key: cord-0909609-fiwox9vf
authors: Farkas, Klaudia; Pigniczki, Daniella; Rutka, Mariann; Szántó, Kata Judit; Resál, Tamás; Bor, Renáta; Fábián, Anna; Szepes, Zoltán; Lázár, György; Molnár, Tamás
title: The complex relationship between viruses and inflammatory bowel disease – review and practical advices for the daily clinical decision-making during the SARS-CoV-2 pandemic
date: 2021-04-12
journal: Therap Adv Gastroenterol
DOI: 10.1177/1756284820988198
sha: f90511d6ffde76db656076c644cd5a5dbdbe18b9
doc_id: 909609
cord_uid: fiwox9vf

The coronavirus disease 2019 (COVID-19) outbreak emerged in December 2019 in China and rapidly spread worldwide. Inflammatory bowel disease (IBD) patients are likely to be more susceptible to viral infections, and this is significantly influenced by the type of therapy they receive. Thus, issues specifically concerning the medical treatment of IBD patients were shortly addressed at the beginning of the pandemic. However, recently available data on the occurrence and outcome of SARS-CoV-2 infection in IBD patients does not address the concerns raised at the beginning of the pandemic. Growing evidence and the rapid changes happening over the past few weeks have helped elucidate the current situation, contribute to our understanding of the disease, and many previously raised questions could now be answered. We hereby summarise available evidence regarding viral infections and IBD, focusing on SARS-CoV infections, and we provide practical recommendations related to patient management during the COVID-19 pandemic era.

A pandemic takes a vast toll on the global economy, on social life and on medical services and supplies. In such a situation, we must recognise the most vulnerable points in medical care and identify the potentially modifiable parts of patient management to avoid unnecessary health damage. New standards for treatment options should be developed that aim towards decreasing susceptibility to the infectious disease. Patients with chronic diseases and those receiving immunosuppressive or biological therapy may be at higher risk of contracting infectious diseases, and the expected consequences and outcomes of a SARS-CoV-2 infection or even a manifest COVID-19 in such patients should be explored. It might prove necessary to implement reasonable therapeutic changes into the daily clinical practice during the current pandemic situation in order to provide the most beneficial outcome.

The present study focuses on the treatment options for inflammatory bowel disease (IBD), considering the above-mentioned issues during the COVID-19 pandemic. We also review the current knowledge on the relationship between viral infections and IBD.

It is well known that genetic, environmental and immunological factors also contribute to the development of IBD. In the case of Crohn's disease (CD), it has been hypothesised that viral infections may trigger an unbalanced immune response. 3 Viral pandemics with different mortality rates have long been a part of human history (Table 1 ), but almost no information is available on their association with IBD. 4 Looking at these pandemics through the lens of a gastroenterologist, each can cause gastrointestinal (GI) complaints with predominantly atypical abdominal symptoms.

In the current situation, it is necessary to be aware of the nature and mortality potential of the Coronaviridae. This family features enveloped, single-stranded RNA viruses classified into four genera. SARS-CoV-2 and SARS-CoV-1 are the members of the β genus, which, together with the Middle East respiratory syndrome coronavirus (MERS-CoV), are the human-infecting species causing respiratory and GI symptoms 4,5 ( Table 2 ). An outbreak of MERS-CoV occurred in 2012. The mortality rate was 2.5-7.5%, and GI symptoms were present in approximately 25% of the patients. Abdominal pain and diarrhoea were most commonly observed and, in some patients, GI symptoms developed even prior to respiratory symptoms (e.g. coughing and pneumonia). Furthermore, measurable faecal levels of viral RNA were present in 14.6% of the examined stool samples.

In SARS-CoV-2 infections, stool viral RNA levels have exhibited a progressive increase from the fifth day of the illness, remaining detectable even until the 30th day. 5 Regarding genome sequences, SARS-CoV-2 and SARS-CoV-1 exhibit 82% similarity. Angiotensin-converting enzyme 2 (ACE-2) cell receptors have been confirmed as viral targets; these are widely present not only in the respiratory tract but also in the GI tract. Based on a current meta-analysis, 17.6% of the patients with COVID-19 have experienced GI symptoms, such as anorexia, diarrhoea, nausea, vomiting and abdominal pain. GI symptoms are seen particularly in patients with more severe forms of COVID-19. 6 Patients with GI symptoms, defined as diarrhoea or nausea/vomiting, at the time of testing, were significantly more likely to test positive for SARS-CoV-2 than negative (61% versus 39%). 7 SARS-CoV-1 infections had a mortality of about 10%, whereas SARS-CoV-2 has a 2%-10% mortality rate. Therefore, coronavirus infections may have similar pathomechanisms and manifestations; nevertheless, they are associated with different mortality rates. This may, in part, be due to differences in virulence but may also reflect differences in the immune response towards the disease. For SARS-CoV-2, continuous activation of different immune cells may result in a 'cytokine storm'. 8 The emergence of a SARS-like virus from bats targeting ACE-2 receptors in 2013 9 had previously raised the potential for worldwide pandemic. We need to bring up the question: could we have been more cautious?

There is no evidence that patients with IBD have been at higher risk for infection and worse disease course during each previous coronavirus epidemic. However, such patients do seem to have an increased susceptibility to viral infections, independently of their medical therapy. Furthermore, a recently published study found that IBD patients have three times higher risk of developing a viral disease with subsequent hospitalisation than the control population. 10 Disease activity and azathioprine therapy were also found to be risk factors for these conditions. Regarding the pathogens, cytomegalovirus (CMV) infection was the main cause of hospitalisation. 10 Meanwhile, patients receiving immunosuppressive and biological therapy are at greater risk of opportunistic infections (OIs), especially those with persistent chronic diseases. Generally, patients receiving combination therapy are at high risk of developing OIs: for pneumonia, the risk is twice as high, whereas patients receiving combination therapy have a 13-fold higher risk of a viral infection than those receiving non-combination therapy. Regarding monotherapies, anti-TNF drugs may predispose to pneumonia, whereas azathioprine is mostly associated with viral infections. 11 Corticosteroid treatment facilitates the development of serious infections. 12 journals.sagepub.com/home/tag 3

With these relationships in mind, IBD patients should be regarded as a high-risk group in the COVID-19 pandemic. However, growing evidence suggests that IBD per se does not increase the risk of coronavirus infection -exemplified by responses coming from different questionnaire surveys, [13] [14] [15] though the first two publications on IBD patients during the pandemic did not report any patients with SARS-CoV-2 infection, neither from China nor from Italy. 16, 17 On the basis of the most recent data (Spain, Italy and SECURE-IBD Registry), we may infer that diarrhoea occurs more frequently amongst SARS-CoV-2-infected IBD patients (21%) than in the general population. 18, 19 The predictors of COVID-19 pneumonia and mortality, however, remain the same as in the general population (i.e. age >65 years, comorbidity), although the risk is further increased by active IBD and corticosteroid therapy. 20, 21 However, the role of corticosteroid therapy is controversial in the COVID-19 pandemic. In the Surveillance Epidemiology of Coronavirus Under Research Exclusion-IBD database, evidence of greater prevalence of milder COVID-19 cases was reported in patients treated with anti-TNF-α than in patients undergoing steroid treatments. As of 15 May 2020, 19% of patients treated with anti-TNF-α agents required hospitalisation and only a minority (3%) experienced unfavourable outcomes, defined as intensive care unit admission, ventilator use, or death. Conversely, 66% of patients taking oral or parenteral steroids needed hospitalisation, with 26% experiencing unfavourable outcomes. 22 Further support to this theory comes from the results of the Italian Group for the Study of Inflammatory Bowel Disease study, which reported 60% reduction in mortality among patients receiving anti-TNF-α antibodies (although not statistically significant); however, corticosteroid use was associated with a trend toward statistical significance, with COVID-19-related pneumonia (p = 0.05) and death (p = 0.064). 23 On the other hand, steroid use should be avoided, if possible, or rapid steroid tapering should be considered owing to the risk of respiratory or opportunistic infection that could complicate the course of COVID-19. Glucocorticoids presumably have various effects in the different phases of the cytokine storm; therefore, they can be recommended as an ultimate last resource if needed. However, in the early phase of the infection, steroids may aggravate the outcome of the diseaseas seen in case of many other infections.

As mentioned above, Brenner et al. developed an IBD registry to monitor SARS-CoV-2 infection. 22, 24 The SECURE Registry aimed to define the impact of COVID-19 on patients with IBD and to evaluate how certain factors might impact on COVID outcomes. However, the registry has some limitations. For instance, some cases with mild symptoms may be lost because of restricted COVID testing, and some cases of IBD-related hospitalisation would incorrectly be associated with COVID-19 if the patient incidentally tested positive for the virus. By the time that this article was written, 701 IBD patients were registered with positive test results, 414 patients with CD and 287 patients with ulcerative colitis (UC). Hospitalisation was required for 28% of CD and 38% of UC patients, whereas 4% and 6% were admitted to intensive care units; the mortality turned out to be 2% and 6%, respectively ( Figure 1 ). Severe complications appeared to be associated with disease activity, and there was a clear correlation with older age (Figures 2 and 3) . Death was most common amongst patients receiving steroid therapy (13%) (Figures 4 and 5) . The surprisingly high death rate in patients administered mesalazine (8%) could be explained at least in part by the age of these patients [79 years (data coming from 9 April)]. However, the safety of mesalazine use is still a controversial issue without any exact (statistical bias?) reason. From another viewpoint, since the registry collects data from all over the world, the high proportion of patients receiving 5-aminosalicylic acid (5-ASA) may reflect countries with poor access to advanced treatments, such as biological therapy; hence, the use of 5-ASAs should be much higher even in CD as well.

What are the factors potentially explaining this unexpected favourable scenario? 1. Age. The average age of the IBD population is lower than the age of the background population. Therefore, only a small proportion of IBD patients are supposed to be in the most vulnerable range (>65 years). 25 Anti-TNF, anti-tumour necrosis factor; AZA, azathioprine; IBD, inflammatory bowel disease; MTX, methotrexate.

journals.sagepub.com/home/tag 7 is necessary since with screening of infections we evaluate the patients' vaccination and their immune status as well. In the case of inappropriate immunisation, proper intervention is necessary to be implemented, in order to proceed with appropriate vaccination if protection is missing. 5. Comorbidities. There is a significantly lower incidence of hypertension and diabetes amongst IBD patients. Both conditions can aggravate the course of COVID-19. 26 6. Non-steroidal anti-inflammatory drugs (NSAIDs). Although it has been suggested to increase the risk of developing COVID-19, NSAIDs are less commonly administered to IBD patients than to the control population. 27 However, recent studies have questioned the link between NSAID exposure and adverse outcomes of COVID-19. [28] [29] [30] Patient management during the COVID-19 pandemic Although several recommendations for managing patients with IBD have been published, none of them could provide a complete solution for all the situations related to the pandemic. Referring to these previous guidelines, we would like to develop a more practical approach to handling the challenges. First of all, we should emphasise that IBD relapses are associated with an increased risk of a more severe course of COVID-19, with the need for corticosteroid use, possible multiple hospital visits or admissions potentially involving colonoscopic examinations. Previous data confirmed that the clinical and demographic variables associated with unfavourable COVID-19 outcomes, such as old age, presence of comorbidities and male gender, were comparable between patients with IBD and the general population. As shown in the study of the Italian Group for the Study of Inflammatory Bowel Disease, those age 65 years and older, comorbidities and active IBD were associated with worse COVID-19 outcomes. Thus, IBD activity at the time of COVID-19 diagnosis is a risk factor for a worse clinical outcome. 20, 23 Moreover, from the viewpoint of pathomechanism, immunohistochemical analyses revealed higher ACE-2 protein expression in inflamed IBD samples as compared with controls. Furthermore, ACE-2 activity in the colon was elevated in non-inflamed colon in IBD patients as compared with controls and active IBD. The average expression of soluble ACE2 was increased in patients with IBD (mainly in CD) and a higher ACE-2:ACE ratio in plasma was noted in patients with IBD as compared with controls without IBD. Cytokines expressed in IBD, such as IFN-gamma, can potentially induce ACE-2 expression, which is consistent with the idea that mucosal inflammation may increase the expression of ACE-2. A study showed higher levels of ACE2 in inflamed intestinal areas in CD patients as compared with patients with UC. Finally, the fusion of SARS-CoV-2 with the host cell membrane is critical for uptake in cells and is modulated by the S protein. Activation of the S protein via proteolytic cleavage is controlled by host trypsin-like proteases, whose activity is upregulated in IBD, and this effect might facilitate infection in patients with IBD. Overall, these findings suggest the possibility that patients with IBD might be particularly more susceptible to COVID-19. 31 The aim above all is to avoid flareups with a continuous and effective medical treatment. Another particularly important factor is detailed risk management. Therapeutic changes should be employed only if the patient is at advanced risk (age older than 65 years, presence of comorbidities, male gender, active IBD, nonadherence to pandemic regulations) of developing COVID-19 (even if not yet infected) or if the patient has a positive test of SARS-CoV-2 or even has manifest COVID-19.

On the basis of the recommendations of the British Society of Gastroenterology, we present a modified approach regarding the risk factors of IBD patients. Three main aspects should be considered: patient-dependent factors, therapy-based factors and other (mainly pandemic-related) factors (Table 3) . Moreover, we present our recommendations based on a comprehensive analysis of the recommendations of the International Organisation for the Study of Inflammatory anti-TNF, anti-tumour necrosis factor; IBD, inflammatory bowel disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Bowel Disease and the guidelines of the American Gastroenterological Association regarding patient management (Tables 4, 5 ). 32, 33 Patient not infected with SARS-CoV-2-IBD in remission • Personalised risk evaluation and therapy modification if necessary (considering age, comorbidities, lymphocytopenia, steroid requirement and combination therapy).

Lymphopenia (lymphocyte count <1.0 × 10 9 /L) is an independent risk factor of COVID-19-related mortality. 34 • Maintenance of remission with unmodified treatment in low-and medium-risk patients. • Taper the dose of corticosteroids, even when using oral budesonide MMX. Evidently, the use of prednisone should be decreased to a dose of at least below 20 mg. 32 • Consider the risk/benefit of combination therapy, stop azathioprine and continue 

? - biological monotherapy in the case of patients with a high risk of infection. Drug-induced risk of viral infections is exemplified by azathioprine and anti-TNF combination therapy. Although azathioprine is supposed to require a few weeks for total elimination, no exact information is available on the elimination time of the drug (half-life of azathioprine is 5 h), and the pandemic may continue for many more months. Azathioprine monotherapy does not confer any such increased risk; therefore, it can be continued. 35 Moreover, risk of relapse is higher if azathioprine monotherapy is ceased when compared with the cessation of azathioprine as a part of combination therapy. • Prioritise the prevention of infection by adequate patient education. • Omit unnecessary appointments with the patients (use electronic prescription, adalimumab receiving points, mobile or online appointments). • Protective equipment and other safety considerations in the biological therapy wards. • Prescribe the maximum possible amount of medications.

+ ? - - - - - - ? - - +=+ + + + - - + - + + +

+ + > > - - + - + + ?

+ + - > - - + - + + - COVID-19 disease + + - > - - + - + ? - +=

• Be aware of the patient's compliance. • Do not start azathioprine due to its slow onset of action and increased risk of infection. Azathioprine causes lymphopenia in 10% of the patients, and every fifth patient receiving azathioprine exhibits a decrease below 0.5 × 10 9 /L. 38 Other pandemic factors comprise environmental factors, such as home and living environment, workplace, commute and travelling mode and other factors, such as compliance of wearing protective equipment and the relevance and frequency of medical attendance and assistance.

Conclusively, it is clear that the COVID-19 pandemic has produced a novel and rather unprecedented challenge in the field of medical care, which is not easy to adapt to. Our responsibility is to attempt to guide our IBD patients through this period safely and to minimise their risk of infection, and COVID-19-related exacerbation of their disease. Meanwhile, it is critical that the patients receive treatment of sufficient quality. This requires extensive clinical experience and a thorough understanding of our patients' compliance, social background and medical history.

Clinicians should be continuously updated and have extensive insight into the current pandemic situation. With this article, we aim to summarise some of the main points of the optimal patient management during the COVID-19 pandemic, and to assist the clinicians in processes of decision-making.

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We would like to acknowledge the work of Mark Marcus Philip MD in linguistic revision of the manuscript. 

The authors declare that there is no conflict of interest.

The manuscript, including related data, tables and figures, has not been previously published, and the manuscript is not under consideration elsewhere.

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: