Inflammatory Bowel Disease and COVID-19

Crohn's Disease (CD)] and Ulcerative Colitis (UC), the main Inflammatory Bowel Diseases (IBD), are no exception. There is concern that these disabling conditions, together with the drugs used to treat them, can put patients at risk of developing complications and other conditions, which is particularly relevant during this pandemic period.

IBD centres across the world have been flooded with requests from patients and general physicians inquiring about the risk of infection in patients with IBD, and asking what precautions to take, particularly regarding, but not limited to, their immunosuppressive treatment.

Conscious of this healthcare challenge, several societies have published guidance on how to protect IBD patients and minimise the risk of infection and how to deal with immunomodulators or biologic agents [3–5]. The general strategy expressed by the British Society of Gastroenterology (BSG), the International Organization for the study of Inflammatory Bowel Disease (IOIBD), the European Crohn's and Colitis Organisation (ECCO) and the Crohn's and Colitis Foundation of America (CCFA) is to reduce contact with health-care settings, thereby reducing the possible exposure to COVID-19.

The primary objective of this letter is to summarise the current epidemiological data of patients with IBD who have been infected with COVID-19.

Are patients with IBD at increased risk for COVID-19 infection?

There has been a high level of concern that IBD patients may be at increased risk of infection with SARS-CoV-2. The reason is that SARS-CoV-2 is known to bind to target cells through angiotensin-converting enzyme 2 (ACE-2), a monocarboxypeptidase constitutively expressed by epithelial cells of the lung, intestine, kidney, and blood vessels but also present in the terminal ileum and colon in concentrations that are amongst the highest in the body. The expression of ACE2 is indeed increased in the inflamed gut of patients with IBD [6].

Most available data, however, do not suggest that COVID-19 occurs more frequently in IBD patients than in the general population. A case series of 1918 IBD patients from Madrid, Spain (including 12 with a confirmed diagnosis of COVID-19) revealed that IBD patients had an age- and sex-adjusted cumulative incidence of COVID‐19 of 4.9 cases per 1000, significantly lower than that in the general population (6.6 per 1000) [7]. However, in a case series of 6000 IBD patients from France and Italy (including 15 with a confirmed diagnosis of COVID-19),  the cumulative incidence of COVID-19 among IBD patients was 2.5 per 1000, quite similar to that in the general population (1.7 per 1000) [8]. As regards mortality due to COVID-19, among IBD patients from Spain it was similar to that among the general population (OR 0.95, 95% CI 0.84–1.06, p=0.36), but in Italy and France it was lower in IBD patients (no deaths in IBD cases vs 13% in the general population). SARS-CoV-2 may, then, require additional cellular attachment-promoting factors to ensure robust infection of host cells, like in the upper respiratory tract [3].

Clinical characteristics and laboratory and radiological findings of COVID-19 among IBD patients seem broadly to be in line with those in the general population. However, certain characteristics of COVID-19 in patients with IBD remain unclear [9, 10]. Taxonera et al. reported that in almost half of IBD patients (42%), diarrhoea was the presenting symptom and could be misinterpreted as an IBD flare [7]. GI symptoms were less frequent (15%–21%) in other case series of COVID-19 patients with IBD [9, 10].

The overall available evidence suggests that IBD patients do not have an increased risk of developing COVID-19 [3, 10–13]. One possible explanation for this observation is the high adherence of this population to protective measures. However, comorbidities associated with IBD must be taken into consideration [13]. A recent study, based on a large, international registry created to monitor outcomes of IBD patients with confirmed COVID-19 (SECURE-IBD), assessed 555 IBD patients: 161 required hospitalisation (31%), 24 stayed in an ICU (5%) and 21 used a ventilator (4%). Age and ≥2 comorbidities were associated with severe COVID-19 among IBD patients, with odds ratios for a composite outcome of ICU treatment, ventilator support and/or death of 1.04 (95% CI 1.01–1.06) and 2.9 (95% CI 1.1–7.8), respectively [14].

Risk associated with treatment

Another aspect relevant to COVID-19 infection in IBD relates to current therapy, as many patients take immunosuppressants to induce and maintain remission as well as to prevent IBD-associated complications. The use of such compounds has been associated with increased risk of infections as they block intracellular signals needed for the host to fight pathogens. On the other hand, it is noteworthy that suppression of the effector cytokine driven-inflammatory response in IBD (e.g. using cytokine blockers) could be beneficial not only in dampening the ongoing mucosal inflammation but also in preventing COVID-19-driven pneumonia. Indeed, the profile of cytokines documented in patients with severe COVID-19 resembles that seen in the inflamed intestine of IBD patients and during the ‘cytokine storm’ syndrome, a life-threatening condition characterised by hyperactivation of T cells and massive production of interleukin-2, interleukin-6, tumour necrosis factor and interferon-γ [3]. 

Overall, the available evidence suggests that IBD patients should stay on IBD medications, even when there is no evidence of a protective effect against severe pneumonia [7, 15]. Steroids seem to be an exception as they are widely known to increase the risk of opportunistic infections and respiratory infections, including influenza, pneumonia and severe infections, and are associated with an increased risk of hospitalisation and mortality in IBD patients [16]. In a US multicentre study including 232 IBD patients with a COVID diagnosis, the risk of severe COVID-19 was higher in an unadjusted analysis of 71 IBD patients who received corticosteroids up to three months before the diagnosis of COVID-19 (31%) compared to patients who did not receive corticosteroids (19%) (RR 1.60, 95%CI 1.01–2.57, p=0.04) [17].

The SECURE-IBD study revealed that systemic corticosteroids [adjusted odds ratio (aOR) 6.9, 95% CI 2.3–20.5], and sulfasalazine or 5-aminosalicylate use (aOR 3.1, 95% CI 1.3–7.7) were considered as risk factors for severe COVID-19 among IBD patients [14]. On the other hand, TNF antagonist treatment was not associated with severe COVID-19, even when there is no evidence of a protective effect against severe COVID-19 (aOR 0.9, 95% CI 0.4–2.2) [14].

IBD patients should therefore stay on biologic IBD medications during the pandemic. A retrospective study comparing the adherence rate to biologics found that adherence decreased from 84.6% in 2019 to 73.6% during the 2020 COVID-19 crisis [17]. Such non-adherence could have dramatic consequences as it is associated with a higher rate of loss of response to biologic therapy, an increased rate of hospitalisation and increased health care cost.

TAKE HOME MESSAGES

• There is no evidence to suggest that COVID-19 occurs more frequently in IBD patients than in the general population.
• Mortality due to COVID-19 is also similar in IBD patients and the general population and may be influenced by classic comorbidities of IBD.
• Diarrhoea is a major symptom of possible SARS-CoV-2 infection; thus all IBD patients presenting diarrhoea should be tested for SARS-CoV-2 infection during the outbreak.
• Apart from corticosteroids, which should be avoided where possible, IBD patients should stay on IBD medications during the pandemic.

References

1. World Health Organization. WHO Director-General’s opening remarks at the media briefing on Covid-19. March 11, 2020.
2. Coronavirus disease  (COVID-19) Situation Report – 208 Data as received by WHO from national authorities by 10:00 CEST, August 15, 2020.
3. Monteleone G, Ardizzone S. Are patients with inflammatory bowel disease at increased risk for Covid-19 infection? J Crohns Colitis, 2020.
4. Al-Ani A, Rentsch C, Prentice R, et al. Practical management of inflammatory bowel disease patients during the COVID-19 pandemic: expert commentary from the Gastroenterological Society of Australia Inflammatory Bowel Disease faculty. Intern Med J 2020;50:798–804.
5. Queiroz NSF, Barros LL, de Azevedo MFC, et al. Management of inflammatory bowel disease patients in the COVID-19 pandemic era: a Brazilian tertiary referral center guidance. Clinics (Sao Paulo) 2020;75:e1909.
6. Garg M, Royce SG, Tikellis C, et al. Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target? Gut 2020;69:841–51.
7. Taxonera C, Sagastagoitia I, Alba C, et al. 2019 novel coronavirus disease (COVID-19) in patients with inflammatory bowel diseases. Aliment Pharmacol Ther 2020;52:276–83.
8. Allocca M, Fiorino G, Zallot C, et al. Incidence and patterns of COVID-19 among inflammatory bowel disease patients from the Nancy and Milan cohorts. Clin Gastroenterol Hepatol 2020;18:2134–5.
9. Bezzio C, Saibeni S, Variola A, et al. Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study. Gut 2020;69:1213–7.
10. Rodriguez-Lago I, de la Picina PR, Elorza A, et al. Characteristics and prognosis of patients with inflammatory bowel disease during the SARS-CoV-2 pandemic in the Basque Country (Spain). Gastroenterology 2020;159:781–3.
11. Norsa, L., Indriolo A, Sansotta N, et al. Uneventful course in patients with inflammatory bowel disease during the severe acute respiratory syndrome coronavirus 2 outbreak in Northern Italy. Gastroenterology 2020;159:371–2.
12. Mao R, Liang J, Shen J, et al. Implications of COVID-19 for patients with pre-existing digestive diseases. Lancet Gastroenterol Hepatol 2020;5:425–7.
13. Gubatan J, Levitte S, Balabanis T, et al. SARS-CoV-2 testing, prevalence, and predictors of COVID-19 in patients with inflammatory bowel disease in Northern California. Gastroenterology 2020. doi:10.1053/j.gastro.2020.05.009 [Epub ahead of print].
14. Brenner EJ, Ungaro RC, Gearry RB, et al. Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry. Gastroenterology 2020;159:481–91.e3.
15. Al-Ani AH, Prentice RE, Rentsch CA, et al. Review article: prevention, diagnosis and management of COVID-19 in the IBD patient. Aliment Pharmacol Ther 2020;52:54–72.
16. Dorrington AM, Selinger CP, Parkes GC, et al., The historical role and contemporary use of corticosteroids in inflammatory bowel disease. J Crohns Colitis 2020. doi:10.1093/ecco-jcc/jjaa053 [Epub ahead of print].
17. Singh S, Khan A, Chowdhry M, et al. Risk of severe COVID-19 in patients with inflammatory bowel disease in United States. A multicenter research network study. Gastroenterology, 2020. doi: 10.1053/j.gastro.2020.06.003. [Epub ahead of print].