key: cord-0731083-9cd2v6bt
authors: Sebastian, S; Gonzalez, H A; Peyrin-Biroulet, L
title: Safety of drugs during previous and current coronavirus pandemics: Lessons for IBD
date: 2020-06-10
journal: J Crohns Colitis
DOI: 10.1093/ecco-jcc/jjaa120
sha: 13b3dc878683612893bae0611eded72a5f05b118
doc_id: 731083
cord_uid: 9cd2v6bt

The Coronavirus 2019 (COVID-19) pandemic has posed challenges in the routine care of patients with inflammatory bowel disease. One of the key challenges needing addressing is the quantification of the risks of immunosuppressive and biologic therapies in IBD patients during the pandemic. The similarities and differences between the previous coronavirus outbreaks and the pathobiology of the infections can give useful information in understanding the risks, and perhaps potential beneficial aspects of drugs used in IBD. Although clinical, immunological and pharmacological data from the experience with the previous coronavirus outbreaks cannot be automatically translated to predict the safety of IBD therapies during COVID-19 pandemic, the signals so far from these outbreaks on IBD patients who are on immunomodulators and biologics are reassuring to patients and clinicians alike.

The 21st century has seen the worldwide spread of three previously unrecognized coronaviruses, the severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), and more recently SARS -COV-2 ( 1) .

Starting from 2002 in China, The SARS-CoV-1 produced, then unprecedented, nosocomial transmission resulting in nearly 9000 deaths across 29 countries (2) . Exactly a decade later another coronavirus MERS-CoV emerged with 2254 laboratory positive cases with at least 800 deaths over 27 countries (3) . The current pandemic SARS-CoV2 originated in Hubei province in China, and was declared a pandemic by World Health Organisation on March 11 2020 (4).

Understandable concerns have been raised on the safety of steroids, immunosuppressive drugs, and biologics used in patients for a variety of indications including immune mediated inflammatory disease such as inflammatory bowel diseases (IBD), which do increase the risk of opportunistic bacterial, viral and fungal infections (5) . The magnitude of the infection-risk in general with the therapies used in IBD is small and vary based on the patient, disease, and drug characteristics (6) . Equally, another aspect needing consideration if patients discontinue their IBD therapies is the potential risk of IBD flares needing hospitalization which will increase the risk of acquiring SARS-CoV-2. Several consensus guidelines recommend continuation of IBD therapies, primarily with the aim of reducing the risk of a flare needing hospitalization or surgery (7, 8, 9) .

Two studies recently showed that IBD patients are not at increased risk of being infected with COVID-19 (10, 11) . By contrast, there is scarce data so far on the risk of SARS-CoV-2 infection in IBD patients who are on therapies which potentially alter the immune response to pathogens (12) . Therefore, continuing concerns remain both from IBD patients and the A c c e p t e d M a n u s c r i p t clinicians managing them, regarding the potential of IBD related drugs causing more frequent infections by SARS-CoV2, and increased risk of severe complications from COVID-19 (13) .

In this review we discuss the immune-pathological aspects of previous and ongoing coronaviruses ( 1 ). The S protein is responsible for viral entry and thus plays a pivotal functional role in viral entry to the host cells, and the non-structural proteins are the key players in viral replication (16) . The SARS-CoV-2 virus enters cells via the same mechanism as SARS-CoV, which is by binding of the surface spike glycoprotein (S protein) on the surface of the virus to angiotensin-converting enzyme 2 (ACE2), a receptor on the cell surface controlling the cleavage of several peptides. ACE2 is expressed in type 2 pneumocytes in the lung, blood vessels, oropharyngeal mucosa, small intestine, colon, and kidneys (17, 18) with remarkably high expression in the epithelial cells of the proximal and distal intestines, and this is also a portal for viral entry (Figure 2 ). Single cell RNA sequencing analysis showed that ACE2 expression in colon cells was positively correlated with the regulation of viral infection and congenital cellular immunity and was negatively correlated with viral transcription, protein translation, phagocytosis, and complement activation [19] . Recently, Garg et al. have described differences in the ACE2 between inflamed and non-inflamed biopsies in patients A c c e p t e d M a n u s c r i p t with IBD, but the mucosal expression or activity was not associated with the use of therapies in IBD (20) . Furthermore, their study indicated that the level of circulating ACE is upregulated in patients with IBD. In addition, a more recent elegant study Maria Abreu and colleagues (21) reported that the expression of ACE2 and TMPRSS2, which are the entry portals for SARS-CoV-2, are not increased in inflamed colon and ileum of patients with IBD and some medical therapies are associated with lower levels of ACE2. Therefore, ACE2- Overall, it is becoming increasingly apparent. that the tug of war between coronaviruses and host antiviral defences are at the core of the pathogenic potential of all coronaviruses determining the clinical course and outcome, and this gives insights on the relative risks of drugs and also opens a window for exploring therapeutic options (34) (Figure 3 

A c c e p t e d M a n u s c r i p t Immunosuppressive drugs and severity of coronavirus infections: opportunity in the face of adversity?

The impact of drugs, in particular, steroids, immunosuppressive and biologics were brought in to sharp focus during the three coronavirus pandemics despite the wide variation in the severity of the outbreaks and the mortality rates. These drugs remain the cornerstones of therapies in IBD and have revolutionised IBD care. The lack of prospective data specific to the SARS-CoV-2 infection to date means that our understanding of the genealogy and immunopathology need to be integrated to the pharmacological aspects of these drugs to shed some light into this challenging conundrum.

Corticosteroids are thought to have a divergent effect on viral infections including SARS COV viruses; on one hand they inhibit host immune response acting on migration and chemokines production leading to impaired viral clearance and the resultant prolonged Moreover, a prospective, randomized double-blinded, placebo-controlled trial compared early hydrocortisone treatment (before day seven of the illness) with a placebo and found that early hydrocortisone therapy was associated with a higher subsequent plasma viral load (61) . In the setting of MERS-CoV, use of corticosteroids for critically ill patients did not improve the 90 Corticosteroids also impair the induction of anti-viral type-I interferon responses to a range of respiratory viruses (64) . Early corticosteroid use did not benefit critically ill patients with ARDS but was independently associated with higher mortality in the setting of severe influenza pneumonia (65) . Overall, the current data does not support the use of corticosteroids in the coronavirus infections (59) and randomised controlled trials are needed before routine use.

There is data suggesting that doses above 20 mg of prednisolone are associated with increased risk of bacterial and viral infections in IBD and even with increased hospitalization suggesting a lower dosing strategy (66, 6760) . In a recent Italian series of IBD patients with COVID-19, a trend towards adverse outcome with concomitant corticosteroids was reported (68) . In a more recent series from New York, the use of steroids appears to predict COVID-19 (OR 1.38, 95% CI 1.07-1.77) (69) . Locally acting steroids such as budesonide and beclomethasone theoretically have some advantages in relation to side effect profile (70, 71) , but no data is available in the setting of coronaviruses. Hence overall, while there is no data A c c e p t e d M a n u s c r i p t on whether current use of steroids increases the risk of severe COVID-19, it seems prudent to minimise the use of systemic steroids, think of alternatives to steroids, and if used, taper to the lowest possible dose quickly.

Broad immunosuppression has the potential to increase susceptibility, persistence, and reactivation of viral infections in patients (72) . Acute respiratory viruses implicated in causing severe disease in immunocompromised patients include respiratory syncytial virus (RSV), influenza viruses A and B, parainfluenza viruses and adenovirus, and immunocompromised patients are generally considered at increased risk of influenza and at higher risk of complicated infection (73, 74) . There is also risk of opportunistic viral infection with thiopurines, but these are mainly DNA viruses such as Hepatitis B and C, Epstein Barr Virus and Human Papilloma Virus. (74) Partial assessment regarding whether immunosuppression is a relevant risk factor for COVID-19 infection and severe course can be guided by the findings of SARS-CoV-1 and MERS-CoV outbreaks (75) . On review of large published cohorts of SARS-CoV1 and MERS-CoV infections (76, 77, 78, 79, 80) , the risk factors for both infections included advanced age and presence of one or more co-morbidities such as diabetes, heart disease ,hypertension, lung disease and obesity. Although there were no specific studies on immunosuppressed individuals including IBD, no fatality was reported in patients undergoing chemotherapy or other immunosuppressive treatments, at any age (76, 78, 79) . Although transplant patients were expected to have poorer outcomes following acquisition of SARS CoV1, at the end of the outbreak no mortality or graft loss had been recorded (75, 77, 79) A c c e p t e d M a n u s c r i p t Atypical presentation of MERS-CoV was reported from Korea in 3 patients on immunosuppressants, all of whom made full recovery without the need for invasive ventilation (81) . In another series of 45 patients with serious MERS-CoV infection, there was a single patient who was on prolonged immunosuppression who also made an uneventful recovery (78) . In a hospital outbreak of MERS-CoV in Jordan, immunosuppressive individuals did not have additional risks (77) . In an analysis of 1253 cases from the epicentre of MERS in Saudi Arabia from 2012-2015, immunosuppressant use was not associated with increased risk for MERS-CoV infection (80) . In another study, with a cohort of 114 patients, one of the patients was on immunosuppressants for double transplant (kidney and liver) and, while requiring intensive unit care, did not die (76) . In a retrospective cohort study of host susceptibility in South Korean MERS outbreak, 3 patients of solid organ transplantation were included but none developed MERS-CoV infection, but 2 out of the 3 patients with autologous cell transplantation did, without any mortality (79) . In an animal model of MERS-CoV using immunosuppressed rhesus macaques, despite increased viral replication, pathology in the lungs was significantly lower in immunosuppressed animals (82) . Intriguingly some immunosuppressive agents used in treatment, including in IBD, have been found to interfere with viral replication (87) . Although the doses used were much higher in comparison to that in treatment of immune disorders such as IBD, thiopurines, when used for haematological malignancies, appeared to be specific inhibitors of SARS CoV-1 virus (88) . (91, 92, 93, 94) . In a monocentric cross-sectional study of 384 patients, 46 of whom ((12%) were on calcineurin inhibitors alone, the immunosuppression with calcineurin inhibitors did not increase the risk of hospitalisation or mortality (95) . Cyclosporine was A c c e p t e d M a n u s c r i p t successfully used in a pregnant patient with acute severe ulcerative colitis with COVID-19 (96) . These promising signals, and the underlying pharmacological basis, have prompted some to suggest consideration of calcineurin inhibitors for treatment of coronavirus infections (97, 98) . In a study of rheumatoid arthritis patients on methotrexate with resolved HBV infection, the incidence of HBV reactivation was very low at 1.93/100 person-years (99) .

The patients on concomitant methotrexate in IBD so far has not reported any additional risks from SARS-CoV-2 (11, 68, 86) Overall, immunosuppressive therapy does neither seem to have a major impact on infection with SARS CoV-1, MERS-CoV and SARS-CoV-2 nor does it seem to lead to a severe disease course in many cases. However, it must be kept in mind that reported case numbers are exceedingly small overall and continued vigilance is needed. Furthermore, anti TNF treatment may diminish the degree of protective immunity resulting from vaccination, but levels achieved appear adequate with other viruses (100).

Paradoxically, it is plausible that the use of biologics may have a beneficial effect in reducing the inflammatory immune responses following COVID-19 by reduction of cytokines, including TNF. TNFα has been implicated in the severe immune-based pulmonary injury caused by SARS-CoV-, suggesting that TNFα inhibitors could be a potential treatment for the acute respiratory disease syndrome caused by coronavirus (101). Coronavirus viral spike protein is able to induce a TNF-α-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain, and this process, which appears to be strictly coupled to TNFα, is essential for the penetration of the virus into the cell. This means TNF inhibitors might be effective in blocking viral entry and the detrimental effects of exuberant TNF-α (102). Anti TNF agents, as an option for therapeutic modulation, were proposed during the SARS-CoV-1 outbreak although no human studies were performed (103). Following this, in a study on 22 piglets to assess the efficacy of an anti-TNFα) therapy for endotoxin respiratory diseases, the investigators observed that TNFα blockade was not associated with decrease in disease severity(104) Subsequently, anti TNF for therapy of viral infections caused by respiratory syncytial virus or influenza virus was studied again in animal models and showed that TNF However, it is important to recognise that it is equally plausible that theoretical possibility of increased viral burden resulting from inability of immune response may result in increases severity of inflammation (107) . Hence some concerns have been raised by some authors in relation to broad immunosuppression in the presence of an overwhelming infective illness (108) . Nevertheless, there is no evidence indicating that TNFα blockade is harmful to patients in the context of severe infections including septic shock (109) . A randomised controlled trial of anti TNF agents with septic shock in intensive care units showed no evidence of increased infections in the anti TNF treated patients (110) .

No patients on anti TNF agents have been recorded in any of the series reported during the SARS-CoV-1 or MERS outbreaks, but there is an increasing amount of literature suggesting that TNFα blockade is not harmful to patients in the context of COVID-19 (111, 112, 113) . These opinions are supported by the case series of patients on anti TNFs for immune mediated inflammatory disorders such as arthritis and inflammatory bowel diseases (10, 11, 68, 86, 114) . In a report of 320 rheumatology patients on disease modifying drugs, half of whom were on anti-TNF agents at the height of the pandemic in northern Italy, Monti et al However, the hospitalisation rates, intensive care treatment and mortality appears to be higher in the 106 patients who are on combination therapy with anti TNF and immunomodulators (36%, 5% and 3% respectively), and therefore further data is required.

Vedolizumab selectively inhibits the interaction of α4β7 with mucosal adhesion molecule -1 preventing the entry of T lymphocytes across the endothelium to the inflamed gastrointestinal mucosa (116) . The receptors are present in GI tract, nasopharyngeal mucosa, and biliary epithelium. The gut-selective mode of action of vedolizumab should theoretically be associated with a lower risk of infections. No increase in viral infections including nasopharyngitis was noted in vedolizumab treated patients in a meta-analysis (117) . Higher, but statistically insignificant, rates of enteric infections occurred in vedolizumab-exposed patients (7.4/100 PYs; 95% CI: 6.6-8.3) to placebo (6.7 PYs; 95% CI: 3.2-10.1) in this metaanalysis (117) . No reactivation of hepatitis B or C was noted in 29 patients with history of Hepatitis B or C in a post marketing surveillance study of the licencing trials (118) . In SIV- of these patients required hospitalisation (10, 11, 86) . The IG-IBD study included 15 patients on vedolizumab, five of whom needed admission but reported no association with risk for COVID-19 pneumonia (68) . The SECURE IBD registry (Accessed on 15 th May 2020) has included data from 107 patients on vedolizumab with a 29% hospitalisation rate; (6% in ICU) and 4% mortality (115).

Therapies targeting JAKs may interfere with normal anti-viral response including inhibition of IFN-γ activity (121) , and may potentially increase the risk of infection and/or reactivation of several viral infectious diseases including a dose dependent risk for VZV observed for Tofacitinib (122). In some studies the use of higher dose of Tofacitinib along with corticosteroids was associated with serious infections (123) .

JAK inhibitors also have anti-viral potential since they lower the pro-inflammatory response mediated by viruses and block many pro-inflammatory cytokines involved in cytokine storm such as IL1-, IL6, IL-8 and TNF (1124). Of relevance would be the IL-6 or IL6_R blockade with JAKs or specific anti IL-6R antibody Tocilizumab (125) . Baricitinib, currently not used in IBD but approved for rheumatoid arthritis, blocks viral endocytosis and assembly of virus particles into pneumocytes, and has shown promising results in clinical trials in SARS-CoV-2 (126, 127) . This potential beneficial effect is not seen with Tofacitinib. Fedratinib, a selective A c c e p t e d M a n u s c r i p t JAK2 inhibitor which inhibits TH17 mediated immune hyperstimulation, is also proposed for treatment of severe COVID-19 infection (128) .

The New York series on IMIDs had 4 patients on Tofacitinib, one among them needing hospitalisation but not ventilation (86) . Two patients on Tofacitinib with COVID-19 have been reported in rheumatology literature, both without severe outcomes (114) . In a case report from Washington (129), a young patient on Tofacitinib continued the treatment uninterrupted following diagnosis of COVID-19 and had complete recovery without the need for hospitalisation. Seventeen patients on vedolizumab have been reported so far to the SECURE IBD registry (115), five of whom needed hospitalisation, with one mortality (Accessed on 15 th May 2020).

Hypothetically, blocking IL12 and IL23 which are involved in cytokine storm may have a beneficial effect in ameliorating the cytokine storm in COVID-19 (130, 131) . Ustekinumab 

Currently there is no data to indicate that therapies used in IBD will result in more severe outcomes in patients. Whether drug-induced immunosuppression will prevent the cytokine storm in patients infected with COVID-19 will require further investigation. Until we have more data, a risk versus benefit grid based approach ( Table 2) 

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