key: cord-300963-1n1f8mf2
authors: Gajendran, Mahesh; Perisetti, Abhilash; Aziz, Muhammad; Raghavapuram, Saikiran; Bansal, Pardeep; Tharian, Benjamin; Goyal, Hemant
title: Inflammatory bowel disease amid the COVID-19 pandemic: impact, management strategies, and lessons learned
date: 2020-10-12
journal: Ann Gastroenterol
DOI: 10.20524/aog.2020.0547
sha: 
doc_id: 300963
cord_uid: 1n1f8mf2

The current outbreak of COVID-19 pandemic caused by SARS-CoV-2 has affected nearly 188 countries. Patients with severe COVID-19 are more commonly elderly and suffer from comorbidities such as hypertension, diabetes mellitus, coronary artery disease, chronic pulmonary disease, obesity, and cancer. Inflammatory bowel disease (IBD) affects as many as 6.8 million people globally, and a significant proportion of them are treated with immunosuppressants. Hence, there is an ongoing concern over the impact of COVID-19 on IBD patients and their susceptibility to it. So far, there are about 1439 IBD patients in the Surveillance Epidemiology of Coronavirus under Research Exclusion (SECURE-IBD) registry reported to be infected with SARS-CoV-2. There are many unique challenges and dilemmas that need to be taken into account when managing an IBD patient with COVID-19. The management of each patient should be individualized. The IBD societies and experts have strongly recommended that patients should not discontinue their IBD medications. If the patients have symptoms of COVID-19 or IBD flare-up, they are recommended to call their IBD physician first to discuss their medication. In addition, IBD patients are urged to practice social distancing strictly to minimize the chances of infection. As COVID-19 is rapidly evolving, our experience and understanding of its impact on the IBD population may potentially change in the near future.

The current COVID-19 pandemic, caused by SARS-CoV-2, has affected nearly 185 countries. This outbreak started as an epidemic in Wuhan, China, and has now spread globally. As of July 21, 2020, there were more than 14.7 million confirmed cases worldwide ( Fig. 1) , with a case fatality rate of 3.64% [1]. The United States (US) has now become the worst affected country in the world, with more than 2 million reported cases and a case fatality rate of 5.5% [1] . The data suggest that older adults aged more than 65 years and those with underlying comorbid conditions have a greater risk of severe COVID-19 [2] [3] [4] [5] [6] [7] .

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gastrointestinal (GI) tract that comprises 2 major forms: ulcerative colitis (UC) and Crohn's disease (CD). In this article, we aim to provide an overview of the implications of the COVID-19 pandemic for IBD patients and outline the available guidance for their management. There has been a proactive approach from several international IBD and GI societies, issuing recommendations to minimize the risk of SARS-CoV-2 infection and provide support to IBD patients. Some of these measures include the issuance of expert recommendations for managing patients with IBD during the COVID-19 outbreak, postponement of elective endoscopy and surgeries, provision of personal protective equipment (PPE), and availability of online consultancy by IBD specialists.

The global prevalence of IBD was estimated to be 6.8 million in 2017, with an increase over the last 2 decades [8] . IBD is most commonly diagnosed between the ages of 20 a and 40, and the majority of IBD patients are in the workingage group [9] [10] [11] . IBD patients are known to make greater use of outpatient services, hospital services, endoscopic and surgical services compared with non-IBD controls [12] . Furthermore, a significant proportion of IBD patients are treated with immunosuppressive medications. Hence, there is ongoing concern about the susceptibility of IBD patients to SARS-CoV-2 infection and its impact on them. According to a recent study from northern California, IBD patients did not have a higher rate of SARS-CoV-2 positivity compared with the general population [13] . IBD patients are more frequently assessed with both esophagogastroduodenoscopies (EGDs) and ileocolonoscopies compared with the non-IBD population [14] . The identification of SARS-CoV-2 RNA in the stool of patients with COVID-19 has raised concerns about possible fecal-oral transmission [15] [16] [17] . Furthermore, EGDs pose an increased risk of transmission to healthcare workers, due to their increased exposure to air droplets and saliva during the procedure.

Patients with IBD have a similar life expectancy to the general population, but infections are overrepresented as a cause of death in the IBD patient population [11, 18] . Most of these infection-related deaths in IBD patients are related to the complications of severe underlying IBD itself, such as intra-abdominal sepsis, but non-disease-related infections are also responsible for a significant number of deaths [19] . In a large retrospective database-based study of 140,480 patients with IBD and non-IBD controls, IBD patients had a 1.5 times greater risk of influenza infection compared with non-IBD patients (95% confidence interval [CI] 1. 49-1.63) [20] . In that study, the use of corticosteroids was found to be independently associated with an increased risk of influenza (odds ratio [OR] 1.22, 95%CI 1.08-1.38) [20] .

SARS-CoV-2 is a positive-sense ribonucleic acid (RNA) virus that consists of a nucleocapsid core with nucleoprotein (N) and 3 membrane proteins: spike glycoprotein (S), membrane protein (M), and envelope small membrane protein (E) [21] . The viral surface membrane proteins facilitate embedding in the cell membrane of host cells, and N proteins play an essential role in replication and RNA packaging [22] . Angiotensin-converting enzyme 2 (ACE2) has been identified as the receptor for SARS-CoV-2 to enter epithelial cells, in a similar fashion to SARS-CoV-1 [23] .

SARS-CoV-2 is mainly spread through direct exposure (droplet, person to person), and it is also presumed to spread through indirect contact (contaminated objects, airborne transmission) [15] . A recent study found that SARS-CoV-2 was viable and infectious in aerosols for 3 or more hours and on surfaces for up to 2 days [24] . It is essential to consider the potential transmission via aerosol when performing aerosolgenerating procedures such as EGD, endotracheal intubation, noninvasive ventilation, bag-valve-mask ventilation, the suction of GI secretions, nebulizer treatment and insertion of a nasogastric tube. In a study by Xiao et al, SARS-CoV-2 RNA was detected in the stool in 53% of the patients hospitalized with COVID-19, raising concerns about potential fecal-oral transmission [17] .

In humans, the ACE2 receptor is highly expressed in the GI system, including the upper esophagus, duodenum, jejunum, ileum, and colon [14, 23] . The ACE2 surface receptor directly interacts with the spike glycoprotein (S protein) of the coronavirus, which results in the entry of the virus into the cells (Fig. 2) and induces the reproduction of new virions intracellularly [25, 26] . Hence, the detection of viral RNA in the feces suggests that the infectious virions are secreted from the virus-infected GI cells [17] . It is still uncertain whether the presence of active bowel inflammation would increase the risk of SARS-CoV-2 infection. In a study by Wang et al (preprint) , RNA sequencing data from the patients with IBD showed that ACE2 expression in the colonocytes was positively associated with viral entry, but negatively associated with viral transcription and protein translation [27] . Hence, the authors concluded that ACE2 expression might play a dual role in mediating the susceptibility and immunity to SARS-CoV-2 infection [27] .

The overall detection rate of SARS-CoV-2 RNA in stool specimens has been reported to be in the range of 53-55% [16, 17] . A recent study by Zhao et al showed that about 44% of COVID-19 patients had positive rectal swabs for SARS-CoV-2 RNA at 1 week after illness onset, which decreased in weeks 2-7 to 30%, 16.7%, 12.3%, 12.3%, 5.2%, and 0.8% respectively [28] . The authors also observed that the SARS-CoV-2 RNA in fecal samples remained for an unexpected longer duration of time at a higher viral load than the paired respiratory samples [28] .

The duration of positive stool ranges from 1 to 43 days, and more than 20% of patients have positive stool RNA even after the negative conversion of the viral RNA in the respiratory tract [16, 17, 28] . In a study by Santarpia et al (preprint) , samples from the toilets in the infected patient room were positive in 81% of the rooms, with a mean concentration of 0.252 copies/µL, suggesting viral shedding during toileting [15] . The endoscopic examination in these patients with positive stool RNA showed normal mucosa with no significant damage to mucous epithelium with hematoxylin and eosin staining. However, numerous plasma cells and lymphocytes with interstitial edema were found in the lamina propria of the stomach, duodenum, and rectum. Most importantly, patients who had positive SARS-CoV-2 in the stool also tested positive for ACE2 and SARS-CoV-2 viral nucleocapsid protein staining in the glandular cells of the GI epithelium [17] . These findings, along with the unremarkable endoscopic findings in infected patients, are reminiscent of SARS-CoV-1 tropism to the intestinal epithelium [29] .

Innate immunity appears to play a vital role in combatting against SARS-CoV-2 infection, but only limited data are available so far. In a study by Chen et al, among 99 patients with COVID-19 pneumonia, 38% had a high neutrophil count, 35% had low lymphocytes, and 84% had elevated C-reactive protein [30] . In a prospective study by Huang et al, among 41 hospitalized COVID-19 patients, patients admitted to the intensive care unit (ICU) were found to have higher neutrophil and lower lymphocyte levels compared with non-ICU patients [31] . The patients in the ICU group were also found to have higher plasma levels of many innate cytokines, including IP-10, MCP-1, MIP-1A, and tumor necrosis factor (TNF)-α. These findings suggest that a "cytokine storm" mediates disease severity in patients who have severe COVID-19, similarly to those with SARS-CoV-1 or MERS-CoV infection [32, 33] . Previous studies based on SARS-CoV-1 showed that the "cytokine storm" was strongly associated with viral sepsis, inflammation-induced lung injury, and acute respiratory distress syndrome (ARDS) [32, 34] . TNF-α plays a vital role across key points of the cytokine cascade of the "cytokine storm" syndrome [35] . Anti-TNF therapy has been shown to significantly reduce levels of cytokines and inflammatory markers in animal studies, with a significant reduction in mortality [36] [37] [38] . However, in previous clinical trials, the use of TNF-α antibodies did not show any mortality benefit in patients with severe sepsis [39, 40] . Currently, there is an ongoing trial to study the efficacy of anti-interleukin (IL) drugs (anakinra, tocilizumab, siltuximab) in halting the cytokine storm and thereby preventing the progression from cytokine release syndrome to ARDS and multi-organ system failure [41] . Innate immunity against viral infection is dependent on the interferon (IFN) type I responses and its downstream cascade, which restricts the viral replication and induces an adaptive immune response [42] . To mount an antiviral response, invasion of the virus should be first recognized by the innate immune cells via pathogen-associated molecular patterns (PAMPs) [42] . For coronaviruses, viral RNA or the intermediates during viral replication, such as dsRNA, function as PAMPs. They are recognized by pattern recognition receptors such as TLR3/TLR7 and the cytosolic RNA sensor, RIG-I/MDA5 [42, 43] . This recognition event activates the downstream signaling cascade, resulting in the expression of type I IFN and other proinflammatory cytokines, the first line of defense against the virus [44] . SARS-CoV-1 and MERS-CoV were known to utilize dampening strategies to suppress the type 1 INF response, closely associated with disease severity [45] . Given the close similarity of SARS-CoV-2 to SARS-CoV-1, it has been speculated that SARS-CoV-2 could be employing similar strategies to evade innate immunity and also may have additional novel mechanisms [42] .

Humoral immunity SARS-CoV-2 infection has a significant impact on both humoral and cellular immunity. Humoral immunity is responsible for antibody production with protection against future infection. In a study by Zhou et al, serology from 7 patients with severe COVID-19 pneumonia showed a peak in IgM at day nine after disease onset and a switch to IgG by week 2 [46] . A similar pattern of antibody production was also seen against the SARS-CoV-1 infection. The IgM antibodies are the first-line antibodies during the acute or early convalescent period, while IgG antibodies are antigen-specific antibodies that peak at week 12 and are supposed to be protective against future infection [47] .

Helper T cells play an essential role in the overall adaptive response, with cytotoxic T cells involved in the killing of the infected cells. The cytokine response generated by the antigenpresenting cells orchestrates the initial T cell response. Patients with COVID-19 were found to have a significant reduction in their peripheral CD4 + and CD8 + T cells, but these cells had a hyperactive status, as evidenced by high proportions of HLA-DR and CD38 double-positive fractions [48] .

So far, there is no evidence to suggest that SARS-CoV-2 infection occurs more frequently in IBD patients compared with non-IBD individuals [13, 49] . Nor is there any known difference between CD and UC in terms of infection risk. It is still uncertain whether the presence of active bowel inflammation would increase the risk of SARS-CoV-2 infection. Similar to the general population, IBD patients are at increased risk of infection if they travel to high-risk regions and if they have had close contact with a COVID-19 patient. With regard to IBD-specific risk factors, it is speculated that patients on immunosuppressive agents, those with active IBD symptoms, malnutrition, and frequent visits to clinics or hospitals are at greater risk of acquiring SARS-CoV-2 infection [50] . In an Italian study of 79 IBD patients, the risk factors associated with COVID-19-related mortality included age >65 years (OR 19.6, 95%CI 2.95-130.6), Charlson comorbidity index >1 (OR 16.6, 95%CI 1.80-153.9), and active IBD (OR 8.5, 95%CI 1.26-56.56) [51] . Table 1 outlines the risk factors for COVID-19 infection and poor outcomes [2] [3] [4] 7, 13, 51] . Recent evidence suggests that the use of proton pump inhibitors is associated with an increased risk of SARS-CoV-2 infection and also potentially increases the risk of poor outcomes, such as death and mechanical ventilation [52, 53] .

The International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) maintains a registry for reporting COVID-19 in IBD patients called SECURE-IBD registry. Using the SECURE-IBD database, IBD physicians can report confirmed cases of COVID-19 in their IBD patients, regardless of severity, including the asymptomatic patients detected through public health screening [54] . As of June 14 th , 2020, there were 1439 IBD patients reported to be infected with COVID-19 ( Fig. 1) in the SECURE-IBD database globally [54] . Table 2 summarizes the latest data from the SECURE-IBD database as of June 14 th , 2020. Brenner et al published the data from the SECURE-IBD registry with 525 reported cases; currently, 1439 cases have been reported. Based on that study, among the 525 cases reported from 33 countries, 31% were hospitalized, 7% had severe COVID-19, and 3% of the patients died [55] .

The most common symptoms in COVID-19 are fever and respiratory symptoms, followed by GI symptoms such as diarrhea, vomiting, anorexia, dysgeusia, and abdominal pain [4, [56] [57] [58] [59] . Based on the SECURE-IBD registry-based study, about 30% of the patients reported an increase in baseline IBD symptoms [55] . Among the IBD patients, diarrhea was the most common symptom (25.5%), followed by abdominal pain (8.4%), nausea (5.7%), and vomiting (3.2%) [55] . In contrast, among non-IBD patients, studies have reported diarrhea in 2-10%, nausea or vomiting in 1-10% and abdominal pain in 2.2-5.8% [60] [61] [62] . The diagnosis of IBD flare-up is challenging in the context of COVID-19, as the typical presenting features of IBD, such as diarrhea, abdominal pain and fever, along with elevated inflammatory markers, may also be secondary to COVID-19 [63, 64] . However, rectal bleeding is not common in COVID-19 [63] . Laboratory tests such as C-reactive protein and ferritin are elevated in both conditions, although occasionally ferritin can be low in UC. Patients with COVID-19 have lymphopenia, whereas in IBD patients, lymphocyte levels are usually normal or elevated. The red blood cell distribution width index has been found to be elevated in nearly half of patients with COVID-19 and has been found to be associated with an increased risk of in-hospital mortality (adjusted OR [aOR] 4.5, 95%CI 1. 4-14. 3) and septic shock (aOR 4.6, 95%CI 1.4-15.1) [65] . In all cases, standard stool tests, such as stool culture and stool Clostridium difficile (C. difficile) toxin, should also be performed. For patients with severe GI symptoms, abdominal computed tomography or endoscopic evaluation should be considered to assess the bowel inflammation to determine appropriate management.

Based on recommendations from the IBD societies, nonimmunosuppressive medications such as 5-aminosalicylates ([5-ASA], mesalamine) and locally acting steroids • Age >65 years [2, 3] • Cardiovascular disease [2] • Chronic pulmonary disease [2] • Males [2] • Hypertension [2] • Diabetes mellitus [2] • Obesity [2] • Cancer [103] • On corticosteroids, especially prednisone ≥20 mg per day [84, 51] • Active IBD [84, 51] [66, 67] . Surprisingly, the study from the SECURE-IBD registry observed that patients on 5-ASA/sulfasalazine treatment had 3 times as great a risk (aOR 3.1, 95%CI 1.3-7.7) of poor outcomes such as ICU admission, mechanical ventilation or death [55] . This finding persisted even after controlling for age, comorbidities, IBD disease characteristics, corticosteroid use, and other factors. Furthermore, in a direct comparison, patients treated with 5-ASA/sulfasalazine had worse outcomes than those treated with TNF inhibitors [55] . Further studies are needed to confirm whether this association is real and to explore the biological mechanisms that may contribute to these poor outcomes.

Prednisone at doses of more than 20 mg per day impairs the immune response [66] [67] [68] . Corticosteroids affect the immune system via multiple mechanisms, including inhibition of adhesion molecules, inducing apoptosis of activated lymphocyte, and decreasing the expression of inflammatory cytokines [69] . Based on a large international registry-based study, among IBD patients, those on systemic corticosteroids had 6.9 times (aOR 6.9, 95%CI 2.3-20.5) greater odds of a poor outcome such as ICU care, mechanical ventilation or death [55] . Studies based on MERS and SARS-CoV-1 have reported delayed viral clearance in patients receiving highdose corticosteroids [70] . The use of short-term steroids for the treatment of ARDS and hyper-inflammation in COVID-19 is controversial. One study by Wu et al showed that in COVID-19 patients with ARDS, treatment with methylprednisolone decreased the risk of mortality by 62% (hazard ratio 0.38, 95%CI 0.20-0.72) [71] .

Immunomodulators, such as azathioprine, 6-mercaptopurine (6-MP) and methotrexate, inhibit the body's immune response to viral infections. Azathioprine and 6-MP interfere with DNA and RNA synthesis, thereby inhibiting the proliferation of T-and B-lymphocytes [72] . Overall, the thiopurines can reduce the number of activated T cells and also affect T-cell function [70] . Methotrexate inhibits DNA synthesis, repair and cellular replication by interfering with folate metabolism [73] . Hence, actively proliferating cells are more susceptible to the effects of methotrexate. There are no data currently available on how the changes in the immune system by these immunomodulatory medications affect the course of IBD patients with COVID-19.

Biologics are the key immunosuppressive medication group used in the management of IBD. These medications include infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, and vedolizumab. Activated macrophages and T-cells secrete TNF, which plays an integral role in cellmediated immunity [74] . TNF-α plays a vital role in inducing bowel inflammation by induction of ILs, facilitating leukocyte migration, activation of neutrophils, and the induction of acute-phase reactants. Thus, TNF inhibitors are very effective against the heightened inflammatory response seen in IBD. However, this impacts the effectiveness of the host immune system response against infectious organisms, especially intracellular pathogens, such as mycobacteria, fungi and viral infections [75] . In a study by Brenner et al, no association was found between TNF inhibitor use and severe COVID-19 [55] . In a prospective study of 65 IBD patients from the University of Miami, the use of TNF inhibitors such as vedolizumab and ustekinumab was associated with lower expression of ACE2 in CD11b-enriched cells [76] . Elevated serum TNF-α levels have been observed in patients with COVID-19 infection, and were positively correlated with disease severity. Even though anti-TNF treatment was explored as a potential treatment for COVID-19, there are no sufficient data to date [77] . Tocilizumab, an IL-6 inhibitor, is currently under investigation for cytokine release syndrome triggered by COVID-19 [78] .

Tofacitinib is an FDA-approved JAK inhibitor for the treatment of moderate-to-severe UC in patients who are refractory to biologic agents. JAK inhibitors are smaller sized molecules, with a rapid onset of action, that cause immunosuppression by blocking multiple pathways of inflammation to control the inflammation of the intestines. In a New York-based study on COVID-19 patients receiving JAK inhibitors for underlying inflammatory disorders, there was no increase in the rate of hospitalizations [79] . However, it is important to consider the higher risk of blood clots in patients on tofacitinib treatment, since COVID-19 infection is strongly associated with hypercoagulability and venous thromboembolism in up to one third of patients with severe infection [80, 81] . Interestingly, another JAK inhibitor, baricitinib, is being explored as a potential medication in the management of SARS-CoV-2 infection through its inhibitory action on Numb-associated kinase (NAK), involved in the endocytosis of SARS-CoV-2 [77] . Tofacitinib does not inhibit NAK.

Cyclosporine A is used in severe steroid-refractory UC patients. It is a polypeptide that suppresses T cell by inhibiting transcription of genes encoding IL-2 [82] . The primary molecular target of cyclosporine is a cytosolic binding protein called cyclophilin, also required by many viruses for replication, including the coronaviruses. It has been speculated that patients on cyclosporine treatment during the COVID-19 pandemic may experience a beneficial effect [83] . So far, no study has reported any benefits or risks of cyclosporine with COVID-19.

The care of the IBD patients has to be individualized based on whether the patient is infected with SARS-CoV-2, has symptomatic manifestations of COVID-19 and shows underlying activity of the IBD. We are still in the phase where studies are being actively published; this will soon help us determine the outcomes in IBD patients, and will also give a better objective measure of which recommendations can be followed and what needs to change. However, as of now, we are still largely dependent on anecdotal evidence, expert opinion and guidance from the societies to manage IBD patients during this current pandemic (Fig. 3) . The societies that have issued guidance include the American Gastroenterological Association (AGA), the British Society of Gastroenterology (BSG), Crohn's and Colitis Canada, the European Crohn's and Colitis Organization, and the IOIBD [67, [84] [85] [86] .

The current evidence shows that IBD patients are not at a higher risk of developing SARS-CoV-2 infection compared with non-IBD patients [13, 66] . Hence, all the societies have recommended that patients continue their IBD medications to sustain remission, because the risk of disease flare-up outweighs the chance of contracting SARS-CoV-2 infection. Furthermore, a relapse in IBD may require steroid therapy or hospitalization, known risk factors for SARS-CoV-2 infection [67] . The emphasis should be on enforcing preventive strategies, such as social distancing and hand hygiene, and to avoid contact with infected individuals [66] . The BSG has categorized IBD patients into 3 categories based on their medications (Table 3 ) [84] . The patients in the highest-risk group have been recommended to practice "shielding", the most stringent version of isolation. The patients in the moderate risk group should follow "stringent social distancing", and those in the lowest risk group should follow "social distancing" practices. In a study published from Wuhan, proactive measures were taken by the medical team by sending educational materials and instructions on COVID-19 prevention to all registered IBD patients (N=318). By enforcing these preventive measures, they were able to achieve a "zero infection" rate among their IBD patients [87] . Another concern was the risk of SARS-CoV-2 infection among IBD patients who are on infusion therapies such as infliximab, vedolizumab and ustekinumab, for which the patients need to go to the infusion centers. However, the consensus statement from the IOIBD recommended continuing infusions in an infusion center, as long as the infusion centers have protocols to screen for COVID-19 exposure and symptoms, including fever checks at the door [66] . It is also recommended that the infusion centers provide a minimum of 2-meter spacing between patients' chairs, provide the patients with gloves, ensure mask and glove use by the providers, and carry out adequate deep cleaning after the patient's departure [67] . Other strategies cited by other societies include moving infusion centers to "clean sites" in order to keep IBD patients away from centers that admit or review patients with COVID-19.

As the testing capability of SARS-CoV-2 becomes widespread, we will encounter patients who are asymptomatic but have had a positive test for SARS-CoV-2 infection. These patients should be closely monitored for the development of COVID-19 for at least 2 weeks. It has been recommended that 5-ASA medications be continued in these patients, but it is unclear why patients on 5-ASA had poor outcomes in the SECURE-IBD study (Table 4 ) [55, 88] . For patients on prednisone, it should be tapered off if feasible, but if this is not possible, then at least the dose should be reduced below 20 mg/d or transitioned to budesonide [67] . Immunosuppressive medications, such as azathioprine, 6-mercaptopurine and methotrexate, should be stopped temporarily [88] . For monoclonal antibody therapies, such as anti-TNF agents, ustekinumab and vedolizumab, the dosing should be delayed for 2 weeks and can be resumed after 2 weeks if the patient has not developed symptoms of COVID-19 [67] . The current approach to monitoring these patients could change with the development of point-of-care tests and serologic antibodies [89] .

There are many unique challenges and dilemmas that need to be taken into account when managing an IBD patient with COVID-19. The management strategy will depend on multiple factors, such as the patient's age, the severity of the COVID-19 infection, the clinical status of the IBD, and the presence of other comorbid conditions. The management of these patients should be individualized, with a 2-pronged approach to manage both COVID-19 and IBD. Adjustment to IBD medications is mainly focused on reducing the level of immunosuppression during active COVID-19, with the goal of preventing complications. Table 4 outlines the critical medication management recommendations from the IOIBD expert panel consensus [66] .

In terms of IBD medications, it is safe to continue nonimmunosuppressive medications, such as topical, rectal therapy and antibiotics [67] . Oral budesonide or beclomethasone may be safely continued to maintain remission. However, if the patient is on systemic corticosteroids, such as prednisone, it should be tapered quickly whenever possible, because of concerns over the immunosuppressive effect of steroids, which could increase the risk of severe infection [55, 90, 91] . In addition, observational studies from past epidemics (SARS-CoV-1, MERS-CoV) showed delayed clearance of viral RNA in patients on corticosteroid therapy [92, 93] . The COVID-19 should be treated with supportive care, and self-quarantine until the symptoms resolve. Patients should be encouraged to contact their healthcare provider by phone for guidance about clinical management. Telemedicine should be utilized in such patients to minimize the spread of infection.

In patients with active GI symptoms suggestive of IBD flare-up, the workup should be targeted to find the cause for the relapse. The stool should be tested for C. difficile and other enteric pathogens. The presence of active inflammation can be assessed by testing C-reactive protein, fecal calprotectin or cross-sectional imaging. According to Joint GI society recommendations, endoscopic procedures should be reserved only for urgent and emergent indications during the COVID-19 pandemic [66] . For mildly active disease, nonimmunosuppressive medications can be used. For moderate to severe disease, the risks and benefits of escalating IBD therapy must be carefully weighed against the severity of the COVID-19 [67] . If the patient has only mild COVID-19, then the IBD flare-up should be treated similarly to the treatment that would have been considered before the pandemic. However, it is still essential to avoid or limit the use of corticosteroids, given their association with poor outcomes. In patients hospitalized for severe IBD who have mild COVID-19, intravenous steroids should be limited to 3 days, and consideration should be given to the use of either infliximab or a calcineurin inhibitor for induction of remission [67] .

In patients hospitalized for severe COVID-19, the priority should be given to the treatment of the COVID-19. In patients presenting with severe COVID-19 along with severe IBD flare-up, the management becomes challenging. Severe IBD, such as acute severe UC (ASUC), is typically managed with high-dose parenteral corticosteroids [94] . If these patients fail to respond adequately, then they are treated with rescue therapy, such as infliximab, along with steroids [94] . According to the RAND appropriateness panel on the management of ASUC in patients with COVID-19 pneumonia, there was uncertainty among the panel regarding the first-line therapy [95] . However, among all the suggested treatments, intravenous steroids were given the highest score by the panel. At that time, the results from the RECOVERY trial were not available [96] . In the RECOVERY trial, the dexamethasone group had a lower mortality rate compared with the usual care group in patients receiving mechanical ventilation (29.3% vs. 41.4%; rate ratio 0.64, 95%CI 0.51-0.81) and among those on supplemental oxygen (23.3% vs. 26.2%; rate ratio 0.82, 95%CI 0.72-0.94) [96] . The dose of dexamethasone used in the RECOVERY trial was 6 mg q.d. for 10 days. The usual intravenous steroids used in ASUC include methylprednisolone (20 mg t.i.d.) or hydrocortisone (100 mg t.i.d.) [97] . Dexamethasone at a 6 mg dose is equivalent to 32 mg of methylprednisolone or 160 mg of hydrocortisone [98] . In addition, dexamethasone is long-acting (26-72 h), whereas methylprednisolone and hydrocortisone last for 8-12 h [98] . Finally, if the patient fails to improve despite rescue therapy or develops complications, then surgical intervention should be undertaken. It was deemed inappropriate to delay surgery, even in patients with COVID-19 pneumonia.

Multiple societies have recommended suspending all routine non-urgent endoscopic procedures during the COVID-19 pandemic [58] . Hence, only urgent and emergent endoscopic procedures are being done currently, which could potentially change a patient's management. Some of the clinical scenarios that would need an endoscopic procedure are the new diagnosis of severe IBD, which needs tissue diagnosis for confirmation of diagnosis, to rule out cytomegalovirus infection in cases where a serum polymerase chain reaction was inconclusive, and when cancer is suspected [99] . The AGA recommends the uses of N95 (or N99 or PAPR) masks and double gloving as a part of PPE for the healthcare worker performing the endoscopic examination, regardless of the COVID-19 status [58, 100] .

COVID-19 is the latest threat to global health; it has developed into a public health emergency and is a reminder of the ongoing challenge of emerging infectious pathogens. The most important question is how to modify the medication regimen in IBD patients with SARS-CoV-2 infection, without increasing the risk of complications from either the COVID-19 or the IBD itself. The data published so far have been reassuring and do not appear to indicate that IBD patients are at greater risk or severe COVID-19 compared with the general population. Most of the guidelines have reinforced the importance of avoiding systemic corticosteroids for managing IBD and maintaining remission by recommending compliance with maintenance medications. If an IBD patient does develop COVID-19, it is important for them to immediately contact the IBD physicians to determine whether to continue the immunosuppressive medications or withhold them until infection resolution. It is essential for the IBD community, including the patient, physicians and advanced practice providers, to recommend and implement stringent prevention strategies. As the SARS-CoV-2 virus is rapidly evolving, our experience and understanding of its impact on the IBD population may potentially change in the near future.

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ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism

The time sequences of oral and fecal viral shedding of coronavirus disease 2019 (COVID-19) patients

Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile

Lung pathology of fatal severe acute respiratory syndrome

Could patients with inflammatory bowel disease treated with immunomodulators or biologics be at lower risk for severe forms of covid-19? Gastroenterology

Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-α polyclonal antibody

Anti-TNFalpha therapy improves survival and ameliorates the pathophysiologic sequelae in acute pancreatitis in the rat

Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis

Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, doubleblind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group

Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-α fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: randomized, double-blind, placebo-controlled phase IIb study*

Treatment of COVID-19 patients with anti-interleukin drugs (COV-AID)

Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic

Molecular immune pathogenesis and diagnosis of COVID-19

SARS and MERS: recent insights into emerging coronaviruses

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Profile of specific antibodies to the SARSassociated coronavirus

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Are patients with inflammatory bowel disease at increased risk for Covid-19 infection?

Chinese IBD Quality Care Evaluation Center Committee. Implications of COVID-19 for patients with pre-existing digestive diseases

Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD). Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study

Increased risk of COVID-19 among users of proton pump inhibitors (preprint)

Prehospitalization proton pump inhibitor (PPI) use and clinical outcomes in COVID-19. medRxiv

SECURE-IBD Database Public Data Update

but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry

COVID-19 presenting as acute pancreatitis

Taste changes (dysgeusia) in COVID-19: a systematic review and metaanalysis

COVID-19 and gastrointestinal endoscopies: current insights and emergent strategies

Putative mechanisms of diarrhea in COVID-19

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Covid-19 and the digestive system

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China

Endoscopy in inflammatory bowel diseases during the COVID-19 pandemic and post-pandemic period

Gastrointestinal symptoms and outcomes in hospitalized coronavirus disease 2019 patients

Red blood cell distribution width (RDW) in hospitalized COVID-19 patients

IOIBD update on COVID19 for patients with Crohn's disease and ulcerative colitis

AGA clinical practice update on management of inflammatory bowel disease during the covid-19 pandemic: expert commentary

IDSA clinical practice guideline for vaccination of the immunocompromised host

The molecular complexity of glucocorticoid actions in inflammation -a four-ring circus

COVID-19 and immunomodulation in IBD

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

In book: Immunotherapy in transplantation

The clinical pharmacology of methotrexate: new applications of an old drug

Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis

Role of tumor necrosis factoralpha in Mycobacterium-induced granuloma formation in tumor necrosis factor-alpha-deficient mice

Expression of SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in the gut of patients with IBD

COVID-19: combining antiviral and anti-inflammatory treatments

Tocilizumab vs CRRT in management of cytokine release syndrome (CRS) in COVID-19 (TACOS)

Covid-19 in immunemediated inflammatory diseases -case series from New York

Drug safety communication -due to an increased risk of blood clots and death with higher dose

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

The role of interleukin-2 during homeostasis and activation of the immune system

Covid-19 infection in psoriasis patients treated with cyclosporin

BSG expanded consensus advice for the management of IBD during the COVID-19 pandemic

COVID-19 AND IBD

COVID-19 ECCO Task Force

Protection of 318 inflammatory bowel disease patients from the outbreak and rapid spread of COVID-19 infection in Wuhan, China

International Organization for the Study of Inflammatory Bowel Disease. Management of patients with Crohn's disease and ulcerative colitis during the coronavirus disease-2019 pandemic: results of an international meeting

Molecular and antibody point-of-care tests to support the screening, diagnosis and monitoring of COVID-19. Oxford COVID-19 Evidence Service 2020

SARS: systematic review of treatment effects

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients

Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome

British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults

Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel

Dexamethasone in hospitalized patients with Covid-19-preliminary report

A comprehensive review and update on ulcerative colitis

Potency and duration of action of glucocorticoids: effects of hydrocortisone, prednisone and dexamethasone on human pituitary-adrenal function

Gastroenterology professional society guidance on endoscopic procedures during the COVID-19 pandemic

AGA Institute. Electronic address: ewilson@gastro.org. AGA Rapid Recommendations for Gastrointestinal Procedures During the COVID-19 Pandemic

The outbreak of COVID-19: An overview

Characteristics of and important lessons from the Coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for disease control and prevention

Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China