key: cord-0753750-n65ctxwa
authors: Chow, Eric J.; Englund, Janet A.
title: SARS-CoV-2 Infections in Children
date: 2022-02-01
journal: Infect Dis Clin North Am
DOI: 10.1016/j.idc.2022.01.005
sha: 1003f481f13a4969949da18211b97a4e67b59dad
doc_id: 753750
cord_uid: n65ctxwa

SARS-CoV-2 infections in children generally have milder presentations but severe disease can occur in all ages. MIS-C and persistent post-acute COVID-19 symptoms can be experienced by children with previous infection and emphasize the need for infection prevention. Optimal treatment for COVID-19 is not known and clinical trials should include children to guide therapy. Vaccines are the best tool at preventing infection and severe outcomes of COVID-19. Children suffered disproportionately during the pandemic not only from SARS-CoV-2 infection but because of disruptions to daily life, access to primary care and worsening income inequalities.

Since the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 2020, acute coronavirus disease 2019 has affected children of all ages. 1, 2 Overall, the number and incidence of reported infections and cases of severe disease in children are fewer than those reported in adults. 3 

Children of all ages are at risk for SARS-CoV-2 infection and severe 5 However, the number of infections and disease severity varies by age with higher number of infections and cases of severe disease in older age-groups. There have been fewer reported cases of in children than in adults and assessments of the true SARS-CoV-2 incidence in the pediatric population has been challenging as early data relied upon observational studies and convenience sampling. Children more frequently experience asymptomatic and mild disease, and early SARS-J o u r n a l P r e -p r o o f low. 25 In August 2021, the cumulative hospitalization rate for pediatric COVID-19 rose to 49.7 per 100,000 individuals. 24 Similarly, SARS-CoV-2 seropositivity had increased in children in England coinciding with the spread of the Delta variant, reduction of lock-down procedures and the start of the academic school year. 26 On November 26, 2021, the Omicron (B.1.1.529) SARS-CoV-2 variant was designated by the WHO as a variant of concern due to early evidence of increased transmissibility 27 and viral mutations allowing the evasion of prior immunity leading to rapid global spread and a spike in infection numbers. 28 In the US, the spread of the Omicron variant 29 was associated with a rapid increase in COVID-19-associated pediatric hospitalizations. 30 With communities pursuing varying stages of re-opening, the identification of new variants and the increased availability of vaccinations for younger age-groups, fluctuations in SARS-CoV-2 cases are likely to continue.

The pandemic has accentuated racial and ethnic disparities among people in the US. [31] [32] [33] [34] [35] [36] A disproportionate number of children with COVID-19 who experience severe outcomes including hospitalizations and death come from communities of underrepresented racial and ethnic groups. 5, 36, 37 Among American Indian and Alaskan Natives, incidence of COVID-19 among those aged <18 years was three times that of white, non-Hispanic individuals. 38 Hispanic and Latinx adults and children have experienced some of the highest rates of SARS-CoV-2 test positivity 39, 40 particularly during community-wide shelter-in-place directives. 35 Among individuals aged <18 years old with SARS-CoV-2 infection, rates of hospitalization were highest among Hispanic and Latinx children. 5, 39 The cause of these disparities is likely multifactorial including disproportionate burden of chronic conditions, 33 decreased access to healthcare and testing, 41 difficulty with social distancing in multigenerational households, 35 and greater J o u r n a l P r e -p r o o f representation in essential and in-person occupations with exposure risk to COVID-19 42 within the Hispanic and Latinx communities. 39 Survey studies also suggest that Black and Hispanic parents had a lower willingness to immediately vaccinate their children against highlighting the need for outreach, education and messaging of the benefits of vaccination to these specific communities. 43 See Chapter 4 on Equity and Racial and Ethnic Disparities.

Lockdown procedures, including closure of schools, 44 were first implemented in 2020 to reduce community transmission. 45, 46 As communities have reopened and schools resumed in-person learning, questions remain about how best to limit the ongoing spread of SARS-CoV-2 and establish the role children play in community transmission. [47] [48] [49] Past experiences with other viruses demonstrate that children carry the community burden of influenza and respiratory syncytial viral infections, 48 and public health interventions 50 such as vaccination of children can reduce community-wide infections. 51-53 Thus far, data show fewer and milder pediatric SARS-CoV-2 infections compared to adult cases.

The primary mode of person-to-person transmission of SARS-CoV-2 is by respiratory spread 54 and the use of face coverings, social distancing and school closures contributed to community mitigation of infection early in the pandemic. 44, [55] [56] [57] Children are both at risk for acquiring infection and spreading SARS-CoV-2. 49, 58, 59 Factors influencing individual transmissibility include symptomology, viral load, and behavioral patterns. 60 Both biological and socialbehavioral factors vary by age as a child aged <5 years has different risks than adolescents.

Vaccination status likely modifies an individual's risk of transmission and vaccine availability to J o u r n a l P r e -p r o o f younger age-groups will further influence SARS-CoV-2 epidemiology. The impact vaccines play in transmission by children will become evident as uptake and availability in younger age-groups continues.

The first reports of pediatric COVID-19 were identified within household transmission investigations, [61] [62] [63] [64] where pediatric index cases of household SARS-CoV-2 infections were less common. 58, 59, [64] [65] [66] One study of household transmissions where the index case was a child showed fewer index cases in the those aged 0-3 years, but a higher risk of household transmission in that age group than in index cases aged 14-17 years. 58 These findings suggest an individual's risk of transmission may have nuanced age-related associations. Younger agegroups may be less likely to socially distance, cover their mouths when sneezing or coughing, or consistently wear masksbehaviors expected of older children and adults. 49 Furthermore, families are likely to physically interact more with younger ill children leading to an increased risk for viral transmission. 49, 67 Secondary attack rates (SAR) are calculated as the rate of infection among susceptible individuals from an index case and can be a helpful measure of person-to-person transmission. A systematic review of factors associated with SAR demonstrated higher rates for adult contacts than for children; pooled SAR was not associated with the index case's age. 68 These studies were limited to smaller sample sizes 69 and more finely defined age data were not available.

The risk of SARS-CoV-2 transmission has also been shown to be higher in exposed contacts of cases with higher viral loads. [70] [71] [72] In one community-based surveillance study, SARS-CoV-2 viral loads were similar regardless of symptoms and age. 73 Children experienced fewer J o u r n a l P r e -p r o o f symptoms for shorter duration when ill with COVID-19 and the presence of symptoms was correlated with a higher viral load than asymptomatic cases. Given that more children experience asymptomatic SARS-CoV-2 and viral load is lower in asymptomatic cases, children may play a smaller role in transmission than adults. The possibility of fecal-oral transmission has been raised as infectious SARS-CoV-2 virus has been cultured from fecal samples of infected individuals 74 with prolonged shedding and higher levels of viral particles in pediatric fecal samples. 75, 76 Thus far, significant fecal oral transmission in close contacts of children with persistent fecal detection of SARS-CoV-2 has not been reported. 75 SARS-CoV-2 reinfection has been documented in children although the degree at which it occurs is unknown. 77 With the appearance of novel variants, immune evasion may become more common.

The understanding of school and daycare-based transmission dynamics of SARS-CoV-2 is evolving. One systematic review of SAR found lower pediatric rates in school than household settings. 78 One early investigation in Ireland, where reported SARS-CoV-2 cases were screened for recent school attendance, reported no confirmed cases among school contacts. 79 An analysis of childcare centers in Washington, DC found a limited number of outbreaks associated with each facility, with the majority of cases acquired outside the facility. 80 A Delta variant outbreak investigation at a California elementary school involving an unvaccinated teacher as the index case found higher risks of infection with seating proximity to the teacher. 81 All students were unvaccinated at the time and had a reported high adherence to social distancing and mask wearing. A study in Los Angeles schools found that school-associated SARS-CoV-2 case rates among those aged 5-17 years were lower than community case rates but fluctuated with changes in the general community incidence. 82 In a series of school-based studies, the risk of a SARS-J o u r n a l P r e -p r o o f CoV-2 outbreak was 3.7 times higher in schools without mask requirements 83 and larger increases of county case rates were seen when school mask mandates were optional. 84 These findings suggest that school-based transmission and community-wide case counts can be mitigated by implementing public health interventions as children return to school.

To minimize disruptions to attendance of in-person learning, some grade schools implemented the "Test to Stay" (TTS) strategy where unvaccinated individuals who experienced a schoolrelated SARS-CoV-2 exposure were allowed to stay in school if certain criteria were met. TTS required that both the index case and the close contact had to have been masked when exposed and during the quarantine period, the close contact may remain in school provided they remain asymptomatic while wearing a mask and practiced social distancing and submitted to regular testing after the exposure. Schools adopting TTS between August and October 2021 in Illinois and California found a low SAR and low tertiary transmission after TTS implementation while minimizing loss of in-person school days. 85, 86

The most significant public health breakthrough during the pandemic has been the development of SARS-CoV-2 vaccines ( years and weighing >40 kg who are not currently infected with SARS-CoV-2, have moderate to severely compromised immune systems, or a history of severe adverse reactions to the approved SARS-CoV-2 vaccines, as pre-exposure prophylaxis. 99 As of January 2022, pediatric data with this new long-acting monoclonal antibody have not been published but approval offers an alternative to vaccinations in those who are unable to mount sufficient immunity to approved vaccines or those whom current vaccines are not clinically recommended.

Vaccine trials and real-world effectiveness studies have shown that SARS-CoV-2 mRNA vaccines are highly effective against COVID-19. Prior to the predominance of SARS-CoV-2 J o u r n a l P r e -p r o o f variants, the Pfizer-BioNTech vaccine reported vaccine efficacy of 95% against confirmed COVID-19 in those aged >16 years. 100 In a subsequent analysis on the safety and efficacy of the same vaccine in participants aged 12-15 years, vaccine efficacy was 100% against confirmed COVID-19 after completion of the two dose series. 101 hospitalizations. 105 Another VE study of the Pfizer-BioNTech vaccine in adolescents aged 12-17 years from July-December 2021 (when the Delta variant was widespread but before the predominance of the Omicron variant), VE against SARS-CoV-2 infection was 92%. 106 In a population-based study of SARS-CoV-2 infection incidence rates also occurring during the Delta variant wave, the incidence rate ratio of laboratory-confirmed SARS-CoV-2 infections was 8.9

comparing unvaccinated to vaccinated adolescents aged 12-17 years. 107 Furthermore, early data show the protective effects of SARS-CoV-2 vaccination against MIS-C with a lower incidence with vaccination 108 and an estimated VE of 91% in adolescents 12-18 years who had completed a primary vaccine series with the Pfizer-BioNTech vaccine. 109 Despite vaccine availability and effectiveness, the percentage of vaccinated eligible children was <65% as of December 30, 2021 with <15% of children aged 5-11 years full vaccinated. 110 In some situations, there may be discordance in vaccine hesitancy between parents and guardians and their children. There remains regional variability of minor consent laws where minors are allowed to consent to medical interventions which include vaccines. 111 Overall, SARS-CoV-2 vaccines have had a favorable safety profile among children aged 5-17 years. 100, 101, 112 Most vaccine reactions to the Pfizer-BioNTech vaccine reported were local or mild systemic reactions 112, 113 with the exception of a small group of individuals, overwhelmingly male adolescents and younger adults, who reported self-limited cases of myocarditis and pericarditis. 114 In a nationwide study, the Pfizer-BioNTech vaccine was associated with an excess risk of 1 to 5 events per 100,000 vaccinated persons of all ages compared to the excess risk of 11.0 events per 100,000 persons after SARS-CoV-2 infection. 115 Myocarditis after SARS-CoV-2 vaccination was more common in younger age-groups, whereas pericarditis more common in older individuals with onset generally within 3 days of vaccination. 116, 117 Among individuals aged <30 years with data reported to the Vaccine Adverse Event Reporting System, cases of myocarditis, pericarditis and myopericarditis after SARS-CoV-2 vaccines occurred in individuals with a median age of 19 years (range: 12-29 years) with 96% hospitalized and no deaths. 118 Given the severe outcomes of SARS-CoV-2 infection J o u r n a l P r e -p r o o f including myocarditis, 119 the ACIP concluded that the benefits of vaccination outweighed the risk posed by these rare adverse events.

The clinical picture and severity of SARS-CoV-2 infection in children of all ages can vary from no symptoms to critical illness. When symptoms develop, most children will experience respiratory tract symptoms or an exacerbation of underlying conditions. Children with COVID-19 not requiring hospitalization have more subclinical, asymptomatic infection and upper respiratory tract symptoms than adults. 8, 120 One systematic review of early studies on pediatric COVID-19 found that 2% of SARS-CoV-2 infections in children were categorized as severe while 0.6% had critical COVID-19, 121 although the spread of variants and increased exposure to SARS-CoV-2 may lead to increased numbers of infection and severe presentations of disease.

As in adults, the incubation period likely ranges from 2-14 days (mean, 6 days). 122, 123 Illness duration is estimated to be a median of 6 days but prolonged illness >28 days can occur. 124 Overall, symptom duration is shorter in younger children. 124 Symptoms vary by age-group (Table 3 ) and study type. In an early surveillance report of pediatric COVID-19, fever and cough were the most commonly reported symptoms with headache a common symptom in older children. 9 In a longitudinal cohort study of infected school-aged children, headache and fatigue were the most common symptoms identified with sore throat, altered taste or smell, and fever also frequently reported. 124 Neonates and infants may experience non-specific symptoms such as feeding difficulty with fever so COVID-19 should be considered in the workup for infectious etiologies. 125 The presence of gastrointestinal (GI) symptoms such as abdominal pain, nausea, vomiting, and diarrhea are also common in pediatric acute COVID-19. Altered taste or smell is more commonly reported in older age-groups. 9, 124 The National Institutes of Health (NIH) developed COVID-19 severity categories to unify treatment recommendations: asymptomatic or presymptomatic, mild, moderate, severe and critical acute COVID-19 (Table 4 ). 126 Given these definitions are extrapolated to pediatric infections, normal vital signs and symptoms will differ by age. The diagnosis of asymptomatic or pre-symptomatic infection in younger children will rely on clinical history provided by the caregiver and findings on physical exam. Minimally symptomatic children will require careful assessment of vital signs and physical exam to ensure appropriate counseling is given. Weak cry, grunting, retractions, nasal flaring, head bobbing may also be indicators of respiratory distress, and acute COVID-19 should be suspected in younger children especially in the absence of alternative explanation. Rapid clinical deterioration with abrupt changes in respiratory status may occur a week into the illness course. 127 In children with critical illness, careful consideration should be given in distinguishing cases of acute COVID-19, MIS-C, and other diseases as evaluation and management may differ.

There remains a paucity of data on risk factors associated with severe outcomes of pediatric acute COVID-19. Data extrapolated from adult reports and observational studies highlight several chronic diseases in children that increase risk for infection, hospitalization, admission to the intensive care unit (ICU) and death. [128] [129] [130] [131] [132] In a study of hospitalized children aged <18 years with COVID-19 when the Delta variant was widespread, 67.5% had one or more underlying medical conditions. 133 In another study of individuals aged <21 years, at least one underlying J o u r n a l P r e -p r o o f medical condition was associated with 75% of SARS-CoV-2. 129 There does not appear to be a significant risk of severe disease associated with male gender, as there is in adults. 134 Some studies suggest that younger children (infants aged <1 year) did not have increased risk for severe disease 131 although early reports showed higher proportions of severe and critical illness in the younger age-groups. 1, 132 In a cross-sectional study of children with acute COVID-19, risk of hospitalization or severe COVID-19 was highest in those with obesity, sleeping disorders, diabetes (type 1 or type 2), congenital heart disease, neurodevelopmental disorders, psychiatric illness, hypertension and seizure disorders. 135 Among children aged 12-18 years, those with asthma were at increased risk for severe illness. 135 Other possible conditions at risk for severe outcomes in children include complex medical conditions, 135 genetic disorders such as trisomy 21, 136 sickle cell disease, 137 congenital heart disease 138 complications associated with pediatric acute COVID-19 has been described including encephalopathy, seizures, encephalitis, Guillain-Barre Syndrome, acute demyelinating syndromes, movement disorders and psychiatric disorders. 144 Acute COVID-19 in children can also be complicated by cardiovascular events including myocarditis, 145, 146 pericarditis, 147, 148 pulmonary embolic events, 149 arrhythmias, 150 and acute myocardial infarction. 151 So-called "COVID toes," or pseudo-chilblains, caused by inflammation of small blood vessels with painful sores can also be seen in pediatric acute COVID-19. 152, 153 GI 154-156 and renal 157 complications have also been described. Invasive mold infections (e.g. pulmonary aspergillosis and mucormycosis) are increasingly recognized complications of severe COVID-19 in adults 158 although rarely reported in children. 159 There remains little information on COVID-19-associated fungal infections in children possibly owing to fewer cases of severe COVID-19.

Diagnosis of SARS-CoV-2 infection requires laboratory confirmation. Suspected cases may be identified based on characteristic symptoms and exposure to an individual with laboratoryconfirmed SARS-CoV-2 infection (see Chapter 6) . Adult acute COVID-19 has been associated with characteristic laboratory abnormalities including lymphopenia in early disease, elevated inflammatory markers, and findings of a hypercoagulable state 160 that have been used to predict severe disease. In pediatric acute COVID-19, laboratory findings have been more variable, differ by age and are less predictive of severe disease. 140, 161 In addition to lymphopenia and hypercoagulability, markers of inflammation in children may be abnormal, including D-dimer, lactate dehydrogenase, fibrinogen, ferritin, procalcitonin, interleukin-6, C-reactive protein, aspartate aminotransferase, alanine aminotransferase and erythrocyte sedimentation rate. 160, 162, J o u r n a l P r e -p r o o f 163 Elevations of creatine kinase, pro B-type natriuretic peptide, and troponin can be seen in those with end organ disease. 162 Significantly elevated inflammatory markers with cardiovascular involvement should also prompt clinical consideration of an MIS-C diagnosis. Chest radiographic findings including characteristic multifocal ground glass opacities and pulmonary consolidations may be the most common imaging abnormalities in pediatric acute COVID-19. 164, 165 Children may have abnormalities of chest imaging even with asymptomatic and presymptomatic infection. 165 Except in cases of severe disease or workup of alternative conditions, computed tomography is unlikely to provide additional clinical information when a diagnosis of acute COVID-19 is already known.

Management of symptomatic acute COVID-19 depends on the severity of the illness (Table 4) and special consideration should be given to the evolution of SARS-CoV-2 variants including the appearance of the Omicron variant, as they alter the landscape of effective monoclonal antibodies and available therapeutics. 166 Most children will not require specific therapy, especially with milder disease. Children with underlying medical conditions may be at greater risk for severe outcomes, thus close follow up and baseline control of chronic illnesses may help mitigate the effects of infections. The mainstay of management in children with mild to moderate acute COVID-19 is supportive care, although cases of poor feeding or dehydration may prompt admission to the hospital for nutritional resuscitation. Children whose symptoms worsen may require higher levels of care due to progression of disease, end-organ complications, and coinfections. If new or worsening symptoms evolve, workup should be pursued to identify the etiology of the clinical change. During the pandemic, the use of antibiotics has exceeded the estimated prevalence of bacterial co-infections, leading to overuse in cases of Continuation of antibiotics should be guided by culture results and risk factors, and generally reserved for severe or critical COVID-19 with presumed or confirmed bacterial co-infection.

Acute COVID-19 can lead to a hypercoagulable state; the use of thromboprophylaxis should be considered based on individual risk factors for coagulopathy. and are not hospitalized for COVID-19 (See Chapter 7). Bamlanivimab-etesevimab and casirivimab-imdevimab were authorized as post-exposure prophylaxis for those exposed and at high risk of severe COVID-19. The EUA for bamlanivimab-etesevimab has also been extended to younger children (from birth and older) including those who are hospitalized between birth and 2 years of age for treatment of mild to moderate acute COVID-19, but circulating variants have limited their use. 168 Hospital admission thresholds may be lower for neonates and young children who develop mild to moderate COVID-19, hence the EUA extension of its use during hospitalization for this younger age-group. There remains limited data regarding the use of monoclonal antibodies in children 169 with pediatric experts recommending against its routine use in children including those with risk factors for severe disease. 170 J o u r n a l P r e -p r o o f Antiviral therapy has formed the basis for COVID-19 therapy early in the illness course.

Remdesivir, a nucleoside analog and viral RNA polymerase inhibitor, has been available through EUA since May 1, 2020. On October 22, 2020, remdesivir became the first US FDA approved antiviral treatment for use in hospitalized individuals aged >12 years and weighing >40 kg with COVID-19. 171 It remains available under EUA to children weighing 3.5 kg to <40 kg or those aged <12 years and weighing >3.5 kg. 171 The data to support the use of remdesivir in COVID-19 has been derived from clinical trials of adult COVID-19. A 5-day course of remdesivir was associated with a reduction in median time to recovery, but not mortality in severe COVID-19. [172] [173] [174] The NIH recommends remdesivir for children >12 years and weighing >40 kg with new or increasing oxygen requirement with risk factors for severe disease 169 and allows for the offlabel treatment of non-hospitalized children with mild to moderate COVID-19 at risk for severe disease within 7 days of symptom onset. 175 They also recommend remdesivir for children aged 177 WHO has recommended against the use of remdesivir for children, citing a lack of important clinical differences in mortality and severe outcomes. 178 In general, remdesivir is well tolerated. Reports of sinus bradycardia associated with its use have been documented in pediatric cases of COVID-19, 179 which appears to self-resolve after drug discontinuation.

In December 2021, the FDA granted EUA to two additional antiviral agents for the treatment of mild to moderate acute COVID-19 which include molnupiravir, 180 187, 192, 193 US cases were soon reported in New York following the first surge of SARS-CoV-2 infections. 192 Initially called the pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), 194, 195 a new case definition and naming of the condition MIS-C was published by the CDC. 196 The name change was made to allow for cases in adults which have now been described. [197] [198] [199] [200] Several epidemiologic case definitions are published to describe MIS-C (Table 5 ) each requiring clinical, virologic and inflammatory marker data. 194, 196, 201 Of note, the CDC case definition specifically requires severe illness and hospitalization highlighting an important distinction between the definitions. Although a clinically significant condition, MIS-C is thought to be rare.

Early estimates in New York State showed that while laboratory-confirmed SARS-CoV-2 infection in people <21 years old was 322 per 100,000 individuals, the number of MIS-C cases over the same timeframe was 2 per 100,000 individuals. 192 Using surveillance data from US jurisdictions reporting MIS-C cases, the incidence between April and June 2020 was estimated to be 5.1 persons per 1,000,000 person-months with 316 MIS-C cases per 1,000,000 SARS-CoV-2 infections. 202 Few MIS-C cases were reported in China and other countries in eastern Asia early in the pandemic with possible explanations including differences in SARS-CoV-2 burden, changes in the virus, or the implementation of different public health interventions. 203 Cases of MIS-C have now been reported in these regions.

Despite efforts to uncover the underlying mechanism of disease, the pathophysiologic cause of the syndrome is not fully understood. 203 Hypotheses based on associations with KD, a form of J o u r n a l P r e -p r o o f childhood vasculitis which shares clinical features with MIS-C, and the clinical course after acute COVID-19, suggests an immune-mediated process possibly driven by auto-antibody activity. 204 Immune profiling in those with KD, acute COVID-19 and MIS-C show differences in cellular subtypes and inflammatory protein composition that distinguish the three different diagnoses. 204 Antibody profiling also showed evidence of possible cardiac specific autorecognition suggesting a mechanism for the cardiovascular and coronary damage characteristic of both MIS-C and KD. 204 Additional research will be needed to further stratify the immune differences between these two conditions and to identify the mechanisms that may provide clues to future therapies.

Children with MIS-C tend to be older and more racially and ethnically diverse than those with KD. 205, 206 One US population-based study of MIS-C found the median age of children with MIS-C to be 9 years 207 with children as young as <1 month old reported in the literature. 192, 205 Whether race is an important risk factor in developing MIS-C after acute COVID-19 is still being investigated. Early studies showed a disproportionate risk of MIS-C in communities of color, 190, 207 initially considered a reflection of disparities seen in acute SARS-CoV-2 infection. 208, 209 However, more recent studies comparing MIS-C and COVID-19 showed an unexplained independent risk of MIS-C that continues to exist for those of Hispanic ethnicity or Black race. 210, 211 Children affected by MIS-C tend to have fewer underlying medical conditions, with obesity a common diagnosis if chronic conditions were present. 192, 207 While MIS-C case definitions allow for the use of SARS-CoV-2 PCR, antibodies, antigen or exposure as virologic confirmation, most children will have evidence of prior infection via SARS-CoV-2 antibodies. 207 As more children are vaccinated, use of anti-SARS-CoV-2 antibody tests other than spike protein J o u r n a l P r e -p r o o f antibodies will be required to differentiate between immunity from prior infection and vaccination. In the absence of SARS-CoV-2 testing, exposure to an individual with diagnosed COVID-19 or COVID-19 compatible symptoms also satisfy case definition requirements.

Clinical features of MIS-C vary by case and by age-group. 192 All current MIS-C case definitions require fever during the illness as part of the diagnosis. Fever may be subjective or measured (>38°C), and is commonly persistent, lasting about 6 days in most children. 193 Many children will present to the hospital still febrile. 192 Other common symptoms at hospital presentation include GI symptoms (e.g., abdominal pain, diarrhea, nausea and vomiting), headache and neck pain, lymphadenopathy, myalgias, fatigue, sore throat and mucocutaneous findings (e.g., rash, red tongue, cracked lips and conjunctivitis). 192, [212] [213] [214] Severe GI complications (e.g.

were frequently diagnosed in children with acute COVID-19 and MIS-C. 213 Chest pain and symptoms of myocarditis are more common in older children and adolescents. 192 Patients with MIS-C may have respiratory symptoms such as cough and shortness of breath, but these are more common in patients with acute COVID-19. 207 At hospital admission, vital signs seen in patients with MIS-C include fever, tachycardia, and tachypnea typically without hypoxemia. 192 Symptoms of shock including hypotension were seen in about one third of the cases described in New York State. 192 Subsets of patients may fulfill criteria for the diagnosis of KD, particularly those in the younger age-groups. 192 Laboratory findings show evidence of severe systemic inflammation. Complete blood count results can include neutrophilia, lymphopenia, anemia and thrombocytopenia. 192, 193, 212 J o u r n a l P r e -p r o o f Inflammatory markers are broadly elevated which generally include C-reactive protein (CRP), erythrocyte sedimentation rate, fibrinogen, ferritin, D-dimer, lactate dehydrogenase, procalcitonin, alanine aminotransferase and IL-6 levels. 192, 193 Other laboratory abnormalities such as hypoalbuminemia, hyponatremia and prolonged international normalized ratio may be present. 192, 193 Evidence of cardiovascular injury with elevated troponin, brain natriuretic peptide (BNP) or N-terminal pro-BNP is also common. 192 Specific level cutoffs and the predictive ability of individual tests for MIS-C diagnosis have not been established, although one observational study found that MIS-C patients may have lower absolute counts of lymphocytes and platelets as well as greater CRP concentrations than children without MIS-C who are evaluated for outpatient febrile illness. 215 MIS-C is frequently associated with echocardiographic findings including evidence of ventricular dysfunction with depressed ejection fraction, pericardial effusion, valvular dysfunction and coronary artery dilatation or aneurysms. 192, 216 Given the prominent GI symptoms at presentation, children with MIS-C may also undergo abdominal imaging to rule out other etiologies including appendicitis. Common abnormal findings seen on abdominal ultrasonography or CT include liver and spleen enlargement, mesenteric adenopathy, trace ascitic or pelvic fluid, inflammation of the intestines and appendix with bowel-wall thickening and fluid filled bowel loops. 192 In children who receive chest radiography, evidence of pulmonary opacities or infiltrates may be present. 217 The hospital course for children with MIS-C may include admission to the ICU for close clinical monitoring, vasopressor support and less frequently mechanical ventilation. 192, 193 ECMO may be required in a small number of patients. 192, 193 Despite the morbidity associated at hospital presentation, children with MIS-C are often discharged within a week of admission, 192 mortality remains low 207 and long-term outcomes including functional outcomes, have been minimal 218 with resolution of most cardiac J o u r n a l P r e -p r o o f findings at subsequent follow up visits. 219 Among those with persistent cardiovascular abnormalities, aneurysmal changes were seen in one group of children followed longitudinally. 219 Whether MIS-C can re-occur in children who experience re-infection is unknown however one published case study showed no reoccurrence of MIS-C with subsequent SARS-CoV-2 infection. 77 American College of Rheumatology, American Academy of Pediatrics and the PIMS-TS National Consensus Management Study Group have provided a tiered guidance approach for the workup and management of MIS-C (Table 6 ). 220 

A picture of long-term symptoms experienced by children after SARS-CoV-2 infection is emerging. First recognized in adults, post-acute sequelae of COVID-19 (PASC) or "long COVID-19," is a constellation of persistent symptoms affecting different organ systems reported by patients recovering from all spectrums of acute COVID-19 including those with asymptomatic infection. 225, 226 Currently, no formal definition or diagnostic criteria describes PASC, and individuals experiencing longer term symptoms likely represent a heterogenous cohort. The prevalence of PASC is unknown, although a review of published reports show variability by study from 4 to 66%. 227 Among the few studies describing persistent symptoms in children, fatigue, persistent cough, difficulties with concentration, chest pain, heart palpitations dyspnea, headache, dizziness, sore throat and sleep disturbances were experienced up to 8 months after acute infection. 228-232 Short-term cognitive and psychiatric complications have also been observed in the aftermath of acute COVID-19 and whether these will persist in the longterm is not known. 233 Similar to adults, these symptoms may relapse and remit over the illness course. Information on the cause and optimal management of these patients is unknown and may require interdisciplinary rehabilitation 234 

In addition to the direct health effects of COVID-19, the pandemic has had adverse collateral health impacts on children due to the impacts of COVID-19 in adults, community-wide mitigation efforts and school closures. Early in the pandemic, the number of primary care preventative and acute care visits decreased. 237 Changes in health-care seeking behavior have led to decreased routine screening tests such as blood lead level testing 238 and a decrease in childhood vaccination rates. 239 Delays in care have exacerbated health related outcomes including appendicitis, 240 asthma exacerbation, 241 and cancer treatment. 242 The global prevalence of depression and anxiety in children highlight the persistent exacerbation of mental health illnesses. 243 In addition to these acute medical issues, the pandemic has altered the daily habits of families resulting in decreases in physical activity 244 and increase in hours of screen time in children. 245 These and other social disruptions have had substantial adverse effects on mental health 246, 247 and behavior. 248 Families units have also been disrupted due to the deaths of parents and caregivers as a result of COVID-19 249 exacerbating income inequalities 250 and food insecurity. 251, 252 Early studies during the pandemic suggested increases in cases of child abuse and neglect, 253, 254 however there is some evidence to suggest that the increase in family time and strengthening of family support systems helped mitigate instances of physical abuse of children. 255 With school closures, learning was adapted to minimize face-to-face contact. 256 Although schools have resumed in-person learning for the most part, the full impact of changes in childhood education during the pandemic has yet to be fully quantified. 262 3. December 16, 2021-CDC ACIP recommendations updated preferring approved mRNA vaccines over Janssen vaccine for primary and booster vaccinations 263 *Moderately to severely immunocompromised persons may include (not limited to) individuals undergoing active treatment for solid tumor and hematologic malignancies, receiving a solidorgan transplant and taking immunosuppressive therapy, receiving chimeric antigen receptor Tcell or hematopoietic cell transplant; individuals who have moderate or severe primary immunodeficiency, advanced or untreated HIV infection, receiving active treatment with high-dose corticosteroids, alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutics agents classified as severely immunosuppressive, tumor necrosis factor blockers and other immunosuppressive or immunomodulatory biologic agents ** High-risk populations include individuals 65 years of age and older; individuals 18-64 years with an underlying medical condition putting them at high risk for severe COVID-19 and individuals 18-64 years with frequent institutional or occupational exposure to SARS-CoV-2 putting them at risk for serious complications of COVID-19 including severe COVID-19; Interim updated CDC list of high-risk underlying conditions include but are not limited to: asthma, cancer, cerebrovascular disease, chronic kidney disease, certain types of chronic lung diseases, certain types of chronic liver disease, cystic fibrosis, diabetes mellitus (type 1 and type 2), Down syndrome, heart conditions, HIV< hypertension, immune deficiencies, certain mental health disorders (i.e. mood disorders, schizophrenia spectrum disorders), obesity (BMI>30 kg/m 2 ) and overweight (BMI >25kg/m 2 but < 30 kg/m 2 ), pregnancy and recent pregnancy, sickle cell disease, smoking (current and former), solid organ or blood stem cell transplantation, substance use disorders, thalassemia, tuberculosis, and use of corticosteroids or other immunosuppressive medications (an ongoing updated list of high-risk underlying conditions can be found on the CDC website) 141 7  1  10  40  22  48   Abdominal pain 7  7  8  21  28  17  Fatigue  ---55  44  61  Dizziness  ---22  14  26  Anorexia  ---22  20  22  Eye soreness  ---19  15  22  Voice change  ---13  11  14  Chest pain  ---10  6  12  Confusion  ---6  3  7  Red Welts  ---3  3  3  Blisters  ---2  1  2 J o u r n a l P r e -p r o o f Remdesivir -can be used as an antiviral in those with severe or critical acute COVID-19 weighing at least 3.5 kg. A multicenter pediatric COVID-19 guideline committee suggests using respiratory support requirement as the indicator for its use. 177 3. Dexamethasone **-can be considered in critical disease particularly in older age-groups 4. Interleukin-6 (e.g., tocilizumab) or interleukin-1 (e.g., anakinra) inhibitors -can be considered in critical disease, preferably in the setting of a clinical trial Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection *Additional features: abnormal fibrinogen, high D-dimer, high ferritin, hypoalbuminemia, acute kidney injury, anemia, coagulopathy, high IL-10, high IL-6, proteinuria, raised CK, raised LDH, raised triglycerides, raised troponin, thrombocytopenia, transaminitis 

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