key: cord-0977111-5vn78b73
authors: Maconi, Giovanni; Bosetti, Cristina; De Monti, Alberta; Boyapati, Ray Kiran; Shelton, Edward; Piazza, Nicole; Gabrielli, Anna Maria Carvalhas; Lenti, Marco Vincenzo; Bezzio, Cristina; Ricci, Chiara; Greco, Salvatore; Romeo, Samanta; Giangregorio, Francesco; Gridavilla, Daniele; Tagliani, Fabio; Massari, Alessandro; Pastorelli, Luca; DiSabatino, Antonio; Saibeni, Simone; Alicante, Saverio; Ferretti, Francesca; Rizzardini, Sandro Ardizzone Giuliano; Galli, Massimo; Ardizzone, Sandro
title: Risk of COVID 19 in patients with inflammatory bowel diseases compared to a control population
date: 2020-12-26
journal: Dig Liver Dis
DOI: 10.1016/j.dld.2020.12.013
sha: 9b9de9a100c1d7c5d3a2ec350b263f478fa819b2
doc_id: 977111
cord_uid: 5vn78b73

BACKGROUND: It is unclear whether patients with inflammatory bowel disease (IBD) are at increased risk of COVID-19. OBJECTIVES: This observational study compared the prevalence of COVID-19 symptoms, diagnosis and hospitalization in IBD patients with a control population with non-inflammatory bowel disorders. METHODS: This multicentre study, included 2733 outpatients (1397 IBD patients and 1336 controls), from eight major gastrointestinal centres in Lombardy, Italy. Patients were invited to complete a web-based questionnaire regarding demographic, historical and clinical features over the previous 6weeks. The prevalence of COVID-19 symptoms, diagnosis and hospitalization for COVID-19 was assessed. RESULTS: 1810 patients (64%) responded to the questionnaire (941 IBD patients and 869 controls). IBD patients were significantly younger and of male sex than controls. NSAID use and smoking were more frequent in controls. IBD patients were more likely treated with vitamin-D and vaccinated for influenza. Highly probable COVID-19 on the basis of symptoms and signs was less frequent in the IBD group (3.8% vs 6.3%; OR:0.45, 95%CI:0.28–0.75). IBD patients had a lower rate of nasopharyngeal swab-PCR confirmed diagnosis (0.2% vs 1.2%; OR:0.14, 95%CI:0.03–0.67). There was no difference in hospitalization between the groups (0.1% vs 0.6%; OR:0.14, 95%CI:0.02–1.17). CONCLUSION: IBD patients do not have an increased risk of COVID-19 specific symptoms or more severe disease compared with a control group of gastroenterology patients.

The novel coronavirus (SARS CoV-2) was first reported in 2 Wuhan in December 2019 and quickly evolved into a global pan- 3 demic [1] [2] [3] . The outbreak rapidly spread to Europe in February 4 2020 with Italy becoming the most impacted country and Lom- 5 bardy, the most affected area [4] . Shortly following the outbreak, 6 the region went into lockdown and the population was instructed 7 to self-isolate at home. Patients with inflammatory bowel disease 8 (IBD) were advised to isolate and take routine precautions against 9 COVID-19 as recommended by the World Health Organization, but 10 to continue their medical therapy, including immunosuppressives 11 or biologics [5 , 6 , 7] . 12 Infection with SARS CoV-2 leading to the coronavirus disease 13 2019 (COVID- 19) can manifest with minor symptoms often mim- 14 icking the common influenza and usually managed at home with 15 isolation. More severe cases are characterized by respiratory func- 16 tion impairment and multi organ failure that require hospitaliza-17 tion and intensive care admission with a current estimate for in- 18 fection fatality rate of 0.5-1% [8 , 9] . Severe and fatal manifestations 19 of COVID-19 are associated with advanced age and pre-existing co- 20 morbidities including cardiovascular disease, diabetes, obesity, res- 21 piratory illnesses and cancer [1 , 2] . 22 It remains uncertain whether IBD patients are more susceptible 23 to COVID-19 or more prone to severe disease. Consequently, there 24 has been significant anxiety among IBD patients and clinicians re-25 garding potential increased susceptibility. This is in part related to 26 IBD management which involves immunosuppression, potentially 27 placing patients at increased risk of opportunistic infections and 28 respiratory illnesses [10 , 11] . However, whether immunomodulators 29 and biologics increase the risk of infection or of developing severe 30 forms of COVID-19, is currently undefined [12] . 31 Initial reports from China demonstrated that the incidence of 32 severe disease might be lower in IBD patients compared with rates 33 in the general population [13] . Similarly, early reports from Italy 34 demonstrated no cases in their IBD population despite continua- 35 tion of immunosuppressive therapy [14] . Furthermore, there have 36 been reports on the safety of IBD therapy demonstrating no associ- 37 ation between treatment with biologics and/or immunomodulators 38 [15] . The recently published series from the SECURE-IBD registry of 39 525 IBD COVID-19 cases noted no increased severity with TNF an- 40 tagonists but a significant association with corticosteroids and the 41 traditional risk factors of increased age and comorbidities [16] . 42 These early reports are reassuring and suggest that IBD patients 43 Results for continuous data are presented as median and in-113 terquartile range and analysed using Mann Whitney U-Test. Cate-114 gorical data are presented as absolute and relative frequencies, and 115 analysed using a chi-square test. 116 The prevalence of likely symptoms, diagnosis and hospital-117 ization for COVID-19 were compared using multivariate logis-118 tic regression models, estimating odds ratios (OR) and their 95% 119 confidence intervals (CI). The models were adjusted for socio-120 demographic variables, i.e., age, sex, area of residence. Moreover, 121 additional models were also adjusted for variables which were sig-122 nificantly different on univariate analysis. All tests were 2-tailed 123 203 Highly probable COVID-19 was less frequent in the IBD group 204 compared to the control group (3.8% vs 6.3%, p 0.006) . The lower 205 rates of highly probable COVID-19 in the IBD group persisted after 206 logistic regression analysis adjusting for age, sex, area of residence 207 and education (OR 0.53; 95% CI 0.33-0.84) and in another model 208 adjusting for smoking, oncologic diseases, rheumatologic diseases, 209 use of acetaminophen, aspirin and NSAIDs, vitamin D intake and 210 vaccination for seasonal influenza (OR 0.45; 95% CI 0.28-0.75) .

Alternative definitions of highly probable COVID-19, including 212 fever, ageusia/anosmia and respiratory symptoms such as cough 213 or dyspnea (OR 0.52; 95% CI 0.30-0.90) or fever, ageusia/anosmia 214 and systemic symptoms such as fatigue or myalgia (OR 0.42; 95% 215 CI 0.26-0.70) provided very similar results, even after adjusting 216 for smoking, oncologic diseases, rheumatologic diseases, use of 217 acetaminophen, aspirin and NSAIDs, vitamin D intake and vacci-218 nation for seasonal influenza. IBD patients treated with biologic 219 therapy showed a comparable rate (15/409; 3.67%) of COVID-19 220 symptoms compared with patients treated with other therapies 221 (21/532; 3.95%). Prevalence of COVID-19 symptoms in active IBD 222 patients was not significantly different from that of patients in 223 clinical remission (3.7% vs 4.1%). 224 

225 One (0.1%) IBD patient and 6 (0.7%) controls were hospitalised 226 for COVID-19 (p 0.08), and the IBD patient died ( Table 4 ). There 227 was no difference in the numbers where data was missing from 228 the completed questionnaire. There was no difference found be-229 tween the groups on logistic regression analysis adjusting for age, 230 sex, area of residence and education (OR 0.15, 95% CI 0.02-1.26) 231 or in another model adjusting for smoking, oncologic diseases, 232 rheumatologic diseases, use of acetaminophen, aspirin and NSAIDs, 233 vitamin D intake and vaccination for seasonal influenza (OR 0.14, 234 95% CI 0.02-1.17). tions requiring hospitalization was less frequent in the IBD group. 243 We identified a number of possible modifiable protective factors 244 including influenza vaccination, lower smoking rate, vitamin D in-245 take and higher vigilance. 246 The low risk of COVID-19 in IBD patients has already been re-247 ported in China, Italy and Spain [13 , 14 , 18] . In a Spanish study only 248 12 of 1918 IBD patients were diagnosed with COVID-19, with lower 249 adjusted incidence ratio of COVID-19 (OR 0.74) compared with the 250 general population, but a similar mortality ratio (OR 0.95) [18] . In 251 addition, severe sequelae of COVID-19 may be less frequent in IBD 252 patients than in control subjects [19] . risk factor and male gender is associated with worse outcomes [8] . with biologics compared to other treatments. [16 , 25 , 26] . However, 283 due to the small number of IBD patients with adverse outcomes, 284 we could not verify these data. centers. This with the intent to obtain best representative results, 320 generalizable to all IBD patients. However, the overall response rate 321 to the questionnaire was affected by geographical reasons (place of 322 the recruiting unit) and responses slightly differed in IBD and con-323 trols according to the place of residence. Therefore, odds of COVID- 324 19, have been estimated by logistic regression analysis adjusted 325 also for the area of residence. We acknowledge that a random sam-326 ple of the general population would have been the ideal control 327 group for this kind of study. This study included a control group 328 of general gastroenterology patients matched for sex, age and ge-329 ographical areas which represented a reasonable and convenient 330 alternative. 331 Another limitation of the study is the low rate of nasopharyn-332 geal swab-PCR based diagnosis and the lack of clear data on the 333 number of swabs performed. Selection bias is thus possible, and 334 any furthermore interpretation of PCR positivity rate should be 335 made with caution. Although we acknowledge that an ideal study 336 of prevalence should have tested all patients for COVID-19, the 337 limited testing capability in Lombardy during early 2020 meant 338 that most patients were unable to be tested despite symptoms. 339 This has been reflected elsewhere in the world in the early phases 340 of this pandemic [8] . With this in mind, we could not assess the 341 confirmed diagnoses of COVID-19, but considered only the "highly 342 suspected COVID-19 based on symptoms. Without confirmation 343 by swab-PCR, this analysis potentially misdiagnosed a propor-344 tion of patients as COVID-19 who actually had other respiratory 345 conditions. However, nasopharyngeal swab-PCR has suboptimal 346 sensitivity, as low as 60% in some reports [36] . We incorporated 347 fever (common but not specific for COVID-19) with change in 348 sense of smell and taste (less common but much more specific 349 for COVID-19) and another symptom (pulmonary or systemic) to 350 optimize the accuracy of highly suspected COVID [37] [38] [39] [40] . It is 351 likely that asymptomatic or pauci-symptomatic patients have been 352 overlooked in this analysis and this might have underestimated 353 the real prevalence of the infection. In our region (10 million 354 of habitants) at that time there were only 72,0 0 0 (0.72%) cases 355 diagnosed with PCR swab, and 13.0 0 0 (0.13%) hospital admissions, 356 a percentage quite similar to that seen in our study [44] 357 There are a number of strengths to this study. This is the largest 358 cohort study of COVID-19 reporting symptoms, diagnosis and out-359 comes in IBD to date. It was conducted in Lombardy at the time 360 when it was the worldwide epicenter of the COVID-19 pandemic. 361 The high rate of community risk for COVID-19 during this period 362 provided a suitable environment for a case-control study of this 363 type. The large number of patients in this study allowed identi-364 fication of modifiable protective factors accounting for the lower 365 rate of COVID-19 in IBD patients including higher use of vitamin D 366 and influenza vaccination, less NSAID use, lower smoking rates and 367 increased vigilance. 368 This study found that IBD patients have a lower risk of COVID-369 19 by highly probable symptomatic criteria and do not have a 370 higher risk of hospitalization compared to controls. It also iden-371 tifies modifiable protective factors. This is reassuring for patients 372 and clinicians and supports the emerging data that IBD patients 373 are not at increased risk of contracting COVID-19 or more severe 374 disease [13 , 14 , 18] . No external funding for this manuscript. 4 4 4 Financial disclosure 445 All authors do not have financial relationships relevant to this 446 article to disclose. 

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