|Year : 2020 | Volume
| Issue : 4 | Page : 51-53
Children are not little adults
Department of Paediatrics, KK Women’s and Children’s Hospital, Bukit Timah Road, Singapore
|Date of Submission||01-Apr-2021|
|Date of Acceptance||04-May-2021|
|Date of Web Publication||06-Jul-2021|
Department of Paediatrics, KK Women’s and Children’s Hospital, 100 Bukit Timah Road.
Source of Support: None, Conflict of Interest: None
Coronavirus has caused a pandemic affecting both adults and children. Although mortality rates in adults are high, that in children has been low, with many children experiencing only mild disease. This article looks at the pathophysiologic mechanisms that may account for the differences observed in children, namely a strong immune response, a lower number of angiotensin-converting enzyme 2, and a lower inflammatory response. Though children in general have mild disease, there is a hyperinflammatory condition known as multisystem inflammatory syndrome, which is likely a postinfectious immunologic response, which is seen mainly in children and adolescents and not adults.
Keywords: COVID-19, paediatric, pathophysiology, SARS-CoV-2
|How to cite this article:|
Goh A. Children are not little adults. Pediatr Respirol Crit Care Med 2020;4:51-3
Coronavirus disease 2019 (COVID-19) caused by coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China but has since swept round the world with more than 20 million people infected and causing the death of over 700,000 people. The disease initially presents as a mild respiratory illness that can progress to a viral pneumonia with acute respiratory distress syndrome and multiple organ failure and death in adults especially in the elderly., In children, the course of the disease is generally milder with low fatality rates. Reports from Italy where the number of infections with COVID-19 was high with 253,275 cases, the findings have found that children between zero and nine years made up about 0.5% and those between 10–19 years about 0.7% of confirmed cases. There were no deaths reported in children despite 35,825 deaths reported in adults. The majority of children were either asymptomatic or had mild disease. A systematic review of SARS-CoV-2 infection in children and newborns confirms the findings that the disease affects children and even newborns less severely than adults. About 2% were admitted to the intensive care unit, and estimated mortality was 0.08%. What is it about children that makes their response to the coronavirus infection so different from adults?
The three main postulations for this difference observed are firstly, a stronger immune response in children; secondly, a lower number of angiotensin-converting enzyme (ACE) 2 in children; and thirdly, a lower inflammatory response in children.
For the first postulation, the milder disease observed in children could be due to “trained immunity.” Trained immunity represents an innate immune memory formed after antigen exposure. Repeat viral infections with cytomegalovirus and influenza A have been shown to trigger a stronger natural killer (NK) cell–mediated secondary innate immune response on reinfection. Trained immunity represents a crossprotection against various pathogens, and it can also be activated by vaccines. In children who have frequent viral infections, the increased activation of antigen-presenting cells led to a nonspecific resistance of the host to reinfection, providing crossprotection to other infections. Children too receive many vaccinations, and it is assumed that vaccines can also induce crossreactivity, thus training the innate immune system. It has been found that vaccinations elicit an NK cytotoxic response. Myśliwska, et al. investigated the relationship between NK activity in the vaccinated population with influenza vaccine and specific immune protection against influenza virus as well as immune protection against other infections. They found that NK activity remained elevated one month after vaccination and concluded that NK cell activation may confer protection against influenza and other respiratory viral infections. Hence, frequent viral infections and vaccination in children could induce an innate immune system with an enhanced state of activation that protects them against different pathogens. Furthermore, children with SARS-CoV-2 infection usually demonstrate normal levels of peripheral blood lymphocytes, which suggest less immune dysfunction.
ACE2 mediates the entry of coronavirus (CoV) into host cells in two independent ways. The first way involves ACE2 receptor–mediated clathrin-dependent endocytosis. When the CoV connects to ACE2, the extracellular domain is cleaved off by specific proteases, such as metalloproteinase ADAM17, and the transmembrane domain is internalised. With the assistance of clathrin, viral particles and host cells fuse that aids viral transport from the cell membrane to the cytoplasm. The second way involves ACE2 receptor-mediated transmembrane serine protease 2 (TMPRSS2)-dependent membrane fusion. TMPRSS2 has been found to compete with the ADAM17 metalloprotease for ACE2 processing, but only cleavage by TMPRSS2 was found to enhance SARS-S protein–driven entry.,
A publication looking at nasal gene expression of ACE2 in children and adults found an age-dependent expression in nasal epithelium. ACE2 gene expression was lowest in young children below the age of 10 years and increased with age. The low levels of ACE2 could suggest a lower affinity for the virus resulting in milder infection. Adolescents and young adults have high levels of ACE2, but most have mild disease. ACE2 expression decreases with increasing age, thus it is higher in young adults than in the elderly, yet the elderly are at greatest risk of severe disease. In a mouse model, membrane-bound ACE2 was demonstrated to play a critical role in anti-inflammation through the renin-angiotensin system (RAS) signalling and the conversion of Ang II to Ang (1–7), which protected the animal against acute lung injury. Hence, it is not just the level of ACE2 expression but the downregulation in ACE2 expression seen in the elderly and adults with comorbidities resulting in increased activity of RAS that promotes the inflammation in the lung and the subsequent severe lung disease.
Thirdly, a lower inflammatory response as evidenced by lower interleukin-6 (IL-6) levels in children. A review of all paediatric cases with reported cytokine levels showed that the majority of children had IL-6 within the normal range (mean: 86.3%; range: 67%–100%) in contrast to adults. The less mature immune system of children may result in a lower capability to elicit a cytokine release against viral infections.
Taken together, these immune pathophysiologic mechanisms in children protect them from severe disease from the SARS-CoV-2. Children also have fewer comorbidities and also do not smoke, which upregulates the ACE2. The upregulation of ACE2 activates the immune system inducing the expression of a variety of inflammatory cytokines resulting in the “cytokine storm” caused by COVID-19.
Are children with chronic illnesses at increased risk of COVID-19? The commonest chronic illness in childhood is allergic diseases such as asthma. Fortunately, allergic disease appears to be “protective” against COVID-19. Children with allergic disease and asthma have eosinophilia. Eosinophils clear viral load, thus improving recovery from viral infections. It was also found that allergic sensitisation was inversely related to ACE2 expression and allergen exposure and challenges significantly reduced ACE2 expression. Even in immunocompromised children, the disease is no worse.
There have been reports of an emerging hyperinflammatory shock syndrome resembling Kawasaki’s disease, which has been termed multisystem inflammatory syndrome (MIS). This is likely to be a postinfectious inflammatory syndrome as most of the children did not have evidence of viral replication., Thus, though children have mild disease with COVID-19, paediatricians have to be aware of this rare sequelae of COVID-19 infection.
In summary, children have milder disease from COVID-19 infection because of their good innate antiviral defences and less exuberant inflammatory cytokine responses than adults. However, children are at higher risk of developing postinfectious hyperinflammatory disease such as MIS compared with adults.
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Conflicts of interest
There are no conflicts of interest.
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