key: cord-0777233-2mm095jl
authors: Prentice, Ralley E.; Tjandra, Doug; Garg, Mayur; Lubel, John S.; Fourlanos, Spiros; Johnson, Doug; Al‐Ani, Aysha; Christensen, Britt
title: Letter: ACE2, IBD and COVID‐19—why IBD patients may be at reduced risk of COVID‐19
date: 2020-09-20
journal: Aliment Pharmacol Ther
DOI: 10.1111/apt.16063
sha: c6c7b28fd1069a06645f455e704dacc9f7656277
doc_id: 777233
cord_uid: 2mm095jl

LINKED CONTENT This article is linked to Taxonera et al paper. To view this article, visit https://doi.org/10.1111/apt.15804

We read with interest the excellent single-centre observational case series by Taxonera et al, 1 evaluating the clinical characteristics and incidence rates of COVID-19 in IBD patients. Although limited by a small sample size, they demonstrated that IBD patients were less likely to acquire COVID-19 than the general population, with an odds ratio of 0.74 (95% CI 0.70-0.77; P < 0.001), 1 with no significant observed difference in standardised mortality risk or case mortality rate. 1 They questaioned whether this lower infection rate may be a consequence of improved adherence with shielding recommendations. 1 We speculate that differential serum angiotensin-converting enzyme-2 (ACE2) levels observed in patients with IBD may contribute.

Large datasets support the findings of Taxonera's study of comparatively low rates of COVID-19 in patients with IBD. 1,2 Experience from Wuhan reported no cases among 318 IBD patients. 3 Additionally, despite over 18 million COVID-19 cases worldwide, as of 5 August 2020, an international IBD COVID-19 registry reported only 1,925 cases in IBD patients. 4 Although undoubtedly multifactorial, there is biological plausibility to this finding. ACE2 and angiotensin (Ang)II play important roles in the blood pressure and volume regulating renin-angiotensin system (RAS) (Figure 1 ). 5 ACE2 catalyses the conversion of AngII to Angiotensin 1-7 and negatively regulates the RAS. ACE2 has two isoforms: a membrane-bound glycoprotein expressed widely on mucosal surfaces of healthy people including ileum, colon and lungs, and a distinct soluble circulating form. 5 SARS-CoV-2 enters cells via the former, but can be bound in circulation to the latter. 6 In mouse models, ACE2 expression in lungs is significantly decreased following SARS-CoV-2 infection, while Ang II levels increase. 7 These changes are purported as an underlying mechanism of acute respiratory distress syndrome (ARDS). Supporting this, recombinant human ACE2 protein protects mice from ARDS. 7 Additionally, preliminary evidence suggests that recombinant ACE2 is safe in human ARDS patients, with biomarker-based suggestion of efficacy-surfactant protein D, a determinant of lung injury, and interleukin-6, an important mediator of the cytokine storm, both decrease following ACE2 therapy. 8 Since SARS-CoV-2 has high affinity for ACE2, 6 minor changes in expression of membrane-bound ACE2 on mucosal surfaces are unlikely to significantly alter an individual's susceptibility to COVID-19. However, soluble ACE2 may competitively inhibit circulating SARS-CoV-2. Plasma ACE2 activity is higher in IBD patients when compared to healthy controls, with a trend towards higher levels in patients with Crohn's disease (CD) than ulcerative colitis (UC). 5 ACE2 activity is significantly higher in non-inflamed biopsies of IBD patients than unaffected controls, but levels are lower in inflamed segment biopsies. 5 Interestingly, rates of ICU/ventilator requirement/death are higher in UC than CD patients (10% vs 6%) and in those with moderate/severe disease activity compared to mild/no disease activity in the SECURE-IBD registry. 4 This observation is speculatively contributed to by the higher serum ACE2 activity in CD patients. 5 Clinical trials investigating the benefit of recombinant ACE2 have already been proposed and may provide further evidence for the central role of ACE2 in the pathogenesis of COVID-19.

Declaration of personal interests: Doug Johnson has served as speaker for Pfizer. Mayur Garg has served on the advisory board of Pfizer and Pharmacosmos and has received speaker fees, research or travel grants F I G U R E 1 The renin-angiotensin system pathway. 5 Am, aminopeptidase; AT1R angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; AT4R, angiotensin type 4 receptor; NEP, neutral endopeptidase; PPR, (pro)renin receptor; RAS, renin-angiotensin system 

novel coronavirus disease (COVID-19) in patients with inflammatory bowel diseases

Covid-19 and immunomodulation in IBD

Protection of 318 inflammatory bowel disease patients from the outbreak and rapid spread of COVID-19 infection in Wuhan

Secure-IBD Database Public Data Update

Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target?

Structural basis of receptor recognition by SARS-CoV-2

Angiotensin-converting enzyme 2 protects from severe acute lung failure

A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome