key: cord-0931875-amchklf2 authors: Ungaro, Ryan C.; Kappelman, Michael D.; Rubin, David T.; Colombel, Jean-Frederic title: COVID-19 and Inflammatory Bowel Disease: Lessons Learned, Practical Recommendations, and Unanswered Questions date: 2020-12-30 journal: Gastroenterology DOI: 10.1053/j.gastro.2020.12.042 sha: 3d513e3d98629d19c73fe94d59446048688f6e4e doc_id: 931875 cord_uid: amchklf2 nan Exclusion (SECURE-IBD), in order to collect evidence on how COVID-19 impacted IBD patients. To date, SECURE-IBD has amassed 3,493 cases with outcomes 3 and published initial analyses. [4] [5] [6] In addition, there were multiple articles published with individual or multi-center experiences, city or regional experiences, and many case reports about IBD or immunemediated disease outcomes. [7] [8] [9] [10] [11] [12] [13] [14] Separately, there was significant activity by translational and basic scientists working to define and describe the pathophysiology of SARS-CoV-2 infections. Early reports and expert opinions were necessary to guide the world in their approach to this unprecedented global problem, but the substantial amount of progress made warrants an updated review and discussion. In this commentary we outline the emerging evidence and lessons learned about COVID-19 and the IBD population, enumerate unanswered questions that remain to be addressed, and provide practical recommendations. Initial expert opinion from the IOIBD at the start of the pandemic suggested that IBD patients were likely not at increased risk to contract SARS-CoV-2. Recent evidence has described the J o u r n a l P r e -p r o o f biologic plausibility that IBD patients may have differential risk for contracting SARS-CoV-2 as the receptor for the virus, angiotensin converting enzyme receptor 2 (ACE2), appears to be differentially expressed in inflamed IBD mucosa with upregulation in the colon but downregulation in the small intestine. 15-17 SARS-CoV-2 receptor expression also appears to be impacted by IBD medications, with infliximab notably being associated with decreased ACE2. 17 Recent reports from large cohorts have provided evidence that IBD patients do not appear to be at increased risk of COVID-19. IBD patients in the US Veterans Affairs (VA) healthcare system had a similar incidence of confirmed SARS-CoV-2 compared to the general VA population (0.23% versus 0.20%, p=0.29). 18 Similar results were seen in two European population-based cohorts. The incidence of COVID-19 in patients with IBD in the Netherlands compared to the general population was comparable (287.6 versus 330.0 per 100,000 patients, p=0.15). 19 A population based cohort study from Denmark found that patients with IBD may actually have lower prevalence of SARS-CoV-2 than the general population (2.5% versus 3.7%, p<0.01). 20 Further, patients with IBD receiving immunosuppressive medications do not appear to be at increased risk of contracting COVID-19. 21, 22 Humoral immune response against SARS-Cov2 leads to the production of antibodies of different classes and serological testing is another tool to assess SARS-Cov2 infection prevalence. 23 Studies from Italy and Germany showed a similar SARS-Cov2 seroprevalence in IBD patients treated with biological therapy as in general population. 24 The sum of these data suggests that IBD patients are not at higher risk of contracting SARS-CoV-2 than the general population. However, it is important to note that these findings may be influenced by social behaviors during the pandemic, in particular the potential for patients with IBD to be more likely to "shield" or social distance due to perceived higher risk. J o u r n a l P r e -p r o o f Emerging evidence suggests that when patients with IBD develop COVID-19, the course of illness may be somewhat more severe. The initial report from SECURE-IBD calculated age and sex-standardized mortality ratios (SMRs), comparing patients with IBD reported to the database to general population data reported from China, Italy, and the United States. Observed SMRs varied from 1.45 to 1.76, suggesting a 50% higher COVID-related mortality in patients with IBD; however, these findings were not statistically significant due to 95% confidence intervals crossing one. 4 As of December 6 th , 2020, a total of 3,493 cases have been reported to SECURE-IBD and while the magnitude of the earlier findings remain unchanged, the increased mortality rate is now statistically significant. For example, the U.S. SMR is 1.4 (95% CI 1.1-1.7). Although the observed excess mortality among IBD patients may be due to reporting bias, potential drivers of COVID-19 mortality among IBD patients may include chronic intestinal inflammation, non-IBD comorbidities, and exposure to corticosteroids and other immunosuppressive medications. In contrast, a separate EHR-based study across 31 institutions compared 232 patients with IBD diagnosed with COVID-19 to propensity matched controls without IBD and found no differences in COVID-19 hospitalization or mortality. 25 Among patients with IBD, as in the general population, key risk factors for more severe COVID-19 infection appear to be advancing age and the presence of comorbid conditions. In the initial report from SECURE-IBD, the primary outcome (ICU/ventilator/death) was observed in 37 (7%) of 525 patients overall. However, among patients over 60 years of age 10/101 (20%) experienced this outcome versus 0 of 29 pediatric cases (<20 years). 4 Older age (>65 years) was also demonstrated to be significantly associated with COVID-19 mortality in an Italian multicenter cohort (OR 19.6, 95% CI 2.95-130.6). 8 Additionally, the number of non-IBD comorbidities is also a risk factor for more severe COVID-19. In the same Italian study, having a Charlson J o u r n a l P r e -p r o o f Comorbidity Index >1 was associated with increased mortality (OR 16.7, 95% CI 1.8-153.9). Similarly, a Dutch nationwide cohort study identified >1 comorbidity as an independent risk factor for hospitalization (OR 4.20, 95%CI 1.58-11.17). 19 In SECURE-IBD, having ≥2 comorbidities was associated with 3-fold risk of requiring ICU, ventilator, or death (aOR, 2.9, 95% CI,1.1-7.8). 4 Aside from age and non-IBD comorbidities, associations between other demographic and clinical characteristics (sex, IBD type, IBD disease activity) and the severity of COVID-19 have been inconsistent or relatively small in magnitude. 4, 8, 19 In terms of the risk of IBD medications, current or recent use of systemic corticosteroids to treat IBD at the time of COVID-19 infection has been consistently associated with more severe outcomes, despite emerging data suggesting that dexamethasone use in severe COVID-19 may reduce mortality. 4 Early in the pandemic, it was appreciated that digestive symptoms occurred in some patients with COVID-19, and this has obvious implications for patients with IBD. In the original report of COVID-19 from Wuhan, China, 48% of the hospitalized patients had digestive symptoms, which were most often diarrhea and abdominal pain, although most of these patients also had concurrent respiratory symptoms and fever. 30 Subsequent studies have confirmed these symptoms as well as nausea and vomiting, with the duration of diarrhea (defined differently) varying from 1 to 14 days. [31] [32] [33] The Centers for Disease Control and Prevention subsequently added digestive symptoms of anosmia, diarrhea, nausea and vomiting to the list of presenting symptoms associated with COVID-19. 34 The presence of these symptoms suggested the possibility of viral entry through the intestinal mucosa, further supported by prior research identifying expression of ACE2, the site of viral binding and endocytosis, throughout the intestinal tract. 17 Also of interest is whether the presence of digestive symptoms predicts the severity of COVID-19. A pooled analysis of multiple studies demonstrated that abdominal pain was associated with increased odds of severe COVID-19 (OR 3.93 [95% CI 1.64-9.38]), but there were only marginally increased odds with nausea or vomiting (OR 1.65 [95% CI 1.06-2.57]), and no association with diarrhea. 35 However there are conflicting data as a recent report on hospitalized COVID-19 patients observed that those with digestive symptoms on admission had lower mortality. 36 The question of whether there is fecal-oral transmission of SARS-CoV2 also has not been resolved. Detailed studies of the antibody response to SARS-CoV-2 in patients with IBD will be crucial not only to understanding the immune response to virus with implications for vaccine research but also because of the possibility of emergence of cross-reactive antibodies which could contribute to long term complications of COVID-19. The vast majority of patients with mild-to-moderate COVID-19 experience robust IgG antibody responses against the viral spike protein and have titers that are stable for approximately 5 months which significantly correlate with SARS-CoV-2 neutralization. 37 However, it is still unclear if the humoral response to SARS-CoV-2 will be attenuated in IBD patients. Data from Germany showed a lower seroprevalence of anti-SARS-CoV-2 antibodies in immune-mediated disease patients on cytokine inhibitors compared with general population although this was not confirmed in a recent study in which biological therapy, including vedolizumab, did not prevent the mounting of an efficient humoral response to SARS-CoV2. 9, 24 Longitudinal seroprevalence studies are necessary. Another aspect to consider is whether the virus may impact the host immune response by inducing autoantibodies, triggering cross-reactive antibodies, or altering IgA-microbe interactions in the gut. Studies have highlighted the possibility that COVID-19 could induce pathogenic autoantibody formation both in adult and pediatric patients with severe COVID-19 and in COVID-19 patients who developed neuropathology. 38 These will be important questions to consider as we address the impact of SARS-CoV-2 on IBD. The accumulating evidence suggests that patients with IBD may be at increased risk of adverse outcomes, particularly patients who are older, have comorbidities, or are undergoing treatment with systemic corticosteroids. We advise that patients should continue on prescribed medications with the exception of corticosteroids which should be tapered off or to lowest possible dose. In addition, de-escalation of combination therapy with thiopurine and anti-TNF should be considered in high-risk patients in stable remission. While the association between J o u r n a l P r e -p r o o f severe COVID-19 and mesalamines requires further data, we would recommend limiting their use in situations of low clinical value (Crohn's disease and after escalating to biologic therapy in ulcerative colitis). Given that lack of adverse impact of biologics on COVID-19 outcomes, patients with asymptomatic or mild COVID-19 may be able to either continue or avoid prolonged holding of needed medications. A summary of clinical implications and recommendations is provided in Table 1 . Despite prolific research regarding COVID-19 and IBD over the past six months, several critical research gaps remain. Observations on impact medications such as aminosalicylates from the SECURE-IBD registry should be validated in large population-based cohorts. It will also be critical to understand the degree of immunity and long-term seroprotection to SARS-CoV-2, and how immunity is affected by the inflammatory disease process and by the treatments for IBD. Studies on the impact of COVID-19 on the natural history of IBD and possible emergence of de novo IBD and other immune-mediated diseases clearly are needed. In addition, it will be essential to evaluate vaccine effectiveness and safety among patients with IBD and how these are impacted by the type and degree of immune suppression, given that patients with IBD and other immune mediated conditions have been excluded from clinical vaccine trials. The IBD community has made significant strides in developing an evidence base with which to inform patients and providers during the COVID-19 pandemic. Based on the current literature and this update, we conclude that for the most part, patients with IBD are not at increased risk Mesalamines may be associated with an increased risk of severe COVID-19 We in general would not avoid use of mesalamines but, until further data are available to confirm or refute this observation, recommend avoiding in situations where their efficacy is limited (Crohn's disease and after escalating to a biologic in ulcerative colitis). COVID-19) -World Health Organization Management of Patients With Crohn's Disease and Ulcerative Colitis During the Coronavirus Disease-2019 Pandemic: Results of an International Meeting SECURE-IBD Database But Not TNF Antagonists, Are Associated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an International Registry Effect of IBD medications on COVID-19 outcomes: results from an international registry Benign Evolution of SARS-Cov2 Infections in Children With Inflammatory Bowel Disease: Results From Two International Databases Prevention of COVID-19 in patients with inflammatory bowel disease in Wuhan, China Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion Covid-19 in Immune-Mediated Inflammatory Diseases -Case Series from New York Temporal Improvement of a COVID-19-Positive Crohn's Disease Patient Treated With Bismuth Subsalicylate Management of Acute Severe Ulcerative Colitis in a Pregnant Woman With COVID-19 Infection: A Case Report and Review of the Literature Case Report of a SARS-CoV-2 Infection in a Patient With Ulcerative Colitis on Tofacitinib Pediatric Crohn's Disease and Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19 Treated with Infliximab Age, Inflammation, and Disease Location Are Critical Determinants of Intestinal Expression of SARS-CoV-2 Receptor ACE2 and TMPRSS2 in Inflammatory Bowel Disease Reduced expression of COVID-19 host receptor, ACE2 is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn's disease. medRxiv Intestinal Inflammation Modulates the Expression of ACE2 and TMPRSS2 and Potentially Overlaps With the Pathogenesis of SARS-CoV-2-related Disease Are Patients With Inflammatory Bowel Disease at an Increased Risk of Developing SARS-CoV-2 than Patients Without Inflammatory Bowel Disease? Results From a Nationwide Veterans' Affairs Cohort Study Clinical Outcomes of Covid-19 in Patients with Inflammatory Bowel Disease: A Nationwide Cohort Study Prevalence and outcomes of COVID-19 among patients with inflammatory bowel disease -A Danish prospective population-based cohort study Immunosuppressive Therapy and Risk of COVID-19 Infection in Patients With Inflammatory Bowel Diseases Impact of Anti-Tumor Necrosis Factor and Thiopurine Medications on the Development of COVID-19 in Patients With Inflammatory Bowel Disease: A Nationwide Veterans Administration Cohort Study Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections Seroprevalence of SARS-CoV2 in IBD patients treated with biological therapy Risk of Severe Coronavirus Disease 2019 in Patients With Inflammatory Bowel Disease in the United States: A Multicenter Research Network Study Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry Search of: covid | tofacitinib -List Results -ClinicalTrials.gov. Accessed December 9 Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Digestive Symptoms in COVID-19 Patients With Mild Disease Severity: Clinical Presentation, Stool Viral RNA Testing, and Outcomes Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis Centers for Disease Control and Prevention Gastrointestinal symptoms associated with severity of coronavirus disease 2019 (COVID-19): a pooled analysis Gastrointestinal involvement attenuates COVID-19 severity and mortality. medRxiv Robust neutralizing antibodies to SARS-CoV-2 infection persist for months Do cross-reactive antibodies cause neuropathology in COVID-19?