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COVID-19 pandemic and exacerbation of ulcerative colitis

BACKGROUND In 2020, the world faced the unprecedented crisis of coronavirus disease 2019 (COVID-19). Besides the infection and its consequences, COVID-19 also resulted in anxiety and stress resulting from severe restrictions on economic and social activities, including for patients with ulcerative colitis (UC). Fresh acute stress exerts stronger influences than continuous stress on UC patients. We therefore hypothesized that the first wave of the COVID-19 pandemic would have serious effects on UC patients and performed this retrospective control study. AIM To determine whether the first wave of the COVID-19 pandemic would have serious effects on UC patients included in a retrospective controlled study. METHODS A total of 289 consecutive UC outpatients seen in March and April 2020 were included in this study. Modified UC disease activity index (UC-DAI) scores on the day of entry and at the previous visit were compared. An increase of ≥ 2 was considered to indicate exacerbation. The exacerbation rate was also compared with that in 256 consecutive control patients independently included in the study from the same period of the previous year in the same manner. RESULTS No significant differences in patient characteristics or pharmacotherapies before entry were seen between the groups. Mean UC-DAI score was significantly higher in subjects during the first wave of COVID-19 (0.67 + 0.07) compared to the previous visit (0.26 + 0.04; P = 0.0000). The exacerbation rate was significantly increased during the first wave of COVID-19, as compared with the previous year (15.9% [46/289] vs 8.9% [23/256]; P = 0.0151). CONCLUSION This study demonstrated that the COVID-19 pandemic caused exacerbations in UC patients, probably through psychological and physical stress.


INTRODUCTION
In 2020, the global population faced an unprecedented crisis in the form of coronavirus disease 2019 (COVID-19) [1]. As the number of infected patients increased, the World Health Organization (WHO) declared a pandemic on March 11 [2]. The number of patients also increased in Japan and the Japanese government declared a state of emergency on April 7 [3]. The number of patients peaked on April 18 and then gradually decreased [4]. This was considered the first wave of COVID-19, which was followed by second and third waves after the government terminated the initial declaration. Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa with bloody diarrhea. The clinical course is usually unpredictable, marked by alternating periods of exacerbation and remission [5].
Many gastroenterologists and patients think that psychological and physical stress factors can exacerbate UC [6][7]. The Great East Japan Earthquake was shown to increase the risk of exacerbations among UC patients [8][9]. Stress undoubtedly contributes to disease course in UC patients. H. Engler et al [10] demonstrated the possibility that neuroendocrine regulation of pro-and anti-inflammatory cytokine production such as IL-10 by peripheral blood immune cells may play roles in flares of UC patients. However, the underlying mechanisms of UC flare by stress remain unclear [10].
Besides the infection and its direct consequences, including the loss of many lives, COVID-19 was shown to bring about anxiety and stress as a result of restrictions on economic and social activities for UC patients as well as everybody else [11][12]. We therefore hypothesized that UC patients would experience serious effects from COVID-19.
This study focused on the first wave of the COVID-19 pandemic in a retrospective controlled study investigating the effects on exacerbations of UC among patients in Koshigaya district, a suburban area of Tokyo, Japan.

Patients
During March and April 2020, representing the period of the first wave of the COVID-19 pandemic, a total of 289 consecutive UC outpatients in one center were enrolled in the study. All included patients regularly visited the clinic. Patients who visited for the first time after exacerbation of symptoms were excluded from the study. All included December 26, 2021 Volume 9 Issue 36 patients visited the clinic at least twice at entry. Only patients who visited for the first time after exacerbation of symptoms were excluded from the study.
Modified UC-DAI scores on the day of entry and at the previous visit were compared for each patient. An increase of ≥ 2 was considered to indicate exacerbation. The exacerbation rate was calculated and compared with that of 256 consecutive control patients independently included in the study from the same period of the previous year (March-April 2019) in the same manner. Modified UC-DAI scores of patients during the first wave of COVID-19 were compared with those at the previous visit. This retrospective study was reviewed and approved by the Ethics Committee of Dokkyo Medical University Saitama Medical Center (approval no. 20100), and written, informed consent was obtained from all UC patients. This study conformed to the ethical guidelines of the 2008 Declaration of Helsinki. All data were obtained from clinical records which were written on the day of the patient visit.
All patients provided informed consent to participate in this study and agreed to publication of the research results. The public were not involved in the design of this study.

Statistical analysis
Quantitative data are presented as mean ± SD. Discrete variables are presented as median and range. The Mann-Whitney U test or χ 2 test was used to compare patients and control patients. The χ 2 test was used to test for differences in exacerbation rates between the groups. Values of P < 0.05 were considered significant.

Characteristics
Characteristics (age, weight, height, smoking rate, sex, pancolitis rate, and medication before entry) were compared between patients and control patients.

Pharmacotherapies
Pharmacotherapies before entry did not differ significantly between patients and control patients ( Table 2).
Mean modified UC-DAI score during the whole pandemic period (March and April 2020) was 0.44 ± 1.04, compared with 0.26 ± 0.73 during the control period. We thus concluded that overall UC-DAI score was significantly higher during the pandemic period than during the control period (P = 0.0192).

Assumed stress of exacerbation during the pandemic
Questionnaires on stress during the pandemic revealed that among the 46 patients who experienced exacerbation during the pandemic, 35 reported stress due to the December 26, 2021 Volume 9 Issue 36  disease, 6 reported stress due to their jobs, 3 reported stress due to staying home, and 2 reported non-specific stress (Figure 3).

DISCUSSION
We demonstrated that the exacerbation rate among UC patients was significantly increased during the first wave of the COVID-19 pandemic, as compared with controls. Inflammatory bowel disease (IBD) flare is induced by psychological and physical stressors [6]. Moreover, Dion et al [14] demonstrated that fresh and acute stress exerts a stronger influence than long-term or continuous stress. In Japan, right after the WHO declaration of a pandemic, the number of patients with COVID-19 increased, peaking on April 18 and gradually decreasing in April. This represented the first wave of COVID-19 in Japan [4]. Many people would have been deeply anxious about the disease during this period [15]. We therefore hypothesized that the first wave of the COVID-19 pandemic would have exerted a greater influence on UC patients than the  second or third waves. The stress on individuals would have been significant during this period, even among patients not actually infected with the virus. No patient included in this study developed COVID-19. We chose the time period right after the WHO declaration of the COVID-19 pandemic for this study. COVID-19 has influenced human lives in many ways. Japan has not experienced city-wide lockdowns as in European countries or the United States. However, COVID-19 has exerted significant effects on exacerbations in UC patients. As depicted in the results, the majority of patients who experienced exacerbation reported non-specific stress. However, they may well have felt unconsciously anxious or uneasy under circumstances in which nobody knew what would happen next. Trindade et al[16] demonstrated that the COVID-19 pandemic seems to have exerted relevant effects on psychological wellbeing in UC patients. In Japan, the government declared a state of emergency, but no lockdowns or curfews. However, residents were still requested to refrain from going out unnecessarily. The operation of many recreational facilities was restricted [3]. Many workers were required to work from home using the internet to reduce the risk of December 26, 2021 Volume 9 Issue 36 infection, but this resulted in mental, physical and social isolation [17]. Together with school closures, many people suffered from the compounding burdens of working at home and caring for children [18]. As we evaluated the effect of the first wave of the COVD-19 pandemic which had already taken place, our study is retrospective and it is essentially impossible to evaluate the findings of endoscopy before the first wave of the pandemic. Therefore, we used the modified UC-DAI (without endoscopic findings) instead of UC-DAI, as we described in the methods, which resulted in less subjective quality of this study. However, we set up two controls: modified UC-DAI at last visits and pairs of modified UC-DAI in the previous year, which provided our study with more subjective verifications.
In conclusion, this study demonstrated that the COVID-19 pandemic caused exacerbations in UC patients, probably through psychological and physical stress, which is new and has not been shown previously. Healthcare professionals involved in managing IBD should pay attention to the psychological responses of patients to this pandemic and of possible ramifications for disease expression.

ACKNOWLEDGMENTS
We would like to thank Takamiya, Aoki, Sugimoto, Suga, and Wakabayashi of Morio Clinic for preparing the patient list.

Research background
In 2020, the global population was faced with the unprecedented crisis of coronavirus disease 2019 (COVID-19). Besides the infection and its consequences, COVID-19 also resulted in anxiety and stress resulting from severe restrictions on economic and social activities.

Research motivation
Fresh, acute stress exerts stronger influences than continuous stress on ulcerative colitis (UC) patients, presenting in forms such as exacerbation.