, and efficacy. Multiple other vaccines using mRNA, viral vector, and inactivated virusbased platforms have been introduced since. As of July 12, 2021, over 3 billion vaccines doses had been administered worldwide [5 && ]. Impact of vaccination and VOC emergence on the frequency and presentation of neurological manifestations remains to be determined.

As of July 2021, there have been no reports of neurologic adverse events following vaccination in children. In adults, GBS variants have been reported following viral vector-based vaccine administration (Oxford-AstraZeneca, Johnson & Johnson's Janssen), but this is rare [93, 94] . Currently, a history of GBS is not considered a contraindication for receiving a SARS-CoV-2 vaccine. In addition, while there was early concern of acute onset peripheral facial nerve palsy following mRNA-based vaccine administration (Pfizer-BioNTech, Moderna) [95, 96] , subsequent evaluation of 320 million vaccination administrations from the WHO database demonstrated no increase over baseline population incidence following vaccination [97] . These data highlight the importance of reporting and monitoring potential vaccine adverse effects through national and international systems, such as the CDC's Vaccine Adverse Event

Reporting System, to determine if there are true associations between specific vaccines and potential neurologic adverse events.

The emergence of multiple novel pathogens in the 21 st century has reinforced the critical need for rapid, prospective, global epidemiologic and clinical data collection when new infectious threats present [3, 35, [37] [38] [39] . Although national and international public health systems in HIC have developed excellent mechanisms to monitor case counts and mortality, most of our understanding of neurological manifestations has initially come from HIC case reports and case series [98] . Prospective global data on neurological manifestations and outcomes of the various SARS-CoV-2 clinical phenotypes are only now beginning to emerge, 17 months into the pandemic, with pediatric data lagging. Investment in research to examine the impact SARS-CoV-2 infection has on the developing brain in the context of the individual and family is greatly needed.

Although the pandemic has highlighted examples of clinical research of good quality despite constraints, it has also highlighted gaps in existing international research infrastructure [99 & ]. Standardized reporting of clinical data, as used in the ISARIC/WHO clinical characterization protocol ], provided timely epidemiological, clinical, and prognostic information during the pandemic for children. Large scale interventional trials in adults (e.g., SOLIDARITY, RECOVERY, ACTT, REMAP-CAP) were instrumental in reducing uncertainty at the bedside and improving outcomes [100] [101] [102] [103] . However, such large-scale interventional trials in children have not yet emerged.

Single-center studies are locally impacted by patient population demographics (e.g., age, comorbidities, social determinants of health) and by the frequency of neurologic manifestations. There is thus a critical need for multicenter, multinational collaboration to better understand neurologic manifestations of pediatric diseases. Clinical research networks in pediatrics (e.g., PALISI, PCCSSG, ESPNIC, ANZICS-PSG, LaRed, PACCMAN, CPCCRN), neurology (e.g., PNCRG, NeuroNEXT), and infectious disease (ISA-RIC) worldwide have produced innovations in epidemiology, pathobiology, and therapeutic efficacy in a variety of disorders. These networks could be leveraged to create a resource previously unavailable to transform pediatric neurologic care worldwide.

We propose establishing an inclusive, global neurology research network platform in advance of the next pandemic to facilitate rapid execution of streamlined and cost-effective neurology-focused pediatric protocols. This platform should incorporate key principles of a Learning Health System, scaled for global application [104] . Necessary steps include: (a) sufficient, equity-oriented funding for platform infrastructure to facilitate participation, (b) coordination among existing and newly created clinical research networks; (c) streamlined, standardized case report form with predefined common data elements; (d) training/education bundles; (e) biorepository with standards for sample collection, transfer, and storage; (f) preexisting and centralized ethical/regulatory approval; and (g) inclusive (e.g., clinical, research, funder, family/patient) and effective leadership structure (Fig. 2) . This platform could facilitate swift understanding of the epidemiological scope of the neurologic problem, generate hypotheses, evaluate potential risk factors and outcomes, and support direct public health efforts. When therapeutic interventions are proposed, this platform may provide the springboard for efficient clinical trials using innovative methodologies such as randomized registry trials and a master protocol to test multiple interventions.

Neurological manifestations of SARS-CoV-2 infection in children are common, heterogenous, and distinct in each clinical phenotype (acute COVID-19, MIS-C, and PASC). Their potential impact on overall pediatric SARS-CoV-2 morbidity and mortality has yet to be determined. A strategy to create an equitable, global neurology-focused platform for future emergent deployment to capture high-quality data and specimens is critically needed to care for and protect children with neurologic manifestations of disease across the globe. 

There are no conflicts of interest.

Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest

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