Post COVID-19 irritable bowel syndrome

Abstract

Objectives
The long-term consequences of COVID-19 infection on the gastrointestinal tract remain unclear. Here, we aimed to evaluate the prevalence of gastrointestinal symptoms and post-COVID-19 disorders of gut–brain interaction after hospitalisation for SARS-CoV-2 infection.

Design
GI-COVID-19 is a prospective, multicentre, controlled study. Patients with and without COVID-19 diagnosis were evaluated on hospital admission and after 1, 6 and 12 months post hospitalisation. Gastrointestinal symptoms, anxiety and depression were assessed using validated questionnaires.

Results
The study included 2183 hospitalised patients. The primary analysis included a total of 883 patients (614 patients with COVID-19 and 269 controls) due to the exclusion of patients with pre-existing gastrointestinal symptoms and/or surgery. At enrolment, gastrointestinal symptoms were more frequent among patients with COVID-19 than in the control group (59.3% vs 39.7%, p<0.001). At the 12-month follow-up, constipation and hard stools were significantly more prevalent in controls than in patients with COVID-19 (16% vs 9.6%, p=0.019 and 17.7% vs 10.9%, p=0.011, respectively). Compared with controls, patients with COVID-19 reported higher rates of irritable bowel syndrome (IBS) according to Rome IV criteria: 0.5% versus 3.2%, p=0.045. Factors significantly associated with IBS diagnosis included history of allergies, chronic intake of proton pump inhibitors and presence of dyspnoea. At the 6-month follow-up, the rate of patients with COVID-19 fulfilling the criteria for depression was higher than among controls.

Conclusion
Compared with controls, hospitalised patients with COVID-19 had fewer problems of constipation and hard stools at 12 months after acute infection. Patients with COVID-19 had significantly higher rates of IBS than controls.

Trial registration number
NCT04691895 .

Full text

1
MarascoG, etal. Gut 2022;0:1–9. doi:10.1136/gutjnl-2022-328483
Neurogastroenterology
Original research
Post COVID- 19 irritable bowelsyndrome
Giovanni Marasco,1,2 Cesare Cremon,1,2 Maria Raffaella Barbaro,1 Giulia Cacciari,1,2
Francesca Falangone,3 Anna Kagramanova,4 Dmitry Bordin,4,5,6 Vasile Drug,7
Egidia Miftode,8 Pietro Fusaroli ,9 Salem Youssef Mohamed,10 Chiara Ricci,11
Massimo Bellini,12 Mohammed Masudur Rahman,13 Luigi Melcarne,14
Javier Santos ,15 Beatriz Lobo,15 Serhat Bor,16 Suna Yapali,17 Deniz Akyol,18
Ferdane Pirincci Sapmaz,19 Yonca Yilmaz Urun,20 Tugce Eskazan,21 Altay Celebi,22
Huseyin Kacmaz,23 Berat Ebik,24 Hatice Cilem Binicier,25 Mehmet Sait Bugdayci,26
Munkhtsetseg Banzragch Yağcı,27 Husnu Pullukcu,18 Berrin Yalınbas Kaya,20
Ali Tureyen,20 İbrahim Hatemi,21 Elif Sitre Koc,17 Goktug Sirin,22 Ali Riza Calıskan,23
Goksel Bengi,25 Esra Ergun Alıs,28 Snezana Lukic,29 Meri Trajkovska,30 Keren Hod,31
Dan Dumitrascu,32 Antonello Pietrangelo,33 Elena Corradini,33 Magnus Simren,34
Jessica Sjölund ,34 Navkiran Tornkvist,34 Uday C Ghoshal ,35
Olga Kolokolnikova,36 Antonio Colecchia,37 Jordi Serra,38 Giovanni Maconi ,39
Roberto De Giorgio ,40 Silvio Danese ,41 Piero Portincasa,42
Antonio Di Sabatino ,43 Marcello Maggio,44 Elena Philippou,45 Yeong Yeh Lee ,46
Daniele Salvi,2 Alessandro Venturi,1 Claudio Borghi,1,2 Marco Zoli,2 Paolo Gionchetti,1,2
Pierluigi Viale,1,2 Vincenzo Stanghellini ,1,2 Giovanni Barbara ,1,2 the GI- COVID19
study group
To cite: MarascoG,
CremonC, BarbaroMR, etal.
Gut Epub ahead of print:
[please include Day Month
Year]. doi:10.1136/
gutjnl-2022-328483
►Additional supplemental
material is published online
only. To view, please visit the
journal online (http:// dx. doi. org/
10. 1136/ gutjnl- 2022- 328483).
For numbered affiliations see
end of article.
Correspondence to
Dr Giovanni Barbara, Azienda
Ospedaliero- Universitaria di
Bologna IRCCS, Bologna, Emilia-
Romagna, Italy;
giovanni. barbara@ unibo. it
Received 15 August 2022
Accepted 23 November 2022
© Author(s) (or their
employer(s)) 2022. No
commercial re- use. See rights
and permissions. Published
by BMJ.
ABSTRACT
Objectives The long- term consequences of COVID- 19
infection on the gastrointestinal tract remain unclear.
Here, we aimed to evaluate the prevalence of
gastrointestinal symptoms and post- COVID- 19 disorders
of gut–brain interaction after hospitalisation for SARS-
CoV- 2 infection.
Design GI- COVID- 19 is a prospective, multicentre,
controlled study. Patients with and without COVID- 19
diagnosis were evaluated on hospital admission
and after 1, 6 and 12 months post hospitalisation.
Gastrointestinal symptoms, anxiety and depression were
assessed using validated questionnaires.
Results The study included 2183 hospitalised patients.
The primary analysis included a total of 883 patients
(614 patients with COVID- 19 and 269 controls)
due to the exclusion of patients with pre- existing
gastrointestinal symptoms and/or surgery. At enrolment,
gastrointestinal symptoms were more frequent among
patients with COVID- 19 than in the control group
(59.3% vs 39.7%, p<0.001). At the 12- month follow-
up, constipation and hard stools were significantly more
prevalent in controls than in patients with COVID- 19
(16% vs 9.6%, p=0.019 and 17.7% vs 10.9%,
p=0.011, respectively). Compared with controls, patients
with COVID- 19 reported higher rates of irritable bowel
syndrome (IBS) according to Rome IV criteria: 0.5%
versus 3.2%, p=0.045. Factors significantly associated
with IBS diagnosis included history of allergies, chronic
intake of proton pump inhibitors and presence of
dyspnoea. At the 6- month follow- up, the rate of patients
with COVID- 19 fulfilling the criteria for depression was
higher than among controls.
WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒The long- term consequences of COVID- 19
infection on the gastrointestinal tract remain
unclear.
⇒Similarly, if SARS- CoV- 2 may be a risk factor for
disorders of gut–brain interaction is unknown.
WHAT THIS STUDY ADDS
⇒At the 12- month follow- up, compared with
controls, patients with COVID- 19 reported
higher rates of postinfection irritable bowel
syndrome (IBS) according to Rome IV criteria.
⇒Factors significantly associated with new IBS
diagnosis included dyspnoea during the acute
phase, history of allergies and chronic intake of
proton pump inhibitors.
HOW THIS STUDY MIGHT AFFECT RESEARCH,
PRACTICE OR POLICY
⇒COVID- 19 is associated with an increased
risk of long- term gastrointestinal symptoms,
including postinfection IBS.
⇒Given the high prevalence of COVID- 19 at the
global level, an increase in new- onset disorders
of gut–brain interaction should be expected
due to COVID- 19.
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2MarascoG, etal. Gut 2022;0:1–9. doi:10.1136/gutjnl-2022-328483
Neurogastroenterology
Conclusion Compared with controls, hospitalised patients with
COVID- 19 had fewer problems of constipation and hard stools at 12
months after acute infection. Patients with COVID- 19 had significantly
higher rates of IBS than controls.
Trial registration number NCT04691895.
INTRODUCTION
The COVID- 19 pandemic, caused by SARS- CoV- 2, has spread
globally with over 533 million confirmed cumulative cases, and
more than 6 million cumulative deaths, as reported by the WHO
on 15 June 2022.1 The clinical course of COVID- 19 can range
from asymptomatic infection to rapidly progressing and life-
threatening disease.2 Older people and those with underlying
medical conditions are more likely to develop serious illness.3
Despite vaccination,4 5 new virus variants6 7 lead to cyclic conta-
gion peaks that are a cause of concern.
Additionally, the so- called long COVID- 19 is an emerging
entity burdening health systems worldwide,8 consisting of
residual effects after SARS- CoV- 2 infection, such as fatigue,
dyspnoea, chest pain, cognitive disturbances, arthralgia and
reduced quality of life.9 A recent metanalysis including 57
studies, with 250 351 COVID- 19 survivors, reported long-
term sequelae, including pulmonary impairment, neurological
disorders, mental health disorders, functional mobility impair-
ments, and general and constitutional symptoms.10 Long- term
and postacute digestive symptoms included abdominal pain,
anorexia, diarrhoea and vomiting.10 We recently reported2 that
compared with non- infected controls, SARS- CoV- 2 infection
was associated with diarrhoea, nausea and other gastrointestinal
symptoms. Moreover, at 1 month after the initial assessment,
patients with COVID- 19 had a greater prevalence of nausea and
acid regurgitation compared with controls.
The hypothetical mechanisms responsible for gastrointestinal
COVID- 19 symptoms and their long- term presence support the
involvement of cellular damage, inflammation, gut dysbiosis,
enteric nervous system dysfunction and a prothrombosis state
induced by the virus.9 11 Moreover, long- term gastrointestinal
COVID- 19 symptoms may resemble postinfection (PI) disorders
of gut–brain interaction (DGBI).12 Indeed, acute gastroenteritis
following infection with bacterial or viral pathogens is the stron-
gest known risk factor for irritable bowel syndrome (IBS) devel-
opment, the so- called PI IBS (PI- IBS).13 Compared with IBS
induced by bacterial infections and other DGBI, fewer studies
have evaluated the incidence of these syndromes following
viral infection. Additionally, the long- term consequences of
COVID- 19 infection on the gastrointestinal tract remain unclear
due to the limitations of previous studies, including small
sample size, limited follow- up, lack of controls and retrospec-
tive design.14–16 Here, we report the results of a prospective,
global, multicentre, controlled study assessing the prevalence
of PI gastrointestinal symptoms in patients who were hospital-
ised with COVID- 19 compared with a non- COVID hospital-
ised control group, who were followed- up for 12 months after
hospitalisation.
METHODS
Design
This study was promoted by the Department of Medical and
Surgical Science at the University of Bologna, Italy and IRCCS
S. Orsola in Bologna, Italy, and was endorsed by the Euro-
pean Society of Neurogastroenterology and Motility (ESNM),
the United European Gastroenterology (UEG), and the Rome
Foundation (RF).The study was carried out in 36 centres in
14 countries: Italy, Bangladesh, Cyprus, Egypt, Israel, India,
Macedonia, Malaysia, Romania, the Russian Federation, Serbia,
Spain, Sweden and Turkey. Country and centre selection were
based on the availability of principal investigators who either
were contacted directly or responded to advertisements on UEG,
ESNM and RF websites.
Patients
For this study, hospitalised patients with or without COVID- 19
were prospectively and consecutively enrolled on hospital
admission, and followed up with symptom reassessment at 1,
6 and 12 months. The enrolment timeframe lasted from 1 to 3
months for each centre. All patients were evaluated according
to standard clinical practice, and gave their written informed
consent. Eligible patients were≥18 and ≤85 years of age, with
or without a diagnosis of COVID- 19 according to the WHO
definition (laboratory- confirmed SARS- CoV- 2 infection),17 with
symptoms severe enough to warrant hospital admission, and
recruited from May to October 2020. Patients were excluded if
they were unable to conform to study protocol (under mechan-
ical ventilation or unable to report data or to sign informed
consent), or were diagnosed with concurrent cancer. The control
group comprised patients hospitalised for reasons other than
COVID- 19—including disease/disorders of gastroenterological,
traumatic, and surgical pertinence—who were prospectively
enrolled within the study timeframe in the internal medicine
units of participating centres.
Assessment
Study data were simultaneously collected from each centre using
an e- Case report form on the REDCap platform. Descriptive
statistics were used to report all demographics, medical history,
laboratory and imaging tests, and other clinical data, including
the presence of gastrointestinal symptoms according to the
Gastrointestinal Symptoms Rating Scale (GSRS) questionnaire
at admission and at 1, 6 and 12 months of follow- up. The GSRS
is a self- administered questionnaire with a well- documented
reliability and validity, and has been developed for the assess-
ment of gastrointestinal symptoms in IBS and peptic ulcer
disease, including a recall period of 1 week.18 On admission,
patients were assessed for the presence of COVID- 19- related
symptoms—including current or previous (1 week before hospi-
talisation) gastrointestinal symptoms, using the GSRS, which
comprises 15 items including common upper and lower gastro-
intestinal symptoms, graded on a 7- point Likert- like scale.18 To
avoid overestimation of gastrointestinal symptoms, the GSRS
was also used to assess the presence of gastrointestinal symptom
onset at least 6 months before hospitalisation, and symptom-
atic patients were excluded from the primary aim analyses.
After enrolment, all patients were contacted by telephone and
interviewed at 1 month to reassess GSRS and hospitalisation
outcomes, and at 6 and 12 months to reassess GSRS and to
complete the Hospital Anxiety and Depression Scale (HADS).19
The HADS is a self- assessment scale useful for detecting states
of depression and anxiety in the setting of an hospital medical
outpatient clinic.19 Data from the HADS were scored for depres-
sion and anxiety as follows: score 0–7, normal; 8–10, border-
line abnormal; and 11–21, abnormal.19 At the 6 and 12 months
assessments, DGBI were diagnosed according to the Rome IV
Diagnostic Questionnaire for Functional Gastrointestinal Disor-
ders in Adults.20
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Neurogastroenterology
Endpoints
The primary endpoint of this study was the assessment of long-
term post- COVID- 19 gastrointestinal symptoms and DGBI.
The secondary endpoints included the assessment of predictive
factors associated with the development of PI DGBI, if a statis-
tically significant between- group difference was found. Explor-
atory endpoints included long- term gastrointestinal symptoms,
and the development of DGBI and anxiety and depression
within the entire study cohort at the 12- month follow- up (2053
patients).
Statistical analysis
Continuous variables were reported as mean and SD, and
categorical variables as number and percentage. Primary and
secondary aim analyses were conducted after excluding subjects
with chronic gastrointestinal symptoms or previous gastrointes-
tinal surgery. Presence of chronic gastrointestinal symptoms was
defined as the report of at least one GSRS item of any severity—
except borborygmi, flatus and eructation, for which the addi-
tional presence of at least one other GSRS item was required due
to their common frequency in the general population, with onset
reported at least 6 months before hospitalisation. Patients without
COVID- 19 diagnosis were used as the control group for the
primary study outcome. Data recorded at admission and during
follow- up evaluations were compared using the χ2 test, Fisher’s
test, Student’s t- test and Mann- Whitney U test, as appropriate.
Significant follow- up data regarding the occurrence of DGBI and
anxiety and depression at 12 months were graphically translated
using histograms. When significant between- group differences
were identified, the data recorded at admission were tested as
predictors of gastrointestinal symptoms at 12 months, according
to GSRS and/or DGBI occurrence in patients with COVID- 19,
using logistic regression univariate and multivariate analysis. We
calculated the estimated OR and 95% CI, and p values of<0.05
(two tailed) were considered statistically significant. The results
obtained from multivariate analysis were translated into graphic
form, using a nomogram for logistic regression. All analyses were
carried out using STATA statistical software (Stata Corp.).
RESULTS
Patients
From 1 May to 30 October of 2020, a total of 2183 hospital-
ised patients were consecutively enrolled from the 36 recruiting
centres. Of these patients, 130 were excluded: 75 for incomplete
or missing questionnaire data, 34 for being unable to conform to
the study protocol during follow- up (death), 14 due to cancer,
and 7 controls due to COVID- 19 diagnosis during follow- up.
Of the remaining 2053 patients, 1314 (64%) had a diagnosis
of COVID- 19. A total of 1170 patients (700 in the COVID- 19
population and 470 in the control group) were excluded from
the primary and secondary aim analyses due to pre- existing
gastrointestinal symptoms and/or surgery (figure 1). Data from
883 subjects without pre- existing gastrointestinal symptoms
(614 COVID- 19 and 269 controls) were used for baseline eval-
uations and follow- up for primary and secondary study aims.
Follow- up evaluations were completed by 772 patients (548
COVID- 19 and 224 controls) at 6 months, and by 623 patients
(435 COVID- 19 and 188 controls) at 12 months. Table 1 pres-
ents the demographics and clinical characteristics of patients
included in the study.
Gastrointestinal symptoms after COVID-19 infection
At enrolment, gastrointestinal symptoms occurred more
frequently in patients with COVID- 19 compared with controls:
106/267 controls (39.7%) versus 364/614 patients with
COVID- 19 (59.3%), p<0.001. Compared with the control
group, patients with COVID- 19 reported higher rates of nausea
(12.6% vs 28.8%, p<0.001), diarrhoea (9.4%, vs 37.3%,
p<0.001), loose stools (7.9% vs 27.2%, p<0.001), and urgency
(4.9% vs 15.9%, p=0.001), and a lower rate of hard stools (12.7
vs 7.7%, p=0.038).
At the 1- month follow- up, compared with controls, patients
with COVID- 19 showed significantly higher rates of nausea
(1.7% vs 8.7%, p=0.015) and acid regurgitation (2.1% vs 8.4%,
p=0.006). At the 6- month follow- up, compared with controls,
patients with COVID- 19 reported lower rates of flatus (19.1%
vs 17.6%, p=0.024), constipation (17.1% vs 8.9%, p<0.001)
and hard stools (17.2% vs 9.6%, p=0.030). At the 12- month
follow- up, compared with controls, patients with COVID- 19
reported significantly lower rates of constipation (16% vs 9.6%,
p=0.019) and hard stools (17.7% vs 10.9%, p=0.011). We
found no other significant between- group differences in GSRS
results.
The rates of gastrointestinal symptom intensity scores in the
study population at enrolment, and at the 1- month, 6- month
and 12 month follow- ups are reported in online supplemental
tables 1−4. For the exploratory endpoints, the occurrence of
long- term gastrointestinal symptoms at the 12- month follow- up
in the entire study cohort (2053 patients) is reported in online
supplemental table 5.
Post COVID-19 disorders of gut–brain interaction
There were no significant differences at the 6- month follow- up
in the rates of epigastric pain syndrome (0% vs 0.6%, p=0.267),
Figure 1 Flow chart of the selection of patients enrolled in the study.
GI, gastrointestinal; GSRS, Gastrointestinal Symptoms Rating Scale.
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Neurogastroenterology
Table 1 Demographics and anamnestic characteristics of patients selected for primary aim analysis in the GI- COVID- 19 study
Controls, n (%) or Mean±SD n=269 COVID- 19, n (%) or Mean±SD n=614 P value
Age 50.9±18.1 49.9±16.1 0.471
Sex, male 164 (62.1) 364 (59.9) 0.532
BMI 26.8±5.5 27.7±5.3 0.023
Smoker <0.001
No 125 (47.5) 436 (71.8)
Current 72 (27.4) 60 (9.9)
Former 66 (25.1) 111 (18.3)
Alcohol consumption 58 (22.3) 95 (15.7) 0.018
Physical activity (at least 30 min 3 times/week) 78 (30) 174 (29.9) 0.976
Comorbidities
Neurological 21 (7.8) 16 (2.6) <0.001
Cardiovascular 105 (39) 173 (28.2) 0.001
Respiratory 31 (11.5) 40 (6.5) 0.012
Liver 16 (6) 19 (3.1) 0.045
Kidney 20 (7.4) 28 (4.6) 0.083
Diabetes 60 (22.3) 89 (14.5) 0.004
Metabolic other than diabetes 32 (11.9) 58 (9.5) 0.268
Musculoskeletal 8 (3) 16 (2.6) 0.757
Psychiatric 9 (3.4) 6 (1) 0.012
Gynaecological 3 (1.1) 1 (0.2) 0.052
Urological 20 (7.4) 21 (3.4) 0.009
Rheumatological 7 (2.6) 14 (2.3) 0.772
Allergies 13 (4.8) 18 (2.9) 0.158
Autoimmune 11 (4.1) 17 (2.8) 0.303
Neoplastic 11 (4.1) 13 (2.1) 0.097
Psychological 11 (4.1) 8 (1.3) 0.009
Haematological 10 (3.7) 7 (1.1) 0.010
Chronic medication intake with GI effect
Proton pump inhibitors 68 (25.3) 74 (12.1) <0.001
Non- steroidal anti- inflammatory drugs 33 (12.3) 33 (5.4) <0.001
Steroids 13 (4.8) 7 (1.1) 0.001
Metformin 16 (6) 31 (5.1) 0.584
Serotonin selective reuptake inhibitors 9 (3.4) 11 (1.8) 0.153
Antipsychotic 4 (1.5) 3 (0.5) 0.125
Iron 5 (1.9) 5 (0.8) 0.177
Fibrates 1 (0.4) 7 (1.1) 0.267
ACE- I 32 (11.9) 56 (9.1) 0.205
Beta- blockers 45 (16.7) 76 (12.4) 0.084
Angiotensin- 2 antagonist 20 (7.4) 56 (9.1) 0.411
Lithium 0 0 –
Carbamazepine 3 (1.1) 1 (0.2) 0.052
Furosemide 25 (9.3) 10 (1.6) <0.001
5- ASA 3 (1.1) 5 (0.8) 0.664
Rifaximin 3 (1.1) 0 0.009
Opiates 4 (1.5) 2 (0.3) 0.053
Anticholinergics 1 (0.4) 1 (0.2) 0.594
Verapamil 3 (1.1) 3 (0.5) 0.297
Levothyroxine 11 (4.1) 19 (3.1) 0.453
Cholestyramine 1 (0.4) 0 0.131
Monoclonal antibodies 1 (0.4) 0 0.131
Digoxin 0 1 (0.2) 0.508
Dopaminergic agents 1 (0.4) 2 (0.3) 0.914
H2 blockers 3 (1.1) 1 (0.2) 0.052
Benzodiazepines 13 (4.8) 11 (1.8) 0.011
Tricyclic antidepressant 3 (1.1) 2 (0.3) 0.150
Antibiotics in the last 3 months 91 (34.5) 132 (21.5) <0.001
Probiotics in the last 3 months 28 (10.7) 46 (7.5) 0.125
ACE- I, ACE inhibitor; 5- ASA, acid 5 amino- salicylic; BMI, body mass index; GI, gastrointestinal; n, number; SD, Standard deviation.
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post- prandial distress syndrome (1.3% vs 1.6%, p=0.757), func-
tional dyspepsia (1.3% vs 2%, p=0.528), IBS (1.3% vs 1.6%,
p=0.587) and functional diarrhoea (0% vs 0.2%, p=0.522) in
controls compared with COVID- 19, respectively (table 2).
At the 12- month follow- up, compared with controls, patients
with COVID- 19 reported significantly higher rates of IBS (0.5%
vs 3.2%, p=0.045) (figure 2). The only control patient who
developed IBS reported IBS with diarrhoea (IBS- D). On the
other hand, among the 14 patients with COVID- 19 who devel-
oped IBS, 4 (28.6%) reported IBS with constipation, 7 (50%)
IBS- D, 1 (7.1%) IBS with mixed bowel habits, and 2 (14.3%)
IBS undefined subtype. Patients with COVID- 19 also reported
higher rates of other DGBI at 12 months; however, no other
significant differences were found (table 2).
Post COVID-19 anxiety and depression
Compared with controls, patients with COVID- 19 showed a
significantly higher rate of depression, according to the HADS,
at the 6- month follow- up: borderline abnormal, 4% versus 9.9%
and abnormal, 2.7% versus 4.2% (p=0.014). A similar trend was
observed for anxiety, according to the HADS, at the 12- month
follow- up, although this difference was not significant (figure 3).
With regards to the exploratory endpoints, the development of
DGBI and anxiety and depression within the entire study cohort
(2053 patients) is reported in online supplemental table 6.
Factors associated with post-COVID-19 DGBI
Baseline rates of antibiotic intake in the previous 3 months,
cough, dyspnoea, headache and antibiotic intake during hospi-
talisation were significantly higher in patients who would
develop post- COVID IBS (online supplemental table 7). All
demographic, anamnestic and clinical data assessed at baseline
(including comorbidities, chronic medication intake, and gastro-
intestinal symptoms significantly associated with COVID- 19,
Table 2 DGBI and anxiety and depression occurrence at the 6- month and 12- month follow- ups in patients selected for primary aim analysis of the
GI- COVID- 19 study
6- Month follow- up 12- Month follow- up
Controls
n (%) n=224
COVID- 19
n (%) n=548 P value
Controls
n (%) n=188
COVID- 19
n (%) n=435 P value
DGBI
Epigastric pain syndrome 0 3 (0.6) 0.267 2 (1.1) 8 (1.8) 0.480
Postprandial distress syndrome 3 (1.3) 9 (1.6) 0.757 3 (1.6) 17 (3.9) 0.134
Functional dyspepsia 3 (1.3) 11 (2) 0.528 4 (2.1) 16 (3.7) 0.314
Chronic nausea and vomiting syndrome 3 (1.3) 6 (1.1) 0.774 3 (1.6) 2 (0.5) 0.145
Cyclic vomiting syndrome 1 (0.5) 0 0.118 – – –
Functional diarrhoea 0 1 (0.2) 0.522 0 1 (0.2) 0.511
Irritable bowel syndrome 2 (0.9) 3 (0.6) 0.587 1 (0.3) 14 (3.2) 0.045
HADS
Depression 0.014 0.1
Normal 209 (93.3) 471 (86) 176 (93.6) 384 (88.3)
Borderline abnormal 9 (4) 54 (9.9) 7 (3.7) 36 (8.3)
Abnormal 6 (2.7) 23 (4.1) 5 (2.7) 15 (3.4)
Anxiety 0.914 0.088
Normal 196 (90.7) 445 (89.7) 174 (92.5) 390 (89.7)
Borderline abnormal 12 (5.6) 31 (6.3) 12 (6.4) 25 (5.8)
Abnormal 8 (3.7) 20 (4) 2 (1.1) 20 (4.5)
DGBI, disorders of gut–brain interaction; HADS, Hospital Anxiety and Depression Scale; n, number.
Figure 2 Disorders of gut–brain interaction diagnosis (DGBI) at the
12- month follow- up in controls and patients with COVID- 19 diagnosis.
EPS, epigastric pain syndrome; FD, functional dyspepsia; IBS, irritable
bowel syndrome; PDS, postprandial distress syndrome.
Figure 3 Hospital Anxiety and Depression Scale (HADS) at 6 and 12
months among controls and patients with COVID- 19 diagnosis.
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Neurogastroenterology
according to GSRS), as well as data from the HADS at the
6- month follow- up, were tested in univariate analysis as inde-
pendent predictors of IBS diagnosis in both the entire study
cohort selected for primary aim evaluations as post- hoc analysis
(online supplemental table 9), and in patients with COVID- 19
at the 12- month follow- up. The post- hoc analysis carried out
in the entire study cohort found that predictive factors for IBS
occurrence were COVID- 19 diagnosis (OR 10.686), history of
allergies (OR 7.642), and chronic intake of proton pump inhibi-
tors (PPI; OR 5.439). As for the group of patients with COVID-
19, the univariate analysis revealed the following as predictive
factors for IBS: history of comorbidities, such as liver diseases
and allergies; chronic intake of PPI; antibiotic intake within the
3 months prior to hospital admission; presence of cough and
dyspnoea at enrollment; in- hospital antibiotic administration;
and the presence of anxiety, according to HADS at the 6- month
follow- up (table 3). In subsequent multivariate analysis, only
three variables remained significant: history of allergies (OR,
10.024; 95% CI 1.766 to 56.891; p=0.009), chronic intake
of PPI (OR, 4.816; 95% CI 1.447 to 16.025; p=0.010), and
dyspnoea (OR, 4.157; 95% CI 1.336 to 12.934; p=0.014).
Figure 4 presents a nomogram assessing the individual risk
factors associated with IBS diagnosis at 12 months.
DISCUSSION
Long- term follow- up of the GI- COVID study provides evidence
that most gastrointestinal symptoms declined after hospitalisa-
tion for SARS- CoV- 2 infection. In fact, compared with controls,
patients with COVID- 19 showed a lower prevalence of consti-
pation and hard stools at the 12- month follow- up. Additionally,
at the 12- month follow- up, patients with COVID- 19 showed a
significantly higher prevalence of IBS compared with control
patients. IBS risk was increased among patients with history of
allergies, chronic intake of PPI and dyspnoea at hospitalisation.
Patients with COVID- 19 also showed higher levels of depression
and anxiety at 6 and 12 months after hospitalisation.
Several previous studies have assessed the development of
long- term gastrointestinal symptoms and DGBI after COVID-
19. However, these studies have been limited by biases, including
small sample size,14 15 21 retrospective14 15 or cross- sectional
design,21 single- centre setting,14 21 and use of historic outpa-
tient16 control group comparators. Moreover, they have suffered
from limited follow- up assessment, at most up to 6 months,14–16
have not used the standardised Rome IV questionnaires,14 16
have not adjusted analyses for the presence of gastrointestinal
symptom or DGBI before the acute bout of SARS- CoV- 2 infec-
tion,14 15 21 or have not assessed the influence of other variables
with gastrointestinal effects.16 As a matter of fact, without
adjusting results for the abovementioned variables, we found no
significant differences in DGBI occurrence in our exploratory
endpoint analysis.
The GI- COVID study2 included a large prospective multi-
centre controlled cohort of hospitalised patients with COVID- 19
diagnosis, compared with a control population of hospitalised
patients without COVID- 19 who were enrolled at the same time
as the study cases. Patients were followed up until 12 months after
hospitalisation, and the results were adjusted for the presence of
previous gastrointestinal symptoms, abdominal surgery, chronic
gastrointestinal diseases and medication intake. The groups did
not differ in GSRS domains at 6 and 12 months, except that the
patients with COVID- 19 had lower rates of constipation and
hard stools compared with control patients. These data are in
contrast with previous reports. A small monocentric study found
Table 3 Univariate and multivariate logistic regression for identifying factors associated with irritable bowel syndrome occurrence at 12 months
follow- up in patients with COVID- 19 of the study group selected for primary aim analysis
Univariate Multivariate
OR (95% CI) P value OR (95% CI) P value
Comorbidities
Liver diseases 4.845 (0.989 to 23.734) 0.052
Allergies 6.212 (1.239 to 31.149) 0.026 10.024 (1.766 to 56.891) 0.009
Chronic medication intake
Proton pump inhibitors 4.030 (1.300 to 12.499) 0.016 4.816 (1.447 to 16.025) 0.010
Antibiotic intake in the previous 3 months 3.158 (1.081 to 9.220) 0.035
Clinical course
Cough 4.935 (1.091 to 22.321) 0.038
Dyspnoea 4.167 (1.369 to 12.680) 0.012 4.157 (1.336 to 12.934) 0.014
In- hospital antibiotic administration 3.945 (0.871 to 17.851) 0.075
Anxiety according to HADS at 6 months 2.081 (0.996 to 4.347) 0.051
CI, Confidence Interval; HADS, Hospital Anxiety and Depression Scale; OR, Odd Ratio; p, p value.
Figure 4 Nomogram reporting a probability score for irritable bowel
syndrome (IBS) development at 12 months after COVID- 19 Infection.
Each predictor is assigned a score on each axis; the sum of all points
for all predictors is computed and denoted as the total score up to 24,
associated with a probability of about 75% for developing IBS. PPI,
proton pump inhibitors.
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7
MarascoG, etal. Gut 2022;0:1–9. doi:10.1136/gutjnl-2022-328483
Neurogastroenterology
more frequent loose stools among COVID- 19 survivors at 6
months compared with controls, and no difference in the rate
of constipation.14 On the other hand, other large retrospective
matched- controlled studies have reported an increased rate of
constipation in patients with COVID- 19,22 23 together with an
increased use of laxatives.22
Compared with controls, we found a higher rate of IBS (3.2%)
in the COVID- 19 group. Interestingly, this rate of IBS is lower
than those previously reported among patients with COVID- 19,
which have ranged from 5.3% according to Rome III criteria at
6 months,16 up to 15.9% according to Rome IV criteria.21 These
discrepancies may be partly explained by our rigorous patient
selection, which may have lowered the occurrence rates in our
cohort. However, our post- COVID- 19 IBS rate is in line with
data from a recent meta- analysis that reported an IBS rate of
6.4% after viral infections.24
No previous data are available regarding predictors of post-
COVID- 19 IBS. We found that predictive factors for post-
COVID- 19 IBS occurrence were consistent with previous
findings in IBS.13 Our data indicated an association of post-
COVID- 19 IBS with history of allergies, which is in line with
previous evidence,25 26 and with the evidence of immune
dysregulation and loss of mucosal homeostasis in patients
with IBS.27–29 We also found an association between baseline
dyspnoea and post- COVID- 19 IBS. A previous large retro-
spective cohort study30 also reported that dyspnoea at hospital
admission was associated with post- COVID- 19 IBS, and
suggested that the severity of the acute infection and systemic
symptoms may be involved in the development of chronic
intestinal symptoms.
Our present results also showed that patients with COVID- 19
reporting chronic use of PPIs were at risk for IBS develop-
ment. PPIs can contribute to alterations of gut microbiota,31 32
and PPI use during COVID- 19 increases the risk of infection
and worsens outcomes.33 Changes in gut microbiota have been
implicated in the pathogenesis of gastrointestinal symptoms2
during the acute phase of COVID- 19,31 as well as in the devel-
opment of long- lasting post- COVID- 19 gastrointestinal symp-
toms.34 35 patients with COVID- 19 have exhibited reduced
microbial diversity, higher levels of Ruminococcus gnavus
and Bacteroides vulgatus, lower levels of Faecalibacterium
prausnitzii, and heavily reduced levels of butyrate- producing
bacteria, including Bifidobacterium pseudocatenulatum and
Faecalibacterium prausnitzii.34
While a number of pathophysiological mechanisms may
be involved in the development of gastrointestinal symptoms
during acute SARS- CoV- 2 infection,11 the mechanisms under-
lying the persistence of symptoms after SARS- CoV- 2 eradica-
tion remain unknown. Besides gut microbiota modifications,
evidence suggests the involvement of gut dysmotility, increased
intestinal permeability and modifications of enteroendocrine
cell function and serotonin metabolism.13
The biological plausibility of COVID- 19 leading to the
development of de novo IBS is based on evidence that SARS-
CoV- 2 can infect the gastrointestinal tract, in particular
the ileum and colon according to the distribution of ACE2
receptors,11 and that outbreaks of viral gastroenteritis evoke
IBS development.36 Indeed, SARS- CoV- 2 nucleic acids have
been found in the small bowel of COVID- 19 survivors up to
6 months after the acute infection, together with persistent
immune activation.37 Other studies have also found persistent
aberrant immunological activation several months after an
initial SARS- CoV- 2 infection,38 39 with enrichment of the cyto-
toxic T- cell pool in patients with long- term gastrointestinal
symptoms.35 Therefore, it is possible to speculate that long-
term SARS- CoV- 2 antigen persistence in the small bowel leads
to persistent immune activation and inflammation, and thus
to post- COVID- 19 gastrointestinal symptoms. This persistent
and delayed immune activity may partly explain the delayed
peak of post- COVID- 19 IBS occurrence at 12 months, as high-
lighted herein, which differs from other PI- IBS that occur soon
after the acute bout of infection.13
Our study has several limitations. First, the outcomes may
have been influenced by a number of other factors not included
in our analysis. Moreover, the prevalence of outcomes may
have been affected by the length of follow- up, which was
limited to 1 year after acute infection and by the use of the
GSRS for the assessment of the presence of gastrointestinal
symptoms before hospitalisation to adjust our results, thus
introducing a recall bias. Second, the exclusion of subjects
with any previous gastrointestinal symptoms reduced the
sample size, which may have lowered our ability to detect
significant increases of DGBI or psychological factors in the
COVID- 19 vs control populations, for a possible type II error.
In addition, at each study time- point we reported about 15%
of random drop- outs, but this may have not influenced the
assessment of our endpoints according to the baseline GSRS
with the exception of eructation, loose stool and borborygmi,
for which less severely affected patients were more likely to
drop- out (online supplemental table 11). Third, we included
a control group of hospitalised patients for reasons other than
gastrointestinal disease and/or surgery, which reported more
comorbidities and medication intake at baseline compared
with patients with COVID- 19, thus possibly reducing the
power of our results. We recorded a very low number of IBS
diagnoses, similar to in other reports.16 Therefore, our multi-
variate model for the evaluation of predictive factors for IBS
occurrence in COVID- 19 suffered an overfitting variable bias.
However, we tried to partially overcome this limitation by
selecting variables according to pathophysiological plausi-
bility. In addition, for hospital access restrictions due to the
COVID- 19 pandemic, patients were interviewed telephon-
ically at follow- up although questionnaire used should have
been self- administred, thus possibly introducing a question-
naire bias. Finally, we conducted our study only including
hospitalised patients from certain countries (about 60% from
Italy and Turkey); therefore, our data may not be generalisable
to outpatients and the global population.
In conclusion, COVID- 19 is associated with a modest
increased risk of long- term gastrointestinal symptoms and
IBS. Given the high prevalence of COVID- 19 at the global
level, an increase in new- onset disorders of gut–brain inter-
action should be expected due to COVID- 19, especially after
hospitalisation for this disease. Future studies are needed to
improve our understanding of the mechanisms underlying
symptom development in these patients, and to identify novel
therapeutic strategies to prevent and treat these conditions.
Author affiliations
1Azienda Ospedaliero- Universitaria di Bologna IRCCS, Bologna, Emilia- Romagna,
Italy
2Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
3Medical- Surgical Department of Clinical Sciences and Translational Medicine,
University Sapienza Rome, Rome, Italy
4Loginov Moscow Clinical Scientific Center, Moscow, Russian Federation
5Tver State Medical University, Tver, Russian Federation
6Medicine and Dentistry, A.I. Yevdokimov Moscow State University of Medicine and
Dentistry, Moscow, Russia
7Gastroenterology, Grigore T Popa University of Medicine and Pharmacy Faculty of
Medicine, Iasi, Romania
on December 20, 2022 by guest. Protected by copyright.http://gut.bmj.com/Gut: first published as 10.1136/gutjnl-2022-328483 on 9 December 2022. Downloaded from

8MarascoG, etal. Gut 2022;0:1–9. doi:10.1136/gutjnl-2022-328483
Neurogastroenterology
8Department of Infectious Diseases, ’Grigore T Popa’ University of Medicine and
Pharmacy, Iasi, Romania
9Gastroenterology Unit, University of Bologna, Imola, Italy
10Internal Medicine Department, Zagazig University, Zagazig, Egypt
11Gastroenterology Unit, University of Brescia, Brescia, Italy
12Department of New Technologies and Translational Research in Medicine and
Surgery, University of Pisa, Pisa, Italy
13Department of Gastroenterology, Sheikh Russel National Gastroliver Institute and
Hospital, Dhaka, Bangladesh
14Gastroenterology Department, Hospital Universitario Parc Tauli, Sabadell, Cataluña,
Spain
15Digestive System Research Unit, Hospital General Vall D’Hebron, Barcelona, Spain
16Ege University School of Medicine, Izmir, Turkey
17Division of Gastroenterology, Acibadem University, Altunizade Acibadem Hospital,
Istanbul, Turkey
18Department of Infectious Diseases, Ege University, Izmir, Turkey
19Division of Gastroenterology, University of Health Sciences, Keciören Education and
Research Hospital, Keciören, Turkey
20Division of Gastroenterology, Eskisehir City Hospital, Eskisehir, Turkey
21Cerrahpasa Faculty of Medicine, Istanbul University- Cerrahpasa, Division of
Gastroenterology, Turkey
22Division of Gastroenterology, Kocaeli University, Kocaeli, Turkey
23Division of Gastroenterology, Adiyaman Education and Research Hospital,
Adiyaman, Turkey
24Division of Gastroenterology, University of Health Sciences, Diyabakır Gazi Yasargil
Education and Research Hospital, Diyarbakır, Turkey
25Division of Gastroenterology, Dokuz Eylül University, Izmir, Turkey
26Division of Gastroenterology, İstanbul Aydın University Florya Liv Hospital, Istanbul,
Turkey
27Division of Gastroenterology, Darıca Farabi Education and Research Hospital,
Kocaeli, Turkey
28Department of Infectious Diseases, İstanbul Aydın University Florya Liv Hospital,
Istanbul, Turkey
29Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Beograd,
Beograd, Serbia
30Clinic of Gastroenterohepatology, Skopje, Macedonia (the former Yugoslav
Republic of)
31Research Division, Assuta Medical Center, Tel Aviv, Tel Aviv, Israel
322nd Medical Department of Internal Medicine, University of Medicine and
Pharmacy, Cluj- Napoca, Romania
33Division of Internal Medicine, University of Modena and Reggio Emilia, Modena,
Italy
34Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg,
Sweden
35Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical
Sciences, Lucknow, Uttar Pradesh, India
36Medsi Clinical Hospital, Moscow, Russian Federation
37Division of Gastroenterology, University of Modena and Reggio Emilia, Modena,
Italy
38CIBERehd, University Hospital Germans Trias i Pujol, Barcelona, Spain
39Gastroenterology, L.Sacco University Hospital, Milan, Italy
40Department of Translational Medicine, University of Ferrara, Ferrara, Italy
41Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University
Vita- Salute San Raffaele, Milano, Italy
42Division of Internal Medicine “A. Murri”, Department of Biomedical Sciences and
Human Oncology, University of Bari “Aldo Moro”, Bari, Italy
43First Department of Internal Medicine, Università degli Studi di Pavia Facoltà di
Medicina e Chirurgia, PV, Lombardia, Italy
44Geriatric Clinic Unit, Department of Clinical and Experimental Medicine, University
of Parma, Parma, Italy
45Department of Life and Health Sciences, Cyprus University of Nicosia, Nicosia,
Cyprus
46School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Kelantan,
Malaysia
Twitter Giovanni Marasco @giomara89, Berat Ebik @BeratEbik and Yeong Yeh Lee
@justntweet
Acknowledgements We thank the European Society of Neurogastroenterology
and Motility, the United European Gastroenterology, and the Rome Foundation for
supporting this study.
Collaborators Alessio Piacentini, Mariam Shengelia, Valeriy Vechorko, Carla
Cardamone, Claudia Agabiti Rosei, Andrea Pancetti, Francesco Rettura, Marc Pedrosa,
Adoración Nieto, Claudia Barber, Alejandro Henao, Caterina Campoli, Dragana
Mijac, Milos Korac, Uros Karic, Aleksandar Markovic, Ana Najdeski, Dafina Nikolova,
Marija Dimzova, Orly Lior, Nadav Shinhar, Ori Perelmutter, Yehuda Ringel, Cristina
Marica Sabo, Ana Chis, Gregorio Bonucchi, Giacomo Pietro Ismaele Caio, Caterina
Ghirardi, Beatrice Marziani, Barbara Rizzello, Ariadna Aguilar, Domenica Maria Di
Paolo, Leonilde Bonfrate, Giovanni Marconi, Michele Di Stefano, Sara Tagliaferri, Juan
Enrique Naves, Andrea Galli, Gabriele Dragoni, Laurentiu Nedelcu, Milena Stevanovic,
Ance Volkanovska Nikolovska, Antonio Capogreco, Alessio Aghemo, Paula Antonia
Mauloni, Sara Del Vecchio, Luca Rotondo, Federica Capuani, Davide Montanari,
Francesco Palombo, Clara Paone, Giada Mastel, Claudia Fontana, Lara Bellacosa,
Rosanna F. Cogliandro.
Contributors GB, GMarasco, CC, and VS designed the study; all authors collected
data for the study; GMarasco carried out statistical analysis; GMarasco, GB, and CC
validated and interpretated data; GB, GMarasco, CC, and VS drafted the manuscript;
and all authors critically revised, approved, and agree on all aspects of the final
version of the manuscript. GB is the guarantor of the article.
Funding GB’s contribution to this research was partly supported by funding
from Fondazione Cassa di Risparmio in Bologna, the Italian Ministry of Education,
University and Research; and Fondazione del Monte di Bologna e Ravenna and
European Grant H2020, DISCOvERIE, SC1- BHC- 01- 2019
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not applicable.
Ethics approval This study involves human participants and was approved by
IRCCS Policlinico S. Orsola Ethical Committee - Coordinating center approval:
399/2020/Oss/AOUBo. Participants gave informed consent to participate in the study
before taking part.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.
Data are available on reasonable request. All figures have associated raw data.
The additional data that support the findings of this study are available from the
corresponding author by request.
Supplemental material This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
This article is made freely available for personal use in accordance with BMJ’s
website terms and conditions for the duration of the covid- 19 pandemic or until
otherwise determined by BMJ. You may download and print the article for any lawful,
non- commercial purpose (including text and data mining) provided that all copyright
notices and trade marks are retained.
ORCID iDs
PietroFusaroli http://orcid.org/0000-0002-4397-9314
JavierSantos http://orcid.org/0000-0002-4798-5033
JessicaSjölund http://orcid.org/0000-0002-3946-0480
Uday CGhoshal http://orcid.org/0000-0003-0221-8495
GiovanniMaconi http://orcid.org/0000-0003-0810-4026
RobertoDe Giorgio http://orcid.org/0000-0003-0867-5873
SilvioDanese http://orcid.org/0000-0001-9867-8861
AntonioDi Sabatino http://orcid.org/0000-0002-0302-8645
Yeong YehLee http://orcid.org/0000-0002-6486-7717
VincenzoStanghellini http://orcid.org/0000-0003-0559-4875
GiovanniBarbara http://orcid.org/0000-0001-9745-0726
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