The risk of severe illness and death from SARS-CoV-2 is extremely low in children and teenagers

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The risk of severe illness and death from SARS-CoV-2, the virus that causes COVID-19, is extremely low in children and teenagers, according to the most comprehensive analyses of public health data, led by a team of researchers including Dr. Rachel Harwood from the University of Liverpool.

However, catching COVID-19 increases the likelihood of serious illness in the most vulnerable young people, those with pre-existing medical conditions and severe disabilities, although these risks remain low overall.

The preliminary findings, published in three new pre-print studies from UCL and the Universities of Liverpool, Bristol and York, will be submitted to the UK’s Joint Committee on Vaccination and Immunization (JCVI), the Department for Health and Social Care (DHSC) and the World Health Organization (WHO), to inform vaccine and shielding policy for the under-18s. The studies did not look at the impact of long COVID.

One preprint study, published on the medRxiv server, found that 251 young people aged under 18 in England were admitted to intensive care with COVID-19 during the first year of the pandemic (until the end of February 2021).

The researchers, seeking to determine absolute risk, said this equated to young people of that age group in England having a one in approximately 50,000 chance of being admitted to intensive care with COVID-19 during that time.

Looking separately at PIMS-TS, a rare inflammatory syndrome in children caused by COVID-19, the researchers found that 309 young people were admitted to intensive care with this condition – equating to an absolute risk of one in 38,911.

A linked preprint study, published on the ResearchSquare server and looking at data for England, concluded that 25 children and young people had died as a result of COVID-19, equating to an absolute risk of death from COVID-19 of one in 481,000, or approximately two in a million.

Senior author on two of the studies, Professor Russell Viner (UCL Great Ormond Street Institute of Child Health), said: “These new studies show that the risks of severe illness or death from SARS-CoV-2 are extremely low in children and young people.

“Those young people at higher risk are those who are also at higher risk from any winter virus or other illness—that is, young people with multiple health conditions and complex disabilities. COVID-19 does however increase the risks for people in these groups to a higher degree than for illnesses such as influenza (seasonal flu).

“Our new findings are important as they will inform shielding guidance for young people as well as decisions about the vaccination of teenagers and children, not just in the UK but internationally.”

Lead author Dr. Joseph Ward (UCL Great Ormond Street Institute of Child Health) said: “Factors linked to a higher risk of severe COVID-19 appear to be broadly consistent for both children and adults. Our study found a higher risk of admission to intensive care among young people of Black ethnicity compared to white, as well as among young people with health conditions such as diabetes, asthma and cardiovascular disease. Young people with multiple conditions had the highest risk.

“These conditions were also risk factors for other illnesses leading to admission to intensive care, but to a lesser degree than for COVID-19.”

Lead author of the third pre-print study, Dr. Rachel Harwood (University of Liverpool) said: “Our meta-analysis found similar risk factors to the other studies, although we also found that obesity increased the risk of severe COVID-19 illness, something we’ve known for some time in adults but is only now becoming evident as an important risk in children and young people too.”

Lead author Dr. Clare Smith (University of Bristol) said: “We found that only 40% of children and young people who had a positive COVID-19 test at the time of death actually died from COVID-19, emphasizing that the risks are lower than simple numbers might suggest. Children and young people with complex neurodisability were at the highest risk of death.”

Senior author Professor Lorna Fraser (University of York) said: “It’s important to remember that the risks are very low for all children and young people. Even when we found higher risks for some groups with severe medical problems, these risks were still very small compared to risks seen in adults.”

Dr. Elizabeth Whittaker (Imperial College London) said: “It is reassuring that these findings reflect our clinical experience in hospital—we see very few seriously unwell children. Although this data covers up to February 2021, this hasn’t changed recently with the Delta variant. We hope this data will be reassuring for children and young people and their families.”

The UCL-led study looked at England’s hospital admissions data for young people between 2015 and 2021 and linked this to data on admissions to intensive care, deaths, and PCR testing.

By looking at pre-pandemic data, the researchers were able to compare young people’s risks of severe disease from SARS-CoV-2 to their risks of severe illness from all other causes and influenza specifically.

In a separate preprint study, researchers looked at data from the National Child Mortality Database (NCMD), a mandatory reporting system in England, to identify all children and young people who died following SARS-CoV-2 infection until the end of February 2021. Sixty-one children died following a positive diagnosis, but the researchers reviewed clinical records to determine that only 25 of these children (41%) died as a result of COVID-19.

Meanwhile, a third linked preprint paper published this week looked at 81 existing studies assessing risk factors for severe illness and death from COVID-19 among young people. It found higher risks among young people who were obese, had more than one health condition, or had a cardiac or neurological condition. Risk, particularly risk of death, was higher in these analyses than in the national English data. The authors suggested this was likely reflecting biases in the published literature but also the inclusion of studies from resource-poor settings with higher mortality.


Children and young people (CYP) have suffered fewer direct effects of the COVID-19 pandemic than adults, as the vast majority of CYP experience few if any symptoms of SARS- CoV-2 infection.(1) However a small minority experience more severe disease (2) and small numbers of deaths have been documented.(3) As severe outcomes amongst CYP are uncommon, our understanding of which are at risk from SARS-CoV-2 is limited, in contrast to adults. Yet identification of CYP at the highest risk from infection and its sequelae is essential for guiding clinicians, families and policymakers about who can safely attend school, and for identifying groups to be prioritised for vaccination.

SARS-CoV-2 infection in CYP has two primary manifestations. The first is acute COVID-19 disease, an acute illness caused by current infection with the virus and often characterised by respiratory symptoms. The second is a delayed inflammatory condition referred to as Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS) or Multisystem Inflammatory Syndrome in Children (MIS-C)(4-6).

Postulated risk factors for developing more severe COVID-19 or PIMS-TS / MIS-C include existing co-morbid conditions, age, sex, ethnicity, socio-economic group, and geographical location (7-10). Existing systematic evaluations are not useful for guiding policy as reviews were undertaken early in the pandemic (11-13), included highly heterogeneous groups and a wide range of outcomes from very small studies(14), and failed to distinguish between acute COVID-19 and PIMS-TS/MIS-C.

Rapid growth in the literature over the past year provides an opportunity to synthesize findings, and better inform policy decisions about vaccination and protective shielding of vulnerable CYP.

We undertook a high-quality systematic review and meta-analysis of the literature from the first pandemic year to identify which CYP were at increased risk of severe disease or death in CYP admitted to hospital with SARS-CoV-2 infection or PIMS-TS / MIS-C. The study was limited to hospitalised CYP to enable the baseline denominator characteristics to be more accurately defined, particularly co-morbidities, and because in itself, hospital admission may be an indicator of severity.

We limited our review to pre-specified potential risk-factors (co- morbidities, age, sex, ethnicity and deprivation), plus a limited number of outcomes denoting severe disease (critical care admission, need for mechanical invasive ventilation or

cardiovascular support) and death. These are relevant to policy on protective shielding and school attendance, and potential vaccination strategies for CYP.

Results

Figure 1 shows the search flow. 23,050 reports were identified. After excluding duplicates and ineligible studies, 81 studies were included in the review. 57 studies were included in the meta-analysis, including a total of 21,412 children (see Table 1). Nine studies were from Asia, fifteen from Europe, one from Africa, twenty-one from North America and eight from South America. One study had global recruitment.

Data from 22 studies (40% of those in the meta-analysis) was included in the IPD meta- analyses, totalling 10,022 children. 26 studies reporting individual co-morbidities were eligible for inclusion in the narrative synthesis. Most studies eligible for inclusion in the meta-analysis were at considerable risk of bias (Figure 2).

We discuss findings from the aggregate and IPD meta-analyses for each set of risk factors and clinical outcomes below. Detailed data from included studies and pooled estimates from the aggregate meta-analyses are provided in Supplementary Table 1. Supplementary figures 1 and 2 show the sensitivity analysis with the largest study excluded. A two-stage meta-analysis using study-level estimates calculated from the IPD data is shown in supplementary figures 3 and 4.

Proportions of hospitalised children with COVID-19 admitted to critical care and who died in the aggregate analysis were 21.8% and 5.9% respectively and for PIMS-TS/MIS-C were 60.4% and 5.2%. In the IPD analysis, the proportion admitted to critical care with COVID-19 was 16.5% (6.7, 26.3) with death reported in 2.1% (-0.1, 4.3). For PIMS-TS/MIS-C, 72.6% (54.4, 90.7) were admitted to critical care and 7.41% (4.0, 10.8) died.

Demographic risk factors for admission to critical care and death

Sex was not associated with pooled risk of admission to critical care or death in either COVID-19 or PIMS-TS in either the aggregate or IPD analyses (Figure 3). Compared with 1-4 year olds, the aggregate analysis found a higher pooled risk of critical care admission amongst 10-14 year olds and a higher risk of death amongst infants for COVID-19.

In contrast, the IPD analysis found higher risk of critical care and death amongst both infants and 10-14 year olds, plus a higher odds of death amongst those >14 years for COVID-19. For PIMS-TS/MIS-C, the aggregate analysis found higher odds of critical care admission in all age-groups over 5 years, but no age-effects on risk of death. Numbers in the IPD analysis for PIMS-TS/MIS-C were very small, with no association of age-group with risk of death or critical care admission.

We were unable to assess the impact of ethnicity and socioeconomic position on clinical outcomes. The reporting of ethnicity data was highly variable and groupings were insufficiently similar across studies to allow meta-analysis. Socioeconomic position was reported by very few studies.

Association of co-morbidities and critical care and death in aggregate meta-analysis
The aggregate meta-analysis compared those with any or specific comorbidities with all other children in each study (Figure 4). The presence of any comorbidity increased odds of critical care and death in COVID-19, with pooled odds ratios of 2.56 (1.77, 3.71) for critical care and 4.16 (1.97, 8.80) for death, both with moderate to high heterogeneity. Pooled odds ratios for PIMS-TS/MIS-C were of a similar order but with wide confidence intervals.

Pooled odds of both critical care admission and death in COVID-19 were increased in children with the following co-morbidities: cardiovascular; gastrointestinal or hepatic;

neurological; chronic kidney disease; endocrine conditions, including diabetes; and metabolic conditions, including obesity. Odds ratios for critical care ranged from 2.5 to 3.1 and for death from 2.9 to 13. The presence of asthma or trisomy 21 was not associated with either outcome, while respiratory conditions were associated with increased odds of critical care but not death. There was an increased odds of death but not of critical care admission in those with malignancy, haematological conditions and immunosuppression for non- malignant reasons.

Few individual comorbidities were associated with odds of critical care or death in PIMS-TS / MIS-C, with the exception of malignancy (OR for death 183 (2.61-12,815) and metabolic diseases including obesity (OR for critical care 1.45 (1.10-1.92)).

Association between co-morbidities and critical care and death in IPD meta-analysis
The IPD analysis compared those with each co-morbidity with children without any co- morbidity and additionally enabled analysis of risk associated with multiple comorbidities, obesity without other comorbidity, and trisomy 21 without cardiovascular disease. Figure 5 shows pooled OR for critical care and death for each comorbidity, and Figure 6 shows the risk difference estimated from the same models compared with children without comorbidities.

In IPD analysis, the presence of any comorbidity increased odds of critical care and death in COVID-19. The pooled odds ratio for admission to critical care was 1.64 (1.59-1.69), with risk difference being 4.6% (2.5, 6.7) greater than the 16.2% prevalence of critical care admission in those without comorbidities. The pooled odds of death from COVID-19 in those with any comorbidity was 2.49 (2.34-2.66), with a risk difference of 2.1% (-0.03, 4.2) above the 1.69% risk in those without comorbidity. For PIMS-TS/MIS-C, pooled odds of critical care was 12.44 (9.74-15.87) and risk difference 21.1% (4.4, 37.8) above baseline risk of 74.5%, and pooled odds of death was 11.23 (0.77, 163.22) with risk difference 21.0% (-3.4, 45.3) above baseline risk of death of 3.1%.

Number of comorbidities increased the odds of critical care and death in COVID-19 in an apparently dose-dependent fashion, with those with ≥3 comorbidities having a odds ratio of

death of 4.98 (3.78, 6.56), twice that of the odds with one comorbidity. Small numbers with PIMS-TS / MIS-C meant that further analysis of co-morbidities could not be undertaken.

All individual comorbidities increased odds of admission to critical care except for malignancy and asthma, the latter associated with reduced odds (-0.6% (-1.0, -0.2). Risk differences for critical care above the risk for the no comorbidities group were highest for cardiovascular, neurological, and gastrointestinal conditions, as well as for obesity. Obesity alone, without other conditions, increased risk difference to the same level as cardiovascular or neurological conditions, although numbers were small in the obesity analyses.

Odds of death in COVID-19 in the IPD analyses was elevated in all comorbidity groups except for asthma, where there was a reduced risk (-0.6% (-0.9, -0.3)). Risk difference additional to the no comorbidity group was highest for malignancy. Trisomy 21 increased risk of death in those with or without comorbid cardiovascular disease.

Narrative findings from studies of specific comorbidities

Twenty-six papers met the inclusion criteria for the narrative synthesis (Table 2), all reporting on the association of co-morbidity with acute COVID-19. Malignancy was the focus of sixteen of the studies, with rates of critical care admission in hospitalised patients ranging from 0-45% and of death in 0-47%. Six of the ten studies reporting deaths in this group of patients noted that some or all of the reported deaths were due to the underlying condition rather than SARS-CoV-2 infection.
Two studies focussed on hospitalised patients with sickle cell disease.

There were fewer than fifteen patients in each study, with 17% of patients being admitted to critical care in one study and reported deaths in 0-10%. Two studies looking at non-malignant immunosuppression described no children requiring critical care admission or death and a study of children with Rheumatic diseases found a rate of critical care admission of 38%. Chronic kidney disease was examined in two studies with small numbers of hospitalised patients, which describe a rate of critical care admission between 0-9% and of death between 0-6%. A study of CYP with cystic fibrosis found that 1 in 24 (4%) of those hospitalised were admitted to critical care and no deaths were described. Finally, two

studies describe the association between pre-existing cardiac co-morbidity and outcome, which show a high proportion of children are admitted to critical care (43-71%) and that 14- 29% are reported to die.

Conclusions and implications

When children are admitted to hospital with SARS-CoV-2 infection, those at greatest risk of severe disease or death are teenagers, those with cardiac or neurological conditions, or 2 or more comorbid conditions, and children who are significantly obese. These groups should be considered higher priority for vaccination and for protective shielding when appropriate. Our findings suggest that established risk factors for severe disease in adults also operate in the early life-course.

Whilst odd ratios for poor outcomes were increased for nearly all comorbidities in children, the absolute increase in risk for most comorbidities was small compared to children without underlying conditions. This emphasises that our findings should be understood within the broader context that risk of severe disease and death from COVID-19 and PIMS-TS/MIS-C in hospitalised children is very low compared with adults.

Our study quantifies the additional risk related to comorbidities in infected children, however it is likely that some or all of this risk relates to the underlying condition rather than SARS-CoV-2 infection. Further population-based research using comparator groups

which identify the risk of severe disease due to COVID-19 and the underlying risk due to comorbidity is required to develop a safe approach to shielding and vaccination for children.

reference link: https://doi.org/10.1101/2021.06.30.21259763


More information: J L Ward et al, Risk factors for intensive care admission and death amongst children and young people admitted to hospital with COVID-19 and PIMS-TS in England during the first pandemic year, medRxiv (2021). DOI: 10.1101/2021.07.01.21259785
Clare Smith et al, Deaths in Children and Young People in England following SARS-CoV-2 infection during the first pandemic year: a national study using linked mandatory child death reporting data, medRxiv (2021). DOI: 10.21203/rs.3.rs-689684/v1

Rachel Harwood et al, Which children and young people are at higher risk of severe disease and death after SARS-CoV-2 infection: a systematic review and individual patient meta-analysis, medRxiv (2021). DOI: 10.1101/2021.06.30.21259763

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