key: cord-0927053-4e027vbd
authors: Lukin, Dana J.; Kumar, Anand; Hajifathalian, Kaveh; Sharaiha, Reem Z.; Scherl, Ellen J.; Longman, Randy S.
title: Baseline Disease Activity and Steroid Therapy Stratify Risk of COVID-19 in Patients with Inflammatory Bowel Disease
date: 2020-05-29
journal: Gastroenterology
DOI: 10.1053/j.gastro.2020.05.066
sha: d9722e4f12c17810aae2893c235069777faa0c31
doc_id: 927053
cord_uid: 4e027vbd

nan

New York City is the epicenter of the United States COVID-19 pandemic caused by the SARS-CoV-2 virus with local population infection rates estimated at 25% 1 . The impact of COVID-19 on patients with inflammatory bowel disease (IBD) within an epicenter is not well understood. Our study aims were to compare clinical outcomes between COVID-19 patients with and without IBD and to investigate the prevalence and risk factors of COVID-19 in IBD patients.

A matched cohort design was used to compare clinical outcomes in COVID-19 patients with or without IBD. The source cohort of all COVID-19-positive patients at two New York hospitals has been previously described 2 (Supplementary methods). The exposure of interest was defined as a pre-existing diagnosis of IBD. Cases (COVID-19 patients with IBD) were matched for decade of age and gender in a 1:2 ratio to unexposed controls (COVID-19 patients without IBD). Outcomes of interest were clinical manifestations of COVID-19, and intensive care unit (ICU) admission, endotracheal intubation, and death among admitted patients. COVID-19 was defined as confirmed (positive SARS-CoV-2 PCR), or highly suspected (new onset fever >37.8 Celsius and >1 new symptom including cough, sore throat, dyspnea, anosmia, diarrhea, with a known close contact with COVID-19) 3 .

A separate longitudinal cohort of active IBD patients was used to estimate the prevalence of COVID-19 in IBD patients and evaluate the effects of disease activity and treatment on risk of COVID-19 infection. Exposures of interest were IBD type, clinical, biochemical, and endoscopic indices of disease activity, and IBD treatment. The outcome of interest was diagnosis of COVID-19, as defined above. The details of methods and description of cohorts are available in the supplementary material.

Eighty confirmed or highly suspected COVID-19 cases with IBD were matched with 160 COVID-19 controls without IBD. Disease characteristics for the IBD cases are reported in supplementary table 1. IBD cases and controls had similar prevalence of comorbidities (Table 1A) , except IBD cases had significantly lower BMI, COPD, and asthma, but higher prevalence of malignancy and immunosuppressive medication use. At presentation, vital signs, hypoxemia, and inflammatory markers were similar between cases and controls (data not shown). IBD cases more frequently presented with gastrointestinal symptoms of diarrhea (45 versus 19%, p<0.001), and abdominal pain (20% versus 5%, p=0.001) compared with non-IBD matched controls (Table 1A) . The primary outcome, a composite of death, ICU admission, or intubation was similar, but numerically lower in IBD cases compared with matched controls (24% versus 35%, p=0.352 (Table 1B) . Among IBD cases, diagnosis of UC was associated with emergency visit or admission (aOR=12.7; p=0.009) in multivariable analysis adjusted for age, fever, and gastrointestinal symptoms. Additionally, the proportion of patients on vedolizumab or receiving no biologic therapy was numerically higher among IBD cases needing emergency visit/hospitalization compared with those who did not (no biologic: 29%; vedolizumab: 30%; ustekinumab 8%; TNF-antagonist: 6%; p=0.197; Suppl. Table 2a ).

In a separate longitudinal cohort of active IBD patients (N=119; median age 44 years, 66 females, 65 CD, 54 UC), 24.4% (N=29) met criteria for COVID-19 (confirmed:9; highly suspected: 20) consistent with rates estimated in the general population of NYC 1,4 . The distribution of age, sex, race/ethnicity, smoking, IBD type, disease location, or extraintestinal manifestations was similar between the IBD patients with or without COVID-19. New onset diarrhea (19.3% vs 11.1%, p<.001) and abdominal pain (12.6% vs 8.9%, p=0.03) were significantly more frequent in IBD patients with COVID-19 than without. A higher proportion of IBD patients with COVID-19 had clinically active UC (92.9% vs 62.5%, p=0.035), endoscopically active CD (92.3% vs 45.7%, p=0.004) or UC (85.7% vs 48.4%, p=0.018), and elevated baseline biomarker levels [C-reactive protein >0.9 mg/dL, p=0.01; fecal calprotectin > 50 ug/mg, p=0.002], compared with those without COVID-19. Proportional baseline corticosteroid use was higher among COVID-19 patients (p=0.04), but no overall differences were noted based on biologic, immunomodulator, or aminosalicylate use. Of 83 patients receiving biologic therapy, COVID-19 infection was similar across therapeutic classes (p=0.315), with fewer overall cases among patients on ustekinumab (13.8%) compared with vedolizumab (30.4%), TNF antagonists (25.0%), or tofacitinib (42.9%).

With the onset of the COVID-19 pandemic, there was initial concern that IBD and immunosuppressive medications would place patients at high risk for infection with and complications from SARS-CoV2. Using one of the largest reported cohorts of COVID-19 positive patients, this matched case-control analysis reveals IBD patients did not experience more severe COVID-19. Older age was a risk for emergency care or hospitalization. While UC was associated with greater risk of severe disease in our cohort, neither baseline IBD activity nor biologic medication predicted need for higher level of care. Reflecting lower rates of obesity and pulmonary disease, IBD patients with COVID-19 experienced less dyspnea or severe outcomes than matched non-IBD controls. However, the increased prevalence of gastrointestinal manifestations of COVID-19 5 within the IBD population highlight the need for COVID-19 evaluation in IBD patients with new gastrointestinal symptoms.

These data provide early evidence tracking incident infection and clinical COVID-19 in a longitudinal IBD cohort. Despite similar overall infection rates in IBD patients and the general pandemic epicenter population, moderate-to-severe IBD activity and corticosteroid use were found to be associated with higher rates of COVID-19. Limitations in SARS-CoV-2 testing and asymptomatic carriage may underestimate the true prevalence in this cohort. These data support societies' guidelines to continue effective steroid-sparing IBD therapy in the epicenter of a pandemic to minimize active disease.

Our data support the emerging idea that IBD and/or medications used for its treatment are not associated with severe outcomes in COVID-19 3, 4 . Within the IBD subset of the inpatient cohort, severe sequelae of COVID-19 were lower than in matched non-IBD controls. Despite the small number of admitted IBD patients, these findings are consistent with a possible blunting of the cytokine release syndrome, associated with severe morbidity and mortality in COVID-19 6 , by altered immune function or immunosuppressive therapy, which may limit disease progression. No significant differences were detected regarding biologic type on COVID-19 risk. These data support the need for further study of intestinal inflammation associated with SARS-CoV-2 infection and GI symptoms 7,8 . Supplementary methods:

The source cohort consisted of 1386 with confirmed or highly suspected COVID-19 patients who presented to our tertiary academic center in New York (including Jill Roberts Center for IBD) or an affiliated smaller non-academic hospital in New York, between February 1 and April 30, 2020. COVID-19 was defined as confirmed (positive SARS-CoV-2 PCR), or highly suspected (new onset fever >37.8 Celsius and >1 new symptom including cough, sore throat, dyspnea, anosmia, diarrhea, with a known close contact with COVID-19). Cases consisted of COVID-19 patients with a diagnosis of IBD (exposed, n=80), and were matched in a 1:2 ratio to the COVID-19 patients without IBD (non-exposed, n=160) according to their decade of age and gender. Demographic and clinical data including co-morbidities relevant to COVID-19 were extracted. Patients were considered to have gastrointestinal (GI) manifestations at presentation if they complained of any of the symptoms of nausea, vomiting, diarrhea, or abdominal pain at time of presentation. For IBD patients, clinical disease activity at baseline was determined using the Harvey Bradshaw Index for Crohn's disease or the partial Mayo Score for ulcerative colitis. Endoscopic activity within 6 months was determined if a colonoscopy report was available and reported as Simple Endoscopic Score for Crohns' Disease (SES-CD) or Mayo endoscopic subscore for UC.

The main exposure in the matched cohort study was presence of IBD. Outcomes of interest were clinical manifestations of COVID-19 on presentation (including fever, cough, dyspnea, myalgia/fatigue, anorexia, altered mental status, nausea, vomiting, diarrhea, abdominal pain, anosmia, and dysgeusia), as well as the composite of ICU admission, endotracheal intubation or death among admitted patients.. Detailed definitions of individual variables have been described elsewhere 2 . Among cases with IBD the association between disease type or IBD treatment and need for emergency visit or admission was evaluated in secondary analysis. IBD treatment was categorized into biologic therapy (including TNF-antagonists, vedolizumab, or ustekinumab), or no biologic use.

This consisted of 119 patients with active IBD who were followed prospectively at our center (SMART IBD longitudinal cohort). The exposures of interest were IBD type, clinical, biochemical, and endoscopic indices of disease activity, and IBD treatment. The outcome of interest was diagnosis of COVID-19, as defined above. Clinical IBD disease activity was determined using partial Mayo score for ulcerative colitis and Harvey Bradshaw Index for Crohn's disease. Biochemical disease activity was evaluated using C-reactive protein, albumin, and fecal calprotectin levels. Endoscopic disease activity was evaluated using last recorded Simple Endoscopic Score for Crohns' Disease (SES-CD) or Mayo endoscopic subscore for UC, and baseline medications used to treat IBD were recorded, as for the matched cohort. IBD treatment was categorized into biologic therapy (including TNF-antagonists, vedolizumab, or ustekinumab), oral or rectal steroids (excluding budesonide), oral or rectal budesonide, aminosalicylates (including 5-aminosalicylic acid and sulfasalazine), immunomodulators (including azathioprine, 6-mercaptopurine, and methotrexate), and combination therapy (biologics plus immunomodulators)

Descriptive statistics were reported as means (standard deviation, SD), median (interquartile range, IQR), or counts and proportions. Conditional logistic regressions and Mantel-Haenszel test were used to compare variables between COVID-19 patients with and without IBD in the matched cohort, and multivariable logistic regression was used to evaluate the effect of IBD type and treatment on emergency visit or hospitalization. In longitudinal IBD cohort, groups were compared using chi square test for categorical variables and student t test for continuous variables. All analyses were based on non-missing data, and missing data were not imputed. All tests were two-tailed with a significance level of alpha = 0.05. Analyses were performed with Stata 13.0 for Windows, StataCorp LP (College Station, TX) and SPSS Version 25.0 (IBM Corp., Armonk, NY). 

Abbreviations: CD: Crohn's disease, CRP: C-reactive protein, ED: emergency department, HBI: Harvey Bradshaw Index, IBD: inflammatory bowel disease