Letter: ACE2, IBD and COVID-19-why IBD patients may be at reduced risk of COVID-19.

We read with interest the excellent single‐centre observational case series by Taxonera et al, 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), with no significant observed difference in standardised mortality risk or case mortality rate. They questaioned whether this lower infection rate may be a consequence of improved adherence with shielding recommendations. 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. , Experience from Wuhan reported no cases among 318 IBD patients. 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.

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). 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. SARS‐CoV‐2 enters cells via the former, but can be bound in circulation to the latter.

FIGURE 1

The renin‐angiotensin system pathway. 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

In mouse models, ACE2 expression in lungs is significantly decreased following SARS‐CoV‐2 infection, while Ang II levels increase. These changes are purported as an underlying mechanism of acute respiratory distress syndrome (ARDS). Supporting this, recombinant human ACE2 protein protects mice from ARDS. 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.

Since SARS‐CoV‐2 has high affinity for ACE2, 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). ACE2 activity is significantly higher in non‐inflamed biopsies of IBD patients than unaffected controls, but levels are lower in inflamed segment biopsies. 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. This observation is speculatively contributed to by the higher serum ACE2 activity in CD patients. 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.