The Incidence of Post-infectious Irritable Bowel Syndrome, Anxiety, and Depression in Iranian Patients with Coronavirus Disease 2019 Pandemic: A Cross-Sectional Study

Background: Irritable bowel syndrome refers to a subgroup of disorders of gut–brain interaction associated with stress-related symptoms, but gastrointestinal infection can also be considered the leading risk factor. It is well reported that coronavirus disease 2019 can also result in gastroenteritis. Therefore, this study aimed to evaluate the incidence of post-infectious irritable bowel syndrome and stressful status among coronavirus disease 2019 patients. Methods: This cross-sectional study was conducted on adults with coronavirus disease 2019 referred to the Infectious Disease Clinic in Iran from November 2020 to February 2021. Patients who met all eligibility criteria were included in the study. The data were collected using a demographic questionnaire, Rome IV criteria questionnaire, and Hospital Anxiety and Depression Scale. Results: Totally, the data obtained from 233 eligible patients (136 women, 97 men; mean age 38.41) 11.52 (years) were collected and analyzed, and 53.2% of the cases had a moderate coronavirus disease 2019. The analysis showed that 27 (11.6%) patients suffered from irritable bowel syndrome symptoms based on Rome IV criteria after the recovery from the infection. Also, Hospital Anxiety and Depression Scale-based symptoms of depression and anxiety that occurred with coronavirus disease 2019 were reported in 27.4% and 36.9%, respectively. Conclusion: Our finding illustrated that irritable bowel syndrome symptoms based on Rome IV could occur in post-infected coronavirus disease 2019 patients. Also, Hospital Anxiety and Depression Scale-based symptoms of depression and anxiety were more common in females and coronavirus disease 2019 infected patients with clinical symptoms including cough, shortness of breath, and sore throat.


INTRODUCTION
Irritable bowel syndrome (IBS) refers to a subgroup of disorders of gut-brain interaction characterized by various gut symptoms including, abdominal pain, diarrhea, constipation, changes in bowel movement, and cramps or bloating; 1,2 its consequences negatively influence a patient's quality of life and bring in increased global health care costs. 3 Irritable bowel syndrome is the most commonly diagnosed gastrointestinal disorder worldwide. The global prevalence of IBS has been estimated to be between 4.1% and 5.5% according to the Rome IV criteria. 4-7 A survey also reported that IBS prevalence among Iranian subjects aged 19-70 years had been about 21.5% (based on Rome III definition). 8 The interaction between the gut-brain axis disturbances and genetic and psychosocial factors contribute to IBS development, but its pathogenesis, as a multifactorial disorder, remains unclear. 9,10 Psychological stress acts as a trigger in developing IBS through its adverse effects on intestinal permeability and motility and hypersensitivity to visceral pain. 11 What is more, physical and mental stress, in turn, could result in changes in gut microbiome composition, dysbiosis, and small intestinal bacterial overgrowth that could be involved in both IBS symptom origination and perpetuation. 1,12 However, it is not yet clear whether the psychological characteristics are present before or after the onset of gastrointestinal symptoms. 13 Today, the rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection spread can be regarded as a primary global health concern all over the world. 14 It has also been reported that coronavirus disease 2019 (COVID-19) caused millions of deaths in late 2019-2020 worldwide. 14 This new acute respiratory syndrome, in addition to typical clinical manifestations, could also lead to gastrointestinal (GI) manifestations, including abdominal pains, diarrhea, nausea, and vomiting. 15 A recent systematic review in this regard revealed that the prevalence of GI symptoms in COVID-19 patients is about 18% and is still increasing. 16 Recently, reports suggest that the incidence of diarrhea varies from 2% to 20% in patients with COVID-19. Pan et al 17 in 2020, examined the clinical characteristics of 204 patients with COVID-19 and observed the digestive symptoms, including diarrhea, vomiting, and abdominal pain in 50.5% of the cases.
Additionally, COVID-19 could adversely impress the nervous system of the GI tract, leading to hypomotility. 18 It has been stated that COVID-19 can enter intestinal cells and cause gastrointestinal symptoms, despite the presence of low-pH gastric secretions and the secretion of bile and digestive enzymes in the GI tract. 19,20 Detection of SARS-CoV-2 through oral and rectal swabs indicates that both gastrointestinal and respiratory tract can be targeted by SARS-CoV-2 together; which may represent a cross-talk between lungs and gut in COVID-19. 18,19 It is also assumed that there is a relationship between the gut-lung axis and the severity of COVID-19 and dysbiosis. 20 Meanwhile, the contribution of intestinal leakage to the severity of COVID-19 as a result of dysbiosis in the gut microbiome is not known. 18,20 On the other hand, the COVID-19 pandemic could also have psychological effects, such as anxiety, frustration, uncontrolled fear, and disabling loneliness for people of all ages. 21 As a result of these stressful situations, gastrointestinal dysfunction and other health complications following the coronavirus could be caused. 22 Alzahrani et al 3 demonstrated that IBS symptoms could exacerbate during the COVID-19 pandemic. It is well reported that COVID-19 infection can also result in gastroenteritis. Therefore, this cross-sectional study aimed to investigate IBS incidence and its correlation with stressful status among COVID-19 individuals after recovery of the disease.

MATERIALS AND METHODS
A prospective cross-sectional study was conducted on adults with COVID-19. 23 They were referred to the Infectious Diseases Clinic of Hazrat Rasool Akram Hospital in Tehran (Iran) to diagnose SARS-CoV-2 infection based on clinical symptoms or due to the severity of the disease from November 2020 to February 2021. The participants undergoing a diagnostic procedure, such as a nasopharyngeal polymerase chain reaction (PCR) test (n = 136) or chest radiograph (n = 96) to show their lung involvement, had a definite diagnosis of coronavirus infection by their physician. The objectives of this study were explained in detail to all patients, and also, participating in this study was fully conscious and based on their desire. Further, written informed consent was obtained from each patient. Meanwhile, all patients received the national protocol of standard treatment without changes.
Patients with COVID-19 were investigated for the study inclusion or exclusion criteria after their recovery periods. The inclusion criteria were as follows: age 18 years old or above, having a definitive diagnosis of coronavirus with different severity (mild, moderate, and severe) using biochemical tests or computed tomography scan of chest and observation of lung involvement, absence of concomitant malignancies (such as cancer, pre-coronary kidney failure, heart failure, liver disorders, etc.). Exclusion criteria for this study were as follows: children, pregnant and lactating women, asymptomatic COVID-19 patients or individuals admitted to the ICU with critical conditions, having neurological diseases and gastrointestinal disorders, and an individual's unwillingness to continue cooperation. Also, eligible participants with mild, moderate, and severe severity of coronavirus infection were included in the study. After at least 6 months of their recovery, all participants completed the stress and Rome IV questionnaires. The patients' information, including (i) demographic data (such as age, gender, past medical history, drug history, and smoking); anthropometric measurements (such as height, weight, and body mass index (BMI)); (ii) biochemical test data (such as COVID-19-SARS-CoV-2 PCR, and anti-SARS-CoV-19 IgG and IgM); (iii) severity of illness based on physician diagnosis and symptoms (such as mild, moderate, and severe); (iv) clinical symptoms (such as fever, cough, shortness of breath, chest pain, redness of the conjunctiva of the eye, sore throat, loss of sense of smell or taste, shivering, pain, feeling exhausted, nausea and vomiting, and diarrhea) were also recorded at the baseline of the study. Notably, all obtained information of each patient was collected using telephone contact by our experts.

Main Points
Rome IV questionnaire was applied to diagnose the types of IBS that assess recurrent abdominal pain or discomfort at least once a week for the past 6 months with at least 2 or more of the following features: (i) related to defecation; (ii) it is associated with changes in stool frequency; (iii) with a change in the shape (appearance) of stools. 23 ,24 In this study, the Hospital Anxiety and Depression Scales (HADs) questionnaire, a 14-item self-rating scale, was also used to evaluate anxiety and depression symptoms in different diseases related to psychological diseases. Each item has a score of 0-3; the higher rates show more significant anxiety or depression symptoms. The total scores in each section were classified from 0 to 21, which were as follows: the score from 0 to 7 showing a standard scale, 8 to 10 indicating a borderline range, and the scores between 11 and 21 representing clinical problems. 25,26 The present study was also prepared following the ethical principles and confirmed by the medical ethics committee of Iran University of Medical Sciences, Tehran, Iran (No: IR.IUMS.REC.1399.514). All participants provided their written informed consent before the collection of the data. Data used for this study were extracted anonymously from the participants.

Statistical analysis
The normality distribution of the variables prior to data analysis was examined by the graphical methods, numerical characteristics, and Shapiro-Wilk's test. Descriptive statistics were also applied to express the qualitative variables using frequencies as numbers, and percentages and the value of continuous data were presented as mean and standard deviation. The independent sample t-test was carried out to compare the continuous variables. A chi-square test or Fisher's exact test was also used to compare the categorical variables of characteristics in COVID-19 patients with and without IBS. Among the tertile of HADS in relation to depression and anxiety, we used a one-way analysis of variance for quantitative variables and a chi-square test for categorical variables. In the end, multivariable logistic regression was performed for COVID and IBS among tertiles of HADS scores. We calculated the odds ratio and 95% CI in adjusted models for age, sex, BMI, the severity of COVID, and past medical history. Statistical Package for the Social Sciences (SPSS) statistical program version 24 (IBM Corp., Armonk, NY, USA) was used to perform the statistical analysis. P < .05 was considered statistically significant.

RESULTS
The current study assessed 565 patients with confirmed COVID-19 in terms of the study inclusion criteria. In total, 233 eligible patients were included in the study (Figure 1). The demographic characteristics of the participants are presented in Table 1 (Table 2). Table 3 shows the characteristics of the individuals reporting IBS symptoms after 6 months of being infected with COVID-19. The proportion of IBS occurrence was higher   in women and people aged 40 years or over. In addition, there was no significant difference between the study participants in terms of severity of COVID-19, BMI, smoking, past medical history, and other factors. The characteristics of the participants among tertile of HADS in relation to depression and anxiety are reported in Tables 4 and 5, respectively. As illustrated in Tables 4 and 5, the trends of depression and anxiety in females were remarkably higher in tertile 3 versus tertile 1; meanwhile, notable declining trends of depression and anxiety were observed among males in the third tertile compared with the firsttertile. Accordingly, patients with fever, cough, shortness of breath, and sore throat experienced higher symptoms of depression. As shown in Table 5, a significant increasing trend of anxiety was shown among patients who had experienced cough, shortness of breath, and sore throat due to COVID-19. The logistic regression model results indicated that the odds of depression and anxiety were higher in COVID-19 patients with IBS symptoms, but the P-trend was not statistically significant (Table 6).

DISCUSSION
Based on the available literature, the COVID-19 pandemic had made significant lifestyle changes and stressful situations. This condition can lead to other acute and chronic diseases related to psychological stress and the nervous system like IBS. 27 The main objective of this cross-sectional study was to evaluate the incidence of IBS and its correlation with stressful status in individuals who recovered from COVID-19. Our results demonstrated that the 27 COVID-19 patients (11.6%) suffered from post-infectious IBS symptoms according to Rome IV criteria; meanwhile, there was no significant relationship between anxiety or depression and the incidence of IBS symptoms. According to the obtained data, it seems that COVID-19 can directly or indirectly influence the gut function after the recovery by causing potential pathophysiological alterations including, dysbiosis, disruption of the intestinal barrier, intestinal inflammation, post-infectious states, gut-lung axis impairment, immune dysregulation, psychological stress, as well as use antibiotics, and other treatments of the acute phase. 28 These are possible factors that can trigger IBS after the COVID-19 recovery, and infected individuals can generally be predisposed to the development of IBS. However, there is a paucity of data on the gastrointestinal sequelae of SARS-CoV-2 infection. 28 Our results revealed that post-infectious IBS could develop in 11.6% of patients with COVID-19 based on Rome IV criteria. Wang et al 29 also investigated the   The results obtained from this study also indicated that 36.9% of patients experienced stress and 27.4% suffered from depression, and patients with severe symptoms including fever, cough, shortness of breath, and sore throat experienced a higher rate of depression and anxiety. Zandifar et al 35 reported that the prevalence of stress and depression in Iranian hospitalized patients with COVID-19 were 97.1% and 97.2%, respectively. The results of another study in London showed that 13.8% and 10.5% of COVID-19 patients discharged from the hospital were screened positive for depression and posttraumatic stress disorder. 36 These studies' differences in reported prevalence values revealed that hospitalization is a potential source of psychological disorders for COVID-19 patients. 37 What is more, different tools for measuring psychological stress affected the reported prevalence values.
The other observations in our study suggested that depression and anxiety were more common in women than in men. Similarly, previous studies indicated that women experienced more stress in the COVID-19 pandemic, significantly influenced by poverty, housing insecurity, and other gender-based differences. 38 Another study confirmed that being female, young, and single were associated with higher depression, anxiety, and stress. 39 However, it could not be extrapolated to more severe effects of COVID-19 on the mental well-being of women. We did not have access to any baseline values known for anxiety and depression status for these patients. Even though psychological dysfunction after COVID-19 infection can be affected by various factors including level of exposure, loss of a family member, society, occupation, age, and gender. 40 The strength point of this study was that the IBS incidence based on Rome IV criteria and its correlation with stress status in COVID-19 patients were investigated for the first time in Iran. However, there are some limitations, such as completing the questionnaire via telephone due to the pandemic situation, a small sample size, and lack of information about the stress status of subjects before COVID-19 infection.

CONCLUSION
Our findings suggested that the post-infectious IBS based on Rome IV criteria might occur in 11.6% of COVID-19 patients and influence the recovery process of these patients. Furthermore, the HADS-based symptom of depression and anxiety were more common in women and COVID-19 infected patients with clinical symptoms, including cough, shortness of breath, and sore throat. Given the end of the COVID-19 pandemic, further studies with a larger sample size are needed to examine its shortterm and long-term GI and psychological complications and find solutions for improving them.
Ethics Committee Approval: The study was approved by the medical ethics committee of Iran University of Medical Sciences, Tehran, Iran (No: IR.IUMS.REC.1399.514).
Informed Consent: Written informed consent was obtained from the patients who participated in this study.