In Spain, the first case of coronavirus disease 2019 (COVID-19), caused by the novel coronavirus known as SARS-CoV-2,1 was detected on January 31, 2020. In the weeks that followed, SARS-CoV-2 spread through the entire country, and the Community of Madrid was the region hit the hardest.2

In order to optimise health care resources, starting in March 20, 2020 urgent paediatric care was centralised at 2 tertiary care hospitals in this autonomous community. These 2 hospitals were tasked with providing emergency, inpatient and intensive care services to a population of approximately 1345000 individuals aged less than 18 years.

Although SARS-CoV-2 can infect individuals of any age, the overall incidence in the paediatric population has been estimated at 1–2%.3–5 The prevalence in Spanish children and adolescents found in a study conducted in May 2020 ranged from 1% to 5%.6 Children develop milder forms of disease and have better outcomes compared to adults.7

The symptoms described most frequently in children with infection by SARS-CoV-2 are similar to the symptoms of an upper respiratory tract infection,8 that is, cough, fever, sore throat, nasal discharge and myalgia.9 Gastrointestinal symptoms are also frequent in this population, including decreased appetite, nausea, vomiting and diarrhoea. A multisystem inflammatory syndrome has been described in children (MIS-C) with infection by SARS-CoV-2 that manifests with shock and may result in multiple organ failure secondary and is considered one of the most severe forms of COVID-19 in the paediatric population.10–12 This syndrome usually presents with high fever and gastrointestinal symptoms (severe abdominal pain is present in nearly all cases).

At present, the spectrum of diseased caused by infection by SARS-CoV-2 is not well defined in the paediatric population. There is a dearth of data on the course of disease and prognostic factors in hospitalised children. The aim of our study was to describe the epidemiological characteristics, different clinical presentations and risk factors for complicated disease in hospitalised children with COVID-19.

In the period under study, 880 patients were admitted to the hospital. A RT-PCR test for detection of SARS-CoV-2 in a nasopharyngeal swab sample was performed in 551, the results of which were positive in 52. Five patients with negative results of the RT-PCR test and a presentation highly suggestive of COVID-19 had detectable levels of IgG antibodies against SARS-CoV-2. We excluded 11 patients because the reason for admission was not directly related to the SARS-CoV-2 infection; all of these patients were asymptomatic or had mild respiratory or gastrointestinal symptoms. We also excluded 7 patients currently undergoing chemotherapy. The final sample included 39 patients (Fig. 1).

Figure 1.

Patients included in the study.

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Despite the global spread of COVID-19, the clinical spectrum of this disease in children is still not well understood. The role played by children in the spread of disease and the mechanism of infection in children also remains unknown. Several studies have described family clusters,7,8,10,14,15 and it seems that it is children who are most frequently infected by adults, probably as a result of the confinement measures imposed to control the spread of the virus. In our study, most children (70%) had a history of exposure to an adult with confirmed or suspected COVID-19 in the household, which suggested that the child was not the index case.

It is widely believed that COVID-19 is milder and less frequent in children compared to adults.16–20 In the period under study, 57 children with infection by SARS-CoV-2 were admitted to one of the two appointed referral hospitals for paediatric inpatient care in the Autonomous Community of Madrid, although they only accounted for 6.4% of total admissions. In the same period, more than 40000 adults were admitted to different hospitals in the same autonomous community with COVID-19.3 This disparity clearly indicates a milder course of disease and lower frequency of COVID-19 in children. Previously published case series reported that 5–67% of infected children had been hospitalised.4,9,14 Based on the current evidence, hospital admission in paediatric patients is more frequent in infants aged less than 1 year and children with underlying disease. In our case series, 12 of the 39 patients were aged less than 1 year (32% of cases), a figure similar to the 40% reported by Cantoni et al. and the 30% reported by Garazzino et al.14 in Italy, although much higher than the percentage described in China (18% in the study by Lu et al.9 and 11% in the study by Dong et al.8) and the 15% reported by the Centers for Disease Control and Prevention (CDC) in the United States.21 Most infants in our hospital had uncomplicated disease with the exception of 1 newborn with apnoea of infancy22 and 1 infant with pneumococcal pneumonia.23 More than half of admitted children were aged more than 6 years, and the median age of children with shock was 10 years. It is not known whether the risk of developing MIS-C in association with COVID-19 is greater in older children.

Admission criteria can vary significantly between facilities. Patients may be admitted as a preventive isolation measure, due to their clinical condition (more severe signs and symptoms) or due to the presence of risk factors for complicated disease. In our hospital, the main criterion for admission was severity. The clinical criteria applied for admission did not differ from the pre-existing hospital protocol for each disease. Most of the patients were previously healthy, and we cannot rule out an increased risk of progression to more severe forms in patients with underlying disease.

Most of our patients presented with fever (87%), which was more frequent compared to the figures reported in China (71%)9 or Italy (36%).15 This could be explained by selection bias, as hospital admission was a criterion for inclusion in our study. In these patients, fever could be indicative of a more severe form of disease.

The symptoms in children with uncomplicated disease were mainly respiratory and similar to those associated with the common cold, flu and flu-like illnesses, bronchiolitis or pneumonia. Some infants aged less than 3 months presented with fever without a source. The clinical manifestations were nonspecific and overlapped with those of other viral or bacterial respiratory tract infections. The results of laboratory tests in this group were mostly normal, save for an isolated elevation of CRP in a few cases. Patients with uncomplicated disease improved with supportive care and were discharged in a few days. Most did not receive any of the drugs proposed for empiric treatment of COVID-19.9,15,24–28

Respiratory infections may also lead to more severe complications, such as apnoea (in very young children), bacterial coinfection or respiratory failure. In our series, one infant had recurrent episodes of apnoea and another developed pneumococcal sepsis and pneumonia with pleural effusion, which progressed to necrotising pneumonia. It is not clear whether the course of disease in the latter case resulted solely from the bacterial infection or from the combination of both infections.

We ought to highlight that 5 weeks after the start of the epidemic outbreak we observed the emergence of a new clinical presentation.10 These patients were older, presented with high fever and reported significant gastrointestinal symptoms (severe abdominal pain, diarrhoea, vomiting) and/or a rash and/or conjunctival hyperaemia. Respiratory symptoms were less frequent in these patients. Most of them presented to the ED with visibly ill appearance and extreme tachycardia. The distinctive feature of this novel presentation was the development of shock shortly after arrival to the ED.29,30. Patients received supportive care and haemodynamic support at the PICU and treatment with antivirals, hydroxychloroquine, antibiotics and anti-inflammatory drugs. All blood cultures were negative. Coronavirus disease 2019 shares some clinical characteristics with other paediatric inflammatory diseases, including Kawasaki disease, myocarditis, toxic shock syndrome, bacterial or intra-abdominal sepsis and macrophage activation syndrome.11 Early detection is crucial. We ought to highlight that these patients exhibited significant elevation of inflammatory markers (CRP, procalcitonin, D-dimer, ferritin) and lymphopaenia, as well as a higher neutrophil/lymphocyte ratio. This ratio has been described as a useful marker in the diagnosis of other illnesses, such as influenza and sepsis.31 There is recent evidence in the literature of an association between the percentage of neutrophils and severe forms of disease in adults, but to date there are no data on the subject for the paediatric population.32 Lactate dehydrogenase did not seem to be a marker of severity in our patients, contrary to the evidence in adults.33 Another salient aspect was that 8 of the 12 patients developed radiological features compatible with pneumonia, despite respiratory symptoms not being the chief complaint at admission.34 Given the clinical manifestations, the results of diagnostic tests and the clustering of cases in a time period that did not coincide with the incidence peaks, we hypothesised that infection by SARS-CoV-2 could trigger an inflammatory response leading to shock. Seven of these patients had a positive result of the RT-PCR tests for SARS-CoV-2, but only 5 had a positive IgG antibody test result, suggesting that this inflammatory response can develop during or after the acute phase.35

There are several limitations to this study. Due to the small sample and the retrospective design, further research is necessary to confirm our findings. Since we only studied patients in our hospital that required inpatient care or with risk factors for severe disease, the data presented here does not reflect the overall incidence of COVID-19 in children and thus cannot be compared to some of the previously published case series. In addition, there was selection bias related to severity that must have affected our findings and conclusions. We were unable to establish the association between infection by SARS-CoV-2 and clinical manifestations in patients in who serology tests were positive but PCR tests were negative. Nevertheless, our study contributes relevant information on the different clinical presentations of COVID-19 in children that may be useful in the early identification of patients at risk of complications.

Our study presents a series of children with infection by SARS-CoV-2 admitted to a single hospital. Patients with isolated respiratory disease and without elevation of classic inflammatory markers had an uncomplicated course of disease. In these cases, empiric use of the drugs proposed for management of COVID-19 was deemed unnecessary. In contrast, older children presenting with fever, gastrointestinal symptoms, elevated inflammatory markers, lymphopaenia and a high neutrophil/lymphocyte ratio exhibited clinical worsening with progression to shock. These patients with complicated disease required intensive care, including supportive care and antiviral and anti-inflammatory medication. Further prospective multicentre studies are required to deepen our knowledge of this new disease in children, such as the EPICO-AEP currently underway in Spain. Its results will contribute to the understanding of the questions we have raised in this article.

This study did not receive any form of funding.

The authors have no conflicts of interest to declare.