Most of the published studies on the transmission of SARS-CoV-2 are observational and use different variables and assessment criteria, which did not allow a meta-analysis of the results. The available reviews are mostly narrative, and while there are a few systematic reviews (SRs), due to the characteristics of the studies that they included we did not believe it would be useful to analyse them in greater detail.

Although the infectious period seems to range from 2 days before the onset of symptoms to 8–10 days after (the pattern in asymptomatic individuals seems to be similar, but it is not well known), some studies have demonstrated that 44% of contagions occur while the primary case is asymptomatic.4 Different authors have found substantial variability in the transmission of SARS-CoV-2 depending on the context.5 The evidence shows that 10%–20% of primary cases are responsible for 80% of secondary cases. There are probably factors at play in transmission other than viral load. Transmission within the household is 10 times more frequent than outside the household.

International epidemiological data and 1 SR have found a risk of secondary transmission in the population aged under 22 years that is 44% lower compared to the adult population. Children are rarely the index case in their families or the cause of outbreaks.6

According to the World Health Organization (WHO), COVID-19 is often more severe in people who are older than 60 years or who have health conditions like high blood pressure, cardiovascular or lung problems, diabetes, obesity or cancer, although individuals of any age may develop severe COVID-19 or die from it.

We searched the literature for data on the risk of developing disease of any severity. The data were obtained from observational studies with a high risk of bias and a low or very low quality of evidence (Table 1).7 The only risk factor that seems supported by evidence of moderate quality is social inequity, which is measured through different indicators and that is significantly correlated to the incidence and mortality of COVID-19.8

In conclusion, although any unvaccinated individual is at risk of being infected, older individuals and individuals with underlying disease are at higher risk of severe COVID-19. The risk of transmission seems higher in adults, elderly individuals in residential facilities, household members of diseased individuals with a dry cough and groups of lower socioeconomic status. Weather and geographical factors may also play a role.

Given the heterogeneity of the selected studies, we made a qualitative synthesis of their results but not a meta-analysis. Table 2 presents the most relevant findings.

We included case series describing at least 10 microbiologically confirmed cases and data on symptoms, as well as SRs including studies of these characteristics. Due to the scarcity of neonatal data, we made an exception and included one SR that analysed isolated case reports and small case series.9 We excluded all the primary sources already included in the selected SRs and sources describing patients that were very likely to be included in larger case series. Most studies had a retrospective observational design and had been conducted in hospital settings (inpatient and emergency care) in the early months of the pandemic. These SRs also had methodological flaws and included heterogeneous results. There was a high risk of bias in all, tending to the underrepresentation of asymptomatic patients and overestimation of the severity of symptoms. Early in the pandemic, tests for microbiological confirmation were ordered nearly exclusively in patients with fever, respiratory symptoms or significant comorbidities, which may have resulted in overestimation of these features. We obtained likelihood ratios for the presence of specific symptoms and a positive reverse-transcriptase polymerase chain reaction (RT-PCR) test for SARS-CoV-2 from a study of greater quality conducted in the community in Canada that included 2463 cases diagnosed between April and September 2020. The best predictor was the combination of 3 symptoms: anosmia/ageusia, nausea/vomiting and headache.10 When it comes to the risk of hospitalization, the data are imprecise, probably due to the absence of uniform criteria for hospital admission and selection biases in different studies. The most consistent risk factors were age less than 1year, especially age less than 3 months, preterm birth and certain underlying diseases.11,12 The results of different studies regarding the risk of admission to the intensive care unit (ICU) were heterogeneous, and the most consistent factors were age less than 1 month and elevation of C-reactive protein.

We collected data on the multisystem inflammatory syndrome in children (MIS-C)13 from studies that included patients with this particular diagnosis, but the data from all other complications was obtained from general studies on the clinical features of SARS-CoV-2 infection. It is possible that instances of these variables were not documented in primary sources, even if they were actually present. Neurologic complications were analysed in a SR of data obtained from studies on the overall clinical presentation and course of the disease (not focused specifically on neurologic features).14

In the early months of the COVID-19 pandemic, the ability to diagnose the disease accurately was of critical importance, so numerous studies analysed the different available RT-PCR techniques. In the months that followed, new diagnostic needs emerged, such as improving the turnaround time of tests, the availability of tests for screening and to conduct population seroprevalence studies or reducing the costs of testing, which resulted in the publication of many works focused on the validity of different types of samples and rapid PCR, antigen and antibody tests.

To establish the gold standard, we analysed data from studies on the correlation and the limits of detection of different RT-PCR tests,15 which were in vitro studies with an appropriate methodological design. When it came to rapid PCR and antigen tests, we searched for studies on their validity and accuracy, most of which, be it individual studies or studies included in meta-analyses, were limited on account of their design and methodology, especially in relation to the inclusion criteria and the reference standard.16 Furthermore, few studies included children and, when they did, their representation was all but negligible. We analysed one study on the validity of antigen tests focused exclusively on the paediatric population, with results that we considered of moderate-to-low quality due to low precision.

To evaluate the usefulness of quantitative SARS-CoV-2 antibody tests, we analysed data from 4 studies, one of which was a review included in a clinical practice guideline.17 All recommendations on the subject are based on evidence of very low quality, as most of the sources were case-control studies with a high risk of bias. The findings of the studies, including those included in meta-analyses, were heterogeneous, and there was little agreement in the definition of key concepts, such as the time elapsed from the onset of symptoms. On the other hand, since most of the studies analysed were conducted on the adult population, the evidence is also indirect.

Once the diagnosis has been established, the evidence in adults shows that certain clinical, laboratory or radiological characteristics may support the diagnosis or have prognostic value. The studies we included in the analysis to determine the indication of blood tests,18 chest radiograph, chest computed tomography19 or ultrasound20 in the paediatric population were observational studies with small samples and of very low quality. It is possible that new studies on the subject may improve the quality of the evidence, although we doubt that it will change the direction of the current recommendations (Table 3).

Since the beginning of the pandemic caused by the novel coronavirus, the global scientific community has made an immense effort to determine which treatments are most appropriate. Still, the experimental evidence in the paediatric population is scarce. The searches we performed did not yield any paediatric randomised controlled trials (RCTs) for the treatments included in the analysis. For this reason, we selected RCTs in adults and paediatric studies irrespective of study design. The main treatment options considered in the analysis were hydroxychloroquine,21 steroid therapy,22 tocilizumab,23 hyperimmune plasma,24 immunoglobulin therapy and remdesivir.25

For each treatment, we performed a quantitative synthesis of critical outcome measures, mainly mortality, the most important outcome, and the need of mechanical ventilation. We also estimated other outcomes for some of the treatments, such as survival times or radiological progression.

We were unable to pool the data on the adverse effects of treatment due to differences in reporting between trials, although the safety profile of some of these drugs had already been established (hydroxychloroquine/steroids). Some of the evaluated treatments are not widely accessible (high cost and long duration of treatment), which results in an unfavourable cost-benefit ratio (tocilizumab).

Overall, the quality of the evidence was considered moderate for some treatments, due to inconsistencies, or in some cases low to very low, due to lack of precision and methodological limitations (remdesivir). We only found evidence to support the use of steroid therapy, and evidence against the use of all other treatments. We expect that as new studies are published, the estimated efficacy of some of these treatments will change and may require reconsidering the current recommendations (Table 4).

The evidence on COVID-19 in the paediatric population and specifically on paediatric patients with MIS-C26 came from observational studies, which outlined a series of therapeutic interventions the efficacy of which cannot be established at present. It seems reasonable to recommend that most paediatric patients with COVID-19 that are asymptomatic or have mild symptoms receive any necessary supportive care. Pharmacological treatment should be reserved for severe cases (chiefly manifesting with MIS-C). In the case of MIS-C, the evidence supports a weak recommendation of combined therapy with intravenous immunoglobulin and methylprednisolone.

The publication of the findings of ongoing trials of the different vaccines that are being investigated has been spotty; for some vaccines, data have been published and kept the community abreast of developments in research, whereas for other vaccines no data have been published to date.33–36

In the European Union, 4 vaccines against COVID-19 had been authorised as of March 11, 2021: Comirnaty (Pfizer-BioNTech), the Moderna COVID-19 vaccine, the AstraZeneca COVID-19 vaccine and the Jannsen COVID-19 vaccine. At the time of this writing (April 23, 2021), there are data on the efficacy of 2 nonreplicating vaccines based on recombinant viral vectors and 2 vaccines based on messenger RNA, which is greater than 60% in all. This document does not include an assessment of the Janssen vaccine because data from clinical trials is not yet available.

The effectiveness data published to date are encouraging.37 In Spain, there is evidence of a decrease in the incidence of COVID-19 in nursing homes for the elderly, which were a priority group in the vaccination drive.

As occurs with other RNA viruses, there may be variants of SARS-CoV-2 that escape neutralization by antibodies, As of March 11, there are 3 variants of concern: B.1.1.7 (UK variant), B.1.351 (South Africa variant) and P.1 (Brazil variant).38

The overall quality of the evidence on vaccines against SARS-CoV-2 is moderate, but this is too low to support vaccination of children, as the evidence is indirect, based on RCTs performed in adults.

The evidence is from well-designed, blinded RCTs, but these trials have not yet completed the follow-up. Some groups are underrepresented in RCTs, like individuals aged more than 55 years or with diseases, and other groups, such as children and pregnant women, have been completely excluded.

Vaccines against COVID-19 are being authorised on an urgent basis due to the severity of the pandemic. In general, the population seems willing to undergo vaccination, although there is unprecedented influence from information delivered through the mass media and social networks, with messages that are at times confusing, contradictory or simply false.

Although the data on the effectiveness of the vaccines are still preliminary, given the efficacy observed in trials and the generally mild-to-moderate severity of its adverse effects, the benefits seem to outweigh the risks and support vaccination of the population (Table 6).

Due to the scarcity of doses and logistic difficulties, the health care authorities have established priority groups to immunise different segments of the population in a stepwise approach.