key: cord-0932168-6zztbja0
authors: Noviello, Daniele; Costantino, Andrea; Muscatello, Antonio; Bandera, Alessandra; Consonni, Dario; Vecchi, Maurizio; Basilisco, Guido
title: Functional gastrointestinal and somatoform symptoms five months after SARS‐CoV‐2 infection: A controlled cohort study
date: 2021-06-01
journal: Neurogastroenterol Motil
DOI: 10.1111/nmo.14187
sha: 9369cdccc9de259316da8ac0d26988303a365e05
doc_id: 932168
cord_uid: 6zztbja0

BACKGROUND: Gastrointestinal infections represent a risk factor for functional gastrointestinal and somatoform extraintestinal disorders. We investigated the prevalence and relative risk (RR) of gastrointestinal and somatoform symptoms 5 months after SARS‐CoV‐2 infection compared with a control cohort. METHODS: One hundred and sixty‐four SARS‐CoV‐2 infected patients and 183 controls responded to an online questionnaire about symptoms and signs during the acute phase of the infection and after 4.8 ± 0.3 months. Presence and severity of gastrointestinal symptoms, somatization, anxiety, and depression were recorded with standardized questionnaires. Stool form and presence of irritable bowel syndrome (IBS) were also recorded. Any association between exposure to infection and symptoms was evaluated by calculating crude and adjusted RR values and score differences with 95% confidence intervals (CI). KEY RESULTS: Fever, dyspnea, loss of smell/taste/weight, diarrhea, myalgia, arthralgia, and asthenia were reported by more than 40% of patients during the acute phase. Compared with controls, adjusted RRs for loose stools, chronic fatigue, and somatization were increased after infection: 1.88 (95% CI 0.99–3.54), 2.24 (95% CI 1.48–3.37), and 3.62 (95% CI 1.01–6.23), respectively. Gastrointestinal sequelae were greater in patients with diarrhea during the acute phase. CONCLUSIONS & INFERENCES: Mild gastroenterological symptoms persist 5 months after SARS‐CoV‐2 infection, in particular in patients reporting diarrhea in the acute phase. Infected patients are at increased risk of chronic fatigue and somatoform disorders, thus supporting the hypothesis that both functional gastrointestinal and somatoform disorders may have a common biological origin.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a single-stranded enveloped RNA beta-coronavirus, responsible for the first 21 st -century pandemic. 1 

can be asymptomatic or responsible for coronavirus disease-2019 (COVID-19) 2 characterized by a range of pulmonary manifestations from fever, dry cough, and dyspnea to pneumonia and acute respiratory distress syndrome. 3 Additionally, several extrapulmonary manifestations have also been described including neurological, hematological, cardiovascular, renal, dermatological, and gastrointestinal ones. 4 The most frequent gastrointestinal manifestation in COVID-19 patients is diarrhea, which has been variably reported in 4%-37% of large series. 3, [5] [6] [7] [8] [9] [10] [11] [12] Less is known about whether gastrointestinal symptoms persist after the resolution of the acute infection.

In a recent large Chinese cohort study, 5% of patients reported diarrhea or vomiting 6 months after SARS-CoV-2 infection. 13 In another retrospective study, the most common gastrointestinal sequelae 90 days after infection were the loss of appetite, nausea, acid reflux, and diarrhea, that were reported by 24%, 18%, 18%, and 15% of the patients, respectively. 14 Bacterial, protozoal, and viral infections of the gastrointestinal tract represent a recognized risk factor for the development of functional gastrointestinal disorders in the upper and lower gastrointestinal tract, known as post-infectious dyspepsia 15, 16 and post-infectious irritable bowel syndrome (IBS). [17] [18] [19] [20] Gastrointestinal infections have also been reported to increase the risk of chronic fatigue and other extraintestinal symptoms (e.g., headache, articular, and muscle pain), which in absence of organic/biological alterations explaining them are known as functional somatic syndromes or somatoform disorders. 19, 21, 22 Whether the origin of these somatoform symptoms was to be searched in a biological, psychological, or social domain is still debated. 23 Since February 2020, SARS-CoV-2 has been hitting Italy. 24 This has provided a unique opportunity to assess the long-term impact of a previously unknown viral infection on the burden of both gastrointestinal and extraintestinal somatoform symptoms. The aim of our study was to assess the frequency and relative risk of gastrointestinal and somatoform symptoms 5 months after the resolution of SARS-CoV-2 infection compared with a control cohort.

In February 2020, a SARS-CoV-2 outbreak occurred in Italy, with extreme severity in Milan and the surrounding Lombardy region.

A first peak was reached at the end of March 2020, while the end of the first wave was recognized in May 2020. 24 Far from that, we launched an online structured questionnaire. All the patients aged between 18 and 60 years who tested positive with a polymerase chain reaction for SARS-CoV-2 at nose pharyngeal swab in the laboratories of our hospital between February and April 2020

were contacted by e-mail. Employees and healthcare professionals who were tested negative at nose pharyngeal swab within the surveillance program of the hospital in the same period were also e-mailed as a control group. Subjects reporting a previous diagnosis of IBS, inflammatory bowel disease (IBD), or celiac disease were excluded.

The study was approved by the local Ethics Committee of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (approval no. 106876 on June 23 rd 2020). All the subjects received an e-mail explaining the rationale of the study for their informed consent to participate. As they agreed, the subjects were directed via a link to an online structured questionnaire on the EU-Survey platform (https:// ec.europa.eu/eusur vey/) supported by the European Commission, which allows to collect sensible data with no user identification via IT tracking, profiling cookies, or geographical location or personal/ socio-demographic/health data. 

Data were automatically collected on EU-Survey. The sample size was calculated assuming the frequency of IBS-like symptoms in the study and control groups of 25% and 5%, respectively; accordingly, 140 subjects in each group would be needed to have a 80% power with a 0.05 type-I error. At univariate analysis, the differences between the two groups for categorical variables and continuous variables were analyzed by Chi-square and Mann-Whitney test, respectively. Adjusted score differences and 95% confidence intervals (CI) between SARS-CoV-2-positive patients and negative controls were obtained from multiple linear regression models containing covariates selected a priori as potential confounders: sex, age, level of education, past surgery, chronic medications, smoking habits, and psychological comorbidity. The same covariates were entered in multiple Poisson regression models with robust variance to compare symptoms frequencies in the two groups and to calculate adjusted risk ratios (RR). 31 Statistical analysis was carried out by software:

The rate of response to the structured questionnaire was 34.6% Table 1 .

were older, with lower frequency of women and lower education level. Job activity, past surgery, chronic medications, and psychiatric disorders were not different in the compared groups.

The frequency of symptoms and signs of SARS-CoV-2-positive patients compared to those reported by negative controls are shown in Figure 1 . Fever, dyspnea, loss of smell, loss of taste, diarrhea, weight loss, myalgia, arthralgia, and asthenia were reported by more than 40% of patients and with a greater frequency 

Gastrointestinal symptoms summarized according to the 5 domains of the SAGIS questionnaire are reported in Table 2 . At univariate analysis, the symptoms in the abdominal pain/discomfort, diarrhea/ incontinence, and gastroesophageal reflux disease/regurgitation domains were more severe in patients with previous SARS-CoV-2 infection than in control subjects with a score difference of +0.16, +0.13, and +0.13, respectively. These differences were lower at multivariable analysis ( Table 2 ). Similar scores of nausea/vomiting and of constipation domains were reported in the two groups at both univariate and multivariable analysis. Table 3 ).

The first most important health concern/problem among gas- (Table 4 ); positive cases, with a score equal or greater than the operational cutoff value of 11 for anxiety were 17 (10%) in patients with previous SARS-CoV-2 infection and 8 (4%) in controls and for depression 9 (5%) and 4 (2%), respectively.

The presence of diarrhea was associated (a) in the acute phase 19.2%, p = 0.05) and of loose stools (21.2% vs. 9.6%, p = 0.04).

The frequency of chronic fatigue (p = 0.05) and elevated somatization scores (p = 0.003) were higher in patients with diarrhea than those without it (Table 5 ). Antibiotic treatments tended to be more frequent in patients with diarrhea (58.8%) than in those without (41.1%) (p=0.03).

Among SARS-CoV-2-positive patients, the subjects with chronic fatigue reported higher somatization scores than those without (61.7 ± 10.8 vs. 50.9 ± 10.9, p = <0.001).

To our knowledge, this is the first controlled cohort study investigating the frequency and relative risk of gastrointestinal and somato- ing from 4% to 37% of large series. 3, [5] [6] [7] [8] [9] [10] [11] [12] In line with these studies, acute diarrhea was reported by more than 50% of our SARS-CoV-2

patients. In our cohort, the presence of diarrhea was associated with an increased hospitalization rate, but among the hospitalized patients it tended to be associated with a less severe disease in line with the results of a recent study reporting a less severe COVID-19

in patients with diarrhea. 32 Less is known about whether gastrointestinal symptoms persist after the resolution of the acute infection. 13, 14 Our results

show that abdominal pain/discomfort, diarrhea/incontinence, and gastroesophageal reflux disease/regurgitation symptoms do per- Fatigue is reported during acute viral infections and is known to persist after the resolution of infection with several different viral and non-viral pathogens. 22 The risk of chronic fatigue increases threefold after Giardia infection 19 and, in a populationbased analysis, it increased 1.35-to 1.82-fold after a previous gastrointestinal infection. 21 Our results indicate that SARS-CoV-2 Note: Adjusted score differences between SARS-CoV-2-positive and negative subjects were obtained from multiple linear regression models containing the covariates sex, age, level of education, past surgery, chronic medications, smoking habits, and psychological comorbidity.

infection elevates the risk of chronic fatigue more than two times according to a recent large Chinese cohort study 13 and with the reports of severe cases of chronic fatigue syndrome/myalgic encephalomyelitis described after SARS infection in the earlier coronavirus epidemics. 35, 36 In line with the increased risk in chronic fatigue, the scores for somatization were higher in our patients following their SARS-CoV-2 infection than in control subjects both at univariate and multivariable analysis.

Somatic symptoms are greater in patients with IBS than in patients with functional diarrhea, 37 are usually associated with anxiety and depression, 37, 38 and are interpreted on the basis of psychological or social disturbances. Interestingly, the increased risk of chronic fatigue and somatization scores in our study was not associated with significant changes in anxiety and depression; moreover, somatization but not anxiety and depression scores were significantly increased in patients with diarrhea during the acute phase. According to the "biology first" hypothesis by Enck and Mazurak, 23 it is conceivable that chronic fatigue and somatization might also have a post-infectious origin to begin with and that anxiety might develop at a further step following the bidirectional brain-to-gut and gut-to-brain interplay over time. 39 If This study comes with some limitations that should be acknowledged. (1) The response rate to the questionnaire was far from optimal in particular for the control group and younger subjects, more prone to respond to an online survey, and female subjects perhaps more interested to take part in a study on functional In conclusion, our study shows that acute SARS-CoV-2 infection may affect the brain-gut axis. Five months after the acute infection, mild gastroenterological symptoms persist, in particular in patients reporting diarrhea in the acute phase of the infection. Infected patients are also at increased risk of chronic fatigue and somatoform disorders, thus supporting the hypothesis that both functional gastrointestinal and somatoform disorders may have a common biological origin.

The authors have no competing interests related to this study.

AC received lecturer fees from Takeda, a sponsorship from Bracco.

MV served as a consultant to Abbvie, MSD, Takeda, Janssen-Cilag, and Celgene. He received lecturer fees from Abbvie, Ferring, Takeda, MSD, Janssen-Cilag, and Zambon.

DN contributed to conceptualization, collection and analysis of data, writing, and review and editing. AC contributed to conceptualization, analysis of data, and review and editing. AM and AB contributed to review and editing. DC contributed to statistical analysis and review and editing. MV contributed to conceptualization and review and editing. GB contributed to conceptualization, analysis of data, writing, review and editing, and supervision. 

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