Why are children so much less likely to get seriously ill with SARS-CoV-2?

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Fundamental differences in the immune response of adults and children can help to explain why children are much less likely to become seriously ill from SARS-CoV-2, according to new research from the Wellcome Sanger Institute, University College London and their collaborators.

The study, published in Nature, is the most comprehensive single-cell study to compare SARS-CoV-2 infection in adults and children across multiple organs. Researchers found that a stronger ‘innate’ immune response in the airways of children, characterised by the rapid deployment of interferons, helped to restrict viral replication early on.

In adults, a less rapid immune response meant the virus was better able to invade other parts of the body where the infection was harder to control.

As part of the Human Cell Atlas1 initiative to map every cell type in the human body, the findings will be a valuable contribution to predict personal risk from SARS-CoV-2. A nasal swab to measure the immune response in newly infected adults could be used to identify those at higher risk who may be candidates for pre-emptive monoclonal antibody treatment. Recent research has also suggested inhalation of interferons could be a viable therapy2.

The immune system that we are born with is not the same as the one we have as adults. The ‘innate’ immune system of children is better able to recognise dangerous viruses or bacteria automatically, triggering ‘naïve’ B and T cells that can adapt to the threat.

Adults have a more ‘adaptive’ immune system containing a huge repertoire of ‘memory’ B and T cell types, which have been trained through past exposure to respond to a particular threat3. Though the adult immune system also has an innate response, it is more active in children.

One of the key mechanisms of both immune systems is a group of proteins called interferons, which are released in the presence of viral or bacterial threats and tell nearby cells to tighten their defences. Interferons are proteins with strong anti-viral activity and their production will typically lead to the activation of B and T cells, which kill infected cells and prevent the pathogen from spreading further.

For this study, researchers at University College London (UCL) and affiliated hospitals4 collected and processed matched airway and blood samples from 19 paediatric and 18 adult COVID-19 patients with symptoms ranging from asymptomatic to severe, as well as control samples from 41 healthy children and adults.

Single-cell sequencing of the samples was done at the Wellcome Sanger Institute to generate a dataset of 659,217 individual cells. These cells were then analysed, revealing 59 different cell types in airways and 34 cell types in blood, including some never previously described.

Analysis showed that interferons were more strongly expressed in healthy children compared to adults, with a more rapid immune response to infection in children’s airways. This would help to restrict viral replication early on and give children an immediate advantage in preventing the virus from infecting the blood and other organs.

“Because SARS-CoV-2 is a new virus, it isn’t something that the adaptive immune system of adults has learned to respond to. The innate immune system of children is more flexible and better able to respond to new threats. What we see at a molecular level are high levels of interferons and a very quick immune response in children that helps to explain why they are less severely affected by COVID-19 than adults.”

Dr Masahiro YoshidaUniversity College London

The study also detailed how the immune system of adults, with its high numbers of ‘killer’ immune cells such as B and T cells, can work against the body once SARS-CoV-2 has spread to other parts of a patient.

“Compared to children, adult blood has a greater number and variety of cytotoxic immune cells, which are designed to kill infected cells to prevent an infection spreading. But it is a fine line between helping and hindering. Once the virus has spread to several areas of the body, organ damage can be caused by the immune system trying and failing to control the infection. Our study shows that not only do children respond better initially, if the virus does enter the blood the cytotoxic response is less forceful.”

Dr Marko Nikolić University College London

Knowing exactly how and why the immune response to SARS-CoV-2 can fail to control the infection or start to harm the body provides scientists with the means to start asking why certain individuals may be at greater risk of serious illness.

These data suggest that newly diagnosed adults could be tested to check interferon levels in the airway. Higher interferon levels, similar to those found in children, would suggest a lower risk of severe disease, whereas low interferon levels would suggest higher risk. Higher risk patients could then be considered for pre-emptive treatments such as monoclonal antibodies, which are expensive and can be in limited supply.

“To put it simply, the innate immune response is better at fighting COVID-19 and children have stronger innate immunity, but immunity is also a complex ballet involving many types of cells. The timing and the types of cells that are triggered will influence how an infection develops, and this will vary between individuals for all sorts of reasons in addition to age. Some of the differences we observe between children and adults may help us to think about how we gauge personal risk for adults as a way of mitigating serious illness and death.”

Dr Kerstin Meyer Wellcome Sanger Institute

In addition, there is growing evidence of the therapeutic benefits of inhaled interferon beta 1a. Based on the study results, this should be particularly the case for patients with weak or absent interferon activation.

“The results are insightful not only for addressing COVID-19, but more broadly for understanding changes in the airway and blood throughout childhood. They demonstrate the power of single-cell resolution to reveal differences in the biology of children and adults, while pointing to very different considerations when thinking about how a specific disease arises and may be treated.”

Jonah CoolChan-Zuckerberg Initiative

More information

­­1 The Human Cell Atlas (HCA) is an international collaborative consortium which is creating comprehensive reference maps of all human cells—the fundamental units of life—as a basis for understanding human health and for diagnosing, monitoring, and treating disease. The HCA will impact every aspect of biology and medicine, propelling translational discoveries and applications and ultimately leading to a new era of precision medicine. The HCA was co-founded in 2016 by Dr Sarah Teichmann at the Wellcome Sanger Institute (UK) and Dr Aviv Regev, then at the Broad Institute of MIT and Harvard (USA). A truly global initiative, there are now more than 2,000 HCA members, from over 75 countries around the world. https://www.humancellatlas.org

2 For further information on these studies, see: https://pubmed.ncbi.nlm.nih.gov/33189161/
and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833737/

This article in The Atlantic is an informative and accessible primer on the human immune system and how it reacts to SARS-CoV-2.

UCL affiliated hospitals including Great Ormond Street Hospital, University College Hospital, Royal Free Hospitals and Whittington Hospital

Publication:

Masahiro Yoshida, Kaylee. B Worlock, Ni Huang and Rik G.H. Lindeboom et al. (2021). Local and systemic responses to SARS-CoV-2 infection in children and adults. Naturehttps://doi.org/10.1038/s41586-021-04345-x

Funding:

This research was funded by Wellcome, the Chan Zuckerberg Initiative, Rosetrees Trust, Action Medical Research, Medical Research Council and the European Union’s Horizon 2020 programme.


  • Children and adolescents currently account for about 15.8% of confirmed COVID-19 cases in United States
  • unclear how well children transmit SARS-CoV-2 compared to infected adults
  • signs and symptoms in children include
    • fever
    • fatigue
    • headache
    • myalgia
    • cough
    • rhinorrhea or nasal congestion
    • new loss of smell or taste
    • sore throat
    • shortness of breath
    • diarrhea
    • abdominal pain
    • nausea and vomiting
    • poor appetite or poor feeding
  • in general, children develop milder illness compared to adults, but they are still at risk for severe illness and complications of COVID-19
  • pediatric presentation of severe COVID-19 is similar to that of adults and includes respiratory failure, shock, myocarditis, acute renal failure, and coagulopathy
  • testing for SARS-CoV-2 recommended in children
    • with symptoms of COVID-19
    • after close contact (< 6 feet distance for ≥ 15 minutes) with person with confirmed or probable SARS-CoV-2 infection
    • with planned invasive medical procedure scheduled
  • professional organizations provide guidance for testing neonates born to mothers with suspected or confirmed COVID-19 and testing in school-aged children
  • important to maintain broad differential while evaluating sick children during pandemic; children with SARS-CoV-2 infection may present with other serious conditions including intussusception or diabetic ketoacidosis
  • management of pediatric patients with COVID-19
    • most children with moderate or mild disease can be managed with supportive care alone
    • decision to admit pediatric patient with mild-to-moderate COVID-19 should be made on case-by-case basis
    • in children with severe COVID-19, supportive care may help to relieve symptoms and should include support of vital organ functions in severe cases including
      • respiratory ventilation and therapies for refractory hypoxemia
      • thromboprophylaxis and antithrombotic therapy
      • management of shock
      • acute kidney injury and renal replacement therapies (RRT)
    • treatment for hospitalized children with COVID-19 may include remdesivir and dexamethasone depending on child’s age and disease severity
    • management of children with COVID-19 and hyperinflammation may also include immunomodulatory treatment
    • management of shock in children with COVID-19 follows standard guidance from 2020 Surviving Sepsis Campaign which can be found in Pediatr Crit Care Med 2020 Feb;21(2):e52
  • multisystem inflammatory syndrome in children (MIS-C) is a new syndrome that occurs in a minority of children with prior SARS-CoV-2 infection
    • spectrum of severity of MIS-C
      • mild cases include minimal signs of inflammation, no signs of cardiac involvement, and no signs of shock (may not initially require treatment)
      • most severe cases require significant vasoactive-inotropic interventions, ventilatory support, and/or moderate or severe organ injury
    • management of MIS-C depends on clinical presentation and severity
  • infection control
    • pediatric population likely contributes to transmission of COVID-19 in the community due to higher prevalence of mild and asymptomatic disease; children, with help from parents, can adopt measures to slow spread of COVID-19 including frequent handwashing and social distancing
    • Centers for Disease Control and Prevention provides guidance for isolation, quarantine, and return to school after illness for school-aged children
  • health maintenance for all children during COVID-19 pandemic
    • children should be kept current on all recommended vaccinations, especially influenza vaccinations
    • developmental surveillance and early childhood screenings should continue as well as referrals for early intervention services as needed
    • all newborns should be seen soon after discharge at age 3-5 days with visits occurring ideally in person
    • American Academy of Pediatrics (AAP) provides interim guidance on supporting emotional and behavioral health needs of children, adolescents, and families during COVID-19 pandemic
  • Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines have been approved or authorized for prevention of COVID-19 in children
  • monoclonal antibody combinations may be considered for postexposure prophylaxis in children who are at high risk for progression to severe COVID-19

State-level reports are the best publicly available and timely data on child COVID-19 cases in the United States. The American Academy of Pediatrics and the Children’s Hospital Association are collaborating to collect and share all publicly available data from states on child COVID-19 cases. The definition of “child” case is based on varying age ranges reported across states (see report Appendix for details and links to all data sources).

As of December 16, almost 7.4 million children have tested positive for COVID-19 since the onset of the pandemic. COVID cases among children are extremely high: nearly 170,000 child cases were added the past week, an increase of nearly 28% over the last 2 weeks. For the 19th week in a row child COVID-19 cases are above 100,000. Since the first week of September, there have been over 2.3 million additional child cases.

The age distribution of reported COVID-19 cases was provided on the health department websites of 49 states, New York City, the District of Columbia, Puerto Rico, and Guam. Since the pandemic began, children represented 17.3% of total cumulated cases. For the week ending December 16, children were 23.7% of reported weekly COVID-19 cases (children, under age 18, make up 22.2% of the US population).

A smaller subset of states reported on hospitalizations and mortality by age; the available data indicate that COVID-19-associated hospitalization and death is uncommon in children.

At this time, it appears that severe illness due to COVID-19 is uncommon among children. However, there is an urgent need to collect more data on longer-term impacts of the pandemic on children, including ways the virus may harm the long-term physical health of infected children, as well as its emotional and mental health effects.

Summary of Findings (data available as of 12/16/21) :

Cumulative Number of Child COVID-19 Cases*

  • 7,366,865 total child COVID-19 cases reported, and children represented 17.3% (7,366,865/42,502,606) of all cases
  • Overall rate: 9,788 cases per 100,000 children in the population

Change in Child COVID-19 Cases*

  • 169,964 child COVID-19 cases were reported the past week from 12/9/21-12/16/21 (7,196,901 to 7,366,865) and children represented 23.7% (169,964/716,504) of the weekly reported cases
  • Over two weeks, 12/2/21-12/16/21, there was a 5% increase in the cumulated number of child COVID-19 cases since the beginning of the pandemic (334,253 cases added (7,032,612 to 7,366,865))

Hospitalizations (24 states and NYC reported)*

  • Among states reporting, children ranged from 1.8%-4.1% of their total cumulated hospitalizations, and 0.1%-1.8% of all their child COVID-19 cases resulted in hospitalization

Mortality (45 states, NYC, PR and GU reported)*

  • Among states reporting, children were 0.00%-0.27% of all COVID-19 deaths, and 6 states reported zero child deaths
  • ​In states reporting, 0.00%-0.03% of all child COVID-19 cases resulted in death

* Note: The numbers in this summary represent cumulative counts since states began reporting. In this summary and full report, the data are based on how public agencies collect, categorize and post information. All data reported by state/local health departments are preliminary and subject to change and reporting may change over time. Notably, in the summer of 2021, some states have revised cases counts previously reported, begun reporting less frequently, or dropped metrics previously reported. For example, due to several changes on their dashboards and the data currently available, AL, NE, and TX data in this report are not current (cumulative data through 7/29/21, 6/24/21, and 8/26/21 respectively). Readers should consider these factors. States may have additional information on their web sites.

For additional information on US child hospitalizations from the CDC, visit https://covid.cdc.gov/covid-data-tracker/#new-hospital-admissions 

For additional information on US child mortality from the CDC, visit https://covid.cdc.gov/covid-data-tracker/#demographics 

^ As of 11/11/21, we are no longer reporting testing data due to the low number of states reporting

Download Full Report (12/16/2021)

Download Full Report (12/9/2021)

Download Full Report (12/2/2021)

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