Meta-analysis

Post-COVID-19 Functional Dyspepsia and Irritable Bowel Syndrome

Giovanni Marasco; Marcello Maida; Cesare Cremon; Maria Raffaella Barbaro; Vincenzo Stanghellini; Giovanni Barbara

Aliment Pharmacol Ther. 2023;58(1):6-15.

Abstract and Introduction

Abstract

Introduction: The burden of post-COVID-19 functional dyspepsia (FD) and irritable bowel syndrome (IBS) remains unclear. The aim of this meta-analysis was to estimate the rate of post-COVID-19 FD and IBS.

Methods: MEDLINE, Scopus and Embase were searched through 17 December 2022. Studies reporting the incidence of FD and/or IBS in COVID-19 survivors and controls (without COVID-19), when available, according to the Rome criteria, were included. Estimated incidence with 95% confidence intervals (CI) was pooled. The odds ratio (OR) with 95% confidence intervals (CI) was pooled; heterogeneity was expressed as I ².

Results: Ten studies met the inclusion criteria and were included in the analysis. Overall, four studies including 1199 COVID-19 patients were considered for FD. Post-COVID-19 FD was reported by 72 patients (4%, 95% CI: 3%–5% and I ² 0%). The pooled OR for FD development (three studies) in post-COVID-19 patients compared to controls was 8.07 (95% CI: 0.84–77.87, p = 0.071 and I ² = 67.9%). Overall, 10 studies including 2763 COVID-19 patients were considered for IBS. Post-COVID-19 IBS was reported by 195 patients (12%, 95% CI: 8%–16%, I ² 95.6% and Egger's p = 0.002 test). The pooled OR for IBS development (four studies) in COVID-19 patients compared to controls was 6.27 (95% CI: 0.88–44.76, p = 0.067 and I ² = 81.4%); considering only studies with a prospective COVID-19 cohort (three studies), the pooled OR was 12.92 (95% CI: 3.58–46.60, p < 0.001 and I ² = 0%).

Conclusions: COVID-19 survivors were found to be at risk for IBS development compared to controls. No definitive data are available for FD.

Introduction

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally with over 647 million confirmed cumulative cases according to the World Health Organization on 17 December 2022.^[1] Beside the burden for healthcare systems and the significant morbidity and mortality led by COVID-19,^[2–4] there is increasing concern about the long-term consequences of COVID-19.^[5] This clinical condition, also known as 'long COVID-19' or 'post-acute sequelae of COVID-19', is characterised by the persistence of residual manifestation or the onset of new symptoms after SARS-CoV-2 infection, including pulmonary impairment, neurologic disorders, mental health disorders, functional mobility impairments and general and constitutional symptoms.^[6,7] A recent cross-sectional study suggested the presence of at least one post-COVID-19 symptom in 59.7% of hospitalised patients and 67.5% of non-hospitalised patients 2 years after infection.^[8]

Among post-COVID-19 manifestation, gastrointestinal symptoms such as abdominal pain, anorexia, diarrhoea, nausea and vomiting have also been reported in a non-negligible rate of patients.^[2,6,9] Taken together, these gastrointestinal symptoms may shape a number of post-infection disorders of gut–brain interaction (DGBI),^[10] conditions characterised by new-onset, Rome criteria-positive disorders after an episode of acute gastroenteritis in individuals who did not have DGBI before the infection.^[11] We recently reported^[12] that 1 year after hospitalisation, patients with COVID-19 had fewer problems of constipation and hard stools but reported higher rates of post-infection irritable bowel syndrome (IBS) compared with non-infected controls. In addition, COVID-19 patients reported higher rates of functional dyspepsia (FD), although without statistical significance.^[12] Previous studies reported heterogeneous results with this regard.^[13,14]

Therefore, the real burden of newly diagnosed FD and IBS affecting COVID-19 survivors still needs to be clarified. Thus, we aimed to assess the incidence of FD and IBS in COVID-19 survivors and its association with COVID-19 diagnosis compared to controls.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Characteristics of the studies included in the meta-analysis.
Study, year	Country	Age (years) COVID-19/controls	Sex (females, %) COVID-19/controls	Design	Setting COVID-19/controls	Follow-up (months)	COVID-19/controls n	FD in COVID-19/controls n (%)	IBS in COVID-19/controls n (%)	Rome criteria	Exclusion of patients with chronic GI disease	Exclusion of patients with previous GI symptoms	Overall NIH quality assessment^a
Noviello D et al., 2021¹³	Italy	44.1 (mean)/39.6 (mean)	40.2%/60.7%	Internet-based survey	Outpatient and hospitalised/healthy controls	4.8 ± 0.3 months	164/183	-	43 (26%)/46 (25.1%)	Rome IV	Yes	No	Good
Blackett JW et al., 2022³⁶	United States	43 (median)	67%	Internet-based survey	Outpatient (92.6%), hospitalised (7.4%)	6 months	749/0	–	13 (1.7%)	Rome IV	No	No	Fair
Nakhli et al., 2022³⁷	United States	≤65 years (79%)	70%	Internet-based survey	Outpatient (60%), hospitalised (24%)	6–9 months	164/0	37 (22.6%)	9 (5.5%)	Rome IV	Yes (IBS)	No	Fair
Blackett JW et al., 2022³⁸	United States	<70 years (63.9%)	49%	Internet-based survey	Hospitalised	At least 6 months	112/0	–	44 (39%)	Rome IV	Yes (IBS)	No	Good
Ghoshal UC et al., 2022¹⁴	India/Bangladesh	29–42 (median)	27.1%	Prospective, retrospective (controls)	Hospitalised/outpatient	6 months	280/264	11 (4.2)/0	15 (5.3%)/1 (0.4%)	Rome IV (IBS)/Rome III FD	Yes (IBS)	No	Good
Austhof E et al., 2022³⁹	United States	42.7–45 (mean)	66.3%	Prospective	–	6 months	49/0	–	5 (10.2%)	Rome IV	Yes	No	Good
Golla R et al., 2022⁴⁰	India	38.02 (mean)/37.94–38.47 (mean)	49%/42.2%	Prospective	Hospitalised/healthy controls	3 months	320/600	8 (2.5%)/0	10 (3.1%)/0	Rome IV	Yes	No	Good
Farsi F et al., 2022⁴¹	Iran	38.41 (mean)	58.4%	Prospective	Hospitalised, outpatient	6 months	233/0	–	27 (11.6%)	Rome IV	No	No	Good
Nazarewska A et al., 2022⁴²	Poland	68 (median)	45.1%	Prospective questionnaire, retrospective cohort	Hospitalised	6 months	257/0	–	15 (5.8%)	Rome IV	Yes (IBS)	No	Fair
Marasco G et al., 2022¹²	Multicentre (Europe based)	49.9 (mean)/50.9 (mean)	40.1%/37.9%	Prospective	Hospitalised	12 months	435/188	16 (3.7%)/4 (2.1)	14 (3.2%)/1 (0.5%)	Rome IV	Yes	Yes	Good

Abbreviations: COVID-19, Coronavirus Disease 2019; FD, functional dyspepsia; GI, gastrointestinal; IBS, irritable bowel syndrome; NIH, National Institutes of Health.
^aThe quality of selected studies was independently assessed by two investigators (MM and GM) using the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.²¹ Overall quality of studies was rated as Good, Fair or Poor. Discrepancies between reviewers concerning qualitative assessment were infrequent (overall inter-observer variation <10%), and disagreements were resolved through discussion.

Table 2. Results of univariable meta-regression analysis for assessing factor influencing post-COVID-19 IBS incidence.
Covariates	Number of studies	Beta coefficient ± SE	Adjusted R ² (%)	p value	p value ± SE after Monte Carlo permutation
Country (North America vs Europe vs Middle East/Asia)	10	0.938 (±0.071)	−4.49%	0.424	0.486 (0.007)
Study design (survey vs retrospective/prospective vs prospective)	10	0.894 (±0.070)	10.08%	0.191	0.221 (0.006)
Study setting (outpatient vs hospitalised vs mixed)	10	1.034 (±0.080)	−11.11%	0.678	0.655 (0.007)
Length of follow-up (<6 vs 6 vs >6 months)	10	1.038 (±0.097)	−11.95%	0.703	0.825 (0.005)
Exclusion of patients with previous gastrointestinal disease (no vs yes)	10	1.095 (±0.176)	−9.59%	0.588	0.728 (0.006)
NIH (fair vs good)	10	1.154 (±0.154)	1.50%	0.311	0.278 (0.006)

Abbreviations: NIH, National Institutes of Health; R ², relative reduction in between-study variance: the value indicates the proportion of between study variance explained by covariate; SE, standard error.