key: cord-0683645-i55q6ccp
authors: Taxonera, Carlos; Sagastagoitia, Iñigo; Alba, Cristina; Mañas, Norberto; Olivares, David; Rey, Enrique
title: 2019 Novel Coronavirus Disease (COVID‐19) in patients with Inflammatory Bowel Diseases
date: 2020-05-02
journal: Aliment Pharmacol Ther
DOI: 10.1111/apt.15804
sha: d3a9576f54b056ff7dba50dde057df560ab464c5
doc_id: 683645
cord_uid: i55q6ccp

BACKGROUND: Data on patients with inflammatory bowel diseases (IBD) who have had 2019 novel coronavirus (SARS‐CoV‐2) disease (COVID‐19) are lacking. AIM: To report the clinical characteristics, including gastrointestinal symptoms, of COVID‐19 in IBD patients, and to assess the risk of COVID‐19 in IBD. METHODS: This case series included consecutive IBD patients with laboratory‐confirmed COVID‐19. Age‐adjusted cumulative incidences were compared with the general population in the Madrid region. RESULTS: Through April 8, 12 patients of 1918 IBD patients were diagnosed of COVID‐19. The average age was 52 years, 75% of the patients were female, and 58.3% had Crohn’s disease. Seven patients (58%) were on maintenance treatment with immunomodulators/biologics, of these 4 with combined therapy (33%). Eight patients (66%) required hospitalization (1 intensive care unit admission, and 2 deaths), and 4 patients were isolated at home. Nine patients had diarrhoea ranging between 4‐10 loose stools per day (mean 5.4, SD 1.6). In 5 patients (42%) diarrhoea was a presenting symptom. In 2 patients, diarrhoea was the only symptom at debut. Cumulative incidence of COVID‐19 was 6.1 per 1000 IBD patients. IBD patients had a lower adjusted incidence ratio of COVID‐19 (OR 0.74, 95% CI 0.70‐0.77; p<0.001), and a similar associated mortality ratio (OR 0.95, 95% CI: 0.84‐1.06; p=0.36), compared with the general population. CONCLUSIONS: IBD patients do not have an increased risk of COVID‐19 and associated mortality compared with the general population. In many IBD patients diarrhoea was a presenting symptom, and sometimes, was the only symptom at onset of COVID‐19.

The World Health Organization (WHO) recently declared 2019 novel coronavirus disease outbreak as a pandemic of international concern.([1] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus causing COVID-19, has spread rapidly throughout the world since it was first identified in Wuhan in December 2019. [2] Currently, Spain has one of the highest number of confirmed COVID-19 cases worldwide, with Madrid being the most affected region.

Elderly individuals and those with other chronic underlying conditions have more severe disease and a higher mortality rate when infected with SARS-CoV-2. [3, 4] Inflammatory bowel diseases (IBD) are chronic, immune-mediated inflammatory diseases affecting people of all ages.

A high percentage of IBD patients require immunosuppressive therapies for inducing and maintaining remission. These patients may have a greater risk of acquisition or progression of serious viral infections, including COVID-19. [5] However, the initial available evidence suggests that IBD patients do not have a increased risk of contracting SARS-CoV-2 infection or development of COVID-19, since no patients have been reported to be infected with SARS-CoV-2 in IBD centres in China. [6] Moreover, a recent study reported that none of the patients with IBD followed at a tertiary referral centre in Italy developed To date, there are limited data on patients with IBD who have had COVID-19. Therefore, there is a need for studies assessing the risk and clinical characteristics of the disease in IBD. The objective of this case series was to describe the clinical characteristics, including gastrointestinal (GI) symptoms, of COVID-19 among IBD patients followed at an IBD Unit. We also aimed to assess the risk of developing COVID-19 and the associated mortality in patients with IBD and compare it with that of the general population.

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This was a single-centre observational case series study evaluating the incidence and clinical characteristics of laboratory-confirmed COVID-19 cases among IBD patients followed at a large IBD Unit in the Madrid region (IBD Unit of Hospital Clínico San Carlos, Madrid). Eligible patients included men or women with an established diagnosis of IBD. The study population comprised all consecutive IBD patients with confirmed diagnosis of SARS-CoV-2 infection by a positive result on real-time reverse transcriptase polymerase chain reaction (RT-PCR) approved assays of nasopharyngeal swab samples. We included both hospitalized patients and outpatients with mild symptoms isolated at home according to recommendations. Patients with symptoms suggestive of COVID-19 without a positive RT-PCR were excluded. The study was approved by the hospital's Ethics Committee. Specific verbal informed consent was obtained for all outpatients and for hospitalized patients if possible.

Baseline demographic and clinical characteristics, as well as treatments for IBD, were extracted for the overall IBD population and for COVID-19 cases from the prospectively maintained database ENEIDA (Table 1) . Clinical, laboratory, and radiological findings, and treatment and outcomes data of inpatients were extracted from electronic medical records using a standardized data collection form. For hospitalized patients, severity was assessed at admission by two validated pneumonia scoring indices (CURB-65 and Pneumonia Severity Index [PSI]). [8] Clinical symptoms from outpatients were obtained by the principal investigator by direct telephone contact. We evaluated activity of IBD through validated indexes: Harvey-Bradshaw index (HBI) for Crohn's disease (CD), and Partial Mayo score (PMS) for ulcerative colitis (UC).

We specifically assess GI symptoms. We defined diarrhoea as passing loose stools (Bristol stool scale 6 or 7) ≥ 4 per day for at least 3 consecutive days. For hospitalized patients, we evaluated whether the onset diarrhoea occurred before or after start of COVID-19 therapies.

Study variables were summarized descriptively using numbers and percentages for discrete variables and the mean and standard deviation (SD) or median and interquartile range (IQR) as appropriate for continuous variables. Cumulative incidence of COVID-19 in IBD was obtained by dividing cases by the overall population of IBD patients included in the database. For the same time period, the cumulative incidence of laboratory-confirmed SARS-CoV-2 infection and associated mortality in the general population of Madrid was extracted [Coordination Centre for

This article is protected by copyright. All rights reserved . Age-sex standardized incidence and mortality rates of COVID-19 in the IBD population were obtained with the direct method using the general population of Madrid as standard. We compared standardized incidence and mortality rates between the IBD population and the general population. Results were presented as odds ratios (OR) and their 95% confidence intervals (CI). Statistical analyses were done using the Epidat 3.1 software.

We performed a systematic search of the PubMed database through to April 30, 2020 to find fulltext case reports or case series using the following search strategy: ("SARS-CoV-2" OR "COVID-19") AND ("IBD" OR "inflammatory bowel diseases" OR "Crohn's disease" OR "ulcerative colitis").

This article is protected by copyright. All rights reserved (Table 2 ). In the remaining 4 patients diarrhoea occurred after admission and initiation hydroxychloroquine alone or together with lopinavir/ritonavir, and was self-limiting after drug discontinuation. All inpatients with diarrhoea had negative results in stool culture and test for Clostridium difficille.

On admission, bilateral abnormalities on chest radiography or computed tomography (CT)

were detected in all but one hospitalized patients. The majority of patients showed lymphopenia and had elevated C-reactive protein, fibrinogen lactate dehydrogenase, ferritin, and D-dimer levels (supplementary Table 1 ). Less than 20% of missing laboratory data). To avoid duplications, certain characteristics of some cases were addressed in the discussion.

Through April 8, 2020 cumulative incidence of laboratory-confirmed COVID-19 in the general population of Madrid was 6.6 cases per 1.000 (43.877 reported cases among an overall population of 6,663 million), with a mortality rate of 0.9 deaths per 1000 (5.800 deaths). In the same period, the crude incidence rate of COVID-19 was 6.2 cases per 1000 patients with IBD, and the age-adjusted rate was 4.9 cases per 1000 (95% CI 4.7-5.0). Patients with IBD had a significantly lower standardized risk of COVID-19 compared with the general population (OR

This study is the first report of a case series of SARS-CoV-2 infection in adult IBD patients. The risk of COVID-19 and associated mortality in patients with IBD was significantly lower than that of the general population in the same region. Although patients reported common symptoms already described for COVID-19, of note was the high rate of diarrhoea, which was sometimes the only symptom at onset.

With the results of the systematic literature search, we identified 24 articles. Eighteen were reviews, editorials, guidances or animal models and were excluded, and 6 articles were analysed (Supplementary material S1: PRISMA flowchart). The first study, evaluating initial evidence emerging from China notes that no patients with IBD have been reported to be infected with SARS-CoV-2 in the IBD Elite Union, or in the 3 largest tertiary IBD centres in Wuhan. [6] The second study reported that among 522 IBD patients followed in a tertiary centre at Bergamo, the province with one the highest rate of infection worldwide, no case of COVID-19 was diagnosed. [7] The third study reported a single case of COVID-19 occurring in an adult patient with UC. [9] The fourth study reported 8 children with IBD who had mild SARS-CoV-2 infection among the 102 sites affiliated with the Paediatric IBD Porto group of ESPGHAN. [10] Two recent studies reported two other cases of COVID-19 in patients with IBD. [11, 12] Through April 8, 457

IBD patients with COVID-19 were included in the SECURE-IBD worldwide reporting database (https://covidibd.org/). This database gives no information about incidence rates or clinical symptoms of COVID-19.

In this case cases series including 12 patients we assessed the risk and the clinical characteristics, including GI symptoms, of COVID-19 in patients with IBD. The data included in our database allowed us to report an incidence of COVID-19 of 6.3 per 1000 patients with IBD.

Given our small sample size and the high impact that missed cases of COVID could have, we believe that the finding of a lower standardized risk of developing COVID-19 in IBD should be treated with caution. The study shows that, despite the high use of immunosuppressive drugs in this population, patients with IBD do not have a higher risk of developing COVID-19 and associated mortality than the general population of the region. One of the possible explanations for this observation may be the correct adherence of this population to protection measures. Clinical characteristics, laboratory, and radiological findings of COVID-19 among IBD patients were in line with reported evidence for the general population. [2] [3] [4] 13] Regarding outcomes, the high case

This article is protected by copyright. All rights reserved fatality rate in our cohort was not significantly different from that of the general population in the region. We consider that both rates were highly biased by the inclusion of more serious cases, while asymptomatic or mild cases remained isolated at home without testing for infection.

The most important finding of the study was the high rate of diarrhoea as a presenting symptom among IBD patients with COVID-19 compared with the previously reported data from

Wuhan and later case series for the general population. [2, 3, [13] [14] [15] [16] [17] [18] [19] In the largest COVID-19 case series, diarrhoea was uncommon (rate 3.8%), which suggests a difference in viral tropism as compared with SARS-CoV, and MERS-CoV. [2] Several other case series have reported rates of diarrhoea ranging between 2% and 12.9%. [3, [13] [14] [15] [16] [17] [18] [19] . In a recent study, diarrhoea was a presenting symptom in 37.1% of patients with COVID-19.

[20] A single case of SARS-CoV-2 induced diarrhoea as presenting symptom has been reported. [21] It has been suggested that the increase in GI symptoms in the later phase of this pandemic could be motivated by the possible mutation of the virus towards greater transmissibility, decreased virulence, and

Like prior coronavirus SARS-CoV and MERS-CoV, SARS-CoV-2 had a high tropism for the GI tract [22] [23] [24] Spike (S) protein of SARS-CoV-2 had a high affinity for angiotensinconverting enzyme 2 (ACE2), abundantly expressed in GI cells, and this enzyme is thought to be responsible for the viral invasion of human cells [24, 25] . ACE2 is overexpressed in the inflamed

This article is protected by copyright. All rights reserved GI tract of IBD patients [26] , with significantly higher expression in CD than in UC [27] . This findings could explain the high rate of GI symptoms in IBD patients with COVID-19 observed in our study. Importantly, SARS-CoV-2 has been identified by RT-PCR in stools samples in over half the patients in the general population, suggesting transmission by a faecal-oral route. [28, 29] Moreover, more than 20% of patients remained positive for viral RNA in stools samples after testing negative in respiratory samples, highlighting importance or faecal tests to control spread. [29] Consequently, gastrointestinal physicians and other healthcare workers treating suspected COVID-19 patients with diarrhoea but without common symptoms would be at increased risk of infection and should take additional protective measures. GI endoscopy centres should be aware of the risk that colonoscopy poses for cross contamination.

[14]

In a large study, thiopurines but not biologics were associated with serious viral infections related to EBV, CMV, VZV and HSV infection. [5] A meta-analysis of clinical trial data including 4135 patients given anti-tumour necrosis factor (TNF) therapy found that the relative risk of developing an opportunistic infection, including severe viral infections, was significantly increased in the anti-TNF arm.

[30] However, the International Organization for the study of Inflammatory Bowel Disease (IOIBD) and the AGA Clinical Practice Update recommended to continue with mesalazine, immunosuppressants, biologics, and JAK-inhibitors for IBD patients during the SARS-CoV-2 pandemic, since inflammation itself may be a risk factor for acquiring 32] Overall, our study support this recommendation given that 36.6% of patients followed at our IBD Unit were receiving immunosuppressants and/or biologics (8.2 % with combination therapy) and the incidence of COVID-19 was lower than that of the general population. Once patients have, however, developed COVID-19 IOIBD and AGArecommended to stop these therapies. [31, 32] In our study, 7 patients (58.3%) were on maintenance treatment with immunosuppressants and/or biologics (4 with combined therapy [33%], 2 with thiopurines alone [16.6%] , and 1 with anti-TNF alone [8.3%] ). Although the proportion of patients receiving combined immunosuppressive and biological treatment was numerically higher than that of the overall cohort of patients with IBD, the small sample size does not allow us to draw any conclusions. In all but one patients, these therapies were temporarily stopped during infection.

Available observational data suggest that corticosteroids increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and led to

This article is protected by copyright. All rights reserved complications in survivors, and so their use is not recommended to treat COVID-19 lung injury. [33] Therefore, given the lack of effectiveness and possible harm, routine corticosteroids should be avoided unless they are indicated for another reason, according to WHO interim guidance. [34] Only patient 2 received corticosteroids before diagnosis of SARS-CoV-2 infection in the belief diarrhoea was motivated by a severe UC flare causing acute kidney failure.

In view of the above, we recommend testing all IBD patients presenting diarrhoea for SARS-CoV-2 infection during the outbreak. Doing so will allow us to discriminate an IBD flare from diarrhoea due to SARS-CoV-2 infection and avoid inappropriate use of corticosteroids or other therapies that may favour the progression of COVID-19. In addition, this strategy helps contain the spread of the SARS-CoV-2 infection by detecting and isolating cases without common symptoms of COVID-19. Besides, faecal tests before discharging or ending isolation of patients with SARS-CoV-2 infection can further help reduce cross contamination.

This study had several limitations. First, the incidence of COVID-19 in our cohort of IBD patients is probably underestimated. Following the instructions of the health authorities, some IBD patients with common symptoms of SARS-CoV-2 infection remain isolated in their homes without being tested for viral RNA. These patients were not included as cases. Given the same approach is taken for the general population, this limitation is unlikely to have a major impact on the comparison of incidences. Second, it cannot be ruled out we missed cases of COVID-19 among the IBD population. To obviate this drawback, on April 8, 2020, an anonymous cross-search was carried out among patients followed at the Unit and the positive results of RT-PCR in our hospital.

This strategy identified patient 7 of our case series. Third, the small sample size prevents us from using logistic regression models to assess risk factors for the acquisition or progression of COVID-19. We consider it particularly important to evaluate the association between corticosteroids and immunosuppressive/biological treatment and COVID-19 through large multicentre studies.

In conclusion, although 37% of IBD patients were receiving monotherapy or combination therapy with immunosuppressive drugs, the incidence of COVID-19 and associated mortality was not increased in this population. In many IBD patients, diarrhoea was a presenting symptom and sometimes the only symptom at onset of COVID-19. Diarrhoea can be misinterpreted as an IBD flare, potentially leading to in appropriate corticosteroid treatment which may contribute to COVID-19 progression. Therefore, we recommend testing all IBD patients presenting diarrhoea

for SARS-CoV-2 infection during the outbreak. Moreover, this strategy may help contain the spread of the infection, including transmission by a faecal-oral route. 

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Age (years), mean (SD) 50 (14) Disease: CD, n (%)

Disease duration (years), median (IQR)

CD Localization: L1, n (%)

CD Behavior: B1, n (%)

UC Extension: E1, n (%)

Azathioprine, n (%) 6-mercaptopurine, n (%)

Montreal classification' of Crohn's disease (CD); Disease location (L): L1 terminal ileum

Disease behavior (B): B1 non stricturing non penetrating; B2 stricturing, B3 penetrating

Tofacitinib* is a JAKinase inhibitor not similar to conventional IMM

Competing interests: CT has served as a speaker or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Gebro Pharma, and Tillots. This activity is not related to the present work. The remaining authors have no conflicts of interest to declare.

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