key: cord-0947778-yn7mj8qp
authors: Rizzello, Prof Fernando; Calabrese, Carlo; Salice, Marco; Calandrini, Lucia; Privitera, Hana; Melotti, Laura; Peruzzi, Giulia; Dussias, Nikolas; Belluzzi, Andrea; Scaioli, Eleonora; Decorato, Anastasio; Siniscalchi, Antonio; Filippone, Eleonora; Laureti, Prof Silvio; Rottoli, Matteo; Poggioli, Prof Gilberto; Gionchetti, Prof. Paolo
title: COVID-19 in IBD: the experience of a single tertiary IBD center
date: 2020-12-26
journal: Dig Liver Dis
DOI: 10.1016/j.dld.2020.12.012
sha: 315475519facfa999cdccd4e0a076d368f5bb89f
doc_id: 947778
cord_uid: yn7mj8qp

BACKGROUND: Italy has been one of the most affected countries in the world by COVID-19. There has been increasing concern regarding the impact of COVID‐19 on patients with inflammatory bowel disease (IBD), particularly in patients treated with immunosuppressants or biologics. The aim of our study is to understand the incidence of COVID-19 in a large cohort of patients with IBD. Furthermore, we analyzed possible risk factors for infection and severity of COVID-19. METHODS: This was an observational study evaluating the impact of COVID-19 on IBD patients in a single tertiary center. A 23 multiple-choice-question anonymous survey was administered to 1200 patients with IBD between March 10(th) and June 10(th) 2020. RESULTS: 1158 questionnaires were analyzed. The majority of patients had Crohn's disease (CD) (60%) and most of them were in clinical remission. Among the 26 patients (2.2%) who tested positive for COVID-19, only 5 (3CD) were on biological treatment and none required hospitalization. Two patients died and were on treatment with mesalazine only. Of the 1158 patients, 521 were on biological therapy, which was discontinued in 85 (16.3%) and delayed in 195 patients (37.4%). A worsening of IBD symptoms was observed in 200 patients on biological therapy (38.4%). Most of these patients, 189 (94.5%), had stopped or delayed biological treatment, while 11 (5.5%) had continued their therapy regularly (p<0.001). CONCLUSIONS: Our data are in line with the current literature and confirm a higher incidence compared to the general population. Biological therapy for IBD seems to not be a risk factor for infection and should not be discontinued in order to avoid IBD relapse.

In December 2019, the novel coronavirus SARS-CoV-2 surfaced from Wuhan, central Hubei Province, China. 1 After rapid spread across the world, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic on 11 March 2020. 2 There are currently more than 7 million confirmed cases across more than 200 countries and there have been almost 400,000 deaths at the time of writing. Italy has been one of the most affected countries with Lombardy, Piedmont and Emilia-Romagna being among the regions with the highest number of confirmed cases and deaths.

The clinical presentation of COVID-19 is quite variable. A large study from the Chinese Center for Disease Control and Prevention showed that among 72,314 affected patients, severity was reported as mild in 81.4%, severe in 13.9%, and critical in 4.7%. 3 The clinical characteristics of mild COVID-19 include symptoms common to other viral infections such as fever, cough, dyspnea, myalgia, fatigue, and diarrhea. In severe cases, COVID-19 may lead to acute respiratory distress syndrome (ARDS), multiple organ failure and death. 4 Risk factors for contracting COVID- 19 have not been fully understood. Healthcare professionals are at greater risk due to increased exposure 5 and there are conflicting data regarding smoking as a risk factor. 6 Severity and mortality of COVID-19 are associated with age, underlying cardiovascular disease, hypertension, chronic pulmonary disease, diabetes and cancer. The fatality rate appears higher in males and smokers. 7 Moreover, angiotensin-converting enzyme 2, used by coronaviruses to penetrate target cells, is expressed by vascular endothelial and intestinal epithelial cells, mainly in the terminal ileum and colon, especially when inflamed. [8] [9] As the pandemic expands, there has been increasing concern regarding the impact of COVID-19 on patients with inflammatory bowel disease (IBD), particularly in patients treated with immunosuppressants or biologics. Specific risk factors for developing COVID-19 in IBD patients are yet to be determined, however the greatest risk factors for other infections in patients with IBD are nutritional status, age, co-morbidities, disease activity and pharmacological treatment.

Indeed, malnutrition deprives the immune system of the components needed to generate an effective immune response. Nutritional deficiency is associated with impaired cell-mediated immunity as well as decreased phagocyte function, cytokine production, secretory antibody affinity and response, and impairment of the complement system. 10 Furthermore, early reports suggest that low vitamin D levels, common in IBD patients, may be associated with an increased risk and/or severity of Disease activity is a significant non-pharmacological risk factor for infections, therefore medical treatment aiming for disease control should be optimized. 12 On the other hand, IBD treatments include corticosteroids, immunosuppressants (such as thiopurines) and immunomodulators (such as TNF-antagonists, non-TNF-targeted biologics and targeted small molecule therapies), which may weaken the immune system and potentially place IBD patients at increased risk of infections and infectious complications. 13 Age is associated with a higher risk of infections in IBD patients, 14 and comorbidities have been described in general as an independent risk factor for infection-related hospitalizations. 15 Consequently, there is a concern that IBD patients are at greater risk of both developing COVID-19 and of a more severe clinical course compared to the general population.

With this in mind, the aim of our study is to understand the incidence of COVID-19 in a large cohort of patients with IBD from a single Italian tertiary referral IBD center. Furthermore, we analyzed possible risk factors for infection and severity of COVID-19 and the impact of the pandemic on IBD management.

This was an observational study evaluating the impact of COVID-19 on IBD patients in a single tertiary IBD center.

A 23 multiple-choice-question anonymous survey (Supplementary Table 1 ) was administered to a total of 1200 patients with Crohn's disease (CD) or Ulcerative Colitis (UC) who had scheduled visits in our IBD center in Bologna between March 10th and June 10 th , 2020. The survey was administered in-person to 680 patients who underwent an outpatient visit and by telephone or email to 520 patients who missed a scheduled visit during the period under review. The follow-up was mainly conducted face-to-face and, only in a minority of patients, by e-mail or telephone.

Telephone triage before patients' access to the outpatient clinic was performed to check for possible symptoms and/or contact with infected persons and for promotion of basic protective measures. A rigorous protocol to avoid infection outbreaks was adopted for patient access to the outpatient clinic and, particularly, checkpoints to investigate suspected symptoms and signs of COVID-19, to test body temperature, and to provide personal protective equipment (PPE) were posted at every public entrance of the hospital. All patients and the entire staff wore PPE and strictly followed the WHO recommendations to prevent infection. If patients were on biological therapy, they were asked to report if treatment was discontinued or delayed due to the pandemic. All patients were asked to describe if they experienced subjective worsening of IBD symptoms during the health emergency. For hospitalized patients, length of stay and need for ventilation support were also recorded. 6 We removed all known duplicates or erroneous reports. We identified additional potential duplicate records based on matching age, sex, IBD disease type, and place of residence, and reviewed these manually. 

We used descriptive statistics to summarize the basic demographic and clinical characteristics of the study population. We summarized continuous variables using means and standard deviations.

We expressed categorical variables as proportions. Comorbidities recorded were hypertension, diabetes, heart disease (ischemic or congestive), and other diseases.

We analyzed a variety of COVID-19 outcomes, including outpatient care only, hospitalization, ventilator requirement, and death from COVID-19 or related complications. Simple data are provided for the overall study population.

Multivariable logistic regression estimated the independent effects of age, sex, disease (CD vs UC), disease activity, smoking, IBD therapy, BMI ≥ 30, and number of comorbidities (0, 1, ≥ 2) on the primary outcome of severe COVID-19. A secondary outcome was the composite of any hospitalization and/or death.

All statistical analyses were performed with a statistical software package (SPSS-20). Two-sided p values < 0.05 were considered statistically significant.

Of 1200 questionnaires, 1158 were analyzed. 42 questionnaires were discarded due to missing data. Demographic, clinical, and IBD treatment-related characteristics are summarized in Table 1 .

The mean age was 44.5 years (range 18-86), and there was a slight predominance of males (55.62%).

The majority of patients had CD (60%) and were in clinical remission (56.7%).

Of the overall population, 521 patients (45%) were on biological treatment for refractory active IBD, 83 (7.2%) were on non-systemic steroids, 77 (6.65%) were on systemic steroids, 787 (67.9%) were on sulfasalazine/mesalazine and 46 (3.9%) were on thiopurines (Table 1 ).

In all 521 (45%) patients on biological treatment the indication was refractory IBD.

As stated in table 1, 292 (25.2%) patients also had spondyloarthritis and 25 (2.2%) had psoriasis.

No comorbidities were present in 555 patients (47.9%); 336 (29%) had a single comorbidity, 148 (12.78%) had two, and 64 (5.52%) had three or more ( Table 1) per 1000 (34,114 deaths). In the high-risk regions of Lombardy, Emilia-Romagna and Piedmont, the incidence was 9.01, 6.27, and 7.10 cases per 1000 inhabitants respectively. 16 On multivariable analysis, age above 70 years (OR 1.08, 95% CI 1.02-1.09) and the presence of ≥ 2 comorbidities (OR 3.1, 95% CI 1.2-7.6) were positively associated with a more aggressive COVID-19 course. No significant association was seen between biological treatment and a more severe COVID-19 course.

There are only limited data on the incidence of COVID-19 in the IBD population. In our study, the incidence of COVID-19 is 22.4 per 1000 patients, higher than that of the overall population. 16 Among the 26 patients who tested positive, 4 were asymptomatic. These data can be explained by the fact that most of our patient cohort came from high-risk regions for COVID-19, where preliminary data from serology studies show that the prevalence of the infection seems to be much higher than that known to date due to an uncountable number of asymptomatic patients. 5, 17 In very early reports from China, no patients with IBD were reported to be infected with SARS-CoV-2 in the IBD Elite Union, which incorporates the seven largest IBD referral centers in China with more than 20000 patients with IBD. 18 An and colleagues described a very low incidence of SARS-CoV-2 infection in 318 patients followed in a prospective database at the Regional Medical IBD Center of China, Renmin Hospital of Wuhan University, Wuhan, China. Patients were educated about virus transmission and invited to strictly avoid non-familiar contact. All drugs were stopped except mesalazine and thalidomide.

Flares were treated with enteral nutrition and/or low-dose steroids. None of the 318 patients living in the high-risk area but closely adherent to the indications developed symptoms suggesting COVID-19. 19 Taxonera et al. reported a cumulative incidence of 6.1 per 10000 patients among IBD patients followed at a large IBD unit in the Madrid Region, lower than that of the overall population. 20 In a very early study, among 522 patients followed in a single IBD center in Bergamo, no case of COVID-19 was reported. 21 Due to the variable presentation of COVID-19, these early reports highlight the need for studies on the prevalence of the disease based on serology.

In our study, 44.8% of patients were on maintenance treatment with biologics and 6.6% were on systemic steroid therapy. Among the 26 patients who tested positive for COVID-19, 5 were on maintenance therapy with biologics (19%) and 4 were in treatment with systemic steroids (15.4%).

Patients on biologics who tested positive did not have a more severe COVID-19 course, and the only two patients who died were on mesalazine monotherapy. Risk factors for a more aggressive course of the disease were in line with current literature: advanced age, male sex and the presence of more than 2 comorbidities.

Examining the risk of severe infection related to the ongoing treatment, Bezzio and colleagues evaluated COVID-19 outcome in 79 patients with IBD. In their study, twenty-two patients (28%) with COVID-19-related pneumonia required hospitalization, 9 (11%) non-invasive ventilation support, 2 (3%) endotracheal intubation and 6 patients (8%) died. Multivariate analysis demonstrated that age over 65 years old, UC diagnosis and disease activity, but not concomitant treatment, were significantly associated with the risk of pneumonia and death. 22 

Bowel Disease (SECURE-IBD), a large international registry that monitors the outcomes of IBD patients with COVID-19, severe infection (defined as intensive care unit admission, ventilator use and death) correlated with age, presence of ≥ 2 comorbidities, steroids and sulfasalazine/mesalazine use, but not with anti-TNF drugs. [23] [24] Furthermore, patients in our study who discontinued or delayed therapy with anti-TNF agents or other biologics showed higher rates of relapse, and in 41% of cases steroid treatment was needed. On the other hand, patients on systemic steroid therapy during the lockdown seemed to be at higher risk for infection, although due to the small sample size no conclusion can be drawn.

These data suggest that TNF antagonists may reduce the severity of COVID-19 infection, while IBD recurrence is a negative prognostic factor. This has led the various scientific societies to advise not to stop therapy with biologics in patients in stable remission for fear of COVID-19 infection. 25 Furthermore, our data seem to confirm the results of early studies results that indicate that continuous steroid treatment could be a risk factor for infection in IBD patients. 26 This study has several limitations. First, the heterogeneity of the clinical presentation of COVID-19 and the small sample size of our cohort of patients prevent us from drawing any final conclusions on the incidence and the risk factors of COVID-19 in the IBD population. Second, the limited number of COVID-19 positive patients in our cohort does not allow us to identify risk factors for severe COVID-19 illness related to the IBD treatment. Large multicenter studies are necessary to evaluate the association between IBD characteristics and COVID-19.

The present study recorded a higher incidence of COVID-19 infection in our IBD cohort than in the general population. These data were probably due to the variable incidence among different regions and to the different methods of diagnosis in asymptomatic subjects in the general population. Current treatment should not be discontinued, particularly biological therapy, in order to avoid IBD relapse. 

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