key: cord-0991227-lkwl1ufq authors: Rubin, David T.; Abreu, Maria T.; Rai, Victoria; Siegel, Corey A. title: Management of Patients with Crohn’s Disease and Ulcerative Colitis During the COVID-19 Pandemic: Results of an International Meeting date: 2020-04-06 journal: Gastroenterology DOI: 10.1053/j.gastro.2020.04.002 sha: f865183b9f899559275622eacdf6567081023c21 doc_id: 991227 cord_uid: lkwl1ufq nan The International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) is the only global organization devoted to the study of and management of the inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis (UC). Membership is composed of physician-scientists who have established expertise in these diseases, and the organization hosts an annual meeting and a number of working groups addressing issues of the epidemiology of IBD, diet and nutrition, and the development and utilization of treatments for IBD. There are currently 89 members of IOIBD representing 26 different countries. The organization has taken particular interest in the COVID-19 pandemic and how it may affect the IBD patient population. This document summarizes the results of two recent virtual meetings of the group and subsequent expert guidance for patients and providers. In December 2019, health officials in Wuhan, China described a series of unexplained pneumonias and shortly thereafter identified the causative agent as a novel coronavirus (named SARS-CoV-2). It is believed that SARS-CoV-2 entered the human population from animals and that the exposure may have been a live food market in that province of China. SARS-CoV-2 can result in a mild or severe respiratory illness called the 2019 coronavirus disease . COVID-19 rapidly spread throughout the world and on March 11, 2020 the World Health Organization declared it a pandemic. 1 At the time of this writing, it has affected over 800,000 people worldwide, and accounted for over 38,700 deaths, and these numbers continue to rise sharply. 2 COVID-19 has now been reported to affect individuals of all ages, with a slight predominance in men. Mortality from COVID-19 is estimated variably from 1.5% to as high as 3%, with identified risk factors of older age and co-morbid illnesses including hypertension, diabetes and other cardiovascular diseases. The risk of COVID-19 or death from COVID-19 in patients treated for immune-mediated diseases is unknown at this time, but it has been presumed that patients who are immunosuppressed are at higher risk for infection with SARS-CoV-2, and may be at increased risk for COVID-19. Treatment of IBD is aimed at controlling an overactive immune response, and currently involves utilization of a number of well-studied classes of immune modifying therapies (Supplemental Table 1 ). Many of these treatments are associated with known increased risks of infections, so the IBD population has been considered an at-risk population for infection with SARS-CoV-2. However, the actual risks of infection or of development of COVID-19 in IBD patients are not known, nor are the appropriate adjustments to treatments to mitigate such risks or reduce complications from the disease. The 2020 annual meeting for IOIBD was scheduled to occur in March but was cancelled due to the emergence of COVID-19. Given how this disease might affect IBD patients and the absence of data, members of the organization recognized the need for rapid international collaboration and held two IBD-COVID-19 webinars, the details of which are summarized here. The overall goal of these webinars was to develop a number of key statements that could be used to guide the management of patients with IBD during this pandemic. Using RAND panel methodology all IOIBD members and selected content experts were asked to participate in a survey prior to the first webinar that included statements related to risks of SARS-CoV-2 and COVID-19 in IBD patients, as well as statements related to disease management under a variety of clinical scenarios. During the first webinar, held on March 20, 2020, IOIBD members shared their direct experiences with COVID-19 in the epicenters of China and Italy (Zhihua Ran and Silvio Danese, respectively), followed by information about the successful population-wide response in Hong Kong (Siew Ng). Also discussed was the organization of international registries. 3, 4 At the time of this first webinar, there were only 15 cases of IBD and COVID-19 reported. Also presented and discussed at length were the possible effects of immunotherapies on infection in IBD patients (Maria Abreu, Markus Neurath), which is summarize below. Next, the results from the first round of voting were reviewed and the group focused on statements in which there was disagreement or uncertainty. Subsequent to this first webinar, as per RAND panel protocol, a second round of voting with modified statements was sent to the participants. These results led to the statements summarized below and presented in their entirety in Table 1 . A second webinar occurred on March 27, 2020 to review results and to continue discussions for ongoing efforts to provide guidance. IOIBD utilized the established RAND/UCLA Method, which utilizes a Delphi panel approach to address the appropriateness of specific medical interventions or medical decisions. 5 We used a modified RAND panel to allow for a rapid cycle of two rounds of voting by the expert panel. The panel was presented a web-based questionnaire that included clinical scenarios specific to IBD patients during the COVID-19 pandemic. The questionnaire was created and iteratively improved by three of the authors (DTR, MTA, CAS) and then distributed electronically to the respondents. The panelists included the membership of IOIBD in addition to other invited specialists in IBD. Respondents rated each of the patient scenarios on a scale of 1 to 9, such that statements rated 1-3 are considered inappropriate, 4-6 are uncertain, and 7-9 are appropriate. After the first round of anonymous voting, the first webinar occurred and related content was reviewed as summarized above and the results of the first round of voting were reviewed. The subsequent discussion focused on scenarios that had a median in the uncertainty range and those with a high standard deviation (SD). The goal of the discussion was to understand views of the panel in preparation for a second round of voting, not necessarily to achieve consensus. The second round questionnaire was nearly identical to the first, except for clarifying a few of the original scenarios and adding two additional sections that were not covered in round one (how to manage patients in IBD clinical trials and when to restart medications if they were being held for active COVID-19 infection). Table 1 is a list of the statements from the second round of voting. The final appropriateness category is based on the second-round voting median. The mean, standard deviation (SD) and disagreement index (DI) were also calculated. The DI expresses the spread of responses and is calculated using a previously described approach 5 Using this formula, agreement is defined as a DI < 1 , while disagreement is defined as a DI ≥ 1. 5 Of the 76 statements in the second-round survey, 26 were rated as appropriate, 19 as uncertain, and 31 as inappropriate. Although agreement is not required, there was agreement (DI < 1) in 64 of 76 scenarios (84%). • The panel agreed that having IBD (either CD or UC) did not increase the risk of becoming infected with SARS-CoV-2 or developing COVID-19 and having an ostomy or J-pouch did not increase the risk for COVID-19. • The panel also agreed that it is safe to continue to receive infusions in an infusion center, assuming that the infusion center has a SARS-CoV-2 screening protocol in place. • The group was in agreement that it is appropriate to reduce the dose or discontinue prednisone to prevent infection from SARS-CoV-2, but voted that it was inappropriate to reduce the dose or stop other IBD therapies to prevent infection from SARS-CoV-2. • There were mixed responses related to the other clinical scenarios and therapies. The key findings regarding the management of medical therapy for IBD in the setting of the COVID-19 pandemic are summarized in Figure 1 . • In regards to the scenario of a patient receiving combination therapy of an anti-TNF and immune modulator, the group was uncertain if the immune modulator should be dose reduced to potentially modify the risk of infection with SARS-CoV-2, but was in agreement and did vote that it is appropriate to discontinue the immune modulator in a patient who is known to be infected with SARS-CoV-2 or when a patient develops COVID-19. • In the scenario of a patient who stopped IBD medications because either they tested positive for SARS-CoV-2 infection or had COVID-19, the group voted that it is appropriate to restart their medications if they do not develop symptoms after two weeks, or when symptoms have completely resolved. • The group was in agreement and voted it was appropriate to postpone nonessential endoscopic procedures. • Furthermore, the panel voted that patients in clinical trials should continue those therapies unless they become infected by SARS-CoV-2 or develop COVID-19. • The group voted that it was appropriate to discontinue the clinical trial drug if a patient tests positive for SARS-CoV-2 or develops COVID-19, but there was some disagreement in the responses. The full results of the first survey (pre-webinar) and post survey are available in Supplementary Table 2 . It is now known that similar to the 2002 SARS-CoV, the 2019 SARS-CoV-2 requires the angiotensin-converting enzyme 2 (ACE-2) receptor to enter the cell as well as TMPRSS2, a serine protease that cleaves the viral spike to permit viral entry. 6 The ACE-2 receptor is found at high levels in alveolar type-2 (AT2) cells in the lung. However, important for IBD, the small intestine is also known to express ACE-2; in a patient that was infected with SARS-CoV-2, ACE-2 and the virus were found in stomach, duodenal, and rectal biopsies. 7 Moreover, single cell transcriptomics of the gut, corroborate that ACE-2 is expressed in the GI tract. 8 The virus has also been found in stool of infected patients for longer periods of time than in sputum, although in smaller amounts. 9 viruses, suggesting there is a positive feed forward loop once patients are infected with virus. In vitro, interferon-gamma (IFN-γ) can induce ACE-2 and the promoter region of ACE-2 contains several immune and cytokine responsive transcription factor binding sites, suggesting that inflammation may increase expression of ACE-2. 8 The other important factor for viral entry is endocytosis. Baricitinib is a JAK1, JAK2 and TYK2 inhibitor currently available for rheumatoid arthritis and in clinical development for IBD and it may inhibit endocytosis. 10 This effect does not occur with the less selective JAK inhibitor, tofacitinib. Early in the disease course for SARS-CoV and MERS-CoV, the innate immune response to the virus through interferon and interferon-stimulated genes (ISG), may limit viral replication but is also subverted by the virus itself. 11 In later stages, the cytokine release syndrome, characterized by high levels of pro-inflammatory cytokines such as IL-6, has been suggested to trigger ARDS in SARS-CoV-2 infections and lead to fatal outcomes. In terms of the therapies we use for IBD and the potential effect on SARS-CoV2, previous experience with high dose steroids as a treatment for SARS-CoV or MERS-CoV was not effective and delayed viral clearance. 12 Therefore, steroids are not recommended as a treatment for SARS-CoV-2, but the doses that were used in these studies are much higher than the doses that are used in IBD. 12 With respect to thiopurines, 6-MP and 6-thioguanine have potential antiviral activity against MERS and SARS, at least in vitro. 13 Many IBD patients are using monotherapy with biologics or the novel small molecule Janus kinase inhibitor, tofacitinib. Anti-TNF therapy may impact viral immunity given that there is a small increased risk of herpes zoster and hepatitis B virus reactivation. While high IL-2R and IL-6 serum levels have been associated with severe COVID-19 cases, no effect on TNF levels was noted. 16 IFN-γ and TNF production by CD4+ T cells have been associated with severe SARS-CoV and, therefore, inhibition of TNF has been proposed as a treatment of the cytokine release syndrome that can occur in some of these patients. 17, 18 Vedolizumab primarily inhibits α-4, β-7 lymphocyte homing of Th17 and Th9 cells as well as regulatory T cells to the intestine. Viral infections are rare with vedolizumab therapy. 19 In patients who had concurrent hepatitis B or C infection, there was no viral reactivation and there was sustained virologic control in SIV-infected macaques after antiretroviral and vedolizumab therapy 20 Vedolizumab has been used for clinical therapy in patients with IBD and early clinical trials in HIV have not shown effects on viral load. 21 With respect to ustekinumab, this agent can prevent Th1+ T cell priming and IFN-γ production by CD4+ T cells and suppress Th17+ T cell activation and cytokine production. There has been no increase in viral infections in IBD or psoriasis patients receiving ustekinumab in large post-marketing registries. 22 Tocilizumab, an anti-IL-6R antibody, is currently being tested in patients with severe COVID-19 and may reduce the severity of ARDS. 23 This meeting was convened by an international group of IBD physician-scientists to develop guidance for the management of patients with IBD during the COVID-19 pandemic. Using a RAND panel methodology, the group developed a series of statements regarding risk of infection and management of therapies that will assist patients and healthcare providers during this uncertain time. These statements are based on expert opinion in the absence of definitive data or in some cases any data. In an IBD patient who tests positive for SARS-CoV-2 and whose IBD meds have been stopped because of this, IBD meds can be restarted after 14 days (provided In an IBD patient who develops COVID-19 and whose IBD meds have been stopped, IBD meds can be restarted after COVID-19 symptoms resolve. 7 1.9 Appropriate 10.00 In an IBD patient who develops COVID-19 and whose IBD meds have been stopped, IBD meds can be restarted after 2 nasopharyngeal PCR tests are negative. Full survey will be submitted as a PDF, and can also be found here: WHO Director-General's opening remarks at the media briefing on COVID-19 -11 Global Cases by Johns Hopkins CSSE The Rand/UCLA Appropriateness Method User's Manual SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology Increasing Host Cellular Receptor-Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection. bioRxiv Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China T cell responses to whole SARS coronavirus in humans A clinical study for the efficacy and safety of Adalimumab Injection in the treatment of patients with severe novel coronavirus pneumonia (COVID-19) Low Frequency of Opportunistic Infections in Patients Receiving Vedolizumab in Clinical Trials and Post-Marketing Setting Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1-infected individuals Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn's Disease: An Integrated Analysis of Phase II/III Clinical Development Programs Effective Treatment of Severe COVID-19 Patients with Tocilizumab Roche to start Phase III trial of Actemra in Covid-19 patients Pharmacokinetics and Immune Reconstitution Following Discontinuation of Thiopurine Analogues: Implications for IBD = inflammatory bowel disease; SARS-CoV-2 = Severe Acute Respiratory Syndrome-CoronaVirus-2; COVID-19 = CoronaVirus Disease The authors thank all the participants of the RAND panel. The authors wish to acknowledge Cindy Traboulsi, Amarachi I. Erondu and Seth R. Shaffer for their assistance in data management and Raymond Kulig and Marischka Konings for invaluable help in logistical coordination. In an IBD patient who tests positive for SARS-CoV-2 and whose IBD meds have been stopped because of this, IBD meds can be restarted after 14 days (provided they have not developed COVID-19). In an IBD patient who develops COVID-19 and whose IBD meds have been stopped, IBD meds can be restarted after COVID-19 symptoms resolve. 7 1.9 Appropriate 10.00In an IBD patient who develops COVID-19 and whose IBD meds have been stopped, IBD meds can be restarted after 2 nasopharyngeal PCR tests are negative.