Pediatric Annals

Feature Article 

An Overview of the Ongoing Clinical Issues of COVID-19

Asif Noor, MD; Leonard R. Krilov, MD

Abstract

Childhood cases of coronavirus disease 2019 (COVID-19) are on the rise as the pandemic continues to rage across the globe. Most children acquire infection from an adult household member. Children may stay asymptomatic, have a pre-symptomatic stage, or present with symptoms (fever, cough, and difficulty breathing being the most common). Nearly one-third of the pediatric cases (32%) in the United States occurred in children age 15 to 17 years. Children are also at risk of a postinfectious hyperinflammatory syndrome called multisystem inflammatory syndrome in children (MIS-C). The risk of vertical transmission is low (2%) in newborns of mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nucleic acid amplification testing (NAAT) is the gold standard for (SARS-CoV-2). Serology should be considered in a child with high clinical suspicion for COVID-19 when NAAT is negative and at least 2 weeks have passed since symptom onset and for assessment of MIS-C. Easy fatigability after COVID-19 infection is reported in adults; however, data in children are lacking. Implementation of early and robust containment strategies coupled with universal COVID-19 vaccination are vital to halt the spread. [Pediatr Ann. 2021;50(2):e84–e89.]

Abstract

Childhood cases of coronavirus disease 2019 (COVID-19) are on the rise as the pandemic continues to rage across the globe. Most children acquire infection from an adult household member. Children may stay asymptomatic, have a pre-symptomatic stage, or present with symptoms (fever, cough, and difficulty breathing being the most common). Nearly one-third of the pediatric cases (32%) in the United States occurred in children age 15 to 17 years. Children are also at risk of a postinfectious hyperinflammatory syndrome called multisystem inflammatory syndrome in children (MIS-C). The risk of vertical transmission is low (2%) in newborns of mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nucleic acid amplification testing (NAAT) is the gold standard for (SARS-CoV-2). Serology should be considered in a child with high clinical suspicion for COVID-19 when NAAT is negative and at least 2 weeks have passed since symptom onset and for assessment of MIS-C. Easy fatigability after COVID-19 infection is reported in adults; however, data in children are lacking. Implementation of early and robust containment strategies coupled with universal COVID-19 vaccination are vital to halt the spread. [Pediatr Ann. 2021;50(2):e84–e89.]

As the world continues to grapple with coronavirus disease 2019 (COVID-19) pandemic, children face the risk of COVID-19 in many forms: acute COVID-19 infection, a unique postinfectious inflammatory syndrome, a decline in routine vaccinations, and school closures creating educational and mental health concerns. Management of infants born to mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another pediatric concern. Additionally, there has been a steady rise in pediatric COVID-19 cases over the course of the pandemic. Children represented 12.6% of all COVID-19 cases in January 2021 as opposed to 1.7% cases in March 2020.1–3 COVID-19 has clearly affected children and those who care for them. In this review article, we highlight ongoing clinical issues pertaining to COVID-19 infection in children.

Clinical Presentation in Children

Demographics

Children of all ages are susceptible to COVID-19 infection. The Centers for Disease Control and Prevention (CDC) provide data weekly on the demographics and clinical presentation of COVID-19 in children. The initial report from January through April 2020 described the age groups affected. Nearly one-third of the pediatric cases (32%) occurred in children age 15 to 17 years, followed by children age 10 to 14 years (27%). Infants younger than age 1 year constituted 15% of cases in children.3 Additionally, in an incidence report from March through December 2020 among persons age 0 to 24 years, most of the cases (57.4%) were in young adults (age 18–24 years). Children and adolescents age 14 to 17 years accounted for 16.3% of the cases, children age 11 to 13 years 7.9%, children age 5 to 10 years 10.9%, and young children and infants age 0 to 4 years accounted for 7.4% of the cases.4

Children from ethnic and racial minorities are affected disproportionately, in a manner similar to adults. Among children hospitalized in 14 states with COVID-19, the cumulative hospitalization rate by late July 2020 was 16.9 per 100,000 population in Hispanic or Latinx children, 10.5 per 100,000 in non-Hispanic Black children, and 2.1 per 100,000 population among White children.4

Incubation Period and Transmission

Most children acquire COVID-19 from an adult household member as the index case.5 Low rates of possible transmission in the school setting from teachers to the students as well as from other students have been reported.6 In contrast to influenza and other respiratory viruses, transmission from adults to children appears to be more common than the reverse scenario.

The incubation period is 14 days, with a median time of 4 to 5 days from exposure to symptom onset. After contracting infection, children may stay asymptomatic, have a pre-symptomatic stage, or present with overt symptoms. In a case series from South Korea, from February to March 2020, the asymptomatic, pre-symptomatic, and symptomatic proportion of the children who were infected was 22%, 20%, and 58% respectively.7

Asymptomatic and pre-symptomatic. Asymptomatic children never develop symptoms after testing positive for SARS-CoV-2. Pre-symptomatic children lack symptoms at the time of SARS-CoV-2 testing but later develop symptoms. In the case series from South Korea, asymptomatic children had detectable virus for a mean of 14.1 days after the initial positive test, and four asymptomatic children (20%) continued to have detectable virus 21 days after initial detection.8 Pre-symptomatic children remained symptom-free for a median of 2.5 days (range of 1–25 days) prior to onset of symptoms despite having detectable virus.

SARS-CoV-2 Asymptomatic Transmission. Case reports early on during the pandemic emphasized transmission of SARS-CoV-2 from asymptomatic persons. Most of these cases were people exposed during travel to Wuhan or other cities in Hubei Province in China who later transmitted the infection to members of their household or other close contacts.8 The estimated asymptomatic proportion of adults is delineated in several studies. The asymptomatic proportion of COVID-19 cases on board a Diamond Prince Cruise ship in Yokohama, Japan was 17.9%.9 Although transmission from asymptomatic adults is well documented, the extent to which it contributes to the pandemic remains uncertain.10 Limited data in childcare facilities suggest that asymptomatic children do play a role in transmission, as 2 of 3 confirmed asymptomatic children were responsible for transmission in three childcare facilities in Salt Lake City, UT.11

Spectrum of symptomatic disease. Symptoms range from mild to severe in nature (Table 1 and Table 2). Most children have mild symptoms, with fever and cough being the most common. Among 17,877 children who had symptoms reported to the CDC, the most common symptoms were fever (46%), cough (37%), headache (15%), diarrhea (14%), and sore throat (13%) in children age 9 years and younger, whereas headache (42%), cough (41%), fever (35%), myalgia (30%), sore throat (29%), shortness of breath (16%), and diarrhea (14%) were the most common symptoms in children age 10 to 19 years.2

Acute COVID-19 Infection in Childrena

Table 1.

Acute COVID-19 Infection in Children

MIS-C in Childrena

Table 2.

MIS-C in Children

Pediatric hospitalization. The COVID-19 hospitalization rate among children younger than 18 age years during the period from March 1 to July 25, 2020, was 8.0 per 100,000 population compared to 164.5 per 100,000 in adults. The highest rate was among children younger than age 2 years (24.8 per 100,000).2,12 Among all hospitalized children, 33.2% were admitted to the intensive care unit (ICU) and 5.8% required mechanical ventilation. The most prevalent underlying medical conditions were obesity (37.8%), chronic lung disease (18%), and prematurity (15.4%). The median time from onset of symptoms to admission was 2 days in a study from a New York City children's hospital.13 In this cohort, 80% of the hospitalized children had fevers.13 The median length of stay in the hospital was 2.5 days and the median length of stay in the ICU was 2 days in the COVID-19–associated hospitalization surveillance network report.2,13

Infant exposed to maternal SARSCoV-2 infection. Another aspect of COVID-19 burden in children relates to the management of infants exposed to mothers with SARS-CoV-2 infection. Near the onset of pandemic there were limited data regarding outcomes in pregnant women and the risk of vertical or horizontal transmission to their newborns. This uncertainty surrounding potential transmission from infected mother to neonate led to a cautious approach, and the initial American Academy of Pediatrics (AAP) guidance on April 2, 2020 recommended separation of mother-newborn dyads to minimize the risk of transmission.14 This was based primarily on data from studies in China.15,16 Since then, the published data have better informed the perinatal risk. In a systematic review, the rate of vertical transmission in 936 infants exposed to maternal COVID-19 infection was 3.2%.17 The data from Perinatal COVID-19 Registry suggests that approximately 2% of infants born to women who test positive for SARS-CoV-2 near the time of delivery have tested positive in the first 24 to 96 hours after birth. SARS-CoV-2 RNA has been detected via reverse transcription polymerase chain reaction (RT-PCR) testing in placental membranes and breast milk in case reports; however, overall rates of vertical transmission are low.18,19 Most of the exposed neonates are not found to have SARS-CoV-2 via nasopharyngeal RT-PCR testing. Nonetheless, neonates born to symptomatic mothers with SARS-CoV-2 were more likely to be born prematurely and to be admitted to the neonatal ICU compared to babies born to asymptomatic mothers diagnosed during universal screening.20 In addition, SARS-CoV-2 infection has significant impact on maternal-newborn dyads with respect to breast-feeding outcomes, as there are lower rates of breast-feeding in separated dyads in the hospital and at home compared to unseparated dyads.21

The latest AAP guidelines from January 202122 suggest rooming in of maternal-newborn dyads and breast-feeding with proper hand hygiene practices and use of facial mask based on observations that the outcomes of neonates born at or near term has been uniformly good unless there was preterm birth due to symptomatic maternal SARS-CoV-2 infection. Additionally, the risk of SARS-CoV-2 infection is similar in maternal-newborn dyads who are separated versus those allowed to room in with appropriate infection prevention measures.

Multisystem inflammatory syndrome in children. On April 26, 2020, pediatricians in the United Kingdom reported a severe inflammatory syndrome with shock-like and Kawasaki-like features in otherwise healthy children.23 This was followed shortly thereafter by recognition of similar cases in the United States. This hyperinflammatory syndrome in otherwise healthy children and adolescents was described as multi-system inflammatory syndrome in children (MIS-C) by the CDC. It is a spectrum of illnesses: mild febrile illness phenotype, severe shock-like phenotype with multiple organ involvement, and Kawasaki-like phenotype. The median age in a multicenter US study was 8.3 years, 62% were boys, and 73% were previously healthy.24 In this cohort, 70% had a positive SARS-CoV-2 test by either RT-PCR or antibody testing, and 88% were hospitalized. In regard to organ system involvement, 92% had gastrointestinal involvement, 80% cardiovascular, 76% hematological, 74% mucocutaneous, and 70% respiratory. Kawasaki-like features of rash and mucous membrane involvement were described in 40% of children in this study.24 In contrast to classic Kawasaki disease, children with MIS-C tend to be older, have severe abdominal pain, acute kidney injury, myocarditis, and laboratory parameters consistent with COVID-19 (markedly elevated N-terminal-pro-B-type natriuretic peptide, troponin, ferritin, triglycerides, and C-reactive protein; thrombocytopenia; and lymphopenia).25,26

Testing Issues in Children

When to test. SARS-CoV-2 testing should be considered in symptomatic children with suspected infection, especially in a symptomatic child exposed to a person with COVID-19 or during community spread. Testing of selected asymptomatic cases should be considered in children after close contact with a laboratory-confirmed case of COVID-19, screening hospitalized children, screening for time-sensitive surgical procedures or in children who undergo aerosol-generating procedures, and prior to receiving immunosuppressive therapy. In the situation of close exposure to COVID-19, the suggested time to test is 5 to 7 days after exposure based on the average incubation.27 Because the time to detectable RNA after exposure is unknown, children with a negative test should still quarantine for 14 days.

When testing for SARS-CoV-2, especially in winter months, screening for other respiratory viruses (eg, influenza, respiratory syncytial virus, or complete respiratory viral panel) may be indicated because symptoms of these viral infections may overlap.

Which Test?

Polymerase chain reaction assays. The nucleic acid amplification test (NAAT) directly detects SARS-CoV-2 virus. The most commonly used NAAT test is RT-PCR. It is the current gold standard and the ideal initial diagnostic test method to detect SARS-CoV-2 infection from the upper respiratory tract. A nasopharyngeal or mid turbinate swab is preferred over oropharyngeal or saliva specimen Sensitivity of mid turbinate, nasopharyngeal, saliva, and oral specimen is 100%, 97%, 85%, and 56%, respectively. The sensitivity and specificity of rapid NAAT versus laboratory-based NAAT testing ranges between 75% and 94%, and 99% to 100%, respectively. The false-negative performance depends on the illness duration.27

Antigen testing. SARS-CoV-2 antigen testing can be performed rapidly and serves as a point-of-care test. Given the lower sensitivity, pediatricians should be aware of the potential for false negatives. The sensitivity is extremely variable from 0% to 94%, with an average of 56.2%.28

Antibody testing. Serological tests detect antibodies against SARS-CoV-2 nucleocapsid or the spike protein. The blood sample can be capillary (finger-stick) or venous (venipuncture). The Infectious Diseases Society of America (IDSA) recommends serology in three select situations: (1) in a child with high clinical suspicion for COVID-19 when NAAT is negative and at least 2 weeks have passed since symptom onset; (2) assessment of MISC in children; and (3) for conducting serosurveillance studies.27

The IDSA suggests using only immunoglobulin (Ig) G or total antibody tests rather than IgM antibody, IgA antibody, or IgM/IgG assays. The positive predictive value is higher, with specificity greater than 99.5% for people with high test probability. In areas of low prevalence, the pretest probability is low and the individual results should be interpreted with caution. In addition, cross-reactivity with other coronavirus is a potential concern.27 The correlate of protection or duration of antibody responses is unknown at present.

Persistent Symptoms

The recovery time from COVID-19 is believed to be 4 weeks after mild illness and 4 to 6 weeks after moderate to severe illness. It is variable and depends upon patient age as well as preexisting comorbidities. In a survey of patients discharged from the hospital in the US, only 39% reported return to baseline health by 2 to 3 weeks after diagnosis.29 Similarly, in an Italian cohort of 143 patients, only 13% were symptom-free after a mean of 60 days.30 The most common symptoms were fatigability (53%), dyspnea (43%), joint pains (27 %), and chest pain (22%).31,32 Data regarding persistent symptoms in children are lacking. Adolescents, especially those with high body mass index, can have severe COVID-19 infection similar to adults. Whether these teenagers will have ongoing symptoms of fatigability after discharge is a concern not yet validated through studies.

Is This Going to Go Away?

As of January 2021, there were more than 97 million cases worldwide and 2 million deaths.31 In the US, COVID-19 infection is raging in certain regions, waning in others, and resurging in some sites.

The two plausible explanations for this rampant spread are high transmissibility and asymptomatic transmission. The average number of secondary transmissions from one infected person is similar or higher to influenza and other SARS viruses such as Middle East respiratory syndrome. The transmissibility or spread potential of an emerging infection in a susceptible population is commonly described using the basic reproductive number or R0. SARS-CoV-2 has an R0 of 2 to 2.5 when compared to the seasonal influenza 2019 rate of 1.7.31,32 In addition, this virus may be transmitted from asymptomatic and pre-symptomatic people. Therefore, early and vigorous containment efforts are required to reduce community circulation. Enhanced surveillance and testing are needed to identify and isolate cases as well as filter out currently infected people (even those who are asymptomatic). Public health strategies such as limiting travel to COVID-19 hotspots, quarantine upon return from such areas, and enhanced tracking can slow but not halt the spread. Similarly, common-sense infection control precautions such as wearing masks, frequent handwashing, and social distancing can help reduce the risk of infection.

Herd immunity and widely available immunization likely hold the key to interrupting the explosive expansion of COVID-19. Herd immunity occurs when a significant portion of a population becomes immune to an infectious disease and the risk of spread from person to person decreases. Individuals in the community not immune are indirectly protected as the transmission is low.

References

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Acute COVID-19 Infection in Childrena

Without symptoms: 42% With symptoms: 58%
Asymptomatic: 22% Presymptomatic: 20% Range from mild, to moderate, to severe Most common symptoms are fever, cough, shortness of breath: 60%–63%

MIS-C in Childrena

Phenotype Prevalence, % Notes
Febrile only Unknown Persistent fevers more than 3 days with mild symptoms
Kawasaki-like 35a Seen in younger children; mucocutaneous involvement
Multiorgan 30 Gastrointestinal, followed by cardiovascular and hematological
Acute respiratory 30 Seen in older children with acute COVID-19 and hyper inflammatory syndrome
Authors

Asif Noor, MD, is a Clinical Assistant Professor. Leonard R. Krilov, MD, is a Professor. Both authors are associated with the Division of Pediatric Infectious Diseases, Department of Pediatrics, NYU Long Island School of Medicine.

Address correspondence to Leonard R. Krilov, MD, NYU Long Island School of Medicine, 120 Mineola Boulevard, Suite 210, Mineola, NY 11501; email: leonard.krilov@nyulangone.org.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20210112-01

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