key: cord-0758005-77903fld
authors: Al‐Ani, Aysha H.; Prentice, Ralley E.; Rentsch, Clarissa A.; Johnson, Doug; Ardalan, Zaid; Heerasing, Neel; Garg, Mayur; Campbell, Sian; Sasadeusz, Joe; Macrae, Finlay A.; Ng, Siew C.; Rubin, David T.; Christensen, Britt
title: Review article: prevention, diagnosis and management of COVID‐19 in the IBD patient
date: 2020-05-26
journal: Aliment Pharmacol Ther
DOI: 10.1111/apt.15779
sha: 8ab467c2f87ef7d6eeb625b9f970c18595970fb8
doc_id: 758005
cord_uid: 77903fld

BACKGROUND: The current COVID‐19 pandemic, caused by SARS‐CoV‐2, has emerged as a public health emergency. All nations are seriously challenged as the virus spreads rapidly across the globe with no regard for borders. The primary management of IBD involves treating uncontrolled inflammation with most patients requiring immune‐based therapies. However, these therapies may weaken the immune system and potentially place IBD patients at increased risk of infections and infectious complications including those from COVID‐19. AIM: To summarise the scale of the COVID‐19 pandemic, review unique concerns regarding IBD management and infection risk during the pandemic and assess COVID‐19 management options and drug interactions in the IBD population. METHODS: A literature review on IBD, SARS‐CoV‐2 and COVID‐19 was undertaken and relevant literature was summarised and critically examined. RESULTS: IBD patients do not appear to be more susceptible to SARS‐CoV‐2 infection and there is no evidence of an association between IBD therapies and increased risk of COVID‐19. IBD medication adherence should be encouraged to prevent disease flare but where possible high‐dose systemic corticosteroids should be avoided. Patients should exercise social distancing, optimise co‐morbidities and be up to date with influenza and pneumococcal vaccines. If a patient develops COVID‐19, immune suppressing medications should be withheld until infection resolution and if trial medications for COVID‐19 are being considered, potential drug interactions should be checked. CONCLUSION: IBD patient management presents a challenge in the current COVID‐19 pandemic. The primary focus should remain on keeping bowel inflammation controlled and encouraging medication adherence.

In December 2019, reports of a novel coronavirus, since named SARS-CoV-2, emerged from Wuhan, central Hubei Province, China. 1-3 The virus causes the disease COVID-19, which manifests as a severe acute respiratory illness that can be complicated by acute respiratory distress syndrome (ARDS), multiorgan failure and even death. 3 Following rapid spread of the virus across the globe, the World Health Organisation (WHO) declared COVID-19 a pandemic on 11

March 2020. 2 There are currently almost 2 million confirmed cases across more than 200 countries with a total death count greater than 100 000 at the time of writing. 2 As the pandemic expands, there has been increasing concern regarding the impact of COVID-19 on patients with IBD.

The primary management of IBD involves treating uncontrolled inflammation with a significant number of patients requiring immune-based therapies. 4 In the last decade, there has been a considerable expansion of the therapeutic armamentarium for patients with IBD to include immunomodulators, TNF antagonists, non-TNFtargeted biologics and targeted small molecule therapies. 5 However, these therapies, in addition to malnutrition which can complicate IBD, may weaken the immune system and potentially place IBD patients at increased risk of infections and infectious complications. 6 Consequently, there is a concern that IBD patients are at greater risk of developing COVID-19 and at increased risk of progressing to a more severe clinical course or even death compared to the general population. In addition, if an IBD patient develops COVID- 19, there is a lack of guidance on medication management and concern regarding drug interactions if trial medications are utilised to treat Therefore the aim of this review is to summarise the evidence and discuss in detail the data regarding the risks of developing COVID-19, strategies that can be implemented to reduce these risks and issues surrounding the treatment of COVID-19, including potential drug interactions and IBD medication management, in the IBD patient cohort.

Coronaviruses (of the family coronaviridae) are a group of related single-stranded, positive sense, enveloped RNA viruses. They are the largest known RNA viruses, ranging from 26 to32 kilobases in size. 7 They are named after their appearance under electron micros- Syndrome Coronavirus 2 (SARS-CoV-2). 9 These viruses are all known to cause respiratory symptoms ranging broadly in severity, both between the different viruses and in different hosts infected with the same virus. Most spread easily and result in relatively mild illness in immunocompetent patients, with certain strains being responsible for almost 30% of the common cold. 10 Other coronaviruses (CoVs), including the SARS-CoV and the MERS-CoV, have previously emerged as epidemics with significant mortality and socioeconomic impact. Compared to SARS-CoV-2, MERS-CoV causes a much more severe illness, with a case-fatality rate (CFR) of up to 30%, but appears to have a lower person-to-person transmission, limiting its global impact. 5 There are still new cases of MERS being reported today. 11 Similarly, the SARS-CoV outbreak in 2002-2003 had a high CFR (9.6%), but its reduced infectivity compared with SARS-CoV-2 lessened its overall impact. 12 This outbreak appears to have been contained. 12 SARS-CoV-2 is the first pandemic coronavirus. Therefore, it poses a threat of uncertain dimensions and represents uncharted territory for the public and global healthcare systems alike. 2,3

SARS-CoV-2, the virus previously known as novel 2019-coronavirus, causes the disease COVID-19. It was first discovered following the reports of an outbreak of pneumonia in China, with initial infections linked to a single seafood market. 1, 13 Genetic studies have shown its genetic sequence is 82% similar to SARS-CoV, and 89% similar to bat-SL-CoVZC45 and bat-SL-CoVZXC21, leading to the postulation that bats served as reservoir host for the new coronavirus' progenitor. 14 Human transmission is thought to have been facilitated by an animal intermediate host, currently hypothesised to be a pangolin. 15 

Human-to-human transmission is believed to be predominantly via direct contact, exhaled droplets and fomites from an infected individual. 16 SARS-CoV-2 can also be detected in saliva, urine and the gastrointestinal tract in both biopsy specimens and stools, although their role in transmission remains unclear. [17] [18] [19] Data suggest it is more easily transmitted than seasonal influenza based on a basic reproduction number (R 0 -the expected number of cases directly generated by one case in the population) of 2-2.5. 20

Entry of coronaviruses into human target cells requires spike (S) protein binding to a cellular receptor followed by S protein priming by host proteases to facilitate cell entry. 21 SARS-CoV-2 human-to-human transmission is enabled by the interaction of the SARS-CoV-2 S-protein with the human angiotensin-converting enzyme 2 (ACE2) receptor. 17, 18 Transmission occurs when the virus enters the nose, mouth or eyes, and potentially the digestive system and attaches to cells that produce ACE2. ACE2 are found in multiple organs and are highly expressed in lung AT2 cells, enterocytes of the small intestine and colon. 22, 23 Once the virus is attached to ACE2 it uses the host serine protease TMPRSS2 for S priming allowing fusion of viral and cellular membranes and viral entry into the cell. 21 Once a person develops initial symptoms of COVID-19, respiratory viral shedding occurs for a median of 20 days in survivors and is sustained until death in nonsurvivors. 24 Of note, prolonged shedding has been demonstrated with other coronaviruses in immunocompromised patients 25 and in immunocompromised animals with MERS-CoV. 25 27 Asymptomatic people are also potential sources of SARS-CoV-2 as transmission may occur in the pre-clinical period (2-14 days) or from an oligosymptomatic individual. 27, 28 Furthermore the virus has been detected in up to 50% of stool specimens and can remain positive for viral RNA following negative respiratory samples in more than 20% of SARS-CoV-2 patients. 19, 22, 29 These characteristics may have implications regarding isolation and decision-making for IBD patients who are infected with SARS-CoV-2 although there are no evidence-based guidelines on this currently.

The major clinical manifestations of COVID-19 are fever (44% on admission and 89% during admission), dry cough (68%), shortness of breath (19%), diarrhoea/vomiting/abdominal pain (20%), generalised myalgia/arthralgia (15%), headache (14%), malaise and bilateral interstitial pneumonia. 15, 19, 30 COVID-19 pneumonia manifests with chest CT imaging abnormalities, even in asymptomatic patients, with rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities that progress to or co-exist with consolidations within 1-3 weeks. 15 While the mechanism of COVID-19 induced gastrointestinal symptoms remains to be clarified, enteric symptoms may occur due to malabsorption secondary to direct damage of the invaded enterocyte in the setting of a viral infection. 18 Furthermore, there is a recent case report of a possible SARS-CoV-2 gastrointestinal infection causing acute haemorrhagic colitis and signalling COVID-19 disease. 31 It is not clear if gastrointestinal symptom rates secondary to COVID-19 differ in patients with IBD but if an IBD patients presents with worsening gastrointestinal symptoms, COVID-19 infection should be considered as a differential.

The median age of an infected individual is 51 years old and the majority of infected individuals range from 30 to 69 years. 16 Fifty-one percent of reported cases is male. Healthcare workers may be at increased risk of infection secondary to close contact with infected patients and exposure to aerosolised virus from medical equipment and procedures including endoscopy. 32 In China healthcare workers made up 3.5% of COVID-19 patients and Italy have reported that 20% of its responding healthcare work force is being infected. 17, 33 Current data suggest that children under the age of 18 years have a low infection rate (2.4%), with a large proportion being identified through contact tracing in adults rather than through symptomatology. 16 

The median incubation period for SARS-CoV-2 is 4-5 days, with most patients having symptom onset before 14 days, but there have been cases with longer incubation. 34 A mean interval of 9.1-12.5 days between illness onset and hospitalisation has been documented highlighting the challenge in the identification and isolation of individuals at an early stage of disease. 35 In recovered cases, the median time from initial symptoms to discharge from hospital was 22 days and in those that succumbed the average time to death was 18.5 days. 35 Overall CFR of COVID-19 are estimated to be approximately 1%-2%, rising to more than 15% in patients aged 80 years and over. 36 Current WHO data surmise that most cases of COVID-19 have mild to moderate disease (80%) with 13.8% experiencing severe disease defined by the following signs and symptoms within 24-48 hours:

shortness of breath; tachypnoea >30 breaths per minute; hypoxia <93%; hypoxaemia with PaO 2 /FiO 2 ratio < 300 and/or pulmonary infiltrates >50% of the lung field. 16 Critical infections occur in 6. 

Risk factors for contracting COVID-19 have not been fully elucidated. Healthcare professionals are at greater risk secondary to increased exposure 32 and it is thought that smoking may exacerbate contraction. 37 For all patients with COVID-19, severity and mortality is associated with age (median age 66 years for critically ill vs 51 years in the overall patient population) and underlying cardiovascular disease, hypertension, chronic pulmonary disease, diabetes and cancer. 16, 17, 38 Severe COVID-19 is less common in children with reports suggesting approximately 5% develop severe disease and 0.6% become critical. 39 The crude fatality rate is higher in males (4.7%) vs females (2.8%) and smokers. 16 26, 40 For IBD patients, the greatest risk factor for general immunosuppression and infections remains pharmacological. 41, 42 Nutritional status, co-morbidities, age and disease activity also contribute. 42 41, 42 Furthermore, low vitamin D levels are prevalent in IBD patients and may be associated with an increased risk and/or severity of influenza and COVID-19. 45, 46 Vitamin D increases anti-inflammatory cytokines and lowers viral replication, which in turn may reduce pro-inflammatory cytokines that propagate lung injury and ARDS. [45] [46] [47] Therefore assessment of vitamin D and supplementation when it is low is reasonable.

As gastrointestinal tract permeability may be increased in IBD 

A diagnosis of COVID-19 should be considered in patients who display fever, cough, anosmia, nausea, vomiting and diarrhoea. Of note, a subgroup of patients may present with mild disease marked by the presence of diarrhoea initially and these patients often experience delayed diagnosis compared to those that present with respiratory symptoms. 51 Biochemical markers of COVID-19 include lymphopenia, thrombocytopenia and leukopenia as well as elevated C-reactive protein (CRP), which may also correlate with severe disease. 17 Less commonly, there may also be elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK) and D-dimer. 17 Recommendations on whom to test for COVID-19 will vary depending on the local guidelines, availability of testing kits and regional transmission dynamics. In high-risk settings where an outbreak has occurred, all patients with clinical features consistent with COVID-19 should be considered for testing. In non-outbreak areas, a case of COVID-19 should be suspected and tested for if a patient has clinical features suggestive of COVID-19 and fits epidemiologic criteria for example international travel or contact with a confirmed COVID-19 case. A patient is also considered a suspect case of COVID-19 regardless of their history if they are admitted to hospital with acute respiratory illness or unexplained fever.

Diagnosis of COVID-19 is via nucleic acid testing of nasopharyngeal and oropharyngeal swabs. 52 Serology testing is currently not widely available. It is important to ensure that routine local protocols for testing in acute pneumonia/pneumonitis are also followed, such as bacterial cultures, urinary antigen testing, acute and convalescent serology and respiratory virus panels. At this stage, faecal sampling is not standard; however, this may be indicated in those with gastrointestinal symptoms. A positive test for COVID-19 must be immediately notified to the relevant communicable diseases agency. 52

Despite a lack of evidence demonstrating any increased susceptibility to COVID-19, 50 (Table 2 ). However, theoretically, there may also be some beneficial effects seen with certain immunosuppressive medications, given the cause of death in COVID-19 is a cytokine storm resulting in ARDS.

Overall, apart from corticosteroids, the risks of IBD therapies, particularly 5-ASAs and biologics, appear limited, and the importance of careful discussion regarding the risks versus benefits of medications with patients and among medical practitioners cannot be overstated. Inappropriate cessation of effective agents due to unjustified fear of adverse events may lead to IBD relapse, which when requiring the use of steroids or hospitalisation may inadvertently strain medical resources and increase the risk of COVID-19 exposure and infection.

Sulfasalazine and the 5-ASA medications are used as first-line induction and maintenance treatment for UC. 5-ASAs have very mild immunosuppressive activity and they are often well tolerated with minimal side effects. There are no reports of these medications being associated with an increased risk of infection and studies of large cohorts evaluating the safety profile of 5-ASAs do not demonstrate an increased risk of serious or opportunistic infections. 53 Sulfasalazine and 5-ASA

• Treatment with 5-ASA therapy should continue without concern for increased risk of contracting or developing severe COVID-19.

• If a patient is in contact with someone who has COVID-19 or develops COVID-19, treatment with 5-ASA should continue. 

Corticosteroids systemically reduce inflammation by turning off multiple inflammatory genes. In patients with COVID-19, a systemic inflammatory response syndrome can perpetuate lung injury with persistent inflammation resulting in ongoing pulmonary damage even subsequent to viral suppression. 54 55 In SARS, corticosteroid treatment was of no clinical benefit in regard to infection resolution but was associated with an increased risk of psychosis, 57 delayed clearance of viral RNA, 58 diabetes 59 and avascular necrosis. 60 Finally, in a systematic review on corticosteroid treatment in influenza patients, corticosteroids were associated with an increased length of stay in intensive care, an increased rate of secondary bacterial and fungal infections and an increase in mortality compared to those who did not receive corticosteroids. 56 However there is limited evidence that they increase the risk of either upper respiratory tract infections or pulmonary infections. 70, 71 In addition, mercaptopurine has been shown to inhibit one of the proteases essential to viral maturation of MERS-CoV in vitro, although no further animal-based models exist to suggest clinical efficacy. 72 Methotrexate has variably been demonstrated to increase the risk of infections in patients with inflammatory diseases. Reassuringly, a recent systematic review reassuringly found that in the nonrheumatoid arthritis inflammatory disease population, there was not an Sulfasalazine and 5-ASA

• Treatment with 5-ASA therapy should continue without concern for increased risk of contracting or developing severe COVID-19.

• If a patient is in contact with someone who has COVID-19 or develops COVID-19, treatment with 5-ASA should continue.

increased risk of infection with methotrexate (1.03, 95% CI0.82-1.3). 73 This applied similarly to respiratory infections specifically. 74

Anti-TNF agents have been shown to increase the risk of upper and lower respiratory tract infections, as well as serious and opportunistic pulmonary infections. 62, 75, 76 Compared with anti-TNF monotherapy, risk of serious infections increases with combination of anti-TNF and an immunosuppressive agent or most significantly in combination with corticosteroids. 77 In a study that did not separate mono-or combination-anti-TNF therapies, the risk of pneumonia was only slightly increased in patients receiving a TNF antagonist Of note, anti-TNF therapy has been employed in the management of severe sepsis, with a meta-analysis demonstrating reduced overall mortality when used in severe sepsis before shock, and improved survival at 30 days in patients with shock or high baseline levels of IL-6. 78 There are no data on the incidence and severity of SARS or COVID-19 in patients on anti-TNF medications. Anti-TNF agents were utilised in the initial phase of the SARs epidemic, although the overall evidence for efficacy is lacking. 79

The main non-TNF antagonist biologics for IBD include the anti-IL12/23 biologic ustekinumab and the anti-integrin therapy, vedolizumab. Reassuringly, the risk of severe respiratory tract infections, severe infections in general or opportunistic infections does not appear to be increased in long-term follow-up studies of ustekinumab in both IBD and psoriasis. [80] [81] [82] Similar data have also been reported for vedolizumab. [83] [84] [85] [86] There is a theoretical concern of an increased risk of respiratory infections, and hence COVID-19, with vedolizumab treatment as vedolizumab binds the T-cell integrin receptor α 4 β 7, inhibiting its binding to MADCAM1 present on the small intestinal endothelium and vasculature. These receptors are also expressed in the T cells occupying the nares, although to a far lesser extent when compared to the intestine. 87 Interestingly, baricitinib, a JAK inhibitor used in rheumatoid arthritis, has a potential therapeutic role in the management of SARS-CoV-2 through both its anti-inflammatory action and Numbassociated kinase (NAK) inhibition. Tofacitinib has no affinity for this particular kinase. NAKs are involved in the function of clathrin, which mediates endocytosis of SARS-CoV-2 into cells resulting in infection. 94 Due to the anti-inflammatory effects of the JAK inhibitors, it has also been speculated that they may be able to combat the elevated levels of cytokines observed in COVID-19 which may potentially further decrease the severity of the infection. 94

If a patient is exposed to or gets infected with COVID-19, the withholding of immunosuppressive medications should be considered where possible. It is important to note that many IBD medications may take months to be eliminated from the body so the utility of withholding these medications in the short term is likely to be limited. (See Table 3 ).

The response to COVID-19 is rapidly evolving and gastroenterologists should regularly review local, institutional and international recommendations. Despite limited data, patients with IBD are theoretically at increased risk of COVID-19 due to proximity to medical facilities and immunosuppression. There are therefore several recommendations that clinics and patients can implement to reduce risks.

Nutrition should be optimised as malnutrition can disrupt the innate immune response, including complement and mucosal secretory antibody formation, and is associated with increased infection risk in IBD patients. 96 Smoking has been associated with worse outcomes and increased mortality in COVID-19 17 and therefore patients should be encouraged to quit smoking.

Immunisation: Immunisation of patients should be strongly encouraged to reduce preventable co-infection with other viruses:

Patients should receive pneumococcus (PCV13 and PPSV 23) and

influenza (quadrivalent inactivated vaccine) vaccination. therapies are summarised in Table 4 . Where interactions exist, it is possible for patients to cease their IBD medications and continue on trial medications.

Remdesivir is a prodrug of the adenosine nucleotide analogue GS- 

Chloroquine is a widely used anti-malarial and autoimmune disease drug. It has a broad spectrum anti-viral action that is exerted 109 Chloroquine is not accessible in Australia and it has been suggested that hydroxychloroquine could be an effective alternative given that it is an identical molecule to chloroquine apart from the addition of a hydroxyl group. 108 

Favipiravir, a guanine analogue, effectively inhibits the RNAdependent polymerase of RNA viruses. This anti-viral effect has efficacy on influenza (approved use), Ebola, yellow fever, chikungunya, norovirus and enterovirus. Activity against COVID-19 has been reported. 112 It is currently being tested in Japan and has no significant drug interactions. In a recent study it has been reported to improve clinical recovery rates at day 7 when compared to arbidol, a flu medication (71% vs. 56%) but there was no difference in auxiliary oxygen or non-invasive ventilation requirements. 113 

IBD patients present a unique challenge in the setting of the current COVID-19 pandemic. Of concern is that, at least theoretically, 

Guarantor of the article: Britt Christensen. 

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