key: cord-0833919-nf9vtra1
authors: Galindo, Ramon; Chow, Heather; Rongkavilit, Chokechai
title: COVID-19 in Children: Clinical Manifestations and Pharmacological Interventions Including Vaccine Trials
date: 2021-05-18
journal: Pediatr Clin North Am
DOI: 10.1016/j.pcl.2021.05.004
sha: 0da0f3cd3d54bedbdf8df5c3e11a762b9e8f11e2
doc_id: 833919
cord_uid: nf9vtra1

Children usually present with milder symptoms of COVID-19 as compared with adults. Supportive care alone is appropriate for most children with COVID-19. Antiviral therapy may be required for those with severe or critical diseases. Currently there has been a rapid development of vaccines globally to prevent COVID-19 and several vaccines are being evaluated in children and adolescents. Currently, only Pfizer-BioNTech mRNA vaccine is approved for emergency authorization use in the pediatric population ages 16 years and older.

There have been reports of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS- infecting children in all age groups, however children still make up a small percentage of the total number of cases of Coronavirus disease 2019 (COVID- 19) infection. As low as 2% of 80,900 COVID-19 cases during the case surge in China were pediatric cases. 1 Similarly, a systematic review showed that children accounted for 1-5% of reported COVID-19 cases. 2 Interestingly, the proportion of children with COVID-19 appears higher in the US. By the end of 2020, 2,128,587 COVID-19 cases in US children have been reported, and children represented 12% of all reported cases in the US. The overall rate was 2,828 cases per 100,000 US children. 3 The difference in prevalence among different geographic locations could be due to multiple factors including case definition used, access to testing, varied sensitivity of the tests used, differences in anatomical respiratory sampling sites, variability in sample collection by personnel, levels of case surge within communities, and other yet unknown host and pathogen factors.

It has been observed since early on in the pandemic that children seem to experience milder symptoms when compared to adults. Correspondingly, in a large case series of 2,135 pediatric patients with COVID-19 in China, 55% of cases were asymptomatic or with mild symptoms. 4 Only 6% of pediatric cases were classified as severe and critical cases. This is fewer compared to the number of severe and critical cases in the adult population, which was found to be about J o u r n a l P r e -p r o o f 18.5%. In a report from the US Centers for Disease Control and Prevention (CDC), 73% of pediatric COVID-19 cases had symptoms of fever, cough, or shortness of breath compared with 93% of adults aged 18-64 years during the same reporting period, and only 6% of all pediatric cases required hospitalization. 5 Thus, the majority of pediatric COVID-19 cases are either asymptomatic or mild in disease severity.

Multiple theories have been suggested to explain why children may contribute to such a small percentage of reported COVID-19 cases and why children may have a milder clinical presentation than adults. In a systematic review and meta-analysis including 32 studies, children and adolescents younger than 20 years had 44% lower odds of infection with SARS-CoV-2 compared with adults 20 years and older, and the finding was most marked in those younger than 10 to 14 years. 6 Davies et al generated a modeling study to determine the manifestation of clinical symptoms based on susceptibility of infection in children versus adults. 7 Their data suggested an "age gradient" in which risk for severe disease increases with age. More specifically, they found that 79% of pediatric patients in the 10 to 19-year-old group are asymptomatic, and that individuals 20 years old and older are two times more susceptible to COVID-19 than those younger than 20 years.

Several potential causes have been implicated in creating this distribution across the different age groups. Having more mild symptoms or being asymptomatic may contribute to reporting bias and account for the low number of reported cases of COVID-19 in children. Those with less J o u r n a l P r e -p r o o f noticeable symptoms are less likely to seek medical care, and in turn the cases are less likely to be confirmed and reported.

Secondly, since children get frequent viral upper respiratory tract infections including coronaviruses that cause common cold, it has also been proposed that infections from other coronaviruses offer some immunity to children, rendering children less susceptible to infection by SARS-CoV-2. This phenomenon may be due to either cross-protection from other types of previous coronavirus infections or non-specific protection from other respiratory viruses. Coinfection with another virus could also compete with SARS-CoV-2 and decrease its replication, and thus result in a milder illness. 8 Thirdly, SARS-CoV-2 utilizes its spike protein to bind with human angiotensin converting enzyme 2 (ACE-2) receptor for host cell entry. 9 In a cohort study of 305 individuals aged 4-60 years, ACE-2 gene expression in nasal epithelium was lowest in children <10 years of age and it increased with age. 10 Low ACE-2 expression could limit SARS-CoV-2 entry into host cells. This could lead to a lower risk of infection and a milder clinical presentation in children. Moreover, the lower prevalence of comorbidities such as diabetes, chronic lung disease, and cardiovascular disease in children may contribute to a milder clinical course as compared to adults. 11 Many pediatric COVID-19 cases have been found to be linked to a family member. In a study with 34 confirmed pediatric cases, 13 (38%) patients were found to have an exposure to COVID-19 from a family member. 12 It has been suggested that if an adult transmits SARS-CoV-2 to a child, the infection would be caused by a second or third generation of virus, and the infection may be milder due to decreased pathogenicity. A retrospective review analyzed the data collected from nine children and their 14 adult family members. 13 It was found that three J o u r n a l P r e -p r o o f children had symptoms of fever or cough, and six were asymptomatic. Four children (44%) had abnormal chest radiograph findings whereas 71% of the adults had abnormal radiograph studies.

Thus, this concept of family clusters may also explain why pediatric patients have a milder presentation. 8, 11 

The most common symptoms in children include fever, upper respiratory symptoms, and gastrointestinal symptoms. Since SARS-CoV-2 attaches to human cells via ACE-2 receptors, the expression of ACE-2 receptors on epithelial cells in the lung and the intestines may account for the manifestations of respiratory and gastrointestinal symptoms, respectively. 8 In a review of 333 pediatric patients, the most common symptoms included cough with a prevalence of 48%, fever (42%), and sore throat (42%). Moreover, 35% of cases were reported to be asymptomatic. 11 Similarly, in a study in Wuhan, China that examined 171 children with confirmed COVID-19, 49% of children had cough, 42% had fever, and 46% had pharyngitis. 2 Other symptoms that have been reported include rhinorrhea, nasal congestion, myalgia, fatigue, shortness of breath, dyspnea, abdominal pain, diarrhea, vomiting, nausea, headache, dizziness, decreased oral intake, and rash. Figure 1 is a compilation of clinical symptom data from three review articles that altogether include 26 studies for a total of 1793 children with COVID-19. 1, 11, 14 

Though most children with COVID-19 are mildly symptomatic or asymptomatic, there have been reported cases of severe infection and even death, albeit few. Reported symptoms of severe and critical disease include hypoxia defined as oxygen saturation less than 92%, acute respiratory distress syndrome, shock, and various organ failure such as encephalopathy, heart failure, abnormal coagulation, and acute kidney injury. 4 According to a review by Zimmerman et al, 9

(3%) of 333 children required admission to pediatric intensive care units, and two of these children had preexisting conditions, namely leukemia and hydronephrosis. 11 The adult and elderly population have experienced more COVID-19 related deaths than the pediatric population. 1 The presence of comorbidities such as cancer, diabetes, cardiovascular disease, chronic lung disease, and a weaker immune system has been implicated in the greater prevalence of death in adults. One study of 44,672 COVID-19 cases found that 26% had comorbidities. 2 Additionally, there were 965 deaths, and only one of these deaths was a pediatric patient. No information was provided on the 14-year-old male in this study. By March 2020, this case was one of the two deaths reported in children with COVID-19. The other child was a 10month-old female with intussusception, encephalopathy, septic shock, and multi-organ failure. 2, 11 In a review of 29 studies with 4300 children included, 19% were asymptomatic, and 37% had no radiographic abnormalities. 16 A small proportion of 0.1% required admission to intensive care units and 4 deaths were reported. Among 208 hospitalized children with complete medical chart J o u r n a l P r e -p r o o f reviews by the US COVID-19-Associated Hospitalization Surveillance Network, 33% were admitted to an intensive care unit; 6% required invasive mechanical ventilation, and one child (0.5%) died. 17 The comorbid conditions included obesity (38%), chronic lung disease (18%), and prematurity (15%). Overall, children with COVID-19 have a good prognosis. However, a serious post-infectious hyper-inflammatory process known as Multisystemic Inflammatory Syndrome in Children (MIS-C) has been described. See details in Chapter 5 in this issue.

COVID-19 in neonates has also been reported. In China, between early December 2019 to February 2020, nine infants (1-11 months of age) were hospitalized. Four had fever, two had mild upper respiratory tract infections, one was asymptomatic, and there was no information on two infants. 18 Another review reported three neonatal cases. 2 One had fever and cough, one had rhinorrhea and vomiting, and the third had respiratory distress. Neonatal complications from COVID-19 infected mothers have been reported as well. In 67 neonates born to 65 mothers who had COVID-19 during pregnancy, twelve had respiratory distress or pneumonia (18%), 9 were born with low birth weight (13%), 2 developed a rash (3%), 2 developed disseminated intravascular coagulation (3%), 1 had asphyxia (2%), and 2 died (3%). 11

Even though severity of COVID-19 seems to increase with increasing age in the general population overall, severity in the pediatric population seems inversely related to age, as depicted by the study performed by Dong et al. 4 Infants were the most susceptible to severe illness, with 10.6% of infants <1 year of age presenting with severe or critical disease. A decreasing frequency of severity with age was demonstrated, with severe illness being reported in 7.3% in J o u r n a l P r e -p r o o f 9 the 1-5 years old group, 4.2% in the 6-10 years old group, 4.1% in the 11-15 years old group and 3.0% in the 16 or older group. In the US, infants <1 year old accounted for the highest percentage (estimated range, 15%-62%) of hospitalization among pediatric patients with COVID-19. 5

Pharmacological Intervention:

The antiviral that has perhaps received the most attention is remdesivir. Remdesivir has a broad spectrum antiviral activity that was first developed to treat hepatitis C and respiratory syncytial virus and subsequently repurposed to treat Ebola virus. 19 

The use of corticosteroids for COVID-19 are primarily based on the results of the multicenter, randomized, open-label RECOVERY trial. 28 Mortality at 28 days was lower among adult patients on invasive mechanical ventilation who received up to 10 days of dexamethasone 6 mg once daily (29.3%) than among those who received the standard of care (41.4%). This benefit was also observed in patients who required supplemental oxygen. No mortality benefit was seen in those who required no supplemental oxygen. According to the National Institutes of Health guidelines, if dexamethasone is not available, alternatives such as prednisone, methylprednisolone, or hydrocortisone can be used. 27 The safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment have not been sufficiently J o u r n a l P r e -p r o o f evaluated in children. However, dexamethasone may be beneficial in children who require mechanical ventilation. Use of dexamethasone for those who require supplemental oxygen support should be considered on a case-by-case basis.

Bamlanivimab is an anti-spike neutralizing monoclonal antibody that was discovered from the convalescent plasma of a patient with COVID-19. This antibody was shown to bind the receptorbinding-domain of the trimeric spike protein in both its up (active) or down (resting) state. This generated interest as the up state has been shown to be required for ACE-2 binding and viral fusion for cell entry. In a study in non-human primates, administration of this antibody in rhesus monkeys reduced SARS-CoV-2 replication in both upper and lower respiratory tract. 29 In the outpatient setting, administration of bamlanivimab to adults with mild to moderate COVID-19 was shown to reduce viral load from baseline compared to placebo and to reduce hospitalizations or emergency department visits. 30 Unfortunately, administration of bamlanivimab among hospitalized adults did not result in reduction of clinical severity nor time to recovery compared to placebo. 31 The REGN-COV2 cocktail is composed of two fully humanized antibodies that were generated from genetically humanized immune systems of mice. The pair of monoclonal antibodies known as casirivimab and imdevimab bind non-competitively to the receptor-binding domain of the SARS-CoV-2 spike protein. 32 The idea behind using pairs rather than a single antibody is to help reduce emergence of escape mutations and in fact REGN-COV2 cocktail was shown to prevent the emergence of spike protein mutants in vitro. 33 In rhesus macaques, the use of the REG-COV2 cocktail was shown to successfully prevent and treat SARS-CoV2 infection. 34 The results of the phase III randomized double-blinded placebo-controlled trial demonstrated that use of the antibody cocktail in non-hospitalized persons >18 years of age with COVID-19 produced a modest reduction in SARS-CoV-2 viral load levels from baseline as compared to placebo at day 7 of infection. 35 This effect was observed among those who had a high baseline viral load.

Secondary endpoints such as hospitalization or emergency room visits were similar between the placebo group and the antibody treated groups. On November 21, 2020 the FDA issued an EUA for casiravimab and imdevimab to be used together in the treatment of mild to moderate COVID-19 in both ambulatory adults and pediatric patients >12 years of age who are at high risk for poor outcome. 27 Currently there is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents. Moreover, there is evidence for potential harm associated with monoclonal antibody infusion reactions or anaphylaxis. As of December 2020, the pediatric expert panel suggested against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab) for treatment of COVID-19 in children J o u r n a l P r e -p r o o f or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. 36 

Convalescent plasma has been used for centuries to treat infectious diseases, however, to date the use of convalescent plasma has only been shown to be of clear value in treatment of Argentine hemorrhagic fever. 37 There are reported cases (n=4) of improvement following convalescent plasma use in children with severe COVID-19. 38 However, to date no clinical studies have systematically evaluated the efficacy of convalescent plasma in pediatrics. In a placebocontrolled trial in adults with severe COVID-19 with evidence of radiologically confirmed pneumonia and signs of respiratory distress, the use of convalescent plasma did not improve the clinical outcome at 7, 14 or 30 days when compared to placebo, nor did it reduce mortality (11.0% in convalescent plasma group vs 11.4% in placebo). 39 Of note, there was no statistically significant difference in transfusion related adverse events between the convalescent plasma and placebo group.

The emergence of SARS-CoV-2 has prompted international efforts to develop effective vaccines at an unprecedented rate. As of January 2021, just 11 months after the announcement of the Table 1 lists the six vaccines whose data have shown promise against COVID-19 as of January 2021.

To better appreciate the latest development of COVID-19 vaccines, a brief discussion on messenger RNA (mRNA)-based vaccines is merited, especially as two of the six vaccines to be discussed below utilize this new mRNA-based vaccine technology. Though the technology has been around since the 1990s, 42 its use in the development of vaccines has largely been hindered by its poor stability, unpredictable immune response and inefficient delivery methods when used in vivo. As a result, vaccine approaches have largely relied on traditional methods utilizing subunits, live attenuated or inactivated pathogens. In the past decade, however, major advancements through the use of modified nucleosides, synthetic cap analogues, incorporation of regulatory genetic elements and purification techniques have resulted in increased stability of mRNA and improved control over its immunogenicity. Furthermore, the use of lipid nanoparticle technology has greatly enhanced the delivery of mRNA into target cells. In 2017, the first successful use of an mRNA-based vaccine was shown to protect mice against Zika virus. 43 Since then, multiple clinical trials have been initiated to test the efficacy of mRNA-based vaccines against rabies and influenza in humans. 44, 45 A review on the latest advancements of mRNAbased vaccine technology is well beyond the scope of this article but has been excellently reviewed elsewhere. 46 In summary, mRNA-based vaccines have been touted to have superiority over traditional vaccines via their improved safety profile, efficacy at delivery and relatively rapid and low-cost production. However, the need for costly laboratory-grade freezers for storage could hinder widespread use of mRNA-based vaccines in real-world settings. candidates and amongst all age groups. 47 Furthermore, the immunogenicity was greatly enhanced after the booster dose. One notable difference between BNT162b1 and BNT162b2 was that the latter was associated with a lower incidence of severe systemic reactions such as fever, fatigue and chills in adults >65 years of age. It is worth mentioning that no participants reported fever The results demonstrated a 95% efficacy at preventing symptomatic COVID-19. The adverse J o u r n a l P r e -p r o o f effects included short-term, mild-to-moderate pain at the injection site along with systemic signs of fatigue, fever and headache. The incidence of serious adverse events was low and was similar to placebo. The vaccine received FDA EUA for persons ages ≥16 years on December 11, 2020.

Since the rollout of Pfizer-BioNTech vaccine there have been 21 reported cases of anaphylaxis among the 1,893,360 first doses (i.e., 11.1 cases per million doses given). 50 53 In addition to eliciting a strong humoral response the 100 µg dose was shown to preferentially stimulate Th1 CD4+ cells over Th2 CD4+ cells, suggesting that the vaccine not only induced a humoral immune response but also stimulated cell mediated immunity. Lastly, the results from phase I study demonstrated that the most common adverse events consisted of headache, fatigue, myalgia, chills and pain at the injection site, all of which were reported to be mild to moderate with majority resolving within a day. 54, 55 Moderna mRNA-1273 vaccine entered phase III trial in July 2020. This is a double-blinded study with over 30,000 participants ≥18 years of age being randomized to receive two doses of either placebo or 100 μg mRNA-1273 vaccine given 28 days apart. 56 The vaccine showed 94.1% efficacy at preventing COVID-19 illness including severe COVID-19 disease. Aside from transient local and systemic reactions, no safety concerns were identified. 57 The vaccine received FDA EUA for persons ages ≥18 years on December 18, 2020. 60 Secondly, the prefusion conformation has been shown to illicit the highest binding and neutralizing antibody titers when compared to other spike protein variants. 61 The preclinical findings demonstrated that the Ad26.COV2.S vaccine is capable of inducing a humoral immune response in rhesus macaques and that the immunogenicity provided protection when animals were challenged with SARS-CoV-2. 62 One potential benefit of this vaccine is that it could induce immunogenicity (i.e., neutralizing antibodies) after a single dose up to day 71 after vaccination as observed in phase I/IIa trial . 63 This would be a benefit over the 2-dose vaccine regimen particularly in the real-world setting. At the time of this writing, it has entered a phase III (ENSEMBLE) study.

J o u r n a l P r e -p r o o f Unlike the previous vaccines discussed thus far, Novavax NVX-CoV2373 vaccine contains purified recombinant full length trimeric SARS-CoV-2 spike protein. The recombinant spike protein is modified such that it is resistant to proteolytic cleavage and stabilized to maintain the prefusion conformation. In addition, the vaccine also contains a patented saponin-based Matrix-M adjuvant that enhances immune response and thereby produces high levels of neutralizing antibodies. In phase I/II study in healthy persons 18-59 years of age, the two-dose 5-μg adjuvanted regimen induced geometric mean anti-spike IgG antibody and neutralization responses that were greater than those observed in convalescent serum of COVID-19 patients. 64 Reactogenicity was absent or mild. At the time of this writing, it is undergoing phase III trials in the United Kingdom, Mexico and the US.

This is an adjuvanted recombinant protein-based vaccine. The phase I/II study involved adults ages 18-49 years. The vaccine demonstrated immune responses comparable to those who had recovered from COVID-19. 65 Unfortunately there was a lower immune response observed among those older than 50 years of age. A phase IIb study using an amended formulation is planned for early 2021.

At the time of this writing there are currently 64 COVID-19 vaccines in clinical trials and 173 in preclinical development, 40 thus it is important we do not overlook the utility of other upcoming vaccines. This is ever more important as scientists have discovered the presence of SARS-CoV2 mutated variants in the United Kingdom, Brazil and South Africa that have a potential to spread rapidly. [66] [67] [68] Published data are lacking whether immunogenicity from current vaccines can J o u r n a l P r e -p r o o f prevent infections by these variants. Our armamentarium against variant strains may rely on the swift identification of new mutations and the rapid development of diverse vaccine candidates.

It is also critical to point out that the clinical trials have not specifically focused on children thus far. It is imperative that we do not delay the development of vaccines for this population. Though children are less likely to suffer from severe COVID-19, children particularly those ≥10 years of age could readily spread COVID-19 as effectively as adults. Furthermore, approximately 12% of all COVID-19 cases are seen in children and some have succumbed to a severe disease. 3 In addition, children have been greatly affected by the pandemic, with large disruptions to in-person school, limited peer interactions, and reduced access to activities that helps develop physical and emotional well-being. Thus, development of COVID-19 vaccines must not only target the adult population but also the pediatric population. It is encouraging that at the time of this writing, Pfizer has enrolled children to the age of 12 years and its EUA for vaccine indications down to the age of 16 years was approved. Moderna is initiating a similar study, as is Janssen.

AstraZeneca vaccine has an approval to enroll children ages 5-12 years in the United Kingdom. Although most children present with no or mild symptoms from COVID-19, more data are needed regarding its long-term effects in children. Antivirals and immune-based therapies may play a role in management of those with severe diseases, however such interventions have not been fully evaluated in pediatrics to date. Development of vaccines is rapidly evolving, and several vaccine candidates are being assessed in the pediatric population.

J o u r n a l P r e -p r o o f

• COVID-19 in children is usually mild, and COVID-19-related deaths in the pediatric population are extremely rare.

• Cases in children have been linked to having a family member with COVID-19.

• Severity in the pediatric population appears inversely related to age, with infants being most susceptible to severe COVID-19.

• Supportive care alone is sufficient for most children and antiviral remdesivir may be appropriate for those with severe or critical illness. 

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