Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website https://www.gastrores.org

Review

Volume 14, Number 1, February 2021, pages 1-12

What Do Influenza and COVID-19 Represent for Patients With Inflammatory Bowel Disease?

Figure 1. Flow diagram showing the study selection (PRISMA guidelines). IBD: inflammatory bowel disease; COVID-19: coronavirus disease 2019; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2. Pathophysiologic aspects of inflammatory bowel disease. The imbalance in the mucinous layer and epithelial cells leads to increased permeability to pathogens and activation of inflammatory pathways. In UC, the response is mediated by TH2, and in DC is mediated by TH1 and TH17 resulting in the synthesis of inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-17, IL-23). This scenario is also represented by a reduction in the activity of Treg cells and reduction of IL-10 and TGF-β. DC: dendritic cell; TNF-α: tumor necrosis factor-α; IFN-γ: interferon gamma; IL: interleukin; TGF-β: transforming growth factor-β; NFκβ: nuclear factor kappa β; TH: T helper cell; UC: ulcerative colitis; CD: Crohn’s disease; ROS: reactive oxygen species.

Figure 3. Possible mechanisms involving influenza and COVID-19 with cytokine storm. COVID-19: coronavirus disease 2019; ARDS: acute respiratory distress syndrome.

Figure 5. Possible pathogenesis for SARS-CoV-2 infection in lung and gut epithelium. ACE-2: angiotensin-converting enzyme 2; CCL: C-C motif chemokines ligand; IP-10: interferon-inducible protein 10; DC: dendritic cell; IFN-γ: interferon gamma; IL: interleukin; MCP-1: monocyte chemoattractant protein-1; NKT: natural killer T cell; ROS: reactive oxygen species; TNF-α: tumor necrosis factor-α.

**Table 1.** Randomized Clinical Trials Showing the Effects of the Vaccine for Influenza in IBD Patients [23, 49-56]
Reference	Country	Population	Intervention/comparison	Outcomes
Anti-HA: antihemagglutinin; Anti-NA: anti-neuraminidase; ASA: 5-acetylsalicylic acid; CD: Crohn’s disease; CDAI: Crohn’s disease activity index; HBI: Harvey Bradshaw index; IBD: inflammatory bowel disease; IL-2: interleukin 2; IM: intramuscular; IS: immunosuppressive; QIV: quadrivalent inactivated influenza vaccine; SC: subcutaneously; TNF: tumoral necrosis factor; UC: ulcerative colitis; HC: health control; yrs: years.
[18]	USA	69 IBD patients (40 on anti-TNF monotherapy, 19 on vedolizumab), and 20 healthy controls (HC) (18 - 64 yrs).	Patients were allocated to receive influenza high dose vaccine or standard dose.	IBD patients on anti-TNF monotherapy that received a high-dose influenza vaccine showed significantly increased post-immunization antibody levels compared with the standard vaccine.
[26]	Japan	44 CD and 88 UC (41-42 yrs) with no significant differences in immunosuppressive therapies, disease activity, and endoscopic findings.	Patients and controls received single or double doses of seasonal QIV. 22 subjects received immunomodulatory monotherapy, 16 received anti-TNF-α single-agent therapy; 15 received immunosuppressant and anti-TNF-α agent.	Single-dose of QIV induced sufficient immunogenicity in IBD patients, and the additional vaccination did not show improvements. Immunogenicity was reduced in patients that were receiving infliximab.
[25]	Canada	115 CD, 22 UC and 1 unclassified IBD (9 - 60 yrs) on the maintenance of infliximab therapy.	Patients received 2012/2013 influenza vaccine at the time of infliximab infusion or midway between infusions.	Serologic protection to the influenza vaccine was achieved in 45-80% of IBD patients on maintenance infliximab therapy. The vaccine timing relative to infliximab infusion did not affect the achievement of serologic protection.
[24]	France	172 CD and 83 UC (18 - 64 yrs) who received at least 3 months of treatment (for those with IS or anti-TNF therapy) or without any indication to start IS therapeutics in the following 3 months.	Patients received the trivalent influenza vaccine for years 2009 - 2010 and 2010 - 2011. Hemagglutination inhibition titers were assessed before, 3 weeks, and 6 months after vaccination. Participants were divided into three groups: patients that had no IS, IS without anti-TNF, and anti-TNF with or without IS.	3 weeks after the first vaccination, the rates of seroprotection were 77%, 75% and 66% for A/H1N12007, 77%, 68% and 52% for A/H3N2 and 97%, 96% and 95% for B strain in groups A, B, and C, respectively. Seroconversion rates for A/H1N12007, A/H3N2, and B strain did not differ according to treatment group. After 6 months of vaccination, seroprotection rates were lower in group C compared to group A, and B. Persistence of seroprotection was lower in patients with anti-TNF.
[23]	Japan	38 CD, 33 UC, and 7 Behcet’s disease; (≥ 20 yrs) receiving IS therapy, immunomodulators and/or anti-TNF-a agents, and 11 HC.	The participants received the trivalent influenza vaccine and randomized into groups of single vaccination and two vaccination booster.	No significant differences were seen in the immune response between 3 weeks post-vaccination in the single vaccination group and 3 weeks post-second vaccination in the booster vaccination group. A higher pre-vaccination titer was related to enough seroprotection rate after vaccination for the H1N1 strain. The second booster of trivalent influenza vaccination did not improve the immune response.
[22]	Hungary	127 CD and 82 UC patients (> 18 yrs) stable for more than 3 months, with no signs of activity and not requiring any treatment modification.	156 patients received influenza vaccination and 53 patients did not (control group). The influenza vaccine used was: A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), B/Wisconsin/1/2010-like B/Hubei-Wujiagang/158/2009. The whole virion vaccine (Fluval AB) was given to 57, and split virion vaccine (IDFlu9) was given to 99 patients.	Post-immunization titers of both influenza subtypes were significantly increased after split virion vaccines compared to the control group and whole virion vaccine group. The antibody titers of influenza B also increased in the split virion vaccine group treated with anti-TNF-α therapy. The levels of IL-2 decreased after the intervention. Disease relapse was observed in only 10% of the patients and was more common in vaccinated patients.
[21]	Italy	36 CD, 26 UC, and 31 HC (18 - 75 yrs). 47 patients were on anti-TNF-α monotherapy and 15 on anti-TNF-α combined with IS.	All the subjects received the MF59-adjuvanted H1N1 vaccine.	Seroprotective titers in UC and CD patients were comparable to HC. The seroconversion rate was lower than HC in IBD patients both on anti-TNF-α monotherapy or combined with IS. There was a suboptimal response to the vaccine in IBD patients on therapy with anti-TNF-α and IS compared to those on anti-TNF-α monotherapy and HC.
[20]	Belgium	407 CD, 159 UC, and 9 indeterminate colitis patients (40.3 yrs) with stable IBD treated with immunomodulators and/or biological therapy.	Patients received influenza H1N1 adjuvanted and non-adjuvanted vaccines. The authors evaluated the risk of the flare of IBD after vaccination and disease activity.	After 4 weeks of intervention, the absence of flare was observed in 377 patients with CD (96.7%) and 151 with UC (95.6%). The risk of IBD flare appears to be not increased after H1N1 vaccination.
[19]	Poland	30 IBD (not specified the type) patients (6 - 18 yrs) with previously diagnosed IBD and 34 HC.	Participants were divided into 3 groups: A, treated with ASA, metronidazole or ciprofloxacin; B, treated with ASA and immunomodulatory; and C, healthy children as control. All the subjects were vaccinated with the split type vaccine with the antigens of influenza strains: A/New Caledonia/20/99 (H1N1), A/California/7/04 (H3N2), and B/Shanghai/361/02.	Anti-HA and anti-NA 1 and 6 months post-vaccination were higher than baseline levels. In group A, the protection rate achieved the highest level for antigens A/H1N1 and B 6 months after vaccination. In group B, the highest protection rate was observed after 6 months. The response rate in group A remained the same 1 and 6 months post-vaccination, while in group B, the highest response rate was noted 6 months after the vaccine.

Table 1. Randomized Clinical Trials Showing the Effects of the Vaccine for Influenza in IBD Patients [23, 49-56]

Reference

Country

Population

Intervention/comparison

Outcomes

Anti-HA: antihemagglutinin; Anti-NA: anti-neuraminidase; ASA: 5-acetylsalicylic acid; CD: Crohn’s disease; CDAI: Crohn’s disease activity index; HBI: Harvey Bradshaw index; IBD: inflammatory bowel disease; IL-2: interleukin 2; IM: intramuscular; IS: immunosuppressive; QIV: quadrivalent inactivated influenza vaccine; SC: subcutaneously; TNF: tumoral necrosis factor; UC: ulcerative colitis; HC: health control; yrs: years.

[18]

USA

69 IBD patients (40 on anti-TNF monotherapy, 19 on vedolizumab), and 20 healthy controls (HC) (18 - 64 yrs).

Patients were allocated to receive influenza high dose vaccine or standard dose.

IBD patients on anti-TNF monotherapy that received a high-dose influenza vaccine showed significantly increased post-immunization antibody levels compared with the standard vaccine.

[26]

Japan

44 CD and 88 UC (41-42 yrs) with no significant differences in immunosuppressive therapies, disease activity, and endoscopic findings.

Patients and controls received single or double doses of seasonal QIV. 22 subjects received immunomodulatory monotherapy, 16 received anti-TNF-α single-agent therapy; 15 received immunosuppressant and anti-TNF-α agent.

Single-dose of QIV induced sufficient immunogenicity in IBD patients, and the additional vaccination did not show improvements. Immunogenicity was reduced in patients that were receiving infliximab.

[25]

Canada

115 CD, 22 UC and 1 unclassified IBD (9 - 60 yrs) on the maintenance of infliximab therapy.

Patients received 2012/2013 influenza vaccine at the time of infliximab infusion or midway between infusions.

Serologic protection to the influenza vaccine was achieved in 45-80% of IBD patients on maintenance infliximab therapy. The vaccine timing relative to infliximab infusion did not affect the achievement of serologic protection.

[24]

France

172 CD and 83 UC (18 - 64 yrs) who received at least 3 months of treatment (for those with IS or anti-TNF therapy) or without any indication to start IS therapeutics in the following 3 months.

Patients received the trivalent influenza vaccine for years 2009 - 2010 and 2010 - 2011. Hemagglutination inhibition titers were assessed before, 3 weeks, and 6 months after vaccination. Participants were divided into three groups: patients that had no IS, IS without anti-TNF, and anti-TNF with or without IS.

3 weeks after the first vaccination, the rates of seroprotection were 77%, 75% and 66% for A/H1N12007, 77%, 68% and 52% for A/H3N2 and 97%, 96% and 95% for B strain in groups A, B, and C, respectively. Seroconversion rates for A/H1N12007, A/H3N2, and B strain did not differ according to treatment group. After 6 months of vaccination, seroprotection rates were lower in group C compared to group A, and B. Persistence of seroprotection was lower in patients with anti-TNF.

[23]

Japan

38 CD, 33 UC, and 7 Behcet’s disease; (≥ 20 yrs) receiving IS therapy, immunomodulators and/or anti-TNF-a agents, and 11 HC.

The participants received the trivalent influenza vaccine and randomized into groups of single vaccination and two vaccination booster.

No significant differences were seen in the immune response between 3 weeks post-vaccination in the single vaccination group and 3 weeks post-second vaccination in the booster vaccination group. A higher pre-vaccination titer was related to enough seroprotection rate after vaccination for the H1N1 strain. The second booster of trivalent influenza vaccination did not improve the immune response.

[22]

Hungary

127 CD and 82 UC patients (> 18 yrs) stable for more than 3 months, with no signs of activity and not requiring any treatment modification.

156 patients received influenza vaccination and 53 patients did not (control group). The influenza vaccine used was: A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), B/Wisconsin/1/2010-like B/Hubei-Wujiagang/158/2009. The whole virion vaccine (Fluval AB) was given to 57, and split virion vaccine (IDFlu9) was given to 99 patients.

Post-immunization titers of both influenza subtypes were significantly increased after split virion vaccines compared to the control group and whole virion vaccine group. The antibody titers of influenza B also increased in the split virion vaccine group treated with anti-TNF-α therapy. The levels of IL-2 decreased after the intervention. Disease relapse was observed in only 10% of the patients and was more common in vaccinated patients.

[21]

Italy

36 CD, 26 UC, and 31 HC (18 - 75 yrs). 47 patients were on anti-TNF-α monotherapy and 15 on anti-TNF-α combined with IS.

All the subjects received the MF59-adjuvanted H1N1 vaccine.

Seroprotective titers in UC and CD patients were comparable to HC. The seroconversion rate was lower than HC in IBD patients both on anti-TNF-α monotherapy or combined with IS. There was a suboptimal response to the vaccine in IBD patients on therapy with anti-TNF-α and IS compared to those on anti-TNF-α monotherapy and HC.

[20]

Belgium

407 CD, 159 UC, and 9 indeterminate colitis patients (40.3 yrs) with stable IBD treated with immunomodulators and/or biological therapy.

Patients received influenza H1N1 adjuvanted and non-adjuvanted vaccines. The authors evaluated the risk of the flare of IBD after vaccination and disease activity.

After 4 weeks of intervention, the absence of flare was observed in 377 patients with CD (96.7%) and 151 with UC (95.6%). The risk of IBD flare appears to be not increased after H1N1 vaccination.

[19]

Poland

30 IBD (not specified the type) patients (6 - 18 yrs) with previously diagnosed IBD and 34 HC.

Participants were divided into 3 groups: A, treated with ASA, metronidazole or ciprofloxacin; B, treated with ASA and immunomodulatory; and C, healthy children as control. All the subjects were vaccinated with the split type vaccine with the antigens of influenza strains: A/New Caledonia/20/99 (H1N1), A/California/7/04 (H3N2), and B/Shanghai/361/02.

Anti-HA and anti-NA 1 and 6 months post-vaccination were higher than baseline levels. In group A, the protection rate achieved the highest level for antigens A/H1N1 and B 6 months after vaccination. In group B, the highest protection rate was observed after 6 months. The response rate in group A remained the same 1 and 6 months post-vaccination, while in group B, the highest response rate was noted 6 months after the vaccine.