key: cord-0063090-8kqfnn5x
authors: Janowski, Andrew
title: Epilogue
date: 2021-05-14
journal: Biochemical and Molecular Basis of Pediatric Disease
DOI: 10.1016/b978-0-12-817962-8.00052-4
sha: 50aae3428830ee15f725c5c4abf7f597b79f7cd8
doc_id: 63090
cord_uid: 8kqfnn5x

nan

For SARS-CoV-1 and SARS-CoV-2, infected children are relatively spared from the complications observed in older adults [11] [12] [13] [14] [15] [16] [17] . This contrasts with outcomes with other viral respiratory diseases, including influenza, respiratory syncytial virus, and human metapneumovirus, where increased morbidity and mortality are observed at both extremes of age (young infants and the elderly) [18] [19] [20] [21] [22] . A small proportion of children do develop severe complications of COVID-19, as the Centers for Disease Control and Prevention (CDC) analysis of pediatric COVID-19 cases diagnosed by nasopharyngeal polymerase chain reaction (PCR) between February-April 2020 estimated that 5.7-20% of pediatric cases required hospitalization [13] . In a meta-analysis of published pediatric COVID-19 cases, only 3.3% required admission to the intensive care unit [15] . These percentages are likely overestimates because many cases go unrecognized and were not well captured during the initial surge of cases in the United States because many children developed either no or mild symptoms of infection [13] . Symptoms of pediatric COVID-19 can be nonspecific and have precluded the development of a clinical diagnostic tool based solely on symptoms. Children may present with fever, cough, myalgia, rhinorrhea, shortness of breath, headache, nausea/vomiting, or diarrhea, but many of these symptoms are present in less than half of symptomatic children [11] [12] [13] [14] [15] [16] .

Various hypotheses have been proposed to explain the differences in the clinical outcomes of COVID-19 in children and adults [23] [24] [25] . Children have fewer comorbidities that increase the risk of poor outcomes, including lower rates of obesity, heart disease, chronic lung disease, and diabetes [11] [12] [13] [14] [15] [16] . Conversely, children are frequently exposed to seasonal coronaviruses (229E, NL63, OC43, and HKU1), which may confer cross-protective immunity [25, 26] . Cross-reactive CD4+ T cell responses to SARS-CoV-2 in unexposed individuals have been identified, supporting the potential for cross-protective immunity to be induced by infection of other non-SARS coronaviruses [26] . The immune response to SARS-CoV-2 may also be altered in children compared to adults, as significant dysregulation occurs with increased age [24] . This leads to an increased risk of development of a hyperimmune response often referred to as a "cytokine storm," and these age-dependent differences have been observed in mouse models of SARS-CoV-1 infection [27] [28] [29] . Children might be at lower risk for becoming infected and transmitting the virus to others, as they may have a reduced expression of angiotensin-converting enzyme 2 (ACE2), the host cell receptor utilized by SARS-CoV-2 to gain entry to cells [30, 31] . All of these hypotheses may contribute to the observed differences in COVID-19 in children when compared to adults.

While the vast majority of children recover from SARS-CoV-2 without significant sequalae, a unique pediatric presentation of COVID-19 has been recognized and has been named multisystem inflammatory syndrome in children (MIS-C) [32] [33] [34] . This condition was first recognized in children weeks after an initial surge of COVID-19 cases in a community, providing an epidemiological link between this disease and SARS-CoV-2 infection [32] [33] [34] . The CDC has defined this condition as a recent SARS-CoV-2 infection by PCR, antigen test, serology, or recent exposure to a known case of COVID-19; the presence of fever, laboratory evidence of inflammation (defined as elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase, interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes, or low albumin), and multisystem (≥2) organ involvement (cardiac, renal, hematologic, respiratory, gastrointestinal, dermatologic, or neurological) [32] . In a cohort of 186 MIS-C patients in the United States, cases were identified from children <1

year of age to age 20, with a higher proportion of cases occurring in males (62%) and 73% were previously healthy [32] . A majority (71%) of children had four or more organ systems involved with the gastrointestinal (92%), cardiovascular (80%), hematologic (76%), mucocutaneous (74%), and respiratory (70%) systems being the most frequently involved [32] . Cardiac injury is one of the most severe complications of MIS-C as 50% of children had elevations of troponin, 73% had elevated B-type natriuretic peptide, and 48% required vasoactive medications to support their blood pressure [32] . The long-term consequences of MIS-C remain unknown and four children with MIS-C had died by the time of publication [32] .

One of the most provocative findings of MIS-C is the overlap in the signs and symptoms that are observed in Kawasaki disease, a medium-vessel vasculitis that can lead to aneurysm of the coronary blood vessels [35, 36] . Children with Kawasaki disease commonly present with persistent fever, rash, conjunctivitis, hand/feet swelling or erythema, lip/tongue changes, and lymphadenopathy [36, 37] . In a subset of children, coronary aneurysms will develop, and similar changes have also been observed in 8% of children with MIS-C [32, 35] . Currently, the etiology of Kawasaki disease remains unknown despite being first described nearly 50 years ago, with some of the epidemiological data being suggestive of an undiscovered virus [37] . Coronaviruses have been previously associated with cases of Kawasaki disease, including coronavirus species 229E and NL63; however, further follow-up studies did not confirm the same association [38] [39] [40] [41] [42] [43] [44] [45] . Given the recent emergence of SARS-CoV-2, this virus cannot be the exclusive cause of Kawasaki disease, but given the emergence of a condition that mimics several of the features of Kawasaki disease, SARS-CoV-2 may provide the important insights into common pathways in the pathogenesis of each disease. Autopsy series of fatal cases of COVID-19 have demonstrated the virus in the predicted tissues of the upper and lower respiratory tracts [46, 47] . SARS-CoV-2 has also been detected in endothelial cells of many organs, including the lungs, heart, and kidneys, and is associated with an extensive disruption and inflammation of endothelial cells [48] . The ACE2 receptor is highly expressed on the surface of many cells of the cardiovascular system, including cardiac myocytes and endothelial cells, providing a mechanistic connection between the viral infection and cardiovascular complications like myocarditis or development of coronary aneurysms [49] . While SARS-CoV-2 has been considered primarily a respiratory infection, viral infection of the cardiovascular system is likely an important determinant of COVID-19 morbidity and mortality. Further study is needed to better understand the consequences of cardiovascular inflammation induced by coronaviruses and may lead to the elucidation of the mechanisms of coronary aneurysm formation in MIS-C and Kawasaki disease.

The diagnostic approach for COVID-19 is the same across the age spectrum, with utilization of a reverse transcription PCR for detection of viral RNA in nasopharyngeal or saliva samples during the acute phase of infection [50] . Other body sites are being examined for detection of SARS-CoV-2 to enhance sensitivity or provide prognostic function as many pediatric patients can have prolonged shedding of viral RNA in stool samples [14] . Utilization of serological testing has been mostly beneficial in categorizing children who were recently infected with SARS-CoV-2 and subsequently developed symptoms consistent with MIS-C [32] . Many of the initial commercial antibody assays used for COVID-19 utilize the nucleocapsid antigen, which may lead to false positives due to the detection of cross-reacting antibodies from other coronaviruses and confound studies of the seroprevalence in regions with low rates of infection [50] .

Other biomarkers have been used to quantify inflammation from pediatric COVID-19 cases and have been used in the case definition of MIS-C, including C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase, IL-6, albumin, and complete blood cell counts [15] . Some of these biomarkers have prognostic function in predicting outcomes in adult COVID-19 cases, including IL-6 and other cytokines, but the utility of these tests in children are unknown, especially given that the few pediatric fatalities have occurred [51, 52] . These tests may provide some benefits in identifying patients with high risk of cardiovascular and hematological complications, as up to 70% of adult fatalities have evidence of hypercoagulable state, 7-28% of hospitalized adults have evidence of myocardial injury, and up to 50% of deaths exhibit concomitant evidence of heart failure [52, 53] .

The SARS-CoV-2 pandemic triggered an unprecedented mobilization of medical providers, scientists, epidemiologists, and experts across many scientific fields to rapidly redirect the efforts to study all the aspects of SARS-CoV-2 and COVID-19. The lessons learned from this pandemic will hopefully serve as an important foundation on how to prevent and mitigate future emerging infections in modern society, as SARS-CoV-2 will not be the last global threat to human health.

SARS and MERS: recent insights into emerging coronaviruses

Zika virus

Ebola virus disease

Covid-19 in critically ill patients in the Seattle region -case series

Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data

Pandemic preparedness and response-lessons from the H1N1 influenza of

What recent history has taught us about responding to emerging infectious disease threats

The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

Covid-19 -navigating the uncharted

Ten weeks to crush the curve

Epidemiology of COVID-19 among children in China

Chinese pediatric novel coronavirus study T SARS-CoV-2 infection in children

Coronavirus disease 2019 in children -United States

Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review

ColumbiaPediatric, Epidemiology, clinical features, and disease severity in patients with coronavirus disease 2019 (COVID-19) in a children's hospital in

Severe acute respiratory syndrome in children

Immunity to RSV in early-life

The burden of respiratory syncytial virus infection in young children

Economic impact of respiratory syncytial virus-related illness in the US: an analysis of national databases

The annual impact of seasonal influenza in the US: measuring disease burden and costs

Respiratory syncytial virus-and human metapneumovirus-associated emergency department and hospital burden in adults, Influenza Other Respir

Possible causes for decreased susceptibility of children to coronavirus

Will children reveal their secret? The coronavirus dilemma

Lessons from COVID-19 in children: key hypotheses to guide preventative and therapeutic strategies

Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo

COVID-19 cytokine storm: the interplay between inflammation and coagulation

HLH Across Speciality Collaboration UK. 2020. COVID-19: consider cytokine storm syndromes and immunosuppression

Nasal gene expression of angiotensin-converting enzyme 2 in children and adults

Airways Expression of SARS-CoV-2 Receptor, ACE2, and TMPRSS2 Is Lower in Children Than Adults and Increases with Smoking and COPD

Centers for Disease Control, prevention multisystem inflammatory syndrome in children investigation team. Multisystem inflammatory syndrome in children in New York state

Hyperinflammatory shock in children during COVID-19 pandemic

Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children

Kawasaki disease as a systemic vasculitis in childhood

The epidemiology and pathogenesis of Kawasaki disease

Association between a novel human coronavirus and Kawasaki disease

Possible involvement of infection with human coronavirus 229E, but not NL63, in Kawasaki disease

Lack of association between New Haven coronavirus and Kawasaki disease

Lack of association between infection with a novel human coronavirus (HCoV), HCoV-NH, and Kawasaki disease in Taiwan

Human coronavirus NL63 is not detected in the respiratory tracts of children with acute Kawasaki disease

Human coronavirus-NL63 infection is not associated with acute Kawasaki disease

Blinded case-control study of the relationship between human coronavirus NL63 and Kawasaki syndrome

Kawasaki disease lacks association with human coronavirus NL63 and human bocavirus

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study

Postmortem examination of patients with COVID-19

Endothelial cell infection and endotheliitis in COVID-19

Coronavirus disease 2019 (COVID-19) and cardiovascular disease: A viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection

Diagnosing COVID-19: the disease and tools for detection

Correction to: Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy