By Micaela A. Witte and Philip R. Fischer, MD, DTM&H
Ms. Witte is a student at Mayo Clinic Alix School of Medicine. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.
Ms. Witte and Dr. Fischer report no financial relationships relevant to this field of study.
SYNOPSIS: In China, children of all ages have been infected with SARS-CoV-2 and seem to follow a relatively mild clinical course.
SOURCE: Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics 2020. doi: 10.1542/peds.2020-0702. [Epub ahead of print].
In early December 2019, the virus that would come to be known as SARS-CoV-2 started its spread from Hubei province throughout China and eventually the world. By March 2, 2020, there were 80,174 cases of COVID-19 in China alone, with incidence rates growing globally. While research has begun to characterize the epidemiology and clinical features of COVID-19 in adult patients, few studies have examined the epidemiological characteristics in pediatric patients.
Dong and colleagues studied 2,141 patients younger than 18 years of age with suspected (65.9%) or confirmed (34.1%) COVID-19 reported to the Chinese Center for Disease Control and Prevention between Jan. 16 and Feb. 8, 2020, to characterize the epidemiological factors and transmission patterns in pediatric patients with COVID-19. Children were characterized as having suspected COVID-19 if they were high risk (i.e., exposed to a known COVID-19 case) and had at least two of the following features: symptoms (i.e., upper respiratory symptoms, digestive symptoms, fever, or fatigue); laboratory abnormalities (i.e., normal or decreased white blood cell count, increased lymphocyte count, or increased C-reactive protein); or abnormal chest X-ray. Children with medium risk (i.e., those who lived in an epidemic area or community with reported COVID-19 cases) or low risk (i.e., those who lived in a non-epidemic area with no reported COVID-19 cases) were classified as having suspected COVID-19 by the same features after ruling out other causes of respiratory infections. Pediatric patients were classified as having confirmed COVID-19 if a nasal, pharyngeal, or blood sample either tested positive for SARS-CoV-2 nucleic acid using real time polymerase chain reaction (RT-PCR) or exhibited highly homologous genetic sequencing with SARS-CoV-2.
The demographic data, location, date of symptom onset, and date of diagnosis were recorded for all confirmed and suspected COVID-19 pediatric cases. In addition, each pediatric case was classified by severity: asymptomatic (i.e., positive SARS-CoV-2 nucleic test without clinical symptoms or chest imaging abnormalities); mild (i.e., symptoms of upper respiratory tract infection or digestive symptoms without auscultory or chest imaging abnormalities); moderate (i.e., lung lesions on chest imaging or more severe respiratory symptoms, such as pneumonia without hypoxemia); severe (i.e., respiratory symptoms that progress to central cyanosis with oxygen saturation less than 92%); and critical (i.e., acute respiratory distress, shock, encephalopathy, myocardial injury, acute kidney injury, or coagulation dysfunction).
A descriptive analysis showed that the median age of these patients was 7 years, and 1,213 patients were male (56.6%). The median time from the onset of symptoms to diagnosis was two days, with most diagnosed within the first week of symptoms. Only 5.9% were classified as severe to critical cases, compared with data showing 18.5% severe to critical cases in adults. Of these severe and critical pediatric cases, 83.2% were suspected cases, with only 16.8% confirmed cases. Furthermore, 4.4% of children were completely asymptomatic.
Young children seemed to be more severely affected than older children, with severe and critical cases making up a larger percentage of their total COVID-19 cases. Specifically, the percentage of severe and critical cases by age range was 10.6% in those < 1 year, 7.3% in those 1-5 years, 4.2% in those 6-10 years, 4.1% in those 11-15 years, and 3.0% in those 16-18 years. There was only one reported death: a 14-year-old boy on Feb. 7. (No further details were given about this individual.)
Modeling of spatial distribution showed the spread from Hubei Province to surrounding areas over time, with the exception of Heilongjiang Province. Furthermore, 45.9% of all pediatric COVID-19 cases were reported in Hubei Province, and 18.5% of all cases were reported in the six bordering provinces.
Modeling of temporal distribution showed a rapid increase in symptom onset since Dec. 26 that peaked around Feb. 1 and was followed by a gradual decline. Diagnoses have continued to rise since Jan. 20, when the first case was diagnosed. On average, the peak in diagnosis lagged behind symptom onset by two to seven days.
In summary, Dong and colleagues found that COVID-19 cases have been reported in all pediatric age groups, with the majority of cases following an asymptomatic to moderate clinical course. The spatial and temporal distribution of these COVID-19 pediatric cases from Hubei Province is similar to that of adult cases.
COMMENTARY
In a review of 72,314 COVID-19 cases on Feb. 11, 2020, the Chinese Center for Disease Control and Prevention found that only 1% of all patients were younger than 10 years of age.1 This reduced vulnerability to infection has been echoed in other studies. For example, a recent report found that of 1,391 children exposed to SARS-CoV-2 and later tested, only 171 (12.3%) were positive for infection.2
Currently, it is unknown whether neonates are at risk of vertical transmission. In four recently published studies, only L. Zeng and colleagues reported neonates with positive SARS-CoV-2 testing after delivery to SARS-CoV-2 positive mothers (three out of 33 infants).3-6 Despite this relatively low rate of positive testing, two studies found that neonates had elevated levels of SARS-CoV-2 antibodies. Specifically, the infant in the case study conducted by Dong and colleagues was positive for both SARS-CoV-2 immunoglobulin G (IgG) and immunoglobulin M (IgM) despite negative SARS-CoV-2 PCR tests.5 Similarly, two of the six neonates studied by H. Zeng and colleagues were positive for both SARS-CoV-2 IgG and IgM, and three were positive for IgG.6 Whether a positive SARS-CoV-2 IgM represents a response to infection or is simply a false positive has not been determined yet.
Furthermore, children who do become infected with SARS-CoV-2 seem to follow a mild course. In the report by Lu and colleagues, 39 (22.8%) of the confirmed COVID-19 cases were completely asymptomatic, although 12 (30.8%) of these children had ground glass opacity on imaging. Only three (1.8%) children (one with intussusception, one with hydronephrosis, and one with leukemia on chemotherapy) had severe symptoms requiring intensive care and ventilation, with one reported death (the child with intussusception).2 Similar findings have been reported in other Chinese provinces, with one study finding 13% of children (n = 31) to be asymptomatic and another finding 28% asymptomatic. In both of these studies, the remaining children reported mild to moderate symptoms, although six children required supplemental oxygen.7,8
Because many of the children with COVID-19 in these reports were suspected cases without confirmatory testing, it is possible that the true population of COVID-19 cases was even milder than reported. This potential case contamination also may explain the discrepancy in the current article by Dong and colleagues, which reported 83% of the severe to critical cases in suspected cases, while only 17% in confirmed cases. Information regarding other risk factors, such as underlying pulmonary pathology and immunocompromised conditions, would further inform conclusions from these data, since these children may be affected disproportionately.9
In addition to reduced susceptibility and milder infection, children with SARS-CoV-2 infection may present differently. For example, children with COVID-19 have been shown to have elevated procalcitonin levels, a finding that has not been reported in adults.3,7,8,10 Specifically, Xia and colleagues found that 80% of affected pediatric patients had elevations in procalcitonin, and Qui and colleagues found that procalcitonin levels greater than 0.5 ng/mL predicted a more aggressive clinical course.8,10 Furthermore, Xia and colleagues found that 50% of patients had consolidation with halos reported on imaging. The authors believe this finding may be related to coinfection, since 40% of patients were infected with at least one other pathogen (i.e., cytomegalovirus, influenza A, influenza B, respiratory syncytial virus, or mycoplasma).10 Supportively, in an earlier study conducted in Norway, 68.1% of hospitalized children with coronavirus were infected with at least one other pathogen.11
These features suggest a modified response to infection in children. However, the mechanism for a different and generally mild COVID-19 course in the pediatric population is not well understood. Dong and colleagues hypothesized that it may have to do with social factors, such as children being more likely to stay home and, thus, having less exposure. They also listed potential physiological factors, such as children having immature ACE2 enzymes, which are thought to serve as receptors for SARS-CoV-2, and a more active immune system with higher antibody levels due to a higher frequency of infection.
With the large proportion of asymptomatic cases, children may greatly affect viral transmission.2,7 Furthermore, research conducted by Jiehao and colleagues found that children may have prolonged nasal and fecal shedding of SARS-CoV-2. Specifically, the average length of time for continued SARS-CoV-2 RNA on nasopharyngeal swab after symptom onset was 12 days. At the time of their publication, the five out of six patients who initially tested positive for fecal SARS-CoV-2 RNA continued to test positive on days 18-30 after symptom onset.12
The work of Dong and colleagues provides valuable information regarding the spread and severity of COVID-19 in the pediatric population. Specifically, through their large sample of patients, they were able to track many of the COVID-19 pediatric cases in China and quantify the severity of their symptoms. However, more research regarding the susceptibility, physiologic response, and treatment of SARS-CoV-2 in children is needed.
REFERENCES
- Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020. doi:10.1001/jama.2020.2648. [Epub ahead of print].
- Lu X, Zhang L, Du H. SARS-CoV-2 Infection in children [correspondence]. N Engl J Med 2020. doi:10.1056/NEJMc2005073. [Epub ahead of print].
- Zeng L, Xia S, Yuan W, et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China. JAMA Pediatrics 2020. doi: 10.1001/jamapediatrics.2020.0878. [Epub ahead of print].
- Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet 2020;395:809-815.
- Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA 2020. doi: 10.1001/jama.2020.4621. [Epub ahead of print].
- Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA 2020. doi: 10.1001/jama.2020.4861. [Epub ahead of print].
- Duan W, Xiuli J, Feng X, et al. Clinical analysis of 31 cases of new coronavirus infection in children in six provinces (autonomous regions) of northern China in 2019. Chinese Journal of Pediatrics 2020; March 2. [Online ahead of print].
- Qui H, Wu J, Hong L, et al. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: An observational cohort study. Lancet Infect Dis 2020; March 25. [Epub ahead of print].
- Cruz A, Zeichner S. COVID-19 in children: Initial characterization of the pediatric disease [correspondence]. Pediatrics 2020. doi: 10.1542/peds.2020-0834.
- Xia W, Shao J, Guo Y, et al. Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults. Pediatric Pulmonol 2020. doi: 10.1002/ppul.24718. [Epub ahead of print].
- Heimdal I, Moe N, Kokstad S, et al. Human coronavirus in hospitalized children with respiratory tract infections: A 9-year population-based study from Norway. J Infect Dis 2019;219:1198-1206.
- Cai J, Xu J, Lin D, et al. A case series of children with 2019 novel coronavirus infection: Clinical and epidemiological features. Clin Infect Dis 2020; doi: 10.1093/cid/ciaa198. [Epub ahead of print].
In China, children of all ages have been infected with SARS-CoV-2 and seem to follow a relatively mild clinical course.
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