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Will Children Reveal their Secret? The Coronavirus Dilemma
PDPI Sulawesi Selatan & Utara, 15 Mei 2020 15:22:33

I was interested to read the recent editorial: “Will children reveal their secret? The coronavirus dilemma” [1]. While well substantiated, the assertion that increased angiotensin converting enzyme 2 (ACE2) expression is protective in terms of COVID-19 outcomes seems to conflict with a large body of literature on the topic. I would therefore like to briefly explore some of the arguments around this, with the hopes of highlighting the main areas of conflict and inciting more research on this aspect of SARS-CoV-2 pathophysiology.

ACE2 is an important component of the renin-angiotensin system (RAS) which acts as the receptor for SARS-CoV-2. Many authors argue that ACE2 is the underlying reason behind many of the risk factors for severe COVID-19. Fang et al. states that treatment of conditions such as hypertension and diabetes with ACE-inhibitors (ACEI) and Angiotensin-II receptor blockers (ARB) results in significant upregulation of ACE2, offering more ports of entry into cells by SARS-CoV-2, resulting in the worse outcomes reported in these patients [2]. In a similar vein Leung et al. studied the expression of ACE2 via immunohistochemistry in human lung biopsies [3]. They found significantly higher expression of ACE2 in smokers and COPD patients compared to healthy controls and argue that this is why smoking status and COPD appear associated with negative COVID-19 outcomes [3]. Finally, a small study which measured the serum levels of ACE2 in patients with COVID-19 found that they were significantly higher (p<0.001) than healthy controls and levels closely correlated to lung injury and viral load [4].

Despite evidence that ACE2 is implicated in the pathology of COVID-19 we should not jump to conclusions about its exact role. Both the study of lung biopsies and the serum measurement of ACE2 had low sample sizes, at 27 and 20 including controls, respectively [2, 3]. Moreover much of the epidemiological evidence could be confounded by the fact that many of the conditions which reportedly raise ACE2 are associated with age and obesity, which are also implicated in negative outcomes of both SARS-CoV-2 infection and that of other respiratory viruses [5]. Equally, systematic reviews of the hypothesised effect of ACEI/ARB on COVID-19 outcomes have so far not found any significant effect [5, 6]. Much of the pathophysiology and epidemiology of SARS-CoV-2 is not yet understood, so it is unsurprising that definitive conclusions are yet to be drawn. Despite this there are clear grounds to question the argument that ACE2 overexpression directly contributes negative COVID-19 outcomes.

There is a growing body of literature which argues that ACE2 upregulation is a protective factor for SARS-CoV-2 outcomes. Models of acute respiratory distress syndrome (ARDS) in ACE2-knockout mice have shown that ACE2 confers a protective effect [7]. Additionally, injecting the SARS-CoV spike into mice already with ARDS dramatically worsens their condition, a process which can then be ameliorated by blocking RAS [7]. Therefore in mice it is possible that ARDS in SARS-CoV is mediated at least in part by ACE2 disruption and resulting RAS dysregulation. Moreover, in vitro reports suggest that SARS-CoV-2 actually downregulates ACE2 after utilising it for cellular entry, resulting in immune cell infiltration, RAS dysregulation and lung injury [5]. Meanwhile, the aforementioned editorial highlights rat models which illustrate a significant decrease in ACE2 expression with age, which, if also exhibited in humans, could form part of the reason that children are far less effected by COVID-19 than adults [1].

This hypothesis is also not without flaws. The murine models illustrate that a complete lack of ACE2 results in dysregulated RAS and more severe ARDS verses normal expression. However, the theoretical comparison in actuality is increased ACE2 expression verses normal or slightly decreased levels. Moreover while rat models show a significant decrease in ACE2 expression with age, Schouten et al. reported no significant differences in lung ACE2 activity between neonates, children, adults and older adults (>65 years old) while Fernández-Atucha et al. found significantly higher ACE2 activity in women aged over 55, and no difference in men [8, 9]. There is also considerable evidence that ACEI/ARB therapy makes no difference in ACE2 expression, meaning arguments surrounding the lack of association between these medications and COVID-19 outcomes may be invalid regardless of how they characterise the role of ACE2 [5].

Much of the literature on ACE2's role in COVID-19 is highly conflicting. I believe that this stems from the fact that basic mechanisms of ACE2 physiology, such as the effect of aging or ACEI/ARB usage on its expression, or how ACE2 levels change during COVID-19 infection, are still debated. Understanding the role of ACE2 could offer insights both into the prognosis of individual COVID-19 cases and therapeutic techniques [1, 4]. Research in this area is therefore vital, particularly robust case-control studies of ACE2 expression and COVID outcomes and genomic studies of ACE2 expression at different ages and disease states [1].

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