From the authors:
We thank G.J. Porter for his comments on our recently published editorial: “Will children reveal their secret? The coronavirus dilemma” . In the editorial, we reviewed some of the strongest evidence that may support our perspective. It was beyond the purpose of our manuscript to provide a full description of the renin–angiotensin–aldosterone system (RAAS) and angiotensin-converting enzyme 2 (ACE2) receptor. We strongly agree that evidence about the role of ACE2 in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is conflicting and our putative perspective was clearly pointed out in the paper. The debate around the role of ACE2 in SARS-CoV-2 infection is ongoing and we appreciate the chance that G.J. Porter has given us to better elucidate some of its main aspects.
Robust evidence against all of the body of literature about ACE2 downregulation in chronic conditions was recently provided by Leunget al . , who demonstrated increased ACE2 expression in lung biopsies of current smokers and in patients with COPD. Despite not investigating the association between their findings and the risk of SARS-CoV-2 infection, they suggested that ACE2 upregulation could partially explain the increased risk of SARS-CoV-2 infection in these subpopulations.
In his letter, G.J. Porter also stresses the uncertainty about the renin–angiotensin system and ACE2 derangement during SARS-CoV-2 infection in children, and their variability under physiological and pathological conditions, providing evidence that we would like to discuss further. To our knowledge, ACE2 serum levels were not investigated in the study by Liuet al . . On the contrary, plasma concentrations of angiotensin II were measured, resulting in a markedly higher concentration of its plasma levels in patients with coronavirus disease 2019 (COVID-19) than in healthy controls. These findings are in accordance with our hypothesis, that ACE2 dysregulation and angiotensin II elevated levels could lead to inflammation and lung injury.
ACE2 age-related expression was also questioned. We agree with G.J. Porter that the results of the preclinical studies about ACE2 age-related expression in rat models cannot be fully translated to humans. In a report by Fernández-Atuchaet al . , 118 healthy individuals, ranging 41–70 years old, were enrolled and serum ACE2 activity was measured. Results showed significantly higher ACE2 activity in older women and no differences in men. However, in that study, children were not investigated. In addition, concerns about serum ACE2 activity measurement have recently been highlighted, as it may not be a reliable indicator of the membrane-bound form [5, 6]. Regarding ACE2 age-related variability, Schoutenet al .  reported no significant difference in lung ACE2 activity among patients of all ages with acute respiratory distress syndrome. However, as the authors state, the results might have been underpowered due to the relatively small sample size of each age group. Moreover, dilution differences of bronchoalveolar lavage return fluid could have influenced the biomarkers’ final concentration. Notably, ACE2 levels were only measured in the alveolar compartment, which does not reflect the pathological response of the whole RAAS.
Finally, Vaduganathanet al .  recently discussed the role of RAAS inhibitors in patients with COVID-19. The study had a clear focus on their protective rather than detrimental effect in SARS-CoV-2 infection, and highlighted that the hypothesis regarding the beneficial role of ACE2 has led to recombinant ACE2 protein administration trials in order to prevent organ injury (ClinicalTrials.gov number, NCT04287686). Recent clinical trials have also offered us the opportunity to clarify that chronic use of angiotensin-II receptor blockers and ACE inhibitors (and thus, hypothetically, the lung-specific upregulation of ACE2) is not associated with an increased risk of COVID-19 or severe outcomes in COVID-19 [8, 9].
In conclusion, we agree with G.J. Porter that the role of ACE2 receptor in SARS-CoV-2 infection and in COVID-19 outcomes is still being debated, especially in children. Data about lung-specific ACE2 expression in healthy children and in those with COVID-19 are lacking. Further studies about the interconnection of RAAS and SARS-CoV-2 infection are needed, especially in the paediatric age group, in order for children to reveal their hidden secret.
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