Summary

Introduction: The frequency, risk factors, and outcome of Severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) infection in patients with inflammatory bowel disease (IBD) remain unclear. This study aimed to investigate the incidence and effects of SARS-CoV-2 infection in IBD.
Materials and Methods: Patients with IBD were recruited retrospectively between March 2020 and March 2021, and those with SARS-CoV-2 infection were analyzed.
Results: A total of 894 patients with IBD were identified during the study period. SARS-CoV-2 was detected in 18 (2.0%) patients, including five (1.2%) of the 430 patients with Crohn’s disease (CD), 12 (2.8%) of 428 patients with ulcerative colitis (UC) and, one (2.8%) of 36 with unclassified IBD. The mean age was 42.2 years. Twelve (66.7%) of the patients were men. None of the patients was vaccinated for Coronavirus disease-2019. Five (27.8%) patients were hospitalized for a median of 10 days; the remaining patients were isolated at home. No intensive care unit admission or mortality occurred. Although a disease flare was not observed, a patient with UC who was on steroids demonstrated temporary terminal ileitis, pneumonitis intestinalis, and recto-vaginal fistulae. Six (33.3%) patients were on biologic agents, with one having concomitant immunomodulator and steroid therapy. The main gastrointestinal (GI) symptom was diarrhea in six (33.3%) patients.
Conclusion: The incidence of SARS-CoV-2 infection was 2.0% (n=18) in patients with IBD. Diarrhea is the most common GI symptom and should not be confused with IBD flare.

Introduction

The world has been struggling with novel Coronavirus disease-2019 (COVID-19) since December 2019 when Severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) was first identified in Wuhan, China^{[1, 2]}. Although the disease is mostly characterized by pneumonia leading to respiratory insufficiency, many other organ systems are involved. The pathophysiology and risk factors for COVID-19 have not been well understood yet. Thus far, literature data suggest that increasing age and comorbidities are the main risk factors for COVID-19 outcomes^[2-4].

Inflammatory bowel disease (IBD) is a spectrum of immune-mediated bowel disorders that mainly consist of Crohn’s disease (CD) and ulcerative colitis (UC)^[5]. Although patients with IBD at risk of opportunistic infections, particularly of viral or bacterial etiology, are treated with immunosuppressors, immunomodulators, or biologic agents^{[6, 7]}, available data showed that in elderly patients with IBD with comorbidities and steroid use appear to be an increased risk of SARS-CoV-2 infection and mortality^[4]. However, data regarding the frequency, risk factors, and outcome of SARS-CoV-2 infection in patients with IBD revealed conflicting results^[8-15]. Moreover, gastrointestinal (GI) symptoms are common among patients with COVID-19; specifically, diarrhea and abdominal pain have been reported in half of the patients, which can mimic primary GI conditions or exacerbation of IBD^[16]. In this study, we aimed to investigate the incidence and outcomes of SARS-CoV-2 infection in patients with IBD followed at our tertiary referral center.

Methods

This retrospective, single-center, and observational study was conducted to investigate the incidence and outcomes of SARS-CoV-2 infection in patients with IBD in a tertiary referral teaching center. The study was approved by a Ankara City Hospital Local Scientific Research Assessment and Ethics Committee (protocol no: 671, decision date: 20.01.2021).

Adult patients followed in the IBD unit of our department were employed in the study for incidence calculation. Among them, patients with confirmed SARS-CoV-2 infection defined by a positive test result of nasopharyngeal swab sample on real-time reverse transcriptase-polymerase chain reaction between March 1, 2020 and March 31, 2021 were evaluated for outcome analysis. Patients with symptoms suggesting COVID-19 but had negative RT-PCR results were excluded from the study.

Patients’ demographic data and IBD history were collected from the IBD database of our clinic. Symptoms, medication, and outcomes regarding SARS-CoV-2 infection were obtained by phone interview. Laboratory and radiological test results were obtained from the electronic file of the patients. Crohn’s disease activity index (CDAI) and Partial Mayo Score were used to assess CD and UC activity, respectively. Patients were also asked for discontinuation of IBD treatment, worsening of IBD symptoms, characteristics and duration of the GI symptoms, and relation with COVID-19 therapies. Diarrhea was defined as ≥4 loose stools (Bristol stool scale 6 or 7) in a day for at least three days. Stool analysis was performed in all patients presenting with diarrhea to rule out infectious pathologies.

Statistical Analysis

Statistical analysis was performed using IBM Statistical Package for the Social Sciences Statistics for Windows, version 26 (IBM Corp., Armonk, NY, USA). Categorical data are presented as numbers and percentages. Continuous variables that were normally scattered are presented as mean and standard deviation (SD); otherwise, the median and interquartile range (IQR) were used. Pearson’s chi-square or Fisher’s exact test was performed for percentage comparisons. An independent sample t-test was performed for parametric data, whereas Mann-Whitney U test was used for nonparametric data.

Results

A total of 894 patients with IBD have been followed in our gastroenterology department, and the characteristics are presented in Table 1. Among those, SARS-CoV-2 infection was detected in 18 (2.0%) patients, five (1.2%) of 430 patients with CD, 12 (2.8%) of 428 patients with UC, and one (2.8%) of 36 with IBD-unclassified (IBD-U) had SARS-CoV-2 infection. The mean age (SD) of the patients with SARS-CoV-2 infection was 42.2 (11.5) years, and 12 (66.7%) patients were male. Of the patients with IBD and SARS-CoV-2 infection, six (33.3%) had at least one underlying comorbidity, with diabetes being the most common, and three (16.7%) were active smokers. The median interval between the onset of SARS-CoV-2 infection symptoms and PCR test confirmation of infection was 0 days (range, 0-3 days). Six (33.3%) of all patients with SARS-CoV-2 infection were taking biologic agents (two adalimumab, two infliximab, and two vedolizumab), of which one was taking concomitant immunomodulator and low-dose (4 mg/day) steroid therapy. Of the patients with SARS-CoV-2 infection, three (16.7%) have used immunomodulators, eight (44.4%) have used mesalazine, and one has used steroid (prednisolone 20 mg/day) with mesalazine. The clinical characteristics and treatments of patients with IBD and SARS-CoV-2 infection are provided in Table 2. None of the patients with SARS-CoV-2 infection, whose details were presented in Table 2, were vaccinated for COVID-19 during the follow-up period. The most frequent non-GI symptom was myalgia (nine patients) followed by fever and arthralgia (eight patients each), and cough (seven patients) (Table 3).

Table 1: Demographic characteristics of all patients with IBD

Table 2: Clinical characteristics and treatments of patients with inflammatory bowel diseases and SARS-CoV-2 infection

Table 3: Clinical characteristics, treatments, and outcomes of patients with inflammatory bowel diseases and SARS-CoV-2 infection

The main GI symptom was diarrhea in six (33.3%) patients, followed by nausea and vomiting in two (11.1%). The median duration of GI symptoms was five (range, 4-8) days. Diarrhea was painless, non-bloody, and lasted for a median of five (range, 4-8) days. In patients five and 12, diarrhea started with the onset of the COVID-19 treatment. Five (27.8%) of the patients with COVID-19 were hospitalized for a median of 10 (range, 5-19) days, whereas the remaining patients were isolated at home. No intensive care unit admission or mortality was observed. The laboratory data of patients with SARS-CoV-2 infection are given in a supplementary table. The mean (SD) values for hemoglobin, leucocyte, lymphocyte, and platelet count were 13.9 g/dl (1.9), 6448 10⁶/L (2320), 1342 10⁶/L (712), and 237 10⁹/L (78), respectively. The median (IQR) levels of C-reactive protein, procalcitonin, and ferritin were 9.9 mg/dl (12), 0.03 µg/L (0.02), and 52 µg/L (163), respectively. The mean (SD) aspartate aminotransferase (AST), alanine aminotransferase, and creatinine values were 24.2 U/L (9.8), 33.0 U/L (18.7), and 0.81 mg/dl (0.22), respectively. The median (IQR) D-dimer level was 0.75 (1.38), whereas mean (SD) values for fibrinogen 3 and lactate dehydrogenase were 7 g/L (1.2) and 261 U/L (78), respectively.

Five (27.8%) of the 18 patients with SARS-CoV-2 infection had CD with a median CDAI of 86 (range, 52-203). Diarrhea was observed in two of them with one concomitant abdominal pain. One patient (20.0%) with CD was hospitalized, whereas the remaining patients were isolated at home. No complication occurred despite steroid and biologic usage. Patient 8 followed for IBD-U was isolated at home and did not develop any GI symptoms or complications. Seven (58.3%) of the 12 patients with SARS-CoV-2 infection and UC had extensive colitis, whereas the remaining had left-sided colitis. The median Partial Mayo Score was 3.5. Moreover, 5 (41.7%) of the patients with UC had GI symptoms, with diarrhea as the most common. In addition, four (33.3%) of the patients with SARS-CoV-2 infection and UC needed hospitalization. One of them (patient 10) having concomitant immunomodulator and low-dose (4 mg/day) steroid therapy did not require hospitalization. A complication was observed in only patient 12 among those with UC who were using steroids (prednisolone 20 mg/day) at the time of SARS-CoV-2 infection and demonstrated temporary terminal ileitis, pneumonitis intestinalis, and recto-vaginal fistulae. The patient was admitted to the COVID-19 unit at our hospital and received favipiravir, methylprednisolone intravenously, and low-molecular-weight heparin. Stool analysis was not positive for parasites or Clostridioides difficile, and stool cultures were negative. Real-time polymerase chain reaction was performed to analyze Cytomegalovirus presence in the serum samples and yielded negative. The patient improved progressively, and recto-vaginal symptoms resolved within one week. After 10 days of hospitalization, she was discharged with a tapered prednisolone schedule. The patient has remained asymptomatic with only mesalazine after steroid treatment.

Discussion

Literature data regarding the course of SARS-CoV-2 infection in patients with IBD are accumulating. Different results have been reported regarding the frequency and outcomes of SARS-CoV-2 infection in patients with IBD^{[3, 13, 17-20]}. In our study, the incidence of SARS-CoV-2 infection in patients with IBD was 2.0%, higher than the incidence in the normal population, as reported between 0.02% and 0.7% in previous studies^{[3, 13, 19]}. Our findings contradict those demonstrating similar^{[17, 18, 20]} or decreased^{[3, 13, 19]} incidence of SARS-CoV-2 infection in patients with IBD.

The increased incidence can be explained by the fact that patients with IBD are more sensitive to SARS-CoV-2 infection because they think their immune systems are weakened. Moreover, because GI symptoms in patients with IBD can also be seen in COVID-19, doctors tend to screen these patients for the presence of SARS-CoV-2 infection more frequently than the normal population^{[8, 21]}. Finally, since our hospital is a referral center, the incidence may have been high because of the high suspicion of SARS-CoV-2 infection in patients who presented to our clinic.

The most common GI symptom was painless and nonbloody diarrhea (33.3%) in patients with SARS-CoV-2 infection and IBD, which is consistent with the previously reported studies in which diarrhea was observed in up to 37.1% of the patients with IBD and SARS-CoV-2 infection^{[3, 22-27]}. Diarrhea can be an admission complaint of patients with SARS-CoV-2 infection^{[22, 28]} or can be the sole manifestation of COVID-19 independent of IBD. SARS-CoV-2 RNA isolation from the stool samples demonstrated intestinal tropism of the virus^[29-31]; thus, GI symptoms may arise with COVID-19 even in the absence of IBD. Gupta et al.^[32] reported two cases of previously healthy adolescents who presented with severe enteritis as the sole manifestation of COVID-19. Moreover, diarrhea can start with the onset of COVID-19 treatment. In our study, diarrhea started in patients 5 and 12 with the onset of hydroxychloroquine combined with favipiravir and favipiravir treatment alone, respectively, which was supported by several studies in the literature^[33-35]. Other rare GI symptoms were nausea and vomiting, which were detected in 11.1% of patients with IBD and SARS-CoV-2 infection. In the present study, the median duration of all-GI symptoms was five (range, 4-8) days, which was consistent with the literature^[36]. The short duration of GI symptoms caused by SARS-CoV-2 infection may indicate that COVID-19 does not cause an IBD flare. The duration of the symptoms may differentiate IBD remission from activation.

Patients with IBD tend to have a mild course of COVID-19 despite the presence of immunosuppressive treatment^{[3, 13-15, 17, 37]}. This situation could be explained by the hampered hyperactivity of the immune response with anti-inflammatory treatments such as anti-tumor necrosis factor (anti-TNF) agents^{[13, 38]}. However, not all drugs used in IBD treatment were associated with decreased COVID-19 severity. Corticosteroid use was also associated with severe COVID-19^{[3, 4, 15, 17, 38]}. Although several studies have reported the safe use of 5-aminosalicylic acid (ASA) in COVID-19^{[15, 39, 40]}, Brenner et al.^[38] reported a more severe COVID-19 course in patients with IBD using 5-ASA preparations. Khan et al.^[15] reported an increased risk of SARS-CoV-2 infection with vedolizumab treatment. In the present study, 16 (88.9%) patients were on 5-ASA therapy (nine patients only have 5-ASA treatment). Three (16.7%) patients were using steroid therapy combined with 5-ASA and methotrexate in patient 3; 5-ASA, azathioprine, and adalimumab in patient 10; and 5-ASA only in patient 12. Four (22.2%) patients were on anti-TNF therapy, whereas two (11.1%) patients were on vedolizumab therapy. A complication was observed only in patient 12 who was on steroid and 5-ASA treatments for UC and experienced temporary terminal ileitis, pneumonitis intestinalis, and recto-vaginal fistulae that improved with COVID-19 treatment. This case shows that, in line with the literature, caution is necessary for the management of complications related to SARS-CoV-2 infection in patients using steroids^[38].

Previous studies have demonstrated that COVID-19 complications were mainly observed in older people and those with comorbidities^{[1, 13, 17, 38]}. The young age and therefore low incidence of comorbidities enable milder disease course in patients with SARS-CoV-2 infection and IBD. Nevertheless, complications regarding GI systems reported with COVID-19 can be mistaken for IBD flare. Coronavirus disease-2019 may lead to severe small bowel and colorectal inflammation, which may mimic an IBD exacerbation. Therefore, during the pandemic, COVID-19-related enteritis should be considered when evaluating patients with IBD with suspected acute IBD flare. A recently published study revealed that the most common abdominal computed tomography imaging features of patients with SARS-CoV-2 infection are colorectal and small bowel wall thickening, intestinal distension, gastritis, and small bowel pneumatosis with portal venous gas and intestinal perforation^[41]. An example of GI complication was ileal perforation following SARS-CoV-2 infection in an inactive CD, which was reported by Santana et al.^[42]. In the present study, six (33.3%) patients had comorbidities such as diabetes, hypertension, cardiovascular disease, and renal cell carcinoma (not on chemotherapy). Despite the increased severity and complication risk of COVID-19, none of our patients had comorbidities and such outcomes.

Study Limitations

The major limitation of this study was the low number of patients with IBD and SARS-CoV-2 infection. This situation precluded further statistical analysis for safety investigations of the drugs used in IBD therapy.

Conclusion

In conclusion, SARS-CoV-2 infection was found in 18 (2.0%) of all patients with IBD. GI symptoms are common and may be the only manifestation in patients with IBD and SARS-CoV-2 infection. During the pandemic, new or exacerbated GI symptoms in patients with IBD should raise the suspicion of COVID-19. Ongoing treatments of IBD should be continued in such patients with COVID-19. Concerns that steroid use may cause a worse prognosis in patients with IBD should be investigated with larger studies.

Ethics

Ethics Committee Approval: The study was approved by a Ankara City Hospital Local Scientific Research Assessment and Ethics Committee (protocol no: 671, decision date: 20.01.2021).

Informed Consent: Not applicable since the presented study was conducted retrospectively.

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: B.B., İ.E.G., İ.Y., Concept: B.B., İ.E.G., İ.Y., Design: B.B., İ.E.G., İ.Y., Data Collection or Processing: B.B., İ.E.G., İ.Y., Analysis or Interpretation: B.B., İ.E.G., İ.Y., Literature Search: B.B., İ.E.G., İ.Y., Writing: B.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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