Letter: intestinal inflammation, COVID‐19 and gastrointestinal ACE2—exploring RAS inhibitors. Authors’ reply

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LINKED CONTENT

This article is linked to Taxonera et al an Garg et al papers. To view these articles, visit https://doi.org/10.1111/apt.15804 and https://doi.org/10.1111/apt.15814.

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EDITORS,

We thank Garg et al for their comments and interest in our case series study reporting the incidence and clinical characteristics of laboratory‐confirmed COVID‐19 cases among IBD patients. ¹ , ² A relevant finding of our study was the high rate of diarrhoea as a presenting symptom among IBD patients with COVID‐19. This in theory could be explained by the high affinity of the SARS‐CoV‐2 spike (S) protein for the angiotensin‐converting enzyme 2 (ACE2), which is overexpressed in the inflamed gastrointestinal (GI) tract of IBD patients and considered to be essential for viral entry into human cells.

Garg et al exhaustively analysed the potential influence of all major components of the renin‐angiotensin system (RAS), including ACE2, on GI symptoms in patients with COVID‐19. ¹ The authors postulated that intestinal inflammation leading to symptoms may occur due to SARS‐CoV‐2‐mediated reduction of mucosal ACE2 following entry, resulting in elevated angiotensin II, reduced angiotensin 1‐7, increased tumour necrosis factor (TNF) and tryptophan deficiency. ³ Since reduced ACE2 expression in the lungs has also been associated with acute respiratory distress syndrome, it has been suggested that drugs targeting RAS may be useful for the treatment of COVID‐19. ⁴ However, in view of additional data showing no effect of ACE inhibitors and angiotensin receptor blockers on ACE2 GI expression, it is unlikely that these drugs could influence SARS‐CoV‐2 infection of the GI tract. ²

The reported evidence, however, suggests other potential therapeutic targets for COVID‐19. In severely ill COVID‐19 patients, biologics may be beneficial through control of the cytokine release storm, which bears some resemblance to the process in IBD flares. IL‐6 levels are significantly elevated in COVID‐19, and treatment with the anti‐IL‐6 antibody tocilizumab dramatically decreases CRP levels, suggesting an improvement in this hyper‐inflammatory state. ⁵ Interestingly, a recent study of patients included in the SECURE‐IBD registry reported that TNF antagonist monotherapy was not associated with and even may have a protective effect against severe COVID‐19. ⁶ Evidence that mucosal or plasma ACE2 expression or activity was not associated with the use of anti‐TNF therapies ³ reinforces the need for trials evaluating these drugs for COVID‐19. ⁷

We agree with the authors’ comment about interest in the relationship between GI symptoms and faecal calprotectin (FC). FC levels seem especially useful in symptomatic IBD patients to confirm an active flare, but elevated FC also occurs in acute bacterial and viral gastroenteritis. ⁸ For example, a study reported high FC levels in COVID‐19 non‐IBD patients with resolved or ongoing diarrhoea. ⁹ Therefore, we believe that FC levels in a COVID‐19 IBD patient with diarrhoea may not be helpful in discriminating between an IBD flare and diarrhoea associated with intestinal cell colonisation by SARS‐CoV‐2. As no relationship was observed between FC and faecal ARS‐CoV‐2‐RNA, FC levels did not seem useful in evaluating the elimination of virus from the faeces. However, FC levels <100 μg/g in patients with GI symptoms could be useful in differentiating between organic and non‐organic gastrointestinal disease, thus avoiding the need for unnecessary endoscopic evaluation during pandemic.