Introduction
Several viral respiratory infections have been implicated in the exacerbation of immune mediated inflammatory diseases (IMID)1-3. There has however been limited investigation and conflicted findings of the long-term outcomes in inflammatory bowel disease (IBD) following COVID-194. We therefore performed a systematic review and meta-analysis of the long-term impact of SARS-CoV-2 infection on the disease course of IBD.
Aims & Methods
To understand the impact of early SARS-CoV-2 variants and to be better prepared for future variants, we aimed to carry out a meta-analysis of the available evidence. We searched MEDLINE and EMBASE for studies investigating the risk of adverse IBD-related outcomes (IBD flares, change in disease activity, change in medication, IBD-related hospitalization, and surgery) following a SARS-CoV-2 infection, compared to IBD patients without a SARS-CoV-2 infection. ROBINS-E for observational studies was used to assess the risk of bias in the included studies. We used random effects model (REM) meta-analysis to calculate pooled hazard ratios (HR) for the risk of adverse IBD outcomes following the acute phase of COVID-19 infection. Subgroup meta-analysis was carried out to assess the risk of the outcomes by IBD subtype (Crohn’s disease (CD) and ulcerative colitis (UC)). Meta-regression was undertaken to assess whether sex or duration of follow-up were significant predictors of IBD-related outcomes.
Results
A total of 3119 studies were identified of which 5 studies were eligible for inclusion after screening using the pre-defined inclusion criteria. The studies were based on cohorts from Denmark, Italy, the US, and a pan-European consortium including a total of 34,977 SARS-CoV-2 positive IBD patients and 53,270 IBD patients without a recorded SARS-CoV-2 infection. Two studies were assessed as having a high risk of bias. REM meta-analysis did not show an increased risk of adverse IBD-related outcomes in IBD patients with a recorded SARS-CoV-2 infection compared to those without (HR:1.05, 95% CI:0.75-1.46) and substantial between-study heterogeneity was identified in the included studies (I2=91%, p<0.01). There was no significant difference in adverse IBD-related outcomes between CD and UC patients (CD HR: 0.91, 95% CI: 0.82-1.02; UC HR: 0.83, CI: 0.75-0.90). Following meta-regression, neither sex nor duration of follow-up were found to be significant predictors of individual study effect size.
| Study | Country | Source Population | Study Period | COVID-19 cohort | Reference cohort | Summary estimates with 95% CI: type of relative estimate | Adverse IBD-outcome | ROBINS-E overall Risk of Bias (RoB)‡
|
| Papa et al., (2022) | Italy | IBD patients from 5 Italian treatment centers | Oct 2020 -Mar 2021 (6) | 95 | 190 | 0.42 (0.08- 2.15): HR | Need for therapy intensification | High RoB |
| Hadi et al., (2022) | USA | TriNetX (40+ US Health Care Organizations) | Jan 2020 – Mar 2021 (3) | 4310 | 22508 | 1.33 (1.18-1.51): RR | Inpatient hospitalisation along with a collection of stool studies, intravenous methylprednisolone requirement or flexible sigmoidoscopy | High RoB |
| Hong et al., (2022) | USA | 5 academic medical centers within New York's Crohn's & Colitis Organization | Feb 2020 – Dec 2021 (11) | 251 | 251 | 0.84 (0.44–1.42): HR
| IBD-related hospitalisation/surgery | Low RoB |
| Bezzio et al., (2022) | Italy | IG-IBD Italian cohort | Mar 2020 – Dec 2020(7) | 219 | 219 | 1.48 (0.90-2.42): OR
| Change in HBI or PMS | Some concerns |
| Nørgård et al., (2023) | Denmark | Danish National IBD Cohort | Mar 2020 – Jul 2022(6) | 30102 | 30102 | 0.85 (0.79-0.91): IRR | Corticosteroid prescription | Some concerns |
| Amiot et al., (2022) | EU I-CARE cohort† | I-CARE
European prospective longitudinal multicenter cohort
| Apr 2020 – Dec (9) | 233 | 5224 |
| Change in HBI or SCCAI | Some concerns |
| Lukin et al., (2021) | USA | I-CARE European prospective longitudinal multicenter cohort | (6 months) | 118 | 118 |
| Change in HBI or PMS | Some concerns |
Abbreviations: HR- Hazard Ratio, RR – Relative Risk, OR – Odds Ratio, IRR – Incidence Rate Ratio, HBI – Harvey Bradshaw Index, SCCAI – Simple Clinical Colitis Activity Index, PMS – Partial Mayo Score.
† Belgium, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, the Netherlands, Poland, Portugal, Spain, Sweden and the United Kingdom.
‡The studies are rated as having a high risk of bias, some concerns or low risk of bias.
Conclusion
In this systematic review and meta-analysis, we find that SARS-CoV-2 infection does not increase the risk of long-term adverse IBD-related outcomes. High-quality studies with longer follow-up periods are required to understand the long-term impact of SARS-CoV-2 infection on IBD outcomes.
References
1. Khan RR, Lawson AD, Minnich LL, Martin K, Nasir A, Emmett MK, et al. Gastrointestinal Norovirus Infection Associated With Exacerbation of Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr. 2009 Mar;48(3):328.
2. Ozdemir B, Atay A, Kayhan MA, Ozin YO, Gokce DT, Altunsoy A, et al. Tissue quantitative RT–PCR test for diagnostic significance of cytomegalovirus infection in patients with inflammatory bowel disease and treatment response: Cytomegalovirus infection in patients with inflammatory bowel disease. Medicine (Baltimore). 2023 Aug 4;102(31):e34463.
3. Dimitroulia E, Pitiriga VC, Piperaki ET, Spanakis NE, Tsakris A. Inflammatory Bowel Disease Exacerbation Associated With Epstein-Barr Virus Infection. Dis Colon Rectum. 2013 Mar;56(3):322.
4. Zollner A, Koch R, Jukic A, Pfister A, Meyer M, Rossler A, et al. Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Diseases. Gastroenterology. 2022;163(2):495–506.
Disclosure
Professor Charlie Lees has acted as a speaker and/or consultant to AbbVie, Janssen, Takeda, Pfizer, Galapagos, GSK, Gilead, Vifor Pharma, Ferring, Dr Falk, BMS, Boehringer Ingelheim, Novartis, Sandoz, Celltrion, Cellgene, Amgen, Samsung Bioepis, Fresenius Kabi, Tillotts, Trellus Health and Iterative Health.