key: cord-0771342-z9csj1bh
authors: Ebrahim Nakhli, Ramin; Shanker, Aaron; Sarosiek, Irene; Boschman, Jeffrey; Espino, Karina; Sigaroodi, Solmaz; Al Bayati, Ihsan; Elhanafi, Sherif; Sadeghi, Amin; Sarosiek, Jerzy; Zuckerman, Marc J.; Rezaie, Ali; McCallum, Richard W.; Schmulson, Max J.; Bashashati, Ali; Bashashati, Mohammad
title: Gastrointestinal symptoms and the severity of COVID‐19: Disorders of gut–brain interaction are an outcome
date: 2022-04-05
journal: Neurogastroenterol Motil
DOI: 10.1111/nmo.14368
sha: dc7a512052c2e66177692f6f6c00d1bd4700e0fa
doc_id: 771342
cord_uid: z9csj1bh

BACKGROUND: Many of the studies on COVID‐19 severity and its associated symptoms focus on hospitalized patients. The aim of this study was to investigate the relationship between acute GI symptoms and COVID‐19 severity in a clustering‐based approach and to determine the risks and epidemiological features of post‐COVID‐19 Disorders of Gut–Brain Interaction (DGBI) by including both hospitalized and ambulatory patients. METHODS: The study utilized a two‐phase Internet‐based survey on: (1) COVID‐19 patients’ demographics, comorbidities, symptoms, complications, and hospitalizations and (2) post‐COVID‐19 DGBI diagnosed according to Rome IV criteria in association with anxiety (GAD‐7) and depression (PHQ‐9). Statistical analyses included univariate and multivariate tests. RESULTS: Five distinct clusters of symptomatic subjects were identified based on the presence of GI symptoms, loss of smell, and chest pain, among 1114 participants who tested positive for SARS‐CoV‐2. GI symptoms were found to be independent risk factors for severe COVID‐19; however, they did not always coincide with other severity‐related factors such as age >65 years, diabetes mellitus, and Vitamin D deficiency. Of the 164 subjects with a positive test who participated in Phase‐2, 108 (66%) fulfilled the criteria for at least one DGBI. The majority (n = 81; 75%) were new‐onset DGBI post‐COVID‐19. Overall, 86% of subjects with one or more post‐COVID‐19 DGBI had at least one GI symptom during the acute phase of COVID‐19, while 14% did not. Depression (65%), but not anxiety (48%), was significantly more common in those with post‐COVID‐19 DGBI. CONCLUSION: GI symptoms are associated with a severe COVID‐19 among survivors. Long‐haulers may develop post‐COVID‐19 DGBI. Psychiatric disorders are common in post‐COVID‐19 DGBI.

A cluster of pneumonia cases was first documented in Wuhan, Hubei Province in China, in December 2019. These incidents were later found to be attributable to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). 1 This pathogen has been responsible for a global pandemic of unprecedented consequences. More than 218 million confirmed cases with SARS-CoV-2 have been reported worldwide, and about 4.52 million lives were lost through September 2021. Vaccines have been developed and are being distributed throughout the world as a prophylactic measure to generate immunity and prevent COVID-19. However, there are disparities in vaccination coverage worldwide, and vaccine hesitancy is a major public health problem. Efforts are still underway to discover and approve safe and efficacious treatments. course, others showed that GI manifestations account for a lesssevere disease. [9] [10] [11] [12] [13] Moreover, it appears that GI symptoms and sequelae are common after resolution of the acute COVID-19 illness. 14, 15 It has been proposed that these sustained symptoms fulfill a specific GI diagnosis, namely Disorders of Gut-Brain Interaction (DGBI), 16 which has been also explored in a recent study. 17 Without any presumption in favor of GI symptoms as a predictive factor of the severity or outcome, the current study pooled and It consisted of questions on demographics, comorbidities, and acute symptoms and included the standardized Rome IV Adult Questionnaire, the Patient Health Questionnaire-9 (PHQ-9) for depression, and General Anxiety Disorder-7 (GAD-7) for Anxiety questionnaire. 18, 19 Phase-2 was in English on the Qualtrics platform and was conducted between March and August 2021.

Recruitment was through advertising on the TTUHSC El Paso website, and through postings on social media platform accounts (Facebook, LinkedIn, and Instagram) of the investigators and online patient support groups. Duplicate responses were not allowed based on the Qualtrics platform. By reading the introduction of the survey and agreeing to proceed, the participants consented to be a part of this anonymous study.

For Phase-1, adults (≥18 years old) with a history of positive or negative COVID-19 test (PCR and/or antibodies) results and with/ without COVID-19 symptoms were included. For Phase-2, subjects with PCR-confirmed COVID-19 at least 6 months before the study with current GI symptoms were invited to participate. Phase-1 and Phase-2 were independently conducted. Therefore, subjects who

• COVID-19 may manifest with gastrointestinal (GI) symptoms. Whether these symptoms are associated with a severe outcome has been mostly studied in hospitalized patients. Furthermore, it has been posited that Disorders of Gut-Brain Interaction (DGBI) are a sequela of COVID-19.

• This work proposes an unsupervised clustering of COVID-19 patients based on the appearance of symptoms. GI symptoms, loss of smell, and chest pain are the most discriminative findings. During the acute phase, GI symptoms were associated with a more severe COVID-19.

• The results of this study reconfirm the occurrence of post-COVID-19 DGBI among COVID-19 long haulers. It also reveals that these post-COVID-19 disorders may or may not be associated with the presence of GI symptoms during the acute phase. participated in Phase-2 may or may not have participated in Phase-1 as well.

In Phase-1, the presence of the following symptoms was analyzed as binary variables: fever, chills, shortness of breath, cough, sputum, bloody sputum, chest pain, chest discomfort, nasal congestion, sore throat, fatigue, red eye, headache, abdominal pain, body ache, nausea /vomiting, diarrhea, loss of taste, loss of smell, skin rash, cyanosis, dizziness, and loss of appetite. The severity of pulmonary and extrapulmonary symptoms was categorically ranked from 1 (minimal) to 5 (very severe) according to the patients' self-assessment. A Questionnaire (PHQ-9) instruments, respectively. 18, 19 The total score (TS) for one was used to determine the severity and was calculated by summation of scores to the individual questions (0-3), where 0 represented "not at all", 1: "several days", 2: "more than half the days", and 3: "nearly every day". Anxiety was graded as follows: mild (TS: 5-9), moderate (TS: [10] [11] [12] [13] [14] , and severe (TS: 15-21). 19 Depression was graded as follows: mild (TS: 5-9), moderate (TS: [10] [11] [12] [13] [14] , moderately severe (TS: [15] [16] [17] [18] [19] , and severe (20) (21) (22) (23) (24) (25) (26) (27) . 18 

In Phase-1, to identify patients with similar symptomatic patterns (referred to as patient clusters), we have used hierarchical clustering, which is an unsupervised machine-learning technique, to cluster the data based on the distances between data points by continuously merging the closest ones until all data samples are merged into one cluster. Detailed information about the analysis is presented in the supplementary material section. In Phase-2, a logistic regression analysis was used. More information on this has been provided in the supplementary material section.

All the analyses of this study were conducted using Python (version 3.9.4). In addition, Pandas (version 1.2.4) was used for data loading and preprocessing, and the cluster maps were plotted using Seaborn (version 0.11.1) which uses SciPy (version 1.6.2) underneath for calculating the dendrograms of hierarchical clustering.

A total of 2222 subjects completed the survey, of which 1780 (80.1%) were tested for SARS-CoV-2 with PCR and/or antibodies, while 442 (19.9%) were not tested (although they reported symptoms of COVID-19). Among tested subjects, 1114 (62.6%) cases were positive, and 666 (37.4%) had negative results. Among the subjects that reported to be tested, only 8 (0.7%) were included based on the antibody criteria before November 2020 when vaccines were not available yet. Of the positive cases, 1092 (98%) reported to be symptomatic, and 401 (60.2%) of those with negative results also claimed that they experienced COVID-19 symptoms. The demographic data and comorbidities among these groups are presented in Table 1 . From symptomatic positive, symptomatic negative, and symptomatic without test cohorts, 70, 88, and 102 participants had not provided enough information about their symptoms and severity, respectively. Therefore, they were excluded from further analysis. The countries of residence for responders are shown in Table S1 .

The multivariate analysis according to the baseline demographics and comorbidities revealed that age greater than 65 years, diabetes, asthma, and Vitamin D deficiency were associated with a more severe COVID-19 in positive-tested symptomatic patients. (Table S2) . (Table 2 ). In concordance with severity, hospitalization was more common among subjects in Cluster 4. Shortness of breath was significantly more common among Clusters 1 and 2, but severe shortness of breath was only more common in Cluster 1 with GI symptoms. Cluster 5 with loss of smell and no GI symptoms or chest pain had the least disease severity with the least frequent hospitalizations and presence of shortness of breath, suggesting a negative association between the loss of smell and disease severity in the absence of GI symptoms (Table 2) .

Specifically in relation to GI symptoms, the presence of abdominal pain in Clusters 1 and 4 was associated with a severe COVID-19, while nausea and vomiting were associated with a severe disease only in Cluster 1. In contrast, in Cluster 4, age >65 years and Vitamin D deficiency were associated with a severe illness ( Table 3) .

The symptomatic cases with negative SARS-CoV-2 test were also clustered according to their symptoms. Although clusters were still separable based on the presence of GI symptoms, loss of smell, and chest pain, (Figure S1), they were somehow different from those of subjects with positive testing. A severe disease was significantly more prevalent among clusters with GI symptoms including abdominal pain and nausea (Clusters 1 and 2), while the cluster defined by no chest pain and no GI symptoms (Cluster 5) had a less severe disease course. In addition, an unexplained cluster (Cluster 4) characterized by GI symptoms, mostly diarrhea, was visible. This cluster was less enriched and was associated with a milder disease. Shortness of breath was more common in Cluster 2 which was dominated by loss of smell and chest pain, similar to Cluster 2 in symptomatic subjects with positive tests. Severe shortness of breath was also more common in Clusters 1 and 2 with GI symptoms. The absence of chest pain was also associated with less prevalent shortness of breath and a lesser disease severity (Table S3 ). In Cluster 2, hypertension was significantly more common among those with severe COVID-19 (Table S4 ).

One hundred and sixty-four subjects with a positive SARS-CoV-2 test completed the survey (70% women, 14% men, and 16% did not specify their sex). Age-group distribution was ≤65 years old: 79%, >65 years old: 4%, did not report their age: 17%, and BMI <25: 21%, and >30: 38%. Hospitalization was reported by 24%, no hospitalization by 60%, and the rest did not report hospitalization status.

Diabetes was reported by 6.7% of respondents and Vitamin D deficiency by 11%.

In total, 108 (66%) subjects fulfilled Rome IV criteria for at least one DGBI; the majority of them (81 subjects; 75%) developed this (Table 13) .

Among all included subjects with positive test result in the Phase-2 study, 33% and 45% had anxiety and depression, respectively. Mild, moderate, and severe anxieties were present in 17%, 5%, and 11% of all subjects with positive test results, respectively, while mild, moderate, moderately severe, and severe depression were present in 15%, 14%, 9%, and 7% of the cases, respectively.

Among subjects with post-COVID-19 DGBI, 48% reported anxiety and 65% reported depression ( Figure 2) . However, the rate of anxiety in subjects with post-COVID-19 DGIB was 24%, 9%, and 15%

for mild, moderate, and severe cases, respectively. For depression, it was 23%, 18%, 14%, and 10% for mild, moderate, moderately severe, and severe cases, respectively. Depression, but not anxiety, was significantly more common in post-COVID-19 DGBI compared with the whole study group.

We had diarrhea, nausea and vomiting, and abdominal pain, respectively.

These numbers are much higher compared with previous studies including those from the United States. The above finding could be interpreted by the differences in study settings and population, as most of our subjects were not hospitalized.

Whether the presence of GI symptoms impacts the severity and outcome of COVID-19 has been investigated in several metaanalyses. 6, 22, 25, [30] [31] [32] One meta-analysis which included 21 studies with 5285 patients showed that abdominal pain was associated with a near 2.8-fold increased risk of severe COVID-19; for nausea/vomiting and diarrhea, no strong association with severe COVID-19 was observed. This meta-analysis which was mainly based on hospitalized COVID-19 patients revealed unstable results during sensitivity analysis for some of the odds ratios and was dominated by studies from China, as only three studies conducted outside China were included. 31 Thus, geographical differences may limit the generalizability of the study results. One of the most recent meta-analyses on the severity of COVID-19 in the presence of GI symptoms, which included 158 studies, showed that the presence of GI symptoms and elevated liver enzymes did not affect mortality or ICU admission rate. This study found geographical variability in GI mortality among COVID-19 patients. 22 In contrast, our study found that the presence of GI symptoms was associated with a severe COVID-19, namely

DGBI a

Functional chest pain 17 2

Functional heartburn 11 8

Reflux hypersensitivity 9 6

Globus 3 0 hospitalization, without any significant effect on ICU admission and intubation rate.

While our study endeavored to highlight the acute symptoms of COVID-19 and determine whether those manifestations heralded the intensity of the disease course in these said patients, it is important to recognize comorbidities and other factors which were associated with more severe disease progression and outcomes. We have found that age older than 65, heavy alcohol intake, diabetes, asthma, and Vitamin D deficiency were associated with a more severe COVID-19. These findings align with previously reported data.

For example, one meta-analysis studied variables in severe and nonsevere COVID-19 patients and showed that the average age in the severe COVID-19 cohort was greater than that of the non-severe counterparts, and male sex was also determined to be a risk factor.

Regarding preexisting comorbidities, diabetes, hypertension, cardiovascular disease, and chronic obstructive pulmonary disease (COPD)

were linked with severe COVID-19. 33 Another meta-analysis echoed the previously described findings. These authors documented a no- 34 In another systematic review and meta-analysis, the investigators reported that age >75 years, male sex, and severe obesity were factors associated with adverse outcomes in COVID-19. They also found that active cancer was associated with an elevated risk of severe outcome.

Interestingly though, this study found that diabetes and hypertension did not confer an increased risk of severe outcomes. 35 One research group disclosed that in their meta-analysis, while Vitamin D deficiency did not correspond with an increased risk of SARS-CoV-2 infection, severe COVID-19 cases revealed an increased prevalence of Vitamin D deficiency compared with mild cases. Moreover,

and mortality due to COVID-19. 36 Some may be surprised that according to another study, asthma was not identified as a risk factor in the development of severe COVID-19. 37 The key point in our study was that clusters with more severe disease did not always possess the comorbidities which are generally associated with severe COVID-19, suggesting that the prediction of severity based on GI symptoms is a unique phenomenon that does not necessarily need to coincide with any comorbidity in order to transpire.

Rome IV criteria for any DGBI in the past 3 months, with symptom onset at least 6 months before diagnosis associated with previously criteria for DGBI before the onset of acute illness should have not been met. 16 Our study documented the characteristics of post- Our study reiterated the presence of post-COVID-19 DGBI in a different population and study design. Recruitment differences due to online data collection of those mainly with post-COVID-19

GI issues, the inclusion of all types of DGBI rather than IBS and dyspepsia which was done in the earlier study, 17 and inclusion of patients with more severe COVID-19 rather than those with mild forms of disease could explain the higher rate of post-COVID-19

DGBI in the current study.

While post-infection DGBI were first reported after bacterial infections (mainly gastroenteritis), viruses may also trigger these conditions. Those viruses predominantly affect the GI tract, causing GI symptoms. As SARS-CoV-2 also affects the GI tract in the acute phase, it is reasonable to consider post-COVID-19 DGBI a postinfection condition. 16 As for the underlying mechanism for the post-COVID-19 DGBI, it is possibly related to the high expression of the angiotensin-converting enzyme-2 (ACE2) in the gut epithelial cells, a receptor that is required for the SARS-CoV-2 virus to infect human cells. 41 The infection of the gut epithelial cells triggers an increase in permeability, a low-grade inflammation with calprotectin secretion, 42 and dysbiosis. 43 Mediators of the low-grade inflammation can stimulate the enteric nerves with projections to the central nervous system, factors that together with the stress of having COVID-19, anxiety, and depression, can generate symptoms of post-COVID-19

DGBI. 16 In fact, these mechanisms have been described and postulated for other post-infection-DGBI, such as PI-IBS. 44 Based on a recent meta-analysis which included 73 articles, the prevalence of anxiety and depressive symptoms and disorders in patients with IBS was 39.1% and 23%, respectively. 45 Our study showed that the prevalence of anxiety and depression were high in post-COVID-19 DGBI, supporting the concept that post-traumatic stress and other psychological factors may be associated with its underlying mechanisms. The association between psychological factors and post-COVID-19 DGBI was also confirmed in the study by Ghoshal et al. 17 Abdominal pain and nausea/vomiting in the acute phase increased the odds of post-COVID-19 functional dyspepsia. Changes in inflammatory signaling, neuronal plasticity, and signaling in the GI tract may explain the chronic changes. 16 In addition, loss of taste increased the odds of post-COVID-19 DGBI, while loss of smell was protective against post-COVID-19 DGBI. As outlined above in

Phase-1 of this study, loss of smell was also associated with a less Limitations of this study include the fact that women were the predominant respondents. Subjects completed the survey anonymously and the subjects could not be followed up. On the other hand, the large sample size overcomes many limitations. Additionally, we did not have access to patients' medical charts, which prevented us from obtaining laboratory and other objective data. As some subjects completed the survey after their recovery, there is a possibility of recall bias. And lastly, because of the nature of our survey, we do not have any data from patients who did not survive COVID-19.

In conclusion, among survivors, GI symptoms were associated with more severe COVID-19 symptoms during the acute phase of the illness. This association was independent of the presence of any comorbidity which could affect the severity of COVID-19 itself.

Future analysis of the available records should address whether this phenomenon was also present among those who died of COVID-19.

In addition, post-COVID-19 DGBI is a new entity which deserves further investigations to determine its prevalence, long-term prognosis, and treatment. While some of the cases with post-COVID-19

DGBI had GI symptoms during the acute phase, some appeared in those with no acute GI symptoms.

This study has been approved by IRB at TTUHSC El Paso (E20143 and E21093) and University of British Columbia (H20-01904). Max J. Schmulson had the license to use the Rome IV questionnaire in the current study. We thank the Rome Foundation for said permission.

Further details are presented in the supplementary content.

The authors do not have anything to disclose in relation to the current paper.

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