The Spectrum of COVID-19 in Children in Spain


 Background: We aimed to identify the spectrum of disease in children with COVID-19, and the risk factors for admission in paediatric intensive care units (PICUs).Methods: We conducted a multicentre, prospective study of children with SARS-CoV-2 infection in 76 Spanish hospitals. We included children with COVID-19 or multi-inflammatory syndrome (MIS-C) younger than 18 years old, attended during the first year of the pandemic.Results: We enrolled 1 200 children. A total of 666 (55.5%) were hospitalized, and 123 (18.4%) required admission to PICU. Most frequent major clinical syndromes in the cohort were: mild syndrome (including upper respiratory tract infection and flu-like syndrome, skin or mucosae problems and asymptomatic), 44.8%; bronchopulmonary syndrome (including pneumonia, bronchitis and asthma flare), 18.5%; fever without a source, 16.2%; MIS-C, 10.6%; and gastrointestinal syndrome, 10%. In hospitalized children, the proportions were: 28.5%, 25.7%, 16.5%, 19.1% and 10.2%, respectively. Risk factors associated with PICU admission were MIS-C (odds ratio [OR]: 37.5,95% CI 22.7 to 57.8), moderate or severe liver disease (OR: 9,95% CI 1.6 to 47.6), chronic cardiac disease (OR: 4.8,95% CI 1.8 to 13) and asthma or recurrent wheezing (OR: 2.8,95% CI 1.3 to 5.8). However, asthmatic children were admitted into the PICU due to MIS-C or pneumonia, not due to asthma flare. Conclusion: Hospitalized children with COVID-19 usually present as one of five major clinical phenotypes of decreasing severity. Risk factors for PICU include MIS-C, elevation of inflammation biomarkers, asthma, moderate or severe liver disease and cardiac disease.


Introduction
Children under 18 years of age represented a minority hospitalized COVID-19 cases during the rst year of the pandemic. 1,2 Their symptoms are usually milder. [3][4][5] Symptoms at presentation have been described in some studies; 6 however, it remains unclear how these symptoms group together into clinically identi able phenotypes.
Only 0.4% of severe cases are children. 7 Risk factors that lead to severe disease in children have been partly described, and include young age, obesity and underlying comorbidities, lymphopenia and elevation of other in ammatory biomarkers including high C-reactive protein (CRP). [8][9][10] The present study aimed to de ne further the spectrum of COVID-19 in children and the risk factors for hospitalization and admission in paediatric intensive care units (PICUs) during the rst year of the pandemic in Spain.

Design
The Epidemiological Study of Coronavirus in Children (EPICO-AEP) is a multicentre cohort study conducted in Spain to assess the characteristics of children with COVID-19. In total, 76 hospitals collected data from the beginning of the epidemic in Spain (March 12 nd ) until March 22 nd 2021. The study was approved by the Ethics Committee of Hospital 12 de Octubre, Madrid (code 20/101), and other participating hospitals. Participants were enrolled after signed or verbal consent from parents/guardians and by the consent of patients older than 12 years.
Eligible participants were children aged from 0 to 18 years who attended in any of the hospitals of the network from the rst patient included in March 12 th 2020 to March 22 nd 2021, with a SARS-CoV-2 infection con rmed by real-time polymerase chain reaction (RT-PCR), rapid antigen test, or children ful lling WHO criteria for multisystem in ammatory syndrome in children (MIS-C). 11 Children hospitalized were enrolled during the whole year. Children attended in the emergency rooms and discharged without admission were recorded only until October 1 st , 2020. Of the patients with MIS-C, 31 were described in a prior research report. 12 The protocol included follow-up until discharge.

Laboratory methods
Respiratory samples for SARS-CoV-2 RT-PCR were obtained from nasopharyngeal swabs and tracheal or bronchial aspirates, when available. Serum samples for SARS-CoV-2 serology were analysed in local clinical microbiology laboratories using commercial kits. The remaining haematological, biochemical and microbiological analyses were performed in the laboratories of each centre following routine validated methodology.

De nitions
Primary diagnoses related to COVID-19 were established according to data supplied by the attending physician. We categorised the diagnoses as the following: MIS-C, pneumonia, bronchitis, bronchiolitis, asthma are or recurrent wheezing, u-like syndrome, upper respiratory tract infection (URTI), fever without source (FWS), gastroenteritis, abdominal pain, skin or mucosae problems and asymptomatic.
Diagnoses de nitions are summarised in Supplementary Table 1 . When more than one simultaneous diagnosis was present, a hierarchy was established to de ne the primary diagnosis.
Admissions in PICUs did not follow uniform prede ned criteria but as per clinical judgement.

Data management and statistical analyses
Researchers from each participating hospital collected pseudo-anonymised data using a standardised clinical research form on the electronic data capture system REDCap. 13 Data included main epidemiological, demographic, clinical and laboratory variables.
In the multivariable model, risk factors associated with PICU admission were MIS-C (OR: 37.5, 95% CI 22.7 to 57.8), moderate or severe liver disease (OR=9, 95% CI 1.6 to 47.6), chronic cardiac disease (OR=4.8, 95% CI 1.8 to 13), asthma or recurrent wheezing, (OR=2.8, 95% CI 1.3 to 5.8). However, out of 18 children with pre-existing asthma or recurrent wheezing, none of them was admitted with asthma are, but ten were admitted with MIS-C and eight with pneumonia.

Discussion
In this study, we have identi ed the spectrum of COVID-19 in children attended in Spanish hospitals during the rst year of pandemic. Initial features of COVID-19 are very unspeci c, and patients may show a very wide spectrum of sign and symptoms, as shown in Figure 3. We have identi ed twelve frequent diagnoses that can be grouped into ve major clinical phenotypes for a more practical approach: MIS-C, bronchopulmonary disease, gastrointestinal disease, fever without a source (FWS) and mild disease. This classi cation better de nes COVID-19 in children than previous de nitions and can guide severity assessment.
We identi ed similar risk factors for critical disease as other studies. 8,18,19 We added some new factors, especially speci c comorbidities. Interestingly, immunosuppression and neoplasia were not risk factors for PICU admission, although most deceased patients had serious immunosuppression or cancer. Most deceased patients were patients with severe comorbidities, and half of them had coinfections.
Asthma or recurrent wheezing, chronic liver and heart diseases are risk factors for PICU admission.
Interestingly, asthmatic patients were not admitted to the PICU due to asthma are, but due to pneumonia or MIS-C. Additionally, obesity, chronic neurological disease and immunosuppressive treatments were risk factors for MIS-C. This may be considered for stepwise immunization strategies in children, so those with signi cant pre-existing comorbidities get immunized rst.
Other risk factors as IL-6, CRP, D-dimer and cytopaenia suggest immune dysregulation and severe in ammation in critical patients. CD4 and natural killer T-cell cytopaenia due to immune dysregulation have been described previously. 20 Immune dysregulation may also be involved in manifestations that are not clearly related to COVID-19 but have been found in this and other cohorts, such as diabetic debut, haemolytic anaemia or appendicitis. A signi cant increase in diabetic ketoacidosis in children was found during the COVID-19 pandemic. 21 A clinical picture consistent with appendicitis in children has been reported, as well as ileitis. 22,23 In this study, some patients with appendicitis, diabetic debut and ileitis were also identi ed concomitantly or soon after SARS-CoV-2 infection.
Immune dysregulation is also involved in MIS-C. Some features of MIS-C, such as shock or cardiac disease, may be responsible for laboratory abnormalities such as high ALT or creatinine (Supplementary Table 5). However, speci c mechanisms for kidney injury secondary to COVID-19 have been previously proposed. 24 The national seroprevalence study ENE-COVID 2 suggests that in December, 400 000 children were seropositive in Spain. Considering that our study included 10% of the 800 private and public hospitals of Spain, including most tertiary public hospitals, likely less than 1% of children with COVID-19 needed hospitalization; and less than 0.05% needed intensive care.
This study included children attended in different hospitals. There is a risk of selection, case identi cation and reporting bias for hospitalization and for PICU admission. Access to SARS-CoV-2 testing was not consistent during the enrolment, especially during the rst wave. The diversity and broadness of the study are strengths, as they provide insight into the disease in a major clinical part of Spain through a prospective collection of data.
Although viral-bacterial coinfection was found in a signi cant proportion of hospitalised children, a full workup for coinfections was not done uniformly, and thus the role of coinfections is not completely clear.
The study included few neonates because most neonates with COVID-19 in Spain were included in a different neonatal registry.
The ethnic origin was not recorded, so we cannot compare our study with other studies suggesting worse outcome in minorities. The categorisation and interpretation of this variable tend to be simplistic--for instance, Black versus others or Caucasians versus others, and the minority factor is often linked to economical and sociodemographic characteristics, which we did not collect. 25,26 We believe that this classi cation is unique and helps to de ne the spectrum of the disease instead of just describing symptoms and signs. Understanding different clinical manifestations, and the heterogeneity of infection and post-infection manifestations, may help in diagnostic strategies.

Conclusion
The infrequent COVID-19 that requires hospitalization in children presents as any of ve major clinical phenotypes of decreasing severity: MIS-C, bronchopulmonary disease, gastrointestinal disease, mild disease, and fever without a source. Risk factors for PICU include MIS-C, in ammation biomarkers, and speci c comorbidities as asthma, moderate or severe liver disease, and cardiac disease. María Bernardino is funded by the Becas Cantera Santander-Fundación Universidad Europea de Madrid.

Con ict of Interest Disclosures
The authors have no con icts of interest relevant to this article to disclose.
Availability of data and material: available or reasonable request.
Code availability: not applicable  Odds Ratio and 95% con dence interval of PICU admission across major phenotypes. Horizontal axis is displayed as log (10)   Signs, and symptoms at presentation of the 1200 enrolled patients. Those present in <5% of patients are not displayed.