key: cord-0865984-mscu0xyc
authors: Suria, Carles; Bosca-Watts, Marta M; Navarro, Pablo; Tosca, Joan; Anton, Rosario; Sanahuja, Ana; Revaliente, Marta; Miguel Minguez, M
title: Management of patients with Intestinal Bowel Disease and COVID-19: a review of current evidence and future perspectives
date: 2021-06-23
journal: Gastroenterol Hepatol
DOI: 10.1016/j.gastrohep.2021.06.005
sha: 68b8038c52492254c284155cd2b7bb876464dcdc
doc_id: 865984
cord_uid: mscu0xyc

The COVID-19 pandemic has been a challenge for countries and health professionals worldwide. Viral entry by ACE-2 receptor and an excessive activation of the immune system are key to understand both incidence and severity of disease. Inflammatory Bowel Disease (IBD) represents a special condition associated with an inordinate response of the immune system to external agents. IBD treatments have been associated to an increased risk of bacterial and viral infections. This has raised the question of possible higher incidence and severity of COVID-19 infection in IBD patients. Several papers have been published during this year of pandemic to answer that question. Moreover, COVID-19 vaccination offers great promise in controlling infection in patients with IBD. Based on current evidence, patients with IBD do not have a higher incidence of COVID-19 than the general population, and they do not have worse disease evolution. Advanced age and presence of a greater number of comorbidities have been associated with worse outcomes, similar to the general population. Corticosteroids are associated to an increased risk of COVID-19 infection, higher hospitalization rate and higher risk of severe COVID-19. 5-ASA / Sulfasalazine and Thiopurines have a possible increased risk of severe COVID-19, although studies are lacking. On the other hand, Anti-TNF may have a possible protective effect. It is recommended to maintain the treatment. Anti-IL-12/23, anti-integrins and tofacitinib have results comparable to anti-TNF. Based on the efficacy, expert recommendations, and the absence of other evidence, it is recommended that patients with IBD be vaccinated.

La pandemia por COVID-19 ha supuesto un reto para los países y sus profesionales sanitarios. La entrada viral en el hospedador a través del receptor ACE-2 y una activación excesiva del sistema inmunológico son claves para comprender tanto la incidencia como la gravedad de la enfermedad. La enfermedad inflamatoria intestinal (EII) representa una condición especial asociada con una respuesta descontrolada del sistema inmunológico a agentes externos. Los tratamientos para la EII se han asociado con un mayor riesgo de infecciones bacterianas y virales. Esto ha planteado la cuestión de una posible mayor incidencia y gravedad de la infección por COVID-19 en pacientes con EII. A lo largo de este año se han publicado varios artículos que tratan de responder esa cuestión. La vacunación contra la COVID-19 ofrece una gran promesa para controlar la infección en pacientes con EII. Según la evidencia actual, los pacientes con EII no tienen mayor incidencia de COVID-19 ni peor evolución de la enfermedad en comparación con la población general. La edad avanzada y la presencia de un mayor número de comorbilidades se han asociado con peores resultados. Los corticosteroides están asociados con un mayor riesgo de infección por COVID-19, una mayor tasa de hospitalizaciones y un mayor riesgo de COVID-19 grave. La mesalazina/sulfasalazina y las tiopurinas presentan un posible aumento del riesgo de COVID-19 grave, aunque se requieren más estudios para demostrar esta asociación. Dentro de los fármacos biológicos, los anti-TNF pueden tener un posible efecto protector. Los anti-IL-12/23, anti-integrinas y tofacitinib presentan resultados comparables con anti-TNF. Se recomienda mantener el tratamiento con agentes biológicos. En base a la eficacia, las recomendaciones de los expertos y la ausencia de otra evidencia, se recomienda la vacunación de pacientes con EII. SARS-Cov-2 is introduced into the human host by binding its surface spike glycoprotein (S protein) with the ACE-2 receptor. SARS-Cov-2 is widely distributed in the lower respiratory tract (alveolar type-2 cells). It is also found in myocardial cells, liver cholangiocytes, proximal kidney tubules, urothelial bladder cells, and gastrointestinal epithelial cells (2) (3) . This binding is followed by production of mediators that lead to the activation of cells of the immune system (monocytes/macrophages, neutrophils, effector T cells). Excessive activation may cause the release of a massive cytokine (cytokines storm syndrome) or provoke ARDS, shock, renal failure, and multi-organ failure (4-6). COVID-19 can produce different gastrointestinal symptoms. One early descriptive study in the province of Wuhan, which included 204 patients infected with COVID-19 confirmed by PCR, reported a frequency of digestive symptoms of 50.5%, with the most common being anorexia (78.6%) and diarrhoea (35%). If anorexia was excluded, the reported frequency was 18.6%. It was also observed that patients with digestive symptoms took longer to go to the hospital from the onset of symptoms (7) . Another study analyzed the clinical characteristics of a subgroup of patients with low severity of COVID-19 and digestive symptoms. In these patients, it was more common to present positive viral RNA in faeces, a more significant delay in viral clearance and a greater diagnostic delay for patients with only respiratory symptoms (8) . In patients with a chronic gastrointestinal disease such as IBD (Inflammatory Bowel Disease), the gastrointestinal symptoms of COVID19 (anorexia, diarrhoea, nausea, vomiting, abdominal pain, fever) (7-8), can mimic symptoms of an IBD flare, so a coronavirus infection should be ruled out in some cases. The term Inflammatory Bowel Disease (IBD) includes Ulcerative Colitis (UC), Crohn's Disease (CD) and unclassifiable colitis (IC). (11) (12) (13) . IBD can also include a wide variety of presentations and clinical manifestations. The main characteristic of IBD is that it is a chronic inflammation of the digestive tract, in different locations, of unknown cause, associated to an excessive immune response causing lesions of variable depth and extent in the intestine. It is characterized by a difficult-to-predict evolution in which periods of more active (flares) and less active disease alternate. In many cases it is associated with the development of extraintestinal manifestations, which is why it is considered a systemic immune-mediated disease. This paper will assess the management of patients with IBD and COVID19, review current evidence and explore future perspectives. Responses to the following questions will be sought: Is COVID-19 more common in IBD patients? Is COVID-19 more serious in IBD patients? Is there any treatment for IBD that increases the risk of COVID-19 or its severity?

What are possible future perspectives for the management of IBD patients upon the introduction of the first vaccines?

The risk of transmission of the SARS-CoV-2 depends on the type and duration of exposure, the use of preventive measures and individual factors (15) . In IBD, two aspects are relevant regarding the risk of infection: the patient's intestinal and systemic proinflammatory state, which may make viral entry easier; and the drugs used for the treatment of IBD (corticosteroids, immunomodulators, biologics, Janus-kinase inhibitors ½), which can increase the susceptibility to viral infections (14) . (19) .

Recent evidence suggests that the severity of COVID-19 is related to the excessive activation of the immune system and IBD is associated with an excessive immune response, both at the intestinal and systemic levels. It could be hypothesized that IBD patients may be at increased risk for severe COVID-19.

Individual risk factors for severe COVID19 include advanced age and different comorbidities (cardiovascular disease, hypertension, chronic lung disease, cancer, obesity) (20-23).

In the review and meta-analysis carried out by Muhammad Aziz et al., in the first series of patients with IBD and COVID-19 who reported outcomes, a hospitalization rate of 40.3% was obtained, an ICU admission of 8.6%, the need for mechanical ventilation (invasive / no invasive) of 10.7% and a mortality of 6.4% (17) . Given that they are initial studies and that the diagnostic methods in the first months of the pandemic were not as available, and was mainly used in severe patients, this percentage may be overestimated.

The multinational cohort of Alloca et al., obtained a hospitalization rate of 24%, a pneumonia rate of 22%, an ICU admission rate of 4% and a mortality of 1%. In the multivariate analysis, age> 65 years was associated with an increased risk of pneumonia and hospitalization. The increase in the Charlson comorbidity index was also associated with an increased risk of pneumonia and hospitalization in the univariate analysis. As a limitation, the authors argue the small sample size and the different mortality and incidence rates reported by the different participating countries (18) .

In the case-control study of Lukin et al., a total of 240 patients were included (80 cases and 160 controls). Among the patients admitted for COVID-19 the primary endpoint, a compound rate of ICU admission, intubation or death was comparable in both groups: 23.5% in IBD patients (4 out of the 17 patients admitted with COVID-19 and IBD) and 35.3% in patients without IBD (12 out of the 34 patients admitted with COVID-19 without IBD). In patients with IBD, advanced age was noted to be a risk factor for consultation in the emergency department or hospitalization (19) .

In August 2020, Brenner EJ and Ungaro RC published the first results of the Surveillance 

Treatments used to control inflammation in IBD -corticosteroids, immunosuppressant's and biological agents -have all been noted to have an increased risk of bacterial and viral infections as adverse events, which include pneumonia due to Influenza virus, among others (14) . Therefore, one may conclude that these drugs could increase the risk of COVID-19 or severe COVID-19.

As discussed above, the SECURE-IBD's first outcomes reported a greater risk of severe COVID-19 (primary endpoint) in patients treated with systemic corticosteroids and 5-ASA /Sulfasalazine. It was seen that the use of Anti-TNF was not associated with more severe COVID-19 and even a global protective effect was observed (Odds Ratio 0.9 95% IC (0.37-2.17)). The authors conclude that it is important to obtain the remission of the disease with steroid-sparing treatments and that patients should continue with anti-TNF as maintenance therapy (24) .

In the previous study of the SECURE-IBD registry, the use of anti-TNF monotherapy was compared to the use of thiopurines monotherapy or combined thiopurines and anti-TNF therapy. The last two regimes were associated with an increased risk of severe COVID-19 compared to monotherapy with anti-TNF. The authors suggest discontinuing thiopurines in selected patients (for instance, elderly patients or patients with multiple comorbidities) with stable remission in combination therapy with anti-TNF. On the other hand, the treatment with mesalamine/sulfasalazine was associated with a higher risk of severe COVID-19 than anti-TNF. However, no dose-response association was seen, which is why the authors consider that more studies are needed to reproduce these results and demonstrate biological plausibility to establish a causal relationship. In clinical practice, they recommend not to discontinue treatment except in certain situations with limited benefit (for example Crohn's disease), especially in older patients. Finally, no significant differences were found in the risk of severe COVID-19 with the use of IL-12/23 and the integrin antagonist compared with the use of anti-TNF monotherapy as a reference group (25) .

Similar results to the SECURE-IBD registry were reported in the multinational cohort study performed by Alloca et al. In the multivariate analysis, the use of corticosteroids was associated with a higher hospitalization rate, whereas the use of monoclonal antibodies was associated with a lower risk of hospitalization and pneumonia. Nevertheless, no statistically significant associations were found between the use of immunomodulators, mesalazine, or different therapies in combination with the main outcomes.

There are mixed results regarding the relationship between 5-ASA and COVID-19

outcomes. As mentioned above in SECURE-IBD resgitry treatment with 5-ASA was associated with a higher risk of severe COVID-19 than anti-TNF. Attaubi M et al published the results of two Danish population-based cohort studies demonstrating no association between COVID-19 outcomes and 5-ASA in patients with IBD and other immunemediated inflammatory diseases (26, 27) . More recently they updated their database and made an analysis of 320 patients with IBD to investigate such association. They did not observe any association between COVID-19 outcomes and the use of 5-ASA even after stratifying the results by several factors like type of IBD and dosing of 5-ASA. The authors conclude that further analysis is needed to confirm the association between 5-ASA and COVID-19 related outcomes (28) .

The results of 37 patients with IBD receiving tofacitinib treatment have recently been reported in the SECURE-IBD registry. No differences were found in the outcomes in comparison with other IBD treatments. There was also no increased risk of thromboembolism, a potentially serious complication that can be found in patients with COVID-19 and an adverse effect of treatment with tofacitinib (29) .

In December 2020, the vaccination process of the population began after the approval of the first vaccines by different drug regulatory agencies. In Europe, the first commercialized vaccine was BNT162b2 produced by BioNTech & Pfizer, an RNA vaccine that encodes the complete protein S of SARS-CoV-2 in a lipid nanoparticle. In the Phase 3 trial published in the New England Journal of Medicine, a 95% efficacy seven days after the second dose was reported (30) . ChAdOx1 nCoV-19 (Oxford/AstraZeneca), and mRNA-1273 (Moderna) vaccines reported overall vaccine efficacy of 70.1% and 94.1% respectively (31, 32) . Patients with immunosupressive treatments were excluded from the three trials and therefore important unanswered questions remain, especially in patients with preexisting conditions. There is currently no evidence against vaccinating IBD patients. 

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