key: cord-0806686-wb1l0o49
authors: Grassi, Tiziana; Varotto, Elena; Galassi, Francesco M.
title: COVID-19, a viral endocrinological disease?
date: 2020-06-05
journal: Eur J Intern Med
DOI: 10.1016/j.ejim.2020.06.003
sha: 42b3128e5a31e7ba162664931c1246c6f374e16a
doc_id: 806686
cord_uid: wb1l0o49

nan

Ever since Chinese health officials informed the WHO of the presence of 44 patients suffering from an anomalous pneumonia apparently linked with the Huanan seafood whole market on 31 st December 2019 [1] , a conspicuous number of scientific publications on COVID-19 have understandably focused either on the main clinical presentation of the novel pathological entity or the response of the immune system to its pathogenic agent, thus following in the footsteps of the established hermeneutical research approach of contemporary infectivological studies. According to this model, multi-organ involvement and damage is the obvious consequence of a primary pathogen-immune system interaction, in which an enhanced response of the latter (exemplified by the cytokine storm) is responsible for the rich semiological constellation described in the specialized literature [2] . While attention has been paid to the role of ACE2 inhibition by SARS-CoV-2 through a tight binding mechanism, either as an ancillary or only recently as an important aspect of this disease [3, 4] , our view is that this very inhibition is truly responsible for the cascade of events ultimately resulting in the described clinical presentation. Building on this, we hereby propose that this paradigm be reversed in that the recorded immune overreaction is regarded as the mere consequence of an originally impaired endocrinological pathway, rather than a direct response to the pathogen itself. The renin-angiotensin-aldosterone system (RAAS) is fundamental in regulating electrolyte balance and blood pressure, and its involvement in the inflammatory response in the liver, kidney, cardiovascular and respiratory sistems has been clarified. The RAAS begins ( fig.1 ) with the enzyme renin secreted by the juxtaglomerular epithelioid cells located in the medial layer of renal afferent arterioles in the kidney [5] . Renin cleaves angiotensinogen into angiotensin I (Ang I), which is in turn converted into angiotensin II (Ang II), a vasoactive octapeptide, by the angiotensin converting enzyme (ACE). Ang II then exerts its biological effects by activating G protein-coupled receptors. ACE is also responsible for the degradation of bradykinin and substance P, two local proinflammatory and protussive peptides that can trigger the release of prostanoids and nitric oxide (NO), and induce the cough reflex [6] . In addition, ACE2, another zinc metallopeptidase and a homologue of ACE, is responsible for producing the heptapeptide Ang (1-7) by cleaving Ang II. It was recently discovered that the ACE2/Ang (1-7)/Mas receptor pathway mitigates airway inflammation [7] . When ACE2 is blocked by the SARS-CoV-2 virus does not occur. Another example supporting a prominent antiinflammatory role by ACE2 is provided by asthma, in which targeting this receptor has been evaluated as a promising strategy in that it can counter the effects of AT1R activation [6] . In the light of this inhibition mechanism it becomes clear that the anti-inflammatory cascade activated by ACE2 is irreversibly blocked with all the expected multisystemic negative outcomes.

In conclusion, we believe that considering COVID-19 an endocrine-originating disorder would help scientists make sense of the non-specific response the immune system shows towards this pathogen, unlike seen in other viral infections such as influenza [8] . Future therapeutical strategies may be directed at tackling the endocrinological RAAS pathway, hence resulting in a better understanding of the nature and presentation of COVID-19. This, beside potentially beneficial clinical implications, could ultimately prove a higher interpretative platform from which medicine may contemplate this new health challenge.

The authors declare they have no conflict of interest. 

WHO Timeline -COVID-19

HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression

Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

Control of renin synthesis and secretion

Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases

Angiotensin-(1-7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation