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Review Article| Volume 68, ISSUE 1, P321-338, February 2021

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Risk Factors for Severity in Children with Coronavirus Disease 2019

A Comprehensive Literature Review

      Keywords

      Key points

      • The ongoing coronavirus disease 2019 (COVID-19) pandemic has affected hundreds of thousands of people.
      • Children have so far accounted for 1.7% to 2% of diagnosed cases of COVID-19.
      • Children often have milder disease than adults, and child deaths have been rare.
      • Risk factors for severe disease from COVID-19 in children are reported to be young age and underlying comorbidities, although this is not confirmed in all studies.
      • It is unclear whether male gender and certain laboratory and imaging findings can also be considered as risk factors, because of insufficient data.

      Introduction

      Until recently, 6 different coronaviruses (CoVs) had been identified in humans (human CoVs [HCoVs]): HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-HKU1, severe acute respiratory syndrome (SARS)-CoVs, and MERS-CoVs. Endemic HCoV-OC43 and HCoV-229E were described in the 1960s, and HCoV-NL63 and HCoV-HKU1 in 2004 and 2005, respectively.
      • McIntosh K.
      • Dees J.H.
      • Becker W.B.
      • et al.
      Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease.
      ,
      • Woo P.C.
      • Lau S.K.
      • Chu C.M.
      • et al.
      Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia.
      The first serious CoV disease outbreak occurred in China in 2002, when the novel SARS-CoV emerged, which was thought to have been transmitted from civet cats or bats to humans.
      • Drosten C.
      • Gunther S.
      • Preiser W.
      • et al.
      Identification of a novel coronavirus in patients with severe acute respiratory syndrome.
      ,
      • Luk H.K.H.
      • Li X.
      • Fung J.
      • et al.
      Molecular epidemiology, evolution and phylogeny of SARS coronavirus.
      The second novel CoV emerged in Saudi Arabia in 2012, the Middle East respiratory syndrome (MERS)–CoV,
      • Cauchemez S.
      • Fraser C.
      • Van Kerkhove M.D.
      • et al.
      Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility.
      which is transmitted from dromedary camels to humans.
      • de Groot R.J.
      • Baker S.C.
      • Baric R.S.
      • et al.
      Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group.
      Collectively, these 2 CoV diseases did not affect children widely, because of the short-term nature of the epidemic of SARS and the rigid transmission route of MERS.
      Since December 2019, SARS-CoV-2 has been recognized as the causal factor of severe pneumonia and potential damage to vital organs in humans. The first cases of SARS-CoV-2 originated in Wuhan in the Hubei province of China, and subsequently spread to other countries throughout the world.
      • Paules C.I.
      • Marston H.D.
      • Fauci A.S.
      Coronavirus infections-more than just the common cold.
      In February 2020, the World Health Organization (WHO) designated the disease CoV disease 2019 (COVID-19).
      A substantial number of studies have already been published on adults with COVID-19, but reports on children with COVID-19 are scarce. This article analyzes the current knowledge on the risk factors for the progression and severity of COVID-19 in infants and children. The possible mechanisms of aberrant clinical features of COVID-19 in children are also presented. To the best of our knowledge, this is the first review addressing the risk factors associated with the progression and severity of COVID-19 in children.

      Methods

      Original research studies published in English between February 26, 2020 and June 10, 2020 were identified using PubMed and Scopus. The search used combinations of the key words “COVID-19,” “SARS-CoV2,” “mechanism,” :risk factor,” “severity,” and “child.” In addition, the reference lists of the retrieved articles were checked for other relevant articles. The initial search yielded 293 articles, of which, after screening of their titles, 72 studies were considered relevant to the aim of this review. Studies on adults and neonates were not included, and 7 studies were excluded because they were in Chinese. Pediatric case reports of COVID-19 were included only if they provided information about risk factors for severe disease. Thus, 23 studies were eventually selected, as shown in Fig. 1, and are discussed here. The factors that may introduce bias into the findings of this article are restriction to articles in English, together with database and citation bias.
      Figure thumbnail gr1
      Fig. 1The literature search on risk factors for severe COVID-19 in childhood (February 26 to June 10, 2020).
      Most of the studies originated in China, the United States, Italy, Spain, and South Korea, despite the large number of patients diagnosed with COVID-19 throughout the world. Some published studies relating to COVID-19 in children do not provide detailed information on the mechanisms, triggering factors, or clinical features, which led to the deterioration of the status of the patients. In addition, the current studies do not provide a uniform definition of severe or critical disease. The information from all the studies related to the risk factors for severe COVID-19 in infants and children is summarized in Table 1.
      Table 1Studies on severity and risk factors of coronavirus disease 2019 in children (February 26 to June 10, 2020)
      First AuthorRegionStudy PeriodNumber of ChildrenMean Age (% of Young Children)Underlying Diseases Present (Diseases)SeverityRisk Factors
      Bialek et al
      CDC COVID-19 Response Team
      Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020.
      United States (33% from New York City, 23% from the rest of New York State, 15% from New Jersey, 29% from other jurisdictions)February 12 to April 2, 2020257211 (<1 y, 15%)23% (chronic lung disease, cardiovascular disease, immunosuppression)5.7%–20% hospitalized, 0.58%–2% admitted to ICU, aged <1 y: 15%–62% hospitalized, 3 deathsChildren aged <1 y, underlying condition
      Dong et al,
      • Dong Y.
      • Mo X.
      • Hu Y.
      • et al.
      Epidemiology of COVID-19 Among Children in China.
      2020
      Chinese CDC, cases from Hubei province and Anhui, Henan, Hunan, Jiangxi, Shanxi, and ChongqingJanuary 16 to February 8, 20202135 suspected and confirmed cases7 (<1 y, 17.6%)Not available90% had asymptomatic to moderate disease

      Severe or critical disease in 10.6% <1 y, 7.3% 1–5 y, 4.1% 6–10 y, 3% >16 y; 1 14-year-old boy died
      Young age
      Lu et al,
      • Lu X.
      • Zhang L.
      • Du H.
      • et al.
      SARS-CoV-2 Infection in Children.
      2020
      Wuhan Children’s Hospital, ChinaJanuary 28 to February 26, 20201716.7 (<1 y, 18%)3 patients (hydronephrosis, leukemia, intussusception)3 patients with invasive mechanical ventilation (all with underlying condition), 1 deathUnderlying condition
      DeBiasi et al,
      • DeBiasi R.L.
      • Song X.
      • Delaney M.
      • et al.
      Severe COVID-19 in children and young adults in the Washington, DC Metropolitan Region.
      2020
      Children’s National Hospital WashingtonMarch 15 to April 30, 20201779.639% (asthma, neurologic condition, DM, obesity, cardiac problem, hematological disease, oncological condition)9 critically ill patientsAdolescents and young adults
      Parri & Leng,
      • Parri N.
      • Lenge M.
      Children with Covid-19 in Pediatric Emergency Departments in Italy.
      2020
      Italy, 17 pediatric emergency departments, the CONFIDENCE studyMarch 3 to March 27, 20201003.3 (40% <1 y, 14% <5 y)27%, cystic fibrosis; neurologic, hematological, cardiac, immunologic, oncological conditions; metabolic disease; prematurity syndrome1% had severe disease, 1% were in critical conditionUnderlying medical condition, young age
      Chao et al,
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • et al.
      Clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 (COVID-19) at a Tertiary Care Medical Center in New York City.
      2020
      Single tertiary children’s hospital, New York CityMarch 15 to April 13, 20206713.1Obesity and asthma33 admitted to ICUHigher levels of CRP, procalcitonin, and proBNP and platelet count
      Whittaker et al,
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      2020
      8 hospitals in United KingdomMarch 23 to May 16, 20205893 had asthma, 1 neurodisability, 1 epilepsy, 1 sickle cell disease, 1 alopeciaAll had multisystem inflammatory syndrome, 50% developed shock, and 14% coronary artery aneurysmIncreased CRP and ferritin levels, older age, black or Asian race
      Shekerdemian et al,
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      2020
      46 North American ICUsMarch 14 to April 3, 2020481383%All admitted to ICU, 23% had multiorgan failure, 2% needed extracorporeal membrane oxygenation, 4% diedUnderlying comorbidities
      Tagarro et al,
      • Tagarro A.
      • Epalza C.
      • Santos M.
      • et al.
      Screening and severity of coronavirus disease 2019 (COVID-19) in Children in Madrid, Spain.
      2020
      30 hospitals in Madrid, SpainMarch 2 to March 16, 202041127% had underlying disease60% hospitalized, 9.7% admitted to ICU, 9.7% needed respiratory support (1 had underlying condition)Perhaps young age, underlying condition
      Qiu et al,
      • Qiu 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.
      2020
      3 hospitals, Zhejiang, ChinaJanuary 17 to March 1, 2020368.3 (<5 y, 28%)Not availableAll patients had mild or moderate typeRadiographic presentation, decreased lymphocyte counts, increased body temperature, high levels of procalcitonin, D-dimers, and creatine kinase-MB
      Belhadjer et al,
      • Belhadjer Z.
      • Méot M.
      • Bajolle F.
      • et al.
      Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.
      2020
      14 ICUs in France and SwitzerlandMarch 22 to April 30, 2020351028% had comorbidities (asthma, overweight)Multisystem inflammatory syndrome–acute cardiac failureCytokine storm and macrophage activation
      Bandi et al,
      • Bandi S.
      • Nevid M.Z.
      • Mahdavinia M.
      African American children are at higher risk for COVID-19 infection.
      2020
      University COVID-19 clinic, Chicago, IL12 March to 20 April, 2020259.7 yNot available (1 sickle cell acute pain crisis)20% hospitalized, 12% admitted to ICU, 1 intubatedOlder age

      African American race
      Zheng et al,
      • Zheng F.
      • Liao C.
      • Fan Q.H.
      • et al.
      Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
      2020
      10 hospitals, Hubei, ChinaFebruary 1 to February 10, 2020253 (<3 y 40%)8% (congenital heart disease, malnutrition, suspected hereditary metabolic diseases)Most patients had mild disease

      Two had critical disease (both with underlying disorder)
      Underlying disorders
      Cheung et al,
      • Cheung E.W.
      • Zachariah P.
      • Gorelik M.
      • et al.
      Multisystem Inflammatory Syndrome Related to COVID-19 in previously healthy children and adolescents in New York City.
      2020
      Columbia University Irving Medical Center/New York-Presbyterian Morgan Stanley Children’s Hospital in New York CityApril 18 to May 5, 20201783 mild asthmaMultisystem inflammatory syndromeInflammatory markers, troponin T, and NT-proBNP levels
      Verdoni et al,
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      2020
      Bergamo province, ItalyFebruary 18 to April 20, 2020107.5NoneMultisystem inflammatory syndromeOlder age, features of macrophage activation
      Riphagen et al,
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • et al.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      2020
      ICU, United KingdomMid-April, 202089NoneMultisystem inflammatory syndromeAfro-Caribbean descent

      Male gender
      Sun et al,
      • Sun D.
      • Li H.
      • Lu X.X.
      • et al.
      Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study.
      2020
      ICU of Wuhan Children’s Hospital, ChinaJanuary 24 to February 24, 202087 (3 children ≤1 y)1 acute lymphoblastic leukemiaAll admitted to ICUIncreased levels of CRP, LDH, procalcitonin, abnormal liver function, cytokine storm, abnormalities on chest CT
      Liu & Zhang,
      • Liu W.
      • Zhang Q.
      Detection of Covid-19 in Children in Early January 2020 in Wuhan, China.
      2020
      3 branches of Tongji Hospital, Wuhan, China)January 7 to January 15, 202063 (4 children ≤3 y)NoneAll 4 patients ≤3 y had pneumonia, 1 admitted to ICUΥoung age
      Cui et al,
      • Cui Y.
      • Tian M.
      • Huang D.
      • et al.
      A 55-Day-Old Female Infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage.
      2020
      Hubei Province, ChinaJanuary 28, 2020155 dNonePneumonia, myocardial injury, acute liver injuryYoung age
      Shi et al,
      • Shi B.
      • Xia Z.
      • Xiao S.
      • et al.
      Severe Pneumonia Due to SARS-CoV-2 and respiratory syncytial virus infection: a case report.
      2020
      Hubei Province, ChinaFebruary 3, 202012 moNoneSevere pneumonia, need for noninvasive ventilationYoung age, coinfection with RSV
      Abbreviations: CDC, Center for Disease Control and Prevention; CRP, C-reactive protein; CT, computed tomography; DM, diabetes mellitus; ICU, intensive care unit; LDH, lactate dehydrogenase; MB, myocardial band; NT-proBNP, N-terminal pro–b-type natriuretic peptide; proBNP, pro–b-type natriuretic peptide; RSV, respiratory syncytial virus.

      Epidemiology of coronavirus disease 2019

      COVID-19 worldwide is less common in children than in adults. A review of 72,314 cases by the Chinese Center for Disease Control and Prevention showed that less than 1% of the cases were in children younger than 10 years and 1% of the cases were in children aged 10 to 19 years.
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention.
      In the United States, among 149,082 reported cases of COVID-19, 1.7% were in children aged less than 18 years.
      CDC COVID-19 Response Team
      Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020.
      From the currently available data, it seems that children tend to have asymptomatic or mild disease more commonly than adults,
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention.
      ,
      • Dong Y.
      • Mo X.
      • Hu Y.
      • et al.
      Epidemiology of COVID-19 Among Children in China.
      but severe cases and even deaths have been reported worldwide in patients younger than 18 years. In a cohort study of 32,583 confirmed cases of COVID-19 from Wuhan, China, 4.1% of severe and critical cases were in patients aged less than 20 years.
      • Pan A.
      • Liu L.
      • Wang C.
      • et al.
      Association of public health interventions with the epidemiology of the COVID-19 Outbreak in Wuhan, China.
      According to a large retrospective study conducted in China, 4 HCoVs, HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1, were more common in children, because their prevalence was 4.3%, and the highest prevalence was among infants aged 7 to 12 months.
      • Zeng Z.Q.
      • Chen D.H.
      • Tan W.P.
      • et al.
      Epidemiology and clinical characteristics of human coronaviruses OC43, 229E, NL63, and HKU1: a study of hospitalized children with acute respiratory tract infection in Guangzhou, China.
      Infection by these 4 strains usually causes acute respiratory disease, with severe manifestations in some children.
      • Corman V.M.
      • Muth D.
      • Niemeyer D.
      • et al.
      Hosts and sources of endemic human coronaviruses.
      Regarding SARS-CoV, only 6 case series have been reported, including a total of 135 pediatric cases, from Canada, Hong Kong, Taiwan, and Singapore.
      • Stockman L.J.
      • Massoudi M.S.
      • Helfand R.
      • et al.
      Severe acute respiratory syndrome in children.
      A milder form of the disease was observed in children compared with adults, and no child death was recorded.
      • Leung C.W.
      • Kwan Y.W.
      • Ko P.W.
      • et al.
      Severe acute respiratory syndrome among children.
      In the MERS-CoV epidemic, pediatric cases were even fewer, because only 2 small case series of children were reported, both originating from Saudi Arabia, 1 of 31 children with a mean age of 10 years
      • Al-Tawfiq J.A.
      • Kattan R.F.
      • Memish Z.A.
      Middle East respiratory syndrome coronavirus disease is rare in children: an update from Saudi Arabia.
      and 1 of 7 children with a mean age of 8 years.
      • Alfaraj S.H.
      • Al-Tawfiq J.A.
      • Altuwaijri T.A.
      • et al.
      Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia.
      In both studies, 42% of the infected children were asymptomatic,
      • Al-Tawfiq J.A.
      • Kattan R.F.
      • Memish Z.A.
      Middle East respiratory syndrome coronavirus disease is rare in children: an update from Saudi Arabia.
      ,
      • Alfaraj S.H.
      • Al-Tawfiq J.A.
      • Altuwaijri T.A.
      • et al.
      Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia.
      and in 1, 2 of the 7 had severe disease,
      • Alfaraj S.H.
      • Al-Tawfiq J.A.
      • Altuwaijri T.A.
      • et al.
      Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia.
      whereas in the other, 2 of the 31 children died (6%).
      • Al-Tawfiq J.A.
      • Kattan R.F.
      • Memish Z.A.
      Middle East respiratory syndrome coronavirus disease is rare in children: an update from Saudi Arabia.

      Risk factors for severity in coronavirus disease 2019 and other coronavirus infections

      The Impact of Age

      Severe acute respiratory syndrome–coronavirus-2

      In a series of 2135 children with suspected and confirmed COVID-19 from China, severe disease was defined as the occurrence of dyspnea, central cyanosis, and oxygen saturation of less than 92%. Critical disease was defined as progression to acute respiratory distress syndrome, shock, encephalopathy, myocardial injury, coagulation dysfunction, and acute kidney injury.
      • Dong Y.
      • Mo X.
      • Hu Y.
      • et al.
      Epidemiology of COVID-19 Among Children in China.
      Severe and critical cases were reported in 10.6% of the children aged less than 1 year, 7.3% of those aged 1 to 5 years, 4.1% of those aged 6 to 10 years, and 3% of the children aged greater than 16 years. One 14-year-old boy died, but no further information was provided about this patient, and the study gave no data on underlying comorbidity or other possible risk factors. It is of note that, of the 2135 children, only 728 had laboratory confirmation, and the severe symptoms in the suspected cases may have been be caused by pathogens other than SARS-CoV-2. Two case reports from the same country, China, referred to children with severe disease, a 55-day-old female infant and a 3-year-old girl with no apparent risk factor apart from the young age.
      • Cui Y.
      • Tian M.
      • Huang D.
      • et al.
      A 55-Day-Old Female Infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage.
      ,
      • Liu W.
      • Zhang Q.
      Detection of Covid-19 in Children in Early January 2020 in Wuhan, China.
      Cases have been reported of infants in China and in Vietnam that, despite their young age, had mild disease, including 10 diagnosed with COVID-19 who were otherwise healthy, with mild or no symptoms.
      • Le H.T.
      • Nguyen L.V.
      • Tran D.M.
      • et al.
      The first infant case of COVID-19 acquired from a secondary transmission in Vietnam.
      ,
      • Wei M.
      • Yuan J.
      • Liu Y.
      • et al.
      Novel coronavirus infection in hospitalized infants under 1 year of age in China.
      In a study of 177 children from the Children’s National Hospital in Washington, DC, the adolescents and young adults were more commonly critically ill than the younger children.
      • DeBiasi R.L.
      • Song X.
      • Delaney M.
      • et al.
      Severe COVID-19 in children and young adults in the Washington, DC Metropolitan Region.
      Another study from the United States reported that the mean age of COVID-19–positive children was significantly higher than those testing negative (9.72 vs 4.85 years). In that study, the ethnicity was examined, and African American children had a significantly higher rate of positive tests for COVID-19: 6.8% versus 1.7% of white children.
      • Bandi S.
      • Nevid M.Z.
      • Mahdavinia M.
      African American children are at higher risk for COVID-19 infection.
      In a study in the United Kingdom, among 58 children, race (black or Asian) was described as a risk factor for COVID-19.
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.

      Other coronaviruses

      In the United States, in the case of other CoVs, specifically 229E, HKU1, NL63, and OC43, age less than 2 years has been reported as a risk factor for severe disease, defined as the need for respiratory support.
      • Varghese L.
      • Zachariah P.
      • Vargas C.
      • et al.
      Epidemiology and clinical features of human coronaviruses in the pediatric population.
      In contrast, in a series of 44 children in China with SARS-CoV, an age of greater than 12 years was associated with severe illness, requiring methylprednisolone therapy and oxygen supplementation.
      • Leung C.W.
      • Kwan Y.W.
      • Ko P.W.
      • et al.
      Severe acute respiratory syndrome among children.
      In adults, older age has been reported to be an independent risk factor for severity and mortality, not only in SARS-CoV-2 but also in the previous epidemics of SARS and MERS.
      • Choi K.W.
      • Chau T.N.
      • Tsang O.
      • et al.
      Outcomes and prognostic factors in 267 patients with severe acute respiratory syndrome in Hong Kong.
      ,
      • Hong K.H.
      • Choi J.P.
      • Hong S.H.
      • et al.
      Predictors of mortality in Middle East respiratory syndrome (MERS).

      The Impact of Male Gender

      Male gender is a risk factor for severe CoV disease in adults.
      • Onder G.
      • Rezza G.
      • Brusaferro S.
      Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.
      A predominance of men was reported in all age subgroups among 2490 pediatric cases of COVID-19 in a series in the United States, but no details were given about the impact of gender on the severity of the disease.
      CDC COVID-19 Response Team
      Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020.
      Among 2143 Chinese children with COVID-19 in the study of Dong and colleagues,
      • Dong Y.
      • Mo X.
      • Hu Y.
      • et al.
      Epidemiology of COVID-19 Among Children in China.
      no significant difference was reported in the number of cases between boys and girls, and no detailed information was given on the gender of the severe and critical cases. In a cross-sectional study of 48 children with COVID-19 admitted to US and Canadian intensive care units (ICUs), 52% were boys.
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      Severe disease has been reported in girls and the current data suggest that, in children, male gender is not an independent risk factor of severe COVID-19.

      Underlying Medical Comorbidity

      Severe acute respiratory syndrome–coronavirus-2

      In a series of 171 children with COVID-19 from the city in China, Wuhan, where SARS-CoV-2 was first described, 3 patients required ICU support and invasive mechanical ventilation, all of whom had underlying comorbidities. One was a 10-month-old male infant with intussusception who developed multiorgan failure and died 4 weeks after admission.
      • Lu X.
      • Zhang L.
      • Du H.
      • et al.
      SARS-CoV-2 Infection in Children.
      The second child had leukemia, in the maintenance chemotherapy phase, and the third, aged 13 months, had bilateral hydronephrosis and calculus of the left kidney.
      • Lu X.
      • Zhang L.
      • Du H.
      • et al.
      SARS-CoV-2 Infection in Children.
      ,
      • Yang P.
      • Liu P.
      • Li D.
      • et al.
      Corona Virus Disease 2019, a growing threat to children?.
      It was not reported whether any of the 168 children who did not need ICU admission had an underlying condition.
      In the recently published The Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) study from Italy, which included 100 children, 27% had an underlying medical condition. Of the 9 children needing respiratory support, 5 were aged less than 1 year and 6 had an underlying condition. The severe (1) and critical (1) cases were both in children with underlying medical conditions.
      • Parri N.
      • Lenge M.
      Children with Covid-19 in Pediatric Emergency Departments in Italy.
      Among 25 pediatric cases of COVID-19 from Hubei province in China, two 1-year-old boys needed invasive mechanical ventilation, both of whom had congenital heart disease. One of them also had malnutrition and a suspected hereditary metabolic disease, and the other had coinfection with Enterobacter aerogenes.
      • Zheng F.
      • Liao C.
      • Fan Q.H.
      • et al.
      Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
      The first report from the United States concerning children with COVID-19 is of 2572 pediatric cases. Among the children for whom hospitalization status was known, 20% were hospitalized. Because of lack of information on specific disease features, hospitalization was considered to be an indicator of serious illness, and it was most often reported in children younger than 1 year. An underlying medical condition was noted in 77% of hospitalized children, in contrast with 12% of those not hospitalized. The most common comorbidities were chronic lung disease (including asthma), cardiovascular disease, and immune suppression. Three deaths were reported, but their association with COVID-19 is still under investigation.
      CDC COVID-19 Response Team
      Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020.
      In another US study, among 48 children admitted to an ICU, 83% had a significant preexisting comorbidity.
      • Shekerdemian L.S.
      • Mahmood N.R.
      • Wolfe K.K.
      • et al.
      Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
      Severe and critical cases have also been reported in children with no underlying comorbidity. Sun and colleagues
      • Sun D.
      • Li H.
      • Lu X.X.
      • et al.
      Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study.
      reported 8 severe and critical cases of children in a hospital in Wuhan, 7 of whom were previously completely healthy. In this study, severe cases were defined as the coexistence of tachypnea, oxygen saturation less than 93%, and arterial partial pressure of oxygen less than or equal to 300 mm Hg, whereas critical cases were defined as the presence of septic shock or the need for mechanical ventilation or ICU admission. The age range of the patients in the 8 severe cases was from 2 months to 15 years, 6 were boys, and only 1 of them had an underlying medical condition (acute lymphocytic leukemia).
      • Sun D.
      • Li H.
      • Lu X.X.
      • et al.
      Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study.
      Information from a registry of 310 hospitals in Madrid, Spain, showed that, of 41 children with COVID-19, 60% were hospitalized, 4 children were admitted to an ICU, and 4 needed respiratory support. Of these children, 1 had a previous condition (recurrent wheezing) and no patient died.
      • Tagarro A.
      • Epalza C.
      • Santos M.
      • et al.
      Screening and severity of coronavirus disease 2019 (COVID-19) in Children in Madrid, Spain.
      In a recent report from Paris, France, of 27 children with severe COVID-19, 70% had an underlying medical condition. Of the 5 children who died, 3 had no underlying comorbidity, suggesting that comorbidities may be a risk factor for severe disease and fatality but that other mechanisms may also be implicated in the severity of the disease.
      • Oualha M.
      • Bendavid M.
      • Berteloot L.
      • et al.
      Severe and fatal forms of COVID-19 in children.
      It seems, therefore, that although underlying medical comorbidity may be a risk factor for severe disease in childhood, it is not the only risk factor for progression of the disease and development of complications. It would be of interest to gather further information on the children with underlying medical problems and assess the percentages with severe or mild disease, and their other risk factors. To date, there is lack of such data in the literature, although, in adults, specific comorbidities are well documented as risk factors not only for admission to the ICU but also for mortality.
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.

      Other coronaviruses

      Severe pediatric disease from other CoVs reported in the United States, specifically 229E, HKU1, NL63, and OC43, defined as need for respiratory support or pediatric ICU admission, has been associated with underlying comorbidity, and, in particular, cardiovascular, chronic respiratory, and genetic/congenital conditions.
      • Varghese L.
      • Zachariah P.
      • Vargas C.
      • et al.
      Epidemiology and clinical features of human coronaviruses in the pediatric population.
      Ogimi and colleagues
      • Ogimi C.
      • Englund J.A.
      • Bradford M.C.
      • et al.
      Characteristics and outcomes of coronavirus infection in children: the role of viral factors and an immunocompromised state.
      in the United States showed that both an immunocompromised state and underlying pulmonary disorder were associated with lower respiratory tract disease or severe lower respiratory tract disease from HCoV. No significant difference was found regarding the severity of illness among hospitalized children with different HCoV types.
      • Varghese L.
      • Zachariah P.
      • Vargas C.
      • et al.
      Epidemiology and clinical features of human coronaviruses in the pediatric population.
      The 2 deaths reported in children with MERS-CoV in Saudi Arabia were in a 2-year-old child with cystic fibrosis
      • Memish Z.A.
      • Al-Tawfiq J.A.
      • Assiri A.
      • et al.
      Middle East respiratory syndrome coronavirus disease in children.
      and a 9-month-old infant with infantile nephrotic syndrome,
      • Thabet F.
      • Chehab M.
      • Bafaqih H.
      • et al.
      Middle East respiratory syndrome coronavirus in children.
      whereas a 14-year-old girl with Down syndrome needed hospital admission but eventually recovered.
      • Memish Z.A.
      • Al-Tawfiq J.A.
      • Assiri A.
      • et al.
      Middle East respiratory syndrome coronavirus disease in children.

      Coinfection with Another Pathogen

      Severe acute respiratory syndrome–coronavirus-2

      Coinfection with other pathogens may be a risk factor for severe disease. One child in Wuhan with a history of congenital heart disease and severe illness was found to have coinfection with E aerogenes.
      • Zheng F.
      • Liao C.
      • Fan Q.H.
      • et al.
      Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
      In a study of 20 pediatric cases from the same region, 40% had an underlying coinfection, but there was no report on their severity.
      • Xia W.
      • Shao J.
      Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults.
      A severe case of COVID-19 has been reported in a Chinese 2-month-old infant who had coinfection with respiratory syncytial virus (RSV).
      • Shi B.
      • Xia Z.
      • Xiao S.
      • et al.
      Severe Pneumonia Due to SARS-CoV-2 and respiratory syncytial virus infection: a case report.

      Other coronaviruses

      The presence of copathogens with more than 1 HCoV strain (229E, HKU1, NL63, and OC43) or other respiratory pathogens is a risk factor for febrile illness. Patients infected with a single strain of HCoV were more likely to present pulmonary rales than those infected by more than 1 HCoV strain or other respiratory pathogens.
      • Zeng Z.Q.
      • Chen D.H.
      • Tan W.P.
      • et al.
      Epidemiology and clinical characteristics of human coronaviruses OC43, 229E, NL63, and HKU1: a study of hospitalized children with acute respiratory tract infection in Guangzhou, China.
      The presence of RSV has been associated with lower respiratory tract disease or severe lower respiratory tract disease from HCoV.
      • Ogimi C.
      • Englund J.A.
      • Bradford M.C.
      • et al.
      Characteristics and outcomes of coronavirus infection in children: the role of viral factors and an immunocompromised state.

      Laboratory Findings

      This article reports only the available laboratory information on the severe cases compared with mild cases, according to the current literature; several publications did not provide relevant data.

      Severe acute respiratory syndrome–coronavirus-2

      Based on currently available data, it is not possible to document a pattern of laboratory values in pediatric COVID-19 according to the severity of the disease. In the study of Qiu and colleagues
      • Qiu 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.
      from China, no laboratory data were reported for severe cases, but only for 36 children with moderate and mild disease. Moderate cases (19 patients) compared with mild cases (17 patients) were associated with increased body temperature, a decrease in lymphocyte counts, higher levels of procalcitonin and creatine kinase-MB (myocardial band), and increased D-dimer levels.
      • Qiu 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.
      Laboratory data from 8 severe pediatric cases in the same country showed normal or increased leukocyte count, and high levels of C-reactive protein (CRP), procalcitonin, and lactate dehydrogenase, whereas half had abnormal liver function tests.
      • Sun D.
      • Li H.
      • Lu X.X.
      • et al.
      Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study.
      In a study of 67 children in the United States, admission to an ICU was associated with higher levels of CRP, procalcitonin, and pro–B-type natriuretic peptide and an increased platelet count.
      • Chao J.Y.
      • Derespina K.R.
      • Herold B.C.
      • et al.
      Clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 (COVID-19) at a Tertiary Care Medical Center in New York City.
      Henry and colleagues
      • Henry B.M.
      • Lippi G.
      • Plebani M.
      Laboratory abnormalities in children with novel coronavirus disease 2019.
      reviewed 2020 case reports and case series providing laboratory data on pediatric cases of COVID-19. In that review, 69.6% of the children had a normal leukocyte count and the investigators commented that the absence of lymphopenia in children may in part be explained by the milder disease. Another assumption was that increased procalcitonin level could be caused by a bacterial coinfection as a complication of COVID-19.
      • Henry B.M.
      • Lippi G.
      • Plebani M.
      Laboratory abnormalities in children with novel coronavirus disease 2019.
      Procalcitonin level was increased in 80% of Chinese pediatric patients in the study of Xia and Shao,
      • Xia W.
      • Shao J.
      Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults.
      and, in that series, 40% of the children had a coinfection.

      Other coronaviruses

      Neutrophilia was a predictor of severe illness among 44 children with SARS.
      • Leung C.W.
      • Kwan Y.W.
      • Ko P.W.
      • et al.
      Severe acute respiratory syndrome among children.
      Lymphopenia was detected in 10 children with SARS, of whom 4 needed oxygen therapy and 2 needed assisted ventilation.
      • Hon K.L.
      • Leung C.W.
      • Cheng W.T.
      • et al.
      Clinical presentations and outcome of severe acute respiratory syndrome in children.

      Risk factors for pediatric multisystem inflammatory syndrome associated with severe acute respiratory syndrome–coronavirus-2

      A syndrome of fever and multisystem inflammatory syndrome (MIS) has recently been described in children with COVID-19. Some of these children presented with shock and multiorgan failure and others had characteristics of Kawasaki disease or a combination of Kawasaki-like disease and shock, named the Kawasaki disease shock syndrome.
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • et al.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      ,
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      These children presented with acute cardiac decompensation,
      • Belhadjer Z.
      • Méot M.
      • Bajolle F.
      • et al.
      Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.
      and some developed coronary artery aneurysms.
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      Among 44 children hospitalized in the United States with MIS, 84.1% had gastrointestinal symptoms as the presenting clinical complaint.
      • Miller J.
      • Cantor A.
      • Zachariah P.
      • et al.
      Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (MIS-C) that is related to COVID-19: a single center experience of 44 cases.
      Most studies to date have reported that MIS presents in children at an older age, with a median age of 8 to 10 years.
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      ,
      • Belhadjer Z.
      • Méot M.
      • Bajolle F.
      • et al.
      Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.
      ,
      • Cheung E.W.
      • Zachariah P.
      • Gorelik M.
      • et al.
      Multisystem Inflammatory Syndrome Related to COVID-19 in previously healthy children and adolescents in New York City.
      In a retrospective study of 35 children with MIS, admitted to ICUs in France and Switzerland, comorbidities were present in 28% of the children, including asthma and being overweight,
      • Belhadjer Z.
      • Méot M.
      • Bajolle F.
      • et al.
      Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.
      but most of the children in other studies reported from Europe, specifically Italy and the United Kingdom, were previously healthy.
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      ,
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      In a study of 8 children from the United Kingdom with MIS, 6 were Afro-Caribbean and 5 were male.
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • et al.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      It has been suggested that black and Asian races may be predisposed to this clinical complication.
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      These limited data indicate a possible gender and race predilection for MIS.
      The laboratory findings in children with MIS were characterized by a marked increase in levels of inflammatory markers such as CRP and ferritin,
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      and a cytokine storm, with specific increase in the level of interleukin (IL)-6 and macrophage activation.
      • Belhadjer Z.
      • Méot M.
      • Bajolle F.
      • et al.
      Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.
      ,
      • Cheung E.W.
      • Zachariah P.
      • Gorelik M.
      • et al.
      Multisystem Inflammatory Syndrome Related to COVID-19 in previously healthy children and adolescents in New York City.
      The patients often had a significant increase in B-type natriuretic peptide and troponin T.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      MIS is considered to be a result of a continuous immune response rather than injury from an acute SARS-CoV-2 infection. The disease presented 2 to 3 weeks after the peak of the infection and most children had negative COVID-19 polymerase chain reaction but positive viral serology.
      • Panupattanapong S.
      • Brooks E.B.
      New spectrum of COVID-19 manifestations in children: Kawasaki-like syndrome and hyperinflammatory response.

      What mechanisms play a role in the atypical picture of coronavirus disease 2019 in children?

      The SARS-CoV-2 is a β CoV of group 2B, with more than 70% similarities in genetic sequence to SARS-nCoV.
      • Hui D.S.
      • Azhar E.I.
      • Madani T.A.
      • et al.
      The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus outbreak in Wuhan, China.
      The established scientific evidence on SARS-novel coronavirus has enabled elucidation of the host defense mechanisms against SARS-CoV-2 and helped to explain the lower susceptibility of children to the virus and the variability between children. The reasons for the different pattern of COVID-19 in children are still unclear, but several hypotheses have been put forward.

      Environment-Epigenetics

      The effect of the environment must be considered a factor with significant impact on infection with COVID-19. Children have healthier airway tracts, because of having less exposure to cigarette smoke, air pollution, chemicals, and industrial pollutants than adults. In adults, these environmental factors, and especially smoking, have a negative epigenetic impact on epithelial and immune cells, leading to increased vulnerability to all respiratory viruses, including SARS-CoV-2.
      • Buro-Auriemma L.J.
      • Salit J.
      • Hackett N.R.
      • et al.
      Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression.
      ,
      • Cai H.
      Sex difference and smoking predisposition in patients with COVID-19.
      CoVs are known to alter the epigenetic cellular mechanisms of the host associated with viral entry, replication, and innate immune control.
      • Schäfer A.
      • Baric R.S.
      Epigenetic landscape during coronavirus infection.
      Most children hospitalized with COVID-19, especially those in the ICU, were less than 3 years of age.
      • Zheng F.
      • Liao C.
      • Fan Q.H.
      • et al.
      Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
      ,
      • Tagarro A.
      • Epalza C.
      • Santos M.
      • et al.
      Screening and severity of coronavirus disease 2019 (COVID-19) in Children in Madrid, Spain.
      This finding may be explained by the immaturity of the immune system in this age period, the low likelihood of wearing face masks in this age group, and the subsequent high viral load.
      • Kam K.Q.
      • Yung C.F.
      • Cui L.
      • et al.
      A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load.
      Another reason for the different clinical picture of COVID-19 in children is that they have fewer underlying disorders that may predispose to severe COVID-19 than adults.
      • Jordan R.E.
      • Adab P.
      • Cheng K.K.
      Covid-19: risk factors for severe disease and death.
      The severity of COVID-19 is higher in children with preexisting conditions, such as asthma, malignancies, cardiovascular disorders, and immunosuppression.
      • Zheng F.
      • Liao C.
      • Fan Q.H.
      • et al.
      Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
      ,
      • Tagarro A.
      • Epalza C.
      • Santos M.
      • et al.
      Screening and severity of coronavirus disease 2019 (COVID-19) in Children in Madrid, Spain.
      In certain chronic diseases, including systemic lupus erythematosus (SLE), epigenetic dysregulation might enable viral entry, replication, and a disproportionate immune response to SARS-CoV-2.
      • Sawalha A.H.
      • Zhao M.
      • Coit P.
      • et al.
      Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients.

      Entry of the Virus into the Cells

      Angiotensin-converting enzyme 2 (ACE2) is a zinc-containing metalloenzyme located on the surface of endothelial and other cells that counters the activity of the related angiotensin-converting enzyme (ACE) by reducing the amount of angiotensin-II.
      • Hamming I.
      • Timens W.
      • Bulthuis M.L.
      • et al.
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
      ACE2 serves as the entry point into cells for NL63 and SARS-CoV, and recent studies indicate that ACE2 is also likely to be the receptor for SARS-CoV-2 and the key region responsible for the interaction.
      • Wang Q.
      • Zhang Y.
      • Wu L.
      • et al.
      Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.
      ,
      • Xu X.
      • Chen P.
      • Wang J.
      • et al.
      Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission.
      Differences in the distribution, maturation, and functioning of ACE2 in the developing phase of childhood is a possible reason for milder SARS-CoV-2 infection. Newborn infants and children have higher ACE activities, with serum levels showing an increase until puberty and progressive reduction after maturity.
      • Bénéteau-Burnat B.
      • Baudin B.
      • Morgant G.
      • et al.
      Serum angiotensin-converting enzyme in healthy and sarcoidotic children: comparison with the reference interval for adults.
      In contrast, ACE2 expression in rat lung has been found to decrease dramatically with age.
      • Xie X.
      • Chen J.
      • Wang X.
      • et al.
      Age- and gender-related difference of ACE2 expression in rat lung.
      Studies have provided evidence that ACE2 also protects against the severe acute lung injury that can be activated by sepsis, SARS, and avian influenza A H5N1 virus infection.
      • Gu H.
      • Xie Z.
      • Li T.
      • et al.
      Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus.
      It may be that children are protected against SARS-CoV-2 because ACE2 is less mature at younger ages.
      Epigenetic alteration of ACE2, which is further exacerbated by virus infections, is another potential mechanism in the severity of COVID-19 in patients with chronic diseases such as SLE.
      • Sawalha A.H.
      • Zhao M.
      • Coit P.
      • et al.
      Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients.
      Another aspect in the variability of severity is the genetic variation of ACE among different populations. The polymorphism D/I in ACE1, an enzyme with amino acid identity and function similar to ACE2, could explain the varying rate of COVID-19 infection between European countries, and, specifically, the prevalence of COVID-19 infections has been shown to be correlated with the ACE D allele frequency.
      • Delanghe J.R.
      • Speeckaert M.M.
      • De Buyzere M.L.
      The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections.

      Immune Antiviral Response

      Frequent exposure of children to viral infections boosts the immune system and possibly enhances the response to SARS-CoV-2, and the presence of other concurrent viruses in the airway mucosa may limit the replication and the viral load of SARS-CoV2.
      • Nickbakhsh S.
      • Mair C.
      • Matthews L.
      Virus-virus interactions impact the population dynamics of influenza and the common cold.
      It has been shown that the number of viral copies is correlated with the severity of COVID-19.
      • Liu Y.
      • Yan L.M.
      • Wan L.
      • et al.
      Viral dynamics in mild and severe cases of COVID-19.
      The immune system undergoes significant changes from birth to adulthood, especially in lymphocyte biology,
      • Simon A.K.
      • Hollander G.A.
      • McMichael A.
      Evolution of the immune system in humans from infancy to old age.
      and the interaction of lymphocytes with SARS-CoV-2 may be different in children from that in adults. It is of note that, when documented, lymphocytopenia is frequent in adults with COVID-19 (83%)
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      but not in children (3%).
      • Lu X.
      • Zhang L.
      • Du H.
      • et al.
      SARS-CoV-2 Infection in Children.
      ,
      • Henry B.M.
      • Lippi G.
      • Plebani M.
      Laboratory abnormalities in children with novel coronavirus disease 2019.
      However, in the 2003 SARS epidemic, lymphocytopenia was reported in 77% of infected children.
      • Leung C.W.
      • Kwan Y.W.
      • Ko P.W.
      • et al.
      Severe acute respiratory syndrome among children.
      The changing level of T lymphocytes with age may also be a reason for the mild disease phenotype in childhood.
      • Kotylo P.K.
      • Fineberg N.S.
      • Freeman K.S.
      • et al.
      Reference ranges for lymphocyte subsets in pediatric patients.
      Interferon-mediated response to HCoVs is essential for the disease course. Virus-induced suppression of interferon-induced pathways leads to viral replication and disease progression, along with the production of other proinflammatory cytokines, such as IL-2, IL-6, and tumor necrosis factor, in the lower respiratory tract and other tissues.
      • He L.
      • Ding Y.
      • Zhang Q.
      • et al.
      Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS.
      In some cases, the increase of cytokine levels is uncontrolled, leading to the detrimental cytokine syndrome, with a poor outcome.
      • Vaninov N.
      In the eye of the COVID-19 cytokine storm.
      The percentage of children with COVID-19 with increased levels of inflammatory markers is reported to be low, and this could be a cofactor for nonsevere disease.
      • Henry B.M.
      • Lippi G.
      • Plebani M.
      Laboratory abnormalities in children with novel coronavirus disease 2019.
      In contrast, an unusual immune response accompanied by cytokine storm and macrophage activation is thought to result in MIS, which has been linked to COVID-19 in children.
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      Another immunologic aspect that could be related to the mild disease in children is trained innate immunity, because of the routine use of various vaccines, including bacillus Calmette-Guérin(BCG). BCG vaccination induces epigenetic changes in monocytes, and increased cytokine production in response to several different pathogens.
      • Kleinnijenhuis J.
      • Quintin J.
      • Preijers F.
      • et al.
      Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity.
      In mice, BCG also enhances nonspecific defense against influenza virus infection.
      • Netea M.G.
      • Schlitzer A.
      • Placek K.
      • et al.
      Innate and adaptive immune memory: an evolutionary continuum in the host's response to pathogens.
      Several studies have identified links between inadequate vitamin D concentrations and the development of upper and lower respiratory tract infections in infants and young children. Although the mechanism of the vitamin D effect on immunity is complex, currently available data support the hypothesis that cathelicidins and defensins can reduce viral replication rates and the levels of proinflammatory cytokines.
      • Zisi D.
      • Challa A.
      • Makis A.
      The association between vitamin D status and infectious diseases of the respiratory system in infancy and childhood.
      Studies in small children with influenza have shown that high doses of vitamin D resulted in fast relief from symptoms, a rapid decrease in viral load, and early disease recovery. In addition, high daily doses of vitamin D have been shown to be effective in the prevention of seasonal influenza.
      • Zhou J.
      • Du J.
      • Huang L.
      • et al.
      Preventive effects of vitamin d on seasonal influenza A in infants: a multicenter, randomized, open, controlled clinical trial.

      Summary

      Although children are less susceptible to COVID-19, and the clinical picture in childhood is often distinct from that in adults, in both age groups chronic underlying medical problems can predispose to severe disease. In contrast with adults, in whom older age is an independent risk factor for severity and mortality, very young age is considered a risk factor for severity in children, although this has recently been questioned, and MIS occurs in older children.
      Although a distinct pattern of laboratory findings has not emerged as being associated with severity of the disease in pediatric cases of COVID-19, lymphopenia seems to be a risk factor for severe disease in children. Increased levels of the inflammatory markers procalcitonin and CRP could be caused by a bacterial coinfection as a complication of COVID-19. The recently described pediatric MIS seems to be the result of continuous immune response rather than an injury from an acute SARS-CoV-2 infection, but further studies are needed to reach definitive conclusions.
      Several other aspects could be implicated in the severity of COVID-19 in children, such as coinfection with RSV, responsiveness of the immune system, vaccination history, levels of vitamin D, and genetic polymorphisms, but the present paucity of data limits the ability to draw such conclusions.
      It is important to further study the potential risk factors for severe disease in children and to clarify the underlying mechanisms in order to improve the management of children with COVID-19 and to help in the development of new forms of treatment.

      Contributors

      S. Tsabouri and A. Makis designed the study, and S. Tsabouri, A. Makis, and C. Kosmeri did the literature search. A. Makis, C. Kosmeri, and E. Siomou were responsible for the data collection. S. Tsabouri and C. Kosmeri collected and analyzed the data. S. Tsabouri, A. Makis, C. Kosmeri, and E. Siomou analyzed data and wrote the article.

      References

        • McIntosh K.
        • Dees J.H.
        • Becker W.B.
        • et al.
        Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease.
        Proc Natl Acad Sci U S A. 1967; 57: 933-940
        • Woo P.C.
        • Lau S.K.
        • Chu C.M.
        • et al.
        Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia.
        J Virol. 2005; 79: 884-895
        • Drosten C.
        • Gunther S.
        • Preiser W.
        • et al.
        Identification of a novel coronavirus in patients with severe acute respiratory syndrome.
        N Engl J Med. 2003; 348: 1967-1976
        • Luk H.K.H.
        • Li X.
        • Fung J.
        • et al.
        Molecular epidemiology, evolution and phylogeny of SARS coronavirus.
        Infect Genet Evol. 2019; 71: 21-30
        • Cauchemez S.
        • Fraser C.
        • Van Kerkhove M.D.
        • et al.
        Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility.
        Lancet Infect Dis. 2014; 14: 50-56
        • de Groot R.J.
        • Baker S.C.
        • Baric R.S.
        • et al.
        Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group.
        J Virol. 2013; 87: 7790-7792
        • Paules C.I.
        • Marston H.D.
        • Fauci A.S.
        Coronavirus infections-more than just the common cold.
        JAMA. 2020; https://doi.org/10.1001/jama.2020.0757
        • Wu Z.
        • McGoogan J.M.
        Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention.
        JAMA. 2020; https://doi.org/10.1001/jama.2020.2648
        • CDC COVID-19 Response Team
        Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020.
        MMWR Morb Mortal Wkly Rep. 2020; 69: 422-426
        • Dong Y.
        • Mo X.
        • Hu Y.
        • et al.
        Epidemiology of COVID-19 Among Children in China.
        Pediatrics. 2020; 145: e20200702
        • Pan A.
        • Liu L.
        • Wang C.
        • et al.
        Association of public health interventions with the epidemiology of the COVID-19 Outbreak in Wuhan, China.
        JAMA. 2020; 323: 1-9
        • Zeng Z.Q.
        • Chen D.H.
        • Tan W.P.
        • et al.
        Epidemiology and clinical characteristics of human coronaviruses OC43, 229E, NL63, and HKU1: a study of hospitalized children with acute respiratory tract infection in Guangzhou, China.
        Eur J Clin Microbiol Infect Dis. 2018; 37: 363-369
        • Corman V.M.
        • Muth D.
        • Niemeyer D.
        • et al.
        Hosts and sources of endemic human coronaviruses.
        Adv Virus Res. 2018; 100: 163-188
        • Stockman L.J.
        • Massoudi M.S.
        • Helfand R.
        • et al.
        Severe acute respiratory syndrome in children.
        Pediatr Infect Dis J. 2007; 26: 68-74
        • Leung C.W.
        • Kwan Y.W.
        • Ko P.W.
        • et al.
        Severe acute respiratory syndrome among children.
        Pediatrics. 2004; 113: e535-e543
        • Al-Tawfiq J.A.
        • Kattan R.F.
        • Memish Z.A.
        Middle East respiratory syndrome coronavirus disease is rare in children: an update from Saudi Arabia.
        World J Clin Pediatr. 2016; 5: 391-396
        • Alfaraj S.H.
        • Al-Tawfiq J.A.
        • Altuwaijri T.A.
        • et al.
        Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia.
        Front Med. 2019; 13: 126-130
        • Cui Y.
        • Tian M.
        • Huang D.
        • et al.
        A 55-Day-Old Female Infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage.
        J Infect Dis. 2020; 221: 1775-1781
        • Liu W.
        • Zhang Q.
        Detection of Covid-19 in Children in Early January 2020 in Wuhan, China.
        N Engl J Med. 2020; 382: 1370-1371
        • Le H.T.
        • Nguyen L.V.
        • Tran D.M.
        • et al.
        The first infant case of COVID-19 acquired from a secondary transmission in Vietnam.
        Lancet Child Adolesc Health. 2020; 4: 405-406
        • Wei M.
        • Yuan J.
        • Liu Y.
        • et al.
        Novel coronavirus infection in hospitalized infants under 1 year of age in China.
        JAMA. 2020; 323: 1313-1314
        • DeBiasi R.L.
        • Song X.
        • Delaney M.
        • et al.
        Severe COVID-19 in children and young adults in the Washington, DC Metropolitan Region.
        J Pediatr. 2020; 223: 199-203.e1
        • Bandi S.
        • Nevid M.Z.
        • Mahdavinia M.
        African American children are at higher risk for COVID-19 infection.
        Pediatr Allergy Immunol. 2020; https://doi.org/10.1111/pai.13298
        • Whittaker E.
        • Bamford A.
        • Kenny J.
        • et al.
        Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
        JAMA. 2020; https://doi.org/10.1001/jama.2020.10369
        • Varghese L.
        • Zachariah P.
        • Vargas C.
        • et al.
        Epidemiology and clinical features of human coronaviruses in the pediatric population.
        J Pediatric Infect Dis Soc. 2018; 7: 151-158
        • Choi K.W.
        • Chau T.N.
        • Tsang O.
        • et al.
        Outcomes and prognostic factors in 267 patients with severe acute respiratory syndrome in Hong Kong.
        Ann Intern Med. 2003; 139: 715-723
        • Hong K.H.
        • Choi J.P.
        • Hong S.H.
        • et al.
        Predictors of mortality in Middle East respiratory syndrome (MERS).
        Thorax. 2018; 73: 286-289
        • Onder G.
        • Rezza G.
        • Brusaferro S.
        Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.
        JAMA. 2020; https://doi.org/10.1001/jama.2020.4683
        • Shekerdemian L.S.
        • Mahmood N.R.
        • Wolfe K.K.
        • et al.
        Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units.
        JAMA Pediatr. 2020; https://doi.org/10.1001/jamapediatrics.2020.1948
        • Lu X.
        • Zhang L.
        • Du H.
        • et al.
        SARS-CoV-2 Infection in Children.
        N Engl J Med. 2020; 382: 1663-1665
        • Yang P.
        • Liu P.
        • Li D.
        • et al.
        Corona Virus Disease 2019, a growing threat to children?.
        J Infect. 2020; 80: 671-693
        • Parri N.
        • Lenge M.
        Children with Covid-19 in Pediatric Emergency Departments in Italy.
        N Engl J Med. 2020; 383: 187
        • Zheng F.
        • Liao C.
        • Fan Q.H.
        • et al.
        Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.
        Curr Med Sci. 2020; 40: 275-280
        • Sun D.
        • Li H.
        • Lu X.X.
        • et al.
        Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study.
        World J Pediatr. 2020; 16: 251-259
        • Tagarro A.
        • Epalza C.
        • Santos M.
        • et al.
        Screening and severity of coronavirus disease 2019 (COVID-19) in Children in Madrid, Spain.
        JAMA Pediatr. 2020; https://doi.org/10.1001/jamapediatrics.2020.1346
        • Oualha M.
        • Bendavid M.
        • Berteloot L.
        • et al.
        Severe and fatal forms of COVID-19 in children.
        Arch Pediatr. 2020; 27: 235-238
        • Zhou F.
        • Yu T.
        • Du R.
        • et al.
        Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
        Lancet. 2020; 395: 1054-1062
        • Ogimi C.
        • Englund J.A.
        • Bradford M.C.
        • et al.
        Characteristics and outcomes of coronavirus infection in children: the role of viral factors and an immunocompromised state.
        J Pediatric Infect Dis Soc. 2019; 8: 21-28
        • Memish Z.A.
        • Al-Tawfiq J.A.
        • Assiri A.
        • et al.
        Middle East respiratory syndrome coronavirus disease in children.
        Pediatr Infect Dis J. 2014; 33: 904-906
        • Thabet F.
        • Chehab M.
        • Bafaqih H.
        • et al.
        Middle East respiratory syndrome coronavirus in children.
        Saudi Med J. 2015; 36: 484-486
        • Xia W.
        • Shao J.
        Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults.
        Pediatr Pulmonol. 2020; 55: 1169-1174
        • Shi B.
        • Xia Z.
        • Xiao S.
        • et al.
        Severe Pneumonia Due to SARS-CoV-2 and respiratory syncytial virus infection: a case report.
        Clin Pediatr (Phila). 2020; 59: 823-826
        • Qiu 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; 20: 689-696
        • Chao J.Y.
        • Derespina K.R.
        • Herold B.C.
        • et al.
        Clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 (COVID-19) at a Tertiary Care Medical Center in New York City.
        J Pediatr. 2020; 223: 14-19.e2
        • Henry B.M.
        • Lippi G.
        • Plebani M.
        Laboratory abnormalities in children with novel coronavirus disease 2019.
        Clin Chem Lab Med. 2020; 58: 1135-1138
        • Hon K.L.
        • Leung C.W.
        • Cheng W.T.
        • et al.
        Clinical presentations and outcome of severe acute respiratory syndrome in children.
        Lancet. 2003; 361: 1701-1703
        • Riphagen S.
        • Gomez X.
        • Gonzalez-Martinez C.
        • et al.
        Hyperinflammatory shock in children during COVID-19 pandemic.
        Lancet. 2020; 395: 1607-1608
        • Verdoni L.
        • Mazza A.
        • Gervasoni A.
        • et al.
        An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
        Lancet. 2020; 395: 1771-1778
        • Belhadjer Z.
        • Méot M.
        • Bajolle F.
        • et al.
        Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.
        Circulation. 2020; https://doi.org/10.1161/CIRCULATIONAHA.120.048360
        • Miller J.
        • Cantor A.
        • Zachariah P.
        • et al.
        Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (MIS-C) that is related to COVID-19: a single center experience of 44 cases.
        Gastroenterology. 2020; https://doi.org/10.1053/j.gastro.2020.05.079
        • Cheung E.W.
        • Zachariah P.
        • Gorelik M.
        • et al.
        Multisystem Inflammatory Syndrome Related to COVID-19 in previously healthy children and adolescents in New York City.
        JAMA. 2020; https://doi.org/10.1001/jama.2020.10374
        • Panupattanapong S.
        • Brooks E.B.
        New spectrum of COVID-19 manifestations in children: Kawasaki-like syndrome and hyperinflammatory response.
        Cleve Clin J Med. 2020; https://doi.org/10.3949/ccjm.87a.ccc039
        • Hui D.S.
        • Azhar E.I.
        • Madani T.A.
        • et al.
        The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus outbreak in Wuhan, China.
        Int J Infect Dis. 2020; 91: 264-266
        • Buro-Auriemma L.J.
        • Salit J.
        • Hackett N.R.
        • et al.
        Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression.
        Hum Mol Genet. 2013; 22: 4726-4738
        • Cai H.
        Sex difference and smoking predisposition in patients with COVID-19.
        Lancet Respir Med. 2020; 8: e20
        • Schäfer A.
        • Baric R.S.
        Epigenetic landscape during coronavirus infection.
        Pathogens. 2017; 6: 8
        • Kam K.Q.
        • Yung C.F.
        • Cui L.
        • et al.
        A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load.
        Clin Infect Dis. 2020; 71: 847-849
        • Jordan R.E.
        • Adab P.
        • Cheng K.K.
        Covid-19: risk factors for severe disease and death.
        BMJ. 2020; 368: m1198
        • Sawalha A.H.
        • Zhao M.
        • Coit P.
        • et al.
        Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients.
        Clin Immunol. 2020; 215: 108410
        • Hamming I.
        • Timens W.
        • Bulthuis M.L.
        • et al.
        Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
        J Pathol. 2004; 203: 631-637
        • Wang Q.
        • Zhang Y.
        • Wu L.
        • et al.
        Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.
        Cell. 2020; 181: 894-904.e9
        • Xu X.
        • Chen P.
        • Wang J.
        • et al.
        Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission.
        Sci China Life Sci. 2020; 63: 457-460
        • Bénéteau-Burnat B.
        • Baudin B.
        • Morgant G.
        • et al.
        Serum angiotensin-converting enzyme in healthy and sarcoidotic children: comparison with the reference interval for adults.
        Clin Chem. 1990; 36: 344-346
        • Xie X.
        • Chen J.
        • Wang X.
        • et al.
        Age- and gender-related difference of ACE2 expression in rat lung.
        Life Sci. 2006; 78: 2166-2171
        • Gu H.
        • Xie Z.
        • Li T.
        • et al.
        Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus.
        Sci Rep. 2016; 6: 19840
        • Delanghe J.R.
        • Speeckaert M.M.
        • De Buyzere M.L.
        The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections.
        Clin Chim Acta. 2020; 505: 192-193
        • Nickbakhsh S.
        • Mair C.
        • Matthews L.
        Virus-virus interactions impact the population dynamics of influenza and the common cold.
        Proc Natl Acad Sci U S A. 2019; 116: 27142-27150
        • Liu Y.
        • Yan L.M.
        • Wan L.
        • et al.
        Viral dynamics in mild and severe cases of COVID-19.
        Lancet Infect Dis. 2020; 20: 656-657
        • Simon A.K.
        • Hollander G.A.
        • McMichael A.
        Evolution of the immune system in humans from infancy to old age.
        Proc Biol Sci. 2015; 282: 20143085
        • Guan W.J.
        • Ni Z.Y.
        • Hu Y.
        • et al.
        Clinical characteristics of coronavirus disease 2019 in China.
        N Engl J Med. 2020; 382: 1708-1720
        • Kotylo P.K.
        • Fineberg N.S.
        • Freeman K.S.
        • et al.
        Reference ranges for lymphocyte subsets in pediatric patients.
        Am J Clin Pathol. 1993; 100: 111-115
        • He L.
        • Ding Y.
        • Zhang Q.
        • et al.
        Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS.
        J Pathol. 2006; 210: 288-297
        • Vaninov N.
        In the eye of the COVID-19 cytokine storm.
        Nat Rev Immunol. 2020; 20: 277
        • Kleinnijenhuis J.
        • Quintin J.
        • Preijers F.
        • et al.
        Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity.
        J Innate Immun. 2014; 6: 152-158
        • Netea M.G.
        • Schlitzer A.
        • Placek K.
        • et al.
        Innate and adaptive immune memory: an evolutionary continuum in the host's response to pathogens.
        Cell Host Microbe. 2019; 25: 13-26
        • Zisi D.
        • Challa A.
        • Makis A.
        The association between vitamin D status and infectious diseases of the respiratory system in infancy and childhood.
        Hormones (Athens). 2019; 18: 353-363
        • Zhou J.
        • Du J.
        • Huang L.
        • et al.
        Preventive effects of vitamin d on seasonal influenza A in infants: a multicenter, randomized, open, controlled clinical trial.
        Pediatr Infect Dis J. 2018; 37: 749-754