Three Hypotheses About Children COVID19 : The Pediatric Infectious Disease Journal

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Letters to the Editor

Three Hypotheses About Children COVID19

García-Salido, Alberto MD, PhD

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The Pediatric Infectious Disease Journal 39(7):p e157, July 2020. | DOI: 10.1097/INF.0000000000002701
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To the Editors:

We have read with interest the recent paper about coronavirus infections in children including new coronavirus disease (COVID-19).1 One of the central questions in this new coronavirus (SARSCOV2) pandemic is why children are less affected than adults.2 We think that three main hypotheses should be considered or studied.

  • (1) Angiotensin-converting enzyme 2 (ACE2) receptor: this receptor is expressed by the alveolar type 2 cells. Maybe a lower presence of ACE2 in children’s lungs influences the clinical expression of COVID19.3 This hypothesis should cautiously be considered. As it has been published, children with less than 1 year are the group at higher risk of complications. This population, empirically, should have lower ACE2 expression. In these cases, the presence of viral or bacterial coinfections must be considered and promptly treated. Maybe they are acting as confounders.
  • (2) Endothelial damage: it has been described that age, cardiovascular diseases and diabetes mellitus are risk factors for severe COVID19. In these cases, previous endothelial damage may facilitate and increase the inflammatory response to SARSCOV2.4,5 In healthy children, the endothelial damage is practically absent. This could help to avoid the spread of the inflammatory process. It will be of great interest to add knowledge about children with similar risk factors like the described in adults.
  • (3) Innate immunity: the first line of defense to SARSCOV2 is the innate immunity. To avoid this, coronavirus blocks the type I interferon route to multiply and increase their copies. The innate immunity in children is well trained not only by community-acquired viral infections5 but also by the use of vaccines also trains it.3 The viral vaccines are mainly administered from 1-year-old in advance. The influence of this about the response to SARSCOV2 infection should be studied. Also, the impact over the evolution of previously administered attenuated RNA vaccines should be analyzed. In that way, the influenza vaccine, which also uses the interferon 1 route, may have an impact on the immune response. This hypothesis about the influenza vaccine should also be considered in the adult population.

In summary, as far as we know, children appear to be least affected by COVID19. This must be an expression of multifactorial causes that nowadays are not well defined. Added to the clinical management, the uses of immunologic and basic science approaches will be of great interest. With these three hypotheses, we try to offer a possible explanation for the differences observed with adults. The study and description of this hypothesis or others may help to develop new therapeutic or prognostic tools.


Work performed in Hospital Infantil Universitario Niño Jesús. Avenida Menéndez, Madrid, Spain.

Alberto García-Salido, MD, PhD
Pediatric Critical Care Unit
Hospital Infantil Universitario Niño Jesús
Madrid, Spain
European Group on Immunology of Sepsis


1. Zimmermann P, Curtis N. Coronavirus infections in children including COVID-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children. Pediatr Infect Dis J. 2020.
2. Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020. pii: e20200702. doi: 10.1542/peds.2020-0702. [Epub ahead of print].
3. Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020;38:1–9.
4. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–1062.
5. Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2020. pii: ciaa248. doi: 10.1093/cid/ciaa248. [Epub ahead of print].
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