We conducted a retrospective cohort study that included patients aged 0–18 years with a diagnosis of SARS-CoV-2 acute infection or MIS-C admitted between January 1, 2020 and December 31, 2021 to a tertiary care children’s hospital in Spain.

The diagnosis of acute infection was made either by detection of SARS-CoV-2 RNA via real-time reverse transcriptase polymerase chain reaction (RT-PCR) in throat swab (TS), nasopharyngeal aspirate (NPA) or saliva samples, or by detection of SARS-CoV-2 antigen in NPA, according to the hospital protocol at the time of admission. The diagnosis of MIS-C was made by applying the WHO classification criteria, which includes, apart from a compatible clinical history and laboratory findings, the evidence of previous SARS-CoV-2 infection (by RT-PCR, antigen test or positive serology with anti-SARS spike antibody [Abbott]) or a known history of contact with a patient with COVID-19.10

We excluded patients readmitted within 90 days with a positive RT-PCR due to the known period of persistent viral shedding, with the exception of immunocompromised patients readmitted with respiratory symptoms and with a positive antigen test, which were considered cases of acute infection.16–18

It is important that we highlight that both the criteria for testing for SARS-CoV-2 infection and the diagnostic methods varied greatly during the study period. At the beginning of the pandemic, due to the scarcity of tests, the RT-PCR test was only used in patients with suspected infection.19,20 From June 2020, routine screening was performed in all admitted patients (which including patients admitted to the child and adolescent psychiatry unit). Following the marketing authorisation of rapid antigenic tests (Roche Laboratories), patients aged more than 1 year with respiratory symptoms lasting 5–10 days were tested with them, while all other patients were assessed with the RT-PCR test.

We reviewed the health records of the selected patients to obtain information on pre-existing medical conditions, the course of disease, imaging features, laboratory and microbiological findings, received treatment and outcomes.

We classified cases as: COVID-19 as the cause of hospitalization (COVID-related admission) and COVID-19 as current infection not related to the hospitalization (non-COVID-related admission).

We classified cases in which SARS-CoV-2 infection was the main reason for admission (direct cause) or in which we considered that the patient would not have needed hospital admission if it were not for the infection (indirect cause) as COVID-related admissions. It would be the case of acute respiratory diseases (bronchiolitis, bronchospasm, pneumonia); MIS-C; observational admission in at-risk patients and febrile infants with neutropenia in whom no other infection was documented. The clinical phenotype of COVID-related admission patients was compared in different periods in relation to the predominant variants (>50% of random samples) in our setting: wild type (March 2020–January 2021), alpha (February 2021–May 2021), delta (June 2021–November 2021), and omicron (December 2021–April 2022).21,22 We ought to underscore that the study period ended on December 31, at the very beginning of the omicron wave.

On the other hand, non-COVID-related admission patients were those who had been admitted for other reasons and tested positive in the screening at admission. Uncertain cases were discussed among researchers until a consensus was reached.

As regards coinfection, patients aged 0–4 years with respiratory symptoms underwent routine testing at admission for respiratory syncytial virus (RSV) and influenza A/B during the epidemic season in addition to the screening for SARS-CoV-2, with tests conducted on TS/NPA samples (Xpert® Xpress CoV-2/Flu/RSV plus-Respiratory [Cepheid] or Allplex™ SARS-CoV-2/FluA/FluB/RSV Assay [Seegene Inc]). Real-time PCR testing for multiple respiratory viruses (BIOFIRE Respiratory 2.1 plus [RP2.1plus] panel [Biomerieux] or QIAstat-Dx Respiratory SARS-CoV-2 panel [Qiagen]) in NPA or tracheal aspirate (TA) samples, in addition to cultures, were performed in all patients admitted to the paediatric intensive care unit (PICU) due to respiratory complications and additional select patients with respiratory comorbidities.

Blood cultures were performed in cases of sepsis or fever and general health deterioration.

When it came to the specific treatment for COVID-19, the guidelines varied considerably over the study period.

All high-risk patients admitted for observation, diagnosed with acute respiratory disease or MIS-C or admitted to the PICU remained in follow-up in the hospital outpatient clinics for at least 3 months after discharge. The rest of the patients were referred for follow-up by their primary care paediatrician.

We made a descriptive analysis, expressing results in terms of median and interquartile range (IQR) or proportions, as applicable. We compared categorical variables with the χ2 and Fisher exact tests and considered P values of less than 0.05 indicative of a statistically significant difference. The statistical analysis was performed with the software Stata, version 15.1.

The study adhered to the principles of the Declaration of Helsinki declaration and was approved by the ethics committee of the hospital (PIC-90-22). Due to the large number of patients in the sample and the lack of experimental activity, the committee approved an exemption to the informed consent requirement. We entered the patient data into a database located in a protected folder on the hospital intranet, and the data was encoded by professionals independent from the research team to safeguard patient privacy.

In the COVID-related admission group, 58 (39%) of the patients had one or more comorbidities. The most frequent were asthma, obesity, neurological diseases, lung diseases and immunodeficiencies. (Table 1).

The most common diagnosis at discharge was pneumonia (23%), followed by febrile illness in an infant aged less than 3 months (21%), MIS-C (18%) and observational admission in high-risk patients (13%) (Table 1).

MIS-C was more frequently observed during the wild type SARS-CoV-2 period, while acute respiratory disease and other diagnosis (including gastrointestinal manifestations) were more frequently observed during the delta variant period (Fig. 2). These differences were statistically significant (P = .012) (Table 2).

Figure 2.

(2.1 and 2.2). Diagnosis at discharge in COVID-related admissions, by patient group and virus variant.

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Of the 150 patients with COVID-related admissions, 24 (16%) required transfer to the PICU: 13 (54%) had MIS-C and needed vasoactive support, 10 (42%) had acute respiratory disease and requiring more aggressive respiratory support, and 1 (4%) had encephalitis requiring close monitoring and observation.

The percentage of patients with acute respiratory disease who required admission to the PICU was 20% (n = 10), while the percentage of the patients with MIS-C who required admission to the PICU was 48% (n = 13).

We classified 123 cases based on severity (excluding the 27 MIS-C cases out of the total 150 to avoid bias leading to overestimation of severity). Eighty three (68%) were classified as mild (no need of respiratory support), 27 (22%) as moderate (need of supplemental low-flow oxygen therapy [LFOT]), 4 (3%) as severe (need of supplemental high-flow oxygen therapy) and 9 (7%) as critical (need of non-invasive ventilation [NIV] or mechanical ventilation [MV]).

A separate analysis of the 49 patients with acute respiratory disease revealed that 39 (79%) needed some kind or respiratory support, chiefly LFOT (Fig. 3). The severity of disease did not vary significantly between the periods corresponding to different variants, although the 4 patients with acute respiratory disease during the omicron wave only received LFOT.

Figure 3.

Respiratory support required by patients with COVID-related respiratory disease, by virus variant.

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None of the patients in our study needed extracorporeal membrane oxygenation support (ECMO).

Table 3 summarises the information on the specific treatment for COVID-19.

Table 4 presents the data concerning coinfection. Bacterial coinfection was detected in 3 cases and viral coinfection in another 6 cases; among the latter, the most frequently isolated pathogen was rhinovirus/enterovirus. Five patients (83% of the patients with viral coinfection) required some type of respiratory support, of who 2 (33%) required PICU admission and NIV/MV. We did not find statistically significant differences in severity (need of respiratory support or PICU admission).

Two patients died from COVID-related conditions, both of who had multiple comorbidities. The first patient was a 12-year-old boy with acute lymphoblastic leukaemia who had received chimeric antigen receptor T-cell (CAR-T) therapy and undergone allogeneic hematopoietic stem cell transplantation complicated by acute and chronic graft-versus-host disease. The second patient was an 8-year-old boy with a history of extremely preterm birth, severe cerebral palsy, epilepsy and recurrent respiratory infections.

One patient reported persistent COVID-19 symptoms (long COVID) during the follow-up. It was a boy aged 14 years who had been admitted to the PICU due to MIS-C and reported persistent dizziness and fatigue for 6 months after the admission.

Three patients were found to have long-term sequelae: one had long-term neurological impairment secondary to encephalitis and the other two developed coronary aneurysms after having MIS-C.

Finally, we ought to mention that 2 patients had had a previous SARS-CoV-2 infection, although the symptoms had been mild and had not required hospitalization.

In the study, 78 (34%) patients were classified as non-COVID-related admissions. Table 5 details the diagnoses that led to their admissions. In most of these patients, the SARS-CoV-2 infection was completely asymptomatic, and only 26 (33%) were oligosymptomatic (mild cold symptoms). None required any form respiratory support.

Of all the children admitted with a SARS-CoV-2 infection during the study period, 34% were not admitted because of COVID-19 as a direct or indirect cause, illustrating that the hospitalization rate for SARS-CoV-2 infection in the paediatric population is probably overestimated. Other authors have analysed this aspect in the past, like Kushner et al.,14 who found that 45% of admissions were classified as unlikely to be caused by SARS-CoV-2. This percentage was slightly higher than the one found in our sample.

Separating and analysing these two groups is important to correctly define the impact of the disease in the paediatric population. Cases considered COVID-related admissions were classified as such because the infection was the primary reason for the admission, but most of these patients did not develop severe COVID. This was the case, for example, of patients with mild symptoms but with underlying disease (high-risk patients) admitted for observation and preventive treatment with remdesivir; or of febrile infants aged less than 3 months in whom no infection other than SARS-CoV-2 could be detected. The latter scenario is a challenge for clinicians in primary care level and emergency care settings, and algorithms have been proposed to better identify children at high risk of bacterial infection.23

Unlike in adults, only one third of COVID-related admissions in children were due to acute respiratory disease, which was also less severe.24–27 It is worth noting that among these patients, pneumonia was the most common diagnosis at discharge (34 patients; 23%), while only 6 (4%) had bronchiolitis, 6 (4%) bronchospasm and another 3 (2%) bronchopneumonia. This confirms the previous reports in the literature about the extremely low incidence of bronchiolitis among infants with SARS-CoV-2 infections.1,28 Pneumonia was more frequent in adolescents, as previously described in both the literature and a previous case review in our hospital.29

In our study, MIS-C was an important cause of COVID-related admission, a form that, while not an acute presentation of SARS-CoV-2 infection, is associated with the greatest severity and morbidity in the paediatric population.11,12,30 The percentage of patients requiring admission to the PICU was higher in patients with MIS-C compared to patients with acute respiratory disease. These results were consistent with the results described by the EPICO-AEP working group for the Spanish cohort.9

The case fatality rate was 4% in patients with acute respiratory disease and 0.9% in the overall group of paediatric patients admitted with COVID-19, which was consistent with the previous literature.2,4,31 The presence of pre-existing comorbidities has been found to be directly correlated to an increased mortality in paediatric patients.32 In our study, the 2 patients who died of COVID-19 had severe comorbidities.

In our study, as previously described,22,33 MIS-C was more frequent in the period that the wild type virus was most prevalent, while acute respiratory disease and other presentations (including gastrointestinal symptoms) were more frequent during the delta variant wave; these differences were statistically significant.

Regarding the severity of the disease, several studies have suggested that the omicron variant is associated with a milder clinical course.24,34 In our study, we did not find significant differences in disease severity between the different periods, probably due to the low number of patients included in the omicron period.

Notwithstanding, our results are similar to those of some previous studies,13,14,31 suggesting that they could be representative of the real impact of SARS-CoV-2 in the paediatric population of western countries.

When it comes to the 2 patients who experienced reinfection, it can be hypothesized (although it could not be conclusively proven in our study) that a different degree of disease severity is associated with each SARS-CoV-2 variant and, furthermore, that the immunity granted by the infection does not guarantee 100% protection against reinfection, which may even be more severe.

In our study, coinfection with RSV was not common. One retrospective study conducted in 32 children aged less than 24 months admitted with respiratory compromise due to COVID-19 found that 18.7% had RSV coinfection.35 We found a much lower incidence of coinfection, although the real incidence could be underestimated because we did not perform the test in all patients. However, coinfection by SARS-CoV-2 and RSV was probably uncommon. In this regard, it has also been described that the COVID-19 pandemic has affected the epidemiological trends of acute bronchiolitis, with a noticeable decline in the incidence of bronchiolitis caused by RSV compared to previous years.36 It would be interesting to analyse the epidemiological changes in all respiratory diseases that require admission, comparing what was observed during the pandemic with previous years.