https://orcid.org/0000-0002-6566-8568
Abstract
Patients with inflammatory bowel disease (IBD) have low vaccination rates for vaccine-preventable diseases. Fear of adverse reactions (AEs) appear to negatively affect vaccination efforts. We aimed to systemically review the risks for AEs following immunization for patients with IBD.
We searched PubMed and Embase until April 15, 2020, for studies evaluating the safety of vaccinations among patients with IBD. The primary outcome was the incidence of systemic and local AEs among vaccinated patients. Secondary outcome was the rate of IBD flare following immunization. We utilized a random effects meta-analysis of proportions using the DerSimonian-Laird approach to estimate the safety of immunizations.
A total of 13 studies with 2116 patients was included in our analysis after fulfilling our inclusion criteria. Seven studies examined the influenza vaccine, 4 the pneumococcal vaccine, 1 the recombinant zoster vaccine, and 1 the hepatitis B vaccine. Follow-up of patients was up to 6 months. The majority of AEs were local, with a pooled incidence of 24% (95% CI, 9%-42%) for all vaccines. Systemic AEs were mostly mild, without resulting in hospitalizations or deaths, with a pooled incidence of 16% (95% CI, 6%-29%) for all vaccines. Flare of inflammatory bowel disease after vaccination found with a pooled incidence of 2% (95% CI, 1%-4%) and we include in the analysis data from all immunizations examined.
Our study demonstrated that AEs after vaccination are mainly local or mildly systemic and do not differ significantly from the expected AE after recommended immunizations for the general population. Thus, gastroenterologists should reinforce that vaccines are safe in patients with IBD.
Introduction
Research advancements in the field of the inflammatory bowel disease (IBD) management have led to increased treatment effectiveness over the past decade, with the addition of a number of new biologic medications. Medications like tumor necrosis factor (TNF) inhibitors, interleukin (IL)-12/23 antibodies, anti-integrin antibodies for Crohn’s disease (CD) and ulcerative colitis (UC), and Janus Kinase (JAK) inhibitors for UC are able to achieve better control of symptoms and enhance mucosal healing.1,2 Due to their mechanism of action, these medications can increase the risk for serious and opportunistic infections. One population-based study reported an incidence rate of opportunistic infections up to 22.4 per 1000 person-years for patients on anti-TNF and thiopurine combination therapy.3 Immunizations for patients with IBD have been extensively studied and applied to ameliorate the increased susceptibility to infections.4,5 The efficacy of various vaccinations has been evaluated and found to be high; thus detailed guidelines have been published.6,7
Adequate immunity against vaccine-preventable disease (VPD) is essential for patients with IBD to effectively protect and decrease the morbidity and mortality from these infections. Strategies towards this goal have been proposed.8 However, vaccination rates among patients with IBD appear to be suboptimal.9 Data from a population-based study showed that less than half of patients with IBD receive the yearly influenza vaccine (48.4%).10 This rate is not significantly different from the 38.3% coverage among adults measured by National Health Interview Survey.11 Compliance, overall, remains below the Healthy People 2020 annual goal for influenza vaccine coverage, which is 70%.12 Concerns regarding vaccine safety among health care providers and patients plays a crucial role in this poor immunization practice.13 In a self-administered questionnaire of 300 participants with IBD, 20.7% indicated the fear of side effects as a limiting factor, and 18% stated that immunization will worsen their IBD disease.14 Furthermore, in a study with 108 caregivers of children with IBD, 40% voiced concerns about vaccine safety, and 46% were worried that immunization would worsen the IBD symptoms.15
Hence, to further investigate the safety of recommended vaccines in patients with IBD, we conducted a systematic review and meta-analysis of observational and clinical trial studies that investigated adverse events following immunizations (AEFIs) in patients with IBD. In addition, we explored the possibility of a flare of IBD after immunization.
Materials and Methods
Search Strategy and Selection Criteria
In order to identify eligible studies, we searched the PubMed and Embase databases from inception to April 15, 2020, using the following search terms: inflammatory bowel disease or Crohn or Crohns or Crohn’s or ulcerative colitis and vaccine or vaccination or immunization.
Three authors (AD, MK, and LD) reviewed the titles and abstracts of all potentially eligible studies. Studies were considered eligible for inclusion if they met all of the following criteria: 1) reported the exact number of patients who experienced AEFI or flare of IBD, or 2) reported the type of vaccine 3), and reported the type of side effect. We excluded the following studies: 1) studies containing mixed patient population for which IBD patient data could not be extracted separately, 2) studies examining a specific side effect, 3) abstracts and case reports, 4) studies published in languages other than English, and 5) studies including pediatric cases.
This systematic review and meta-analysis was performed in line with Meta-analysis of Observational Studies in Epidemiology guidelines.16 The complete checklist of reporting criteria can be found on Supplementary Table 1.
Data Extraction
Screening, evaluation and data extraction from eligible studies were performed independently by 2 authors (AD and MK). Discrepancies were resolved by a third reviewer (LD) and consensus. For each of the included studies, the following information was extracted: author and publication year, study period, country and region, follow-up period, vaccine type, number of patients, and number and type of adverse events (AEs).
Exposure and Outcome Assessment
Our primary outcome of interest was the incidence of local and systemic AEFI, computed overall and separately by vaccine type. Secondary outcome was increased IBD activity after immunization. We considered any of the following to be a systemic AE: shivering, fever, fatigue, headache, flu-like illness, rhinorrhea, sore throat, anorexia, nausea, diarrhea, arthralgia, myalgia, and stomach pain. We considered any of the following to be a local AE: stiffness, pain, erythema, warmth, swelling and induration at the injection site, extremity limitations, and ecchymosis. For IBD flares, study authors assessed IBD activity using any of the following indexes: Harvey-Bradshaw Index (HBI) for CD, the Simple Clinical Colitis Activity Index (SCCAI), the Mayo score (partial or full), the Modified Truelove-Witts Activity Index, and the Clinical Disease Activity Index (CDAI). We also analyzed the most commonly seen systemic and local AEs.
Quality Assessment
For quality assessment and risk of bias of observational studies, the National Institutes of Health (NIH) quality assessment tool for before-after (pre-post) studies with no control group for quality assessment and bias assessment was used. The quality assessment of the studies was done by 2 independent authors (AD and MK). A disagreement on the score was discussed with a third reviewer (LD) and was resolved by consensus. Five studies were evaluated as good, 7 studies as fair, and 1 study as poor (Supplementary Table 2).
Statistical Analyses
We performed a random effects meta-analysis of proportions to estimate the safety of vaccination among patients with IBD, using the DerSimonian and Laird approach. The Freeman Tukey double arcsine transformation was used to stabilize the variances. We stratified our data by vaccination-related local AEs. A random effects meta-analysis of proportions was carried out for every AE, and a combined random-effects estimate was calculated using the DerSimonian and Laird approach.
We assessed the heterogeneity among studies and subgroups using the I2 statistic. The Egger test was used to explore publication bias and small study effects. No publication bias was found (P=.077, bias=8.98). Stata v15 (Stata Corporation, College Station, TX) was used to perform the statistical analysis. The statistical significance threshold was set at 0.05.
Results
We identified 3322 citations through a literature search, but after duplicates were removed, we initially assessed 2438 references. We excluded 2272, as they were not relevant. We then reviewed 166 full-text citations for inclusion, based on predetermined eligibility criteria. We removed 153 articles. Among them, 120 did not include data on AEFIs or IBD flares, 7 were examining only a specific AE, 17 were published in a language other than English, and 9 did not describe the exact number of patients with AEFIs. Finally, 13 studies with 2116 patients were found to be eligible based on our criteria and were included in our study.17–29 A flow diagram outlining our selection process, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, is provided in Figure 1.
Flowchart of study selection. Abbreviations: IBD, inflammatory bowel disease.
In Table 1 we summarize the basic characteristics of the 13 included studies with 2116 participants. Seven studies examined the influenza vaccine.17,19–23,28 Among them, 3 studies examined the monovalent pandemic H1N1 influenza vaccine.17,19,28 Three studies examined the trivalent (H1N1/H3N2/InfluenzaB) influenza vaccine.20,21,23 One study examined both the trivalent and quadrivalent influenza vaccine in IBD patients.22 Four studies used the pneumococcal vaccine; of those, 1 with 13-valent pneumococcal conjugated vaccine (PCV13), 2 with 23-valent pneumococcal polysaccharide vaccine (PPSV23), and 1 using both vaccines.18,24,25,27 One examined the recombinant herpes zoster vaccine (RZV; Shingrix).26 One assessed the hepatitis B vaccine, Engerix-B.29 Twelve articles included data on AEFIs.17–28 Eleven articles included data on increased IBD activity after vaccination.17–19,21,23,24,26–29
Characteristics of 13 studies investigating the adverse events after immunization for patients with IBD, 2011–2020.
| Reference | Study Design, Date of Study (years) | Location | Inclusion Criteria | Exclusion Criteria | Subtype of IBD (CD, UC, IC), Female (%), Mean/Median Age (years) | Vaccine | Adverse Effects Observed | Flare Assessment | Adverse Effect Follow-up Postimmunization |
|---|---|---|---|---|---|---|---|---|---|
| Rahier et al.17 | Multicenter observational cohort study (2009-2010) | Belgium, Austria, France, UK, Italy, Spain, Nethelands, Hungary, Finland, Malta, Germany, Israel | Adults with IBD and active treatment | Active inflammatory disease | 575 (407 CD; 159 UC; 9 IC), 53.9% Female, Mean age: 40.3 (SD 13.9) | Influenza (H1N1, Pandemrix, Focetria, FluvalP, Celvapan) | Pain, erythema, warmth, swelling, shivering, fever, fatigue, headache, myalgia/arthalgia, flu-like illness | Harvey-Bradshaw Index and partial Mayo score | 7 days |
| Pittet et al.18 | Multicenter prospective study (2014-2016) | Switzerland | Adults with IBD | 1) Active disease 2) Pregnancy 3) Pneumococcal immunization within 5-years or influenza immunization in the previous 4 weeks 4) Previous severe immunization reactions 5) Fever in past 24hrs | 306 (213 CD; 93 UC), 52% Female, Median age: 42.7 | PCV13 (Prevenar 13, Pfizer) | Erythema, induration, pain, extremity limitations, fever, rash, anorexia, fatigue, headache, nausea, diarrhea, arthralgia, myalgia | Crohn’s Disease Activity Index and Modified Truelove-Witts Severity Index | Weeks 1, 2, 4, 6, and 8 |
| Cullen et al.19 | Single-center observational prospective study (2009-2010) | USA | Adults with IBD | 1) Previous H1N1 influenza vaccine or H1N1 influenza infection 2) Allergy to eggs or other vaccine components | 105 (57 CD; 48 UC), 47% Female, Median age: 43.7 | Influenza (H1N1, nonadjuvant influenza-A 2009 monovalent vaccine, Sanofi Pasteur) | Flu-like illness, rhinorrhea, sore throat, pain at injection site | Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index | Weeks 4, 10, and 6-months |
| Matsumoto et al.20 | Single-center prospective study (2012-2013) | Japan | Adults with IBD and active treatment | 1) Prior vaccination against 2012 influenza vaccine 2) History of anaphylactic reaction to vaccine components or acute illness at time of vaccination | 78 (38 CD; 33 UC; 7 intestinal Behcet\'s disease), 43% female, Mean age: 43.9 | Influenza (2012/2013 seasonal trivalent inactivated vaccine; Biken) | Pain, swelling | None | 3 weeks |
| DeBruyn et al.21 | Single-center prospective randomized study (2012-2013) | Canada | Patients aged 9-60 years and active treatment | 1) Pregnancy 2) Hypersensitivity to previous influenza vaccine or it\'s components | Vaccine at time of infusion group: 69 (58 CD; 11 UC), 47.8% Female, Median age: 33 Vaccine between infusions group: 68 (57 CD; 10 UC), 48.5% Female, Median age: 34.7 | Infleuenza (2012/2013 inactivated trivalent vaccine, Fluviral, GlaxoSmithKline, Agriflu, Novartis) | Nausea, pain, fatigue, myalgia, headache | Harvey-Bradshaw Index and Pediatric Ulcerative Colitis Activity Index | 72 hrs |
| Caldera et al.22 | Single-center randomized prospective study (2016-2018) | USA | Adults with IBD and active treatment | 1) Known influenza vaccine allergy 2) Systemic corticosteroid use within 3 months 3) Other condition requiring immunosuppression for treatment | High dose vaccine: 25 (20 CD; 5 UC), 36% female. Median age: 29 Standard dose vaccine: 15 (13 CD; 2 UC), 33% female, Median age 43 | Influenza (Inactivated trivalent high dose vaccine, Fluzone, Sanofi Pasteur and inactivated quadrivalent vaccine Fluzone, Sanofi Pasteur) | Pain, erythema, swelling, fever, headache, myalgia/arthalgia, fatigue | None | 7 days |
| Launay et al.23 | Multicenter prospective study (2009) | France | Adults with IBD and active treatment | 1) Steroid use without immunosuppressant or anti-TNF-α 2) Recent fever/infection 3) Allergy to vaccine components 4) Recent influenza vaccination 5) History of progressive neuropathy or Guillain–Barré syndrome 6) HIV, HBV or HCV infection 7) Cellular therapy, immunoglobulin infusion, treatment with monoclonal antibodies other than anti-TNF within the last 3 months | Non immunosuppressed 31 patients (16 CD; 15 UC), 61% female, Mean age: 44 Immunosuppressed without anti-TNF 77 patients (64 CD; 13 UC), 60% female, Mean age: 38 On anti-TNF with or without immunosuppression 117 patients (92 CD; 25 UC), 66% female, Mean age: 38 | Influenza (Vaxigrip; Sanofi Pasteur MSD) | Fever, chills, headache, stiffness, fatigue, pain, erythema, swelling, ecchymosis | Harvey-Bradshaw Index and Mayo score | 180 days |
| Lee et al.24 | Multicenter observational prospective study (2012) | Korea | Adults with CD and active treatment | 1) Known reaction to the pneumococcal vaccine 2) Steroid use within 3 months 3) Vaccination within 4 weeks 4) Pregnancy 5) History pneumococcal disease | 197 (197 CD), 33% female, Mean age: 32.4 | PPV23 (Prodiax-23, MSD Korea) | Pain, erythema, swelling, fever, chills, fatigue, myalgias/arthalgias | Harvey-Bradshaw Index | 4 weeks |
| Kantso et al.25 | Multicenter randomized prospective study (2013-2014) | Denmark | Adults with CD with or without active treatment | 1) Pregnancy 2) Previous pneumococcal vaccination | PPV23 77 (77 CD) 65% Female Mean age: 44.61 PCV-13 74 (74 CD), 69% Female, Mean age: 43.68 | PPV23 (Pneumovax, Merck) PCV13 (Prevenar13, Pfizer) | Soreness, fever, headache, stomach, pain, nausea, soresness | None | 4 weeks |
| Satyam et al.26 | Single-center observational prospective study (2018-2019) | USA | Adults with IBD | N/A | 67 (39 CD; 28 UC), 54% Female, Median age: 63 | Recombinant zoster (Shingrix, GlaxoSmithKline) | Pain, erythema, swelling, myalgia, fatigue, headache, fever, chills, nausea | Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index | 14 days |
| Fiorino et al.27 | Single-center observational prospective study (Data not available) | Italy | Adults with IBD | N/A | 96 (54 CD; 42 UC), 43% Female, Mean age: 42 | PSV-23 (Pneumovax, Merck) | Fever, erythema | Harvey-Bradshaw Index and Mayo score | 72 hrs |
| Andrisani et al.28 | Single-center observational prospective study (2009-2010) | Italy | Adults with IBD and active treatment | N/A | 62 (36 CD; 26 UC), 55% Female, Mean age: 40 | Influenza (H1N1, Focetria, Novartis) | Headache, fatigue, shivering | Harvey-Bradshaw Index and partial Mayo score | 72 hrs |
| Etzion et al.29 | Single-center prospective, randomized, single-blind, controlled study (Data not available) | Israel | 1) Pregnancy 2) Previous HBV vaccination 3) Major illness within 30 days 4) Malignancies within 2 years 5) Chronic diseases other than IBD associated with immune aberrations | 77 (57 CD; 15 UC), 50% Female, Mean age: 37.8 | Hepatitis B (Engerix, GlaxoSmithKline, and Sci-B-Vac, SciGen) | Not defined | Clinical Disease Activity Index and partial Mayo score | N/A |
| Reference | Study Design, Date of Study (years) | Location | Inclusion Criteria | Exclusion Criteria | Subtype of IBD (CD, UC, IC), Female (%), Mean/Median Age (years) | Vaccine | Adverse Effects Observed | Flare Assessment | Adverse Effect Follow-up Postimmunization |
|---|---|---|---|---|---|---|---|---|---|
| Rahier et al.17 | Multicenter observational cohort study (2009-2010) | Belgium, Austria, France, UK, Italy, Spain, Nethelands, Hungary, Finland, Malta, Germany, Israel | Adults with IBD and active treatment | Active inflammatory disease | 575 (407 CD; 159 UC; 9 IC), 53.9% Female, Mean age: 40.3 (SD 13.9) | Influenza (H1N1, Pandemrix, Focetria, FluvalP, Celvapan) | Pain, erythema, warmth, swelling, shivering, fever, fatigue, headache, myalgia/arthalgia, flu-like illness | Harvey-Bradshaw Index and partial Mayo score | 7 days |
| Pittet et al.18 | Multicenter prospective study (2014-2016) | Switzerland | Adults with IBD | 1) Active disease 2) Pregnancy 3) Pneumococcal immunization within 5-years or influenza immunization in the previous 4 weeks 4) Previous severe immunization reactions 5) Fever in past 24hrs | 306 (213 CD; 93 UC), 52% Female, Median age: 42.7 | PCV13 (Prevenar 13, Pfizer) | Erythema, induration, pain, extremity limitations, fever, rash, anorexia, fatigue, headache, nausea, diarrhea, arthralgia, myalgia | Crohn’s Disease Activity Index and Modified Truelove-Witts Severity Index | Weeks 1, 2, 4, 6, and 8 |
| Cullen et al.19 | Single-center observational prospective study (2009-2010) | USA | Adults with IBD | 1) Previous H1N1 influenza vaccine or H1N1 influenza infection 2) Allergy to eggs or other vaccine components | 105 (57 CD; 48 UC), 47% Female, Median age: 43.7 | Influenza (H1N1, nonadjuvant influenza-A 2009 monovalent vaccine, Sanofi Pasteur) | Flu-like illness, rhinorrhea, sore throat, pain at injection site | Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index | Weeks 4, 10, and 6-months |
| Matsumoto et al.20 | Single-center prospective study (2012-2013) | Japan | Adults with IBD and active treatment | 1) Prior vaccination against 2012 influenza vaccine 2) History of anaphylactic reaction to vaccine components or acute illness at time of vaccination | 78 (38 CD; 33 UC; 7 intestinal Behcet\'s disease), 43% female, Mean age: 43.9 | Influenza (2012/2013 seasonal trivalent inactivated vaccine; Biken) | Pain, swelling | None | 3 weeks |
| DeBruyn et al.21 | Single-center prospective randomized study (2012-2013) | Canada | Patients aged 9-60 years and active treatment | 1) Pregnancy 2) Hypersensitivity to previous influenza vaccine or it\'s components | Vaccine at time of infusion group: 69 (58 CD; 11 UC), 47.8% Female, Median age: 33 Vaccine between infusions group: 68 (57 CD; 10 UC), 48.5% Female, Median age: 34.7 | Infleuenza (2012/2013 inactivated trivalent vaccine, Fluviral, GlaxoSmithKline, Agriflu, Novartis) | Nausea, pain, fatigue, myalgia, headache | Harvey-Bradshaw Index and Pediatric Ulcerative Colitis Activity Index | 72 hrs |
| Caldera et al.22 | Single-center randomized prospective study (2016-2018) | USA | Adults with IBD and active treatment | 1) Known influenza vaccine allergy 2) Systemic corticosteroid use within 3 months 3) Other condition requiring immunosuppression for treatment | High dose vaccine: 25 (20 CD; 5 UC), 36% female. Median age: 29 Standard dose vaccine: 15 (13 CD; 2 UC), 33% female, Median age 43 | Influenza (Inactivated trivalent high dose vaccine, Fluzone, Sanofi Pasteur and inactivated quadrivalent vaccine Fluzone, Sanofi Pasteur) | Pain, erythema, swelling, fever, headache, myalgia/arthalgia, fatigue | None | 7 days |
| Launay et al.23 | Multicenter prospective study (2009) | France | Adults with IBD and active treatment | 1) Steroid use without immunosuppressant or anti-TNF-α 2) Recent fever/infection 3) Allergy to vaccine components 4) Recent influenza vaccination 5) History of progressive neuropathy or Guillain–Barré syndrome 6) HIV, HBV or HCV infection 7) Cellular therapy, immunoglobulin infusion, treatment with monoclonal antibodies other than anti-TNF within the last 3 months | Non immunosuppressed 31 patients (16 CD; 15 UC), 61% female, Mean age: 44 Immunosuppressed without anti-TNF 77 patients (64 CD; 13 UC), 60% female, Mean age: 38 On anti-TNF with or without immunosuppression 117 patients (92 CD; 25 UC), 66% female, Mean age: 38 | Influenza (Vaxigrip; Sanofi Pasteur MSD) | Fever, chills, headache, stiffness, fatigue, pain, erythema, swelling, ecchymosis | Harvey-Bradshaw Index and Mayo score | 180 days |
| Lee et al.24 | Multicenter observational prospective study (2012) | Korea | Adults with CD and active treatment | 1) Known reaction to the pneumococcal vaccine 2) Steroid use within 3 months 3) Vaccination within 4 weeks 4) Pregnancy 5) History pneumococcal disease | 197 (197 CD), 33% female, Mean age: 32.4 | PPV23 (Prodiax-23, MSD Korea) | Pain, erythema, swelling, fever, chills, fatigue, myalgias/arthalgias | Harvey-Bradshaw Index | 4 weeks |
| Kantso et al.25 | Multicenter randomized prospective study (2013-2014) | Denmark | Adults with CD with or without active treatment | 1) Pregnancy 2) Previous pneumococcal vaccination | PPV23 77 (77 CD) 65% Female Mean age: 44.61 PCV-13 74 (74 CD), 69% Female, Mean age: 43.68 | PPV23 (Pneumovax, Merck) PCV13 (Prevenar13, Pfizer) | Soreness, fever, headache, stomach, pain, nausea, soresness | None | 4 weeks |
| Satyam et al.26 | Single-center observational prospective study (2018-2019) | USA | Adults with IBD | N/A | 67 (39 CD; 28 UC), 54% Female, Median age: 63 | Recombinant zoster (Shingrix, GlaxoSmithKline) | Pain, erythema, swelling, myalgia, fatigue, headache, fever, chills, nausea | Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index | 14 days |
| Fiorino et al.27 | Single-center observational prospective study (Data not available) | Italy | Adults with IBD | N/A | 96 (54 CD; 42 UC), 43% Female, Mean age: 42 | PSV-23 (Pneumovax, Merck) | Fever, erythema | Harvey-Bradshaw Index and Mayo score | 72 hrs |
| Andrisani et al.28 | Single-center observational prospective study (2009-2010) | Italy | Adults with IBD and active treatment | N/A | 62 (36 CD; 26 UC), 55% Female, Mean age: 40 | Influenza (H1N1, Focetria, Novartis) | Headache, fatigue, shivering | Harvey-Bradshaw Index and partial Mayo score | 72 hrs |
| Etzion et al.29 | Single-center prospective, randomized, single-blind, controlled study (Data not available) | Israel | 1) Pregnancy 2) Previous HBV vaccination 3) Major illness within 30 days 4) Malignancies within 2 years 5) Chronic diseases other than IBD associated with immune aberrations | 77 (57 CD; 15 UC), 50% Female, Mean age: 37.8 | Hepatitis B (Engerix, GlaxoSmithKline, and Sci-B-Vac, SciGen) | Not defined | Clinical Disease Activity Index and partial Mayo score | N/A |
Abbreviations: IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; IC, indeterminate colitis; SD, standard deviation; mo, months; TNF-α, tumor necrosis factor-α; PPSV, pneumococcal polysaccharide vaccine; PCV, pneumococcal conjugate vaccine; IS, immunosuppresive; HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus, HBsAg, hepatitis B antigen; anti-HBc, anti-hepatits B core; anti-HBs, anti-hepatitis B surface.
Characteristics of 13 studies investigating the adverse events after immunization for patients with IBD, 2011–2020.
| Reference | Study Design, Date of Study (years) | Location | Inclusion Criteria | Exclusion Criteria | Subtype of IBD (CD, UC, IC), Female (%), Mean/Median Age (years) | Vaccine | Adverse Effects Observed | Flare Assessment | Adverse Effect Follow-up Postimmunization |
|---|---|---|---|---|---|---|---|---|---|
| Rahier et al.17 | Multicenter observational cohort study (2009-2010) | Belgium, Austria, France, UK, Italy, Spain, Nethelands, Hungary, Finland, Malta, Germany, Israel | Adults with IBD and active treatment | Active inflammatory disease | 575 (407 CD; 159 UC; 9 IC), 53.9% Female, Mean age: 40.3 (SD 13.9) | Influenza (H1N1, Pandemrix, Focetria, FluvalP, Celvapan) | Pain, erythema, warmth, swelling, shivering, fever, fatigue, headache, myalgia/arthalgia, flu-like illness | Harvey-Bradshaw Index and partial Mayo score | 7 days |
| Pittet et al.18 | Multicenter prospective study (2014-2016) | Switzerland | Adults with IBD | 1) Active disease 2) Pregnancy 3) Pneumococcal immunization within 5-years or influenza immunization in the previous 4 weeks 4) Previous severe immunization reactions 5) Fever in past 24hrs | 306 (213 CD; 93 UC), 52% Female, Median age: 42.7 | PCV13 (Prevenar 13, Pfizer) | Erythema, induration, pain, extremity limitations, fever, rash, anorexia, fatigue, headache, nausea, diarrhea, arthralgia, myalgia | Crohn’s Disease Activity Index and Modified Truelove-Witts Severity Index | Weeks 1, 2, 4, 6, and 8 |
| Cullen et al.19 | Single-center observational prospective study (2009-2010) | USA | Adults with IBD | 1) Previous H1N1 influenza vaccine or H1N1 influenza infection 2) Allergy to eggs or other vaccine components | 105 (57 CD; 48 UC), 47% Female, Median age: 43.7 | Influenza (H1N1, nonadjuvant influenza-A 2009 monovalent vaccine, Sanofi Pasteur) | Flu-like illness, rhinorrhea, sore throat, pain at injection site | Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index | Weeks 4, 10, and 6-months |
| Matsumoto et al.20 | Single-center prospective study (2012-2013) | Japan | Adults with IBD and active treatment | 1) Prior vaccination against 2012 influenza vaccine 2) History of anaphylactic reaction to vaccine components or acute illness at time of vaccination | 78 (38 CD; 33 UC; 7 intestinal Behcet\'s disease), 43% female, Mean age: 43.9 | Influenza (2012/2013 seasonal trivalent inactivated vaccine; Biken) | Pain, swelling | None | 3 weeks |
| DeBruyn et al.21 | Single-center prospective randomized study (2012-2013) | Canada | Patients aged 9-60 years and active treatment | 1) Pregnancy 2) Hypersensitivity to previous influenza vaccine or it\'s components | Vaccine at time of infusion group: 69 (58 CD; 11 UC), 47.8% Female, Median age: 33 Vaccine between infusions group: 68 (57 CD; 10 UC), 48.5% Female, Median age: 34.7 | Infleuenza (2012/2013 inactivated trivalent vaccine, Fluviral, GlaxoSmithKline, Agriflu, Novartis) | Nausea, pain, fatigue, myalgia, headache | Harvey-Bradshaw Index and Pediatric Ulcerative Colitis Activity Index | 72 hrs |
| Caldera et al.22 | Single-center randomized prospective study (2016-2018) | USA | Adults with IBD and active treatment | 1) Known influenza vaccine allergy 2) Systemic corticosteroid use within 3 months 3) Other condition requiring immunosuppression for treatment | High dose vaccine: 25 (20 CD; 5 UC), 36% female. Median age: 29 Standard dose vaccine: 15 (13 CD; 2 UC), 33% female, Median age 43 | Influenza (Inactivated trivalent high dose vaccine, Fluzone, Sanofi Pasteur and inactivated quadrivalent vaccine Fluzone, Sanofi Pasteur) | Pain, erythema, swelling, fever, headache, myalgia/arthalgia, fatigue | None | 7 days |
| Launay et al.23 | Multicenter prospective study (2009) | France | Adults with IBD and active treatment | 1) Steroid use without immunosuppressant or anti-TNF-α 2) Recent fever/infection 3) Allergy to vaccine components 4) Recent influenza vaccination 5) History of progressive neuropathy or Guillain–Barré syndrome 6) HIV, HBV or HCV infection 7) Cellular therapy, immunoglobulin infusion, treatment with monoclonal antibodies other than anti-TNF within the last 3 months | Non immunosuppressed 31 patients (16 CD; 15 UC), 61% female, Mean age: 44 Immunosuppressed without anti-TNF 77 patients (64 CD; 13 UC), 60% female, Mean age: 38 On anti-TNF with or without immunosuppression 117 patients (92 CD; 25 UC), 66% female, Mean age: 38 | Influenza (Vaxigrip; Sanofi Pasteur MSD) | Fever, chills, headache, stiffness, fatigue, pain, erythema, swelling, ecchymosis | Harvey-Bradshaw Index and Mayo score | 180 days |
| Lee et al.24 | Multicenter observational prospective study (2012) | Korea | Adults with CD and active treatment | 1) Known reaction to the pneumococcal vaccine 2) Steroid use within 3 months 3) Vaccination within 4 weeks 4) Pregnancy 5) History pneumococcal disease | 197 (197 CD), 33% female, Mean age: 32.4 | PPV23 (Prodiax-23, MSD Korea) | Pain, erythema, swelling, fever, chills, fatigue, myalgias/arthalgias | Harvey-Bradshaw Index | 4 weeks |
| Kantso et al.25 | Multicenter randomized prospective study (2013-2014) | Denmark | Adults with CD with or without active treatment | 1) Pregnancy 2) Previous pneumococcal vaccination | PPV23 77 (77 CD) 65% Female Mean age: 44.61 PCV-13 74 (74 CD), 69% Female, Mean age: 43.68 | PPV23 (Pneumovax, Merck) PCV13 (Prevenar13, Pfizer) | Soreness, fever, headache, stomach, pain, nausea, soresness | None | 4 weeks |
| Satyam et al.26 | Single-center observational prospective study (2018-2019) | USA | Adults with IBD | N/A | 67 (39 CD; 28 UC), 54% Female, Median age: 63 | Recombinant zoster (Shingrix, GlaxoSmithKline) | Pain, erythema, swelling, myalgia, fatigue, headache, fever, chills, nausea | Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index | 14 days |
| Fiorino et al.27 | Single-center observational prospective study (Data not available) | Italy | Adults with IBD | N/A | 96 (54 CD; 42 UC), 43% Female, Mean age: 42 | PSV-23 (Pneumovax, Merck) | Fever, erythema | Harvey-Bradshaw Index and Mayo score | 72 hrs |
| Andrisani et al.28 | Single-center observational prospective study (2009-2010) | Italy | Adults with IBD and active treatment | N/A | 62 (36 CD; 26 UC), 55% Female, Mean age: 40 | Influenza (H1N1, Focetria, Novartis) | Headache, fatigue, shivering | Harvey-Bradshaw Index and partial Mayo score | 72 hrs |
| Etzion et al.29 | Single-center prospective, randomized, single-blind, controlled study (Data not available) | Israel | 1) Pregnancy 2) Previous HBV vaccination 3) Major illness within 30 days 4) Malignancies within 2 years 5) Chronic diseases other than IBD associated with immune aberrations | 77 (57 CD; 15 UC), 50% Female, Mean age: 37.8 | Hepatitis B (Engerix, GlaxoSmithKline, and Sci-B-Vac, SciGen) | Not defined | Clinical Disease Activity Index and partial Mayo score | N/A |
| Reference | Study Design, Date of Study (years) | Location | Inclusion Criteria | Exclusion Criteria | Subtype of IBD (CD, UC, IC), Female (%), Mean/Median Age (years) | Vaccine | Adverse Effects Observed | Flare Assessment | Adverse Effect Follow-up Postimmunization |
|---|---|---|---|---|---|---|---|---|---|
| Rahier et al.17 | Multicenter observational cohort study (2009-2010) | Belgium, Austria, France, UK, Italy, Spain, Nethelands, Hungary, Finland, Malta, Germany, Israel | Adults with IBD and active treatment | Active inflammatory disease | 575 (407 CD; 159 UC; 9 IC), 53.9% Female, Mean age: 40.3 (SD 13.9) | Influenza (H1N1, Pandemrix, Focetria, FluvalP, Celvapan) | Pain, erythema, warmth, swelling, shivering, fever, fatigue, headache, myalgia/arthalgia, flu-like illness | Harvey-Bradshaw Index and partial Mayo score | 7 days |
| Pittet et al.18 | Multicenter prospective study (2014-2016) | Switzerland | Adults with IBD | 1) Active disease 2) Pregnancy 3) Pneumococcal immunization within 5-years or influenza immunization in the previous 4 weeks 4) Previous severe immunization reactions 5) Fever in past 24hrs | 306 (213 CD; 93 UC), 52% Female, Median age: 42.7 | PCV13 (Prevenar 13, Pfizer) | Erythema, induration, pain, extremity limitations, fever, rash, anorexia, fatigue, headache, nausea, diarrhea, arthralgia, myalgia | Crohn’s Disease Activity Index and Modified Truelove-Witts Severity Index | Weeks 1, 2, 4, 6, and 8 |
| Cullen et al.19 | Single-center observational prospective study (2009-2010) | USA | Adults with IBD | 1) Previous H1N1 influenza vaccine or H1N1 influenza infection 2) Allergy to eggs or other vaccine components | 105 (57 CD; 48 UC), 47% Female, Median age: 43.7 | Influenza (H1N1, nonadjuvant influenza-A 2009 monovalent vaccine, Sanofi Pasteur) | Flu-like illness, rhinorrhea, sore throat, pain at injection site | Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index | Weeks 4, 10, and 6-months |
| Matsumoto et al.20 | Single-center prospective study (2012-2013) | Japan | Adults with IBD and active treatment | 1) Prior vaccination against 2012 influenza vaccine 2) History of anaphylactic reaction to vaccine components or acute illness at time of vaccination | 78 (38 CD; 33 UC; 7 intestinal Behcet\'s disease), 43% female, Mean age: 43.9 | Influenza (2012/2013 seasonal trivalent inactivated vaccine; Biken) | Pain, swelling | None | 3 weeks |
| DeBruyn et al.21 | Single-center prospective randomized study (2012-2013) | Canada | Patients aged 9-60 years and active treatment | 1) Pregnancy 2) Hypersensitivity to previous influenza vaccine or it\'s components | Vaccine at time of infusion group: 69 (58 CD; 11 UC), 47.8% Female, Median age: 33 Vaccine between infusions group: 68 (57 CD; 10 UC), 48.5% Female, Median age: 34.7 | Infleuenza (2012/2013 inactivated trivalent vaccine, Fluviral, GlaxoSmithKline, Agriflu, Novartis) | Nausea, pain, fatigue, myalgia, headache | Harvey-Bradshaw Index and Pediatric Ulcerative Colitis Activity Index | 72 hrs |
| Caldera et al.22 | Single-center randomized prospective study (2016-2018) | USA | Adults with IBD and active treatment | 1) Known influenza vaccine allergy 2) Systemic corticosteroid use within 3 months 3) Other condition requiring immunosuppression for treatment | High dose vaccine: 25 (20 CD; 5 UC), 36% female. Median age: 29 Standard dose vaccine: 15 (13 CD; 2 UC), 33% female, Median age 43 | Influenza (Inactivated trivalent high dose vaccine, Fluzone, Sanofi Pasteur and inactivated quadrivalent vaccine Fluzone, Sanofi Pasteur) | Pain, erythema, swelling, fever, headache, myalgia/arthalgia, fatigue | None | 7 days |
| Launay et al.23 | Multicenter prospective study (2009) | France | Adults with IBD and active treatment | 1) Steroid use without immunosuppressant or anti-TNF-α 2) Recent fever/infection 3) Allergy to vaccine components 4) Recent influenza vaccination 5) History of progressive neuropathy or Guillain–Barré syndrome 6) HIV, HBV or HCV infection 7) Cellular therapy, immunoglobulin infusion, treatment with monoclonal antibodies other than anti-TNF within the last 3 months | Non immunosuppressed 31 patients (16 CD; 15 UC), 61% female, Mean age: 44 Immunosuppressed without anti-TNF 77 patients (64 CD; 13 UC), 60% female, Mean age: 38 On anti-TNF with or without immunosuppression 117 patients (92 CD; 25 UC), 66% female, Mean age: 38 | Influenza (Vaxigrip; Sanofi Pasteur MSD) | Fever, chills, headache, stiffness, fatigue, pain, erythema, swelling, ecchymosis | Harvey-Bradshaw Index and Mayo score | 180 days |
| Lee et al.24 | Multicenter observational prospective study (2012) | Korea | Adults with CD and active treatment | 1) Known reaction to the pneumococcal vaccine 2) Steroid use within 3 months 3) Vaccination within 4 weeks 4) Pregnancy 5) History pneumococcal disease | 197 (197 CD), 33% female, Mean age: 32.4 | PPV23 (Prodiax-23, MSD Korea) | Pain, erythema, swelling, fever, chills, fatigue, myalgias/arthalgias | Harvey-Bradshaw Index | 4 weeks |
| Kantso et al.25 | Multicenter randomized prospective study (2013-2014) | Denmark | Adults with CD with or without active treatment | 1) Pregnancy 2) Previous pneumococcal vaccination | PPV23 77 (77 CD) 65% Female Mean age: 44.61 PCV-13 74 (74 CD), 69% Female, Mean age: 43.68 | PPV23 (Pneumovax, Merck) PCV13 (Prevenar13, Pfizer) | Soreness, fever, headache, stomach, pain, nausea, soresness | None | 4 weeks |
| Satyam et al.26 | Single-center observational prospective study (2018-2019) | USA | Adults with IBD | N/A | 67 (39 CD; 28 UC), 54% Female, Median age: 63 | Recombinant zoster (Shingrix, GlaxoSmithKline) | Pain, erythema, swelling, myalgia, fatigue, headache, fever, chills, nausea | Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index | 14 days |
| Fiorino et al.27 | Single-center observational prospective study (Data not available) | Italy | Adults with IBD | N/A | 96 (54 CD; 42 UC), 43% Female, Mean age: 42 | PSV-23 (Pneumovax, Merck) | Fever, erythema | Harvey-Bradshaw Index and Mayo score | 72 hrs |
| Andrisani et al.28 | Single-center observational prospective study (2009-2010) | Italy | Adults with IBD and active treatment | N/A | 62 (36 CD; 26 UC), 55% Female, Mean age: 40 | Influenza (H1N1, Focetria, Novartis) | Headache, fatigue, shivering | Harvey-Bradshaw Index and partial Mayo score | 72 hrs |
| Etzion et al.29 | Single-center prospective, randomized, single-blind, controlled study (Data not available) | Israel | 1) Pregnancy 2) Previous HBV vaccination 3) Major illness within 30 days 4) Malignancies within 2 years 5) Chronic diseases other than IBD associated with immune aberrations | 77 (57 CD; 15 UC), 50% Female, Mean age: 37.8 | Hepatitis B (Engerix, GlaxoSmithKline, and Sci-B-Vac, SciGen) | Not defined | Clinical Disease Activity Index and partial Mayo score | N/A |
Abbreviations: IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; IC, indeterminate colitis; SD, standard deviation; mo, months; TNF-α, tumor necrosis factor-α; PPSV, pneumococcal polysaccharide vaccine; PCV, pneumococcal conjugate vaccine; IS, immunosuppresive; HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus, HBsAg, hepatitis B antigen; anti-HBc, anti-hepatits B core; anti-HBs, anti-hepatitis B surface.
Local Adverse Events
Ten studies reported data on local AEs (Figure 2), including 5 for influenza vaccine,17,20–23 4 for pneumococcal vaccine, 2 for PCV-13, 3 for PPSV-23,18,24,25,27 and 1 for herpes zoster vaccine.26 Pooled incidence was 24% (95% confidence interval [CI], 9%-42%) for all vaccines. The vaccine associated with the highest risk of local AE after immunization was RZV, with a pooled incidence 75% (95% CI, 63%-84%). For the PCV-13 vaccine, the pooled incidence was 56% (95% CI, 51%-62%). For the PPSV-23 vaccine, the pooled incidence was 56% (2% CI, 0%-7%). For the influenza vaccine, the pooled incidence was 29% (95% CI, 17%-44%).
Meta-analysis of local adverse events following immunization among patient with inflammatory bowel disease. Abbreviations: ES, effect size; CI, confidence interval; PPSV, pneumococcal polysaccharide vaccine; PCV, pneumococcal conjugate vaccine.
Systemic Adverse Events
Eleven studies reported data on systemic AEFIs (Figure 3). Six studies evaluated the influenza vaccine,17,19,21–23,28 4 studies analyzed the pneumococcal vaccines, and 1 assessed the RZV.18,24–27 Follow-up of patients ranged from 72 hours to 3 months. Pooled incidence was 16% (95% CI, 6–29%) for all vaccines. The vaccine associated with the highest risk of systemic AEFIs was RZV, with a pooled incidence of 57% (95% CI, 45–68%). For the PCV-13 vaccine, the pooled incidence was 41% (95% CI, 35%-46%) and 1% for PPSV-23 (95% CI, 0%-3%). For the influenza vaccine, the pooled incidence was 18% (95% CI, 8%-31%). No hospitalizations or deaths resulting from immunizations were reported.
Meta-analysis of systemic adverse events following immunization among patient with inflammatory bowel disease. Abbreviations: ES, effect size; CI, confidence interval; PPSV, pneumococcal polysaccharide vaccine; PCV, pneumococcal conjugate vaccine.
Increased Activity of IBD After Immunization
Ten studies reported data on increased activity of IBD after vaccination (Figure 4). Five studies with influenza vaccines, 3 studies with pneumococcal vaccines, 1 with RZV vaccine, and 1 with hepatitis B vaccine.17–19,21,23,24,26–29 Only 2 studies mentioned in their methods that IBD flare was an exclusion.17,18 Patients were followed up to 180 days, with a range of 3-180 days. For the evaluation of the IBD flares, 8 studies used the HBI, 2 the SCCAI, 5 the Mayo score (partial or full), 1 the Modified Truelove-Witts Activity Index, and 1 the CDAI. The vaccine associated with the highest risk was influenza with 3% (95% CI, 1%-7%). For PPSV-23 immunization, the pooled incidence was 0% (95% CI, 0%-1%) For the hepatitis B vaccine, the pooled incidence was 0% (95% CI, 0%-5%). For the PCV-13 vaccine, the pooled incidence was 3% (95% CI, 2%-6%) from 1 study. For RVZ, the pooled incidence was 1% (95% CI, 0%-8%).
Meta-analysis of increased activity of inflammatory bowel disease after vaccination. Abbreviations: ES, effect size; CI, confidence interval; PPSV, pneumococcal polysaccharide vaccine; PCV, pneumococcal conjugate vaccine.
Most Common Adverse Events
Pain, swelling, and erythema at the immunization site are the most commonly found local AEFIs, regardless of vaccine type (Figure 5). Pain was found in 9 studies, with a pooled incidence of 24% (95% CI, 12%-39%).17,18,20–26 Swelling was encountered in 6 studies total, with a pooled incidence of 10% (95% CI, 4%-20%).17,20,22–24,26 Erythema was seen in 7 studies, with a pooled incidence of 9% (95% CI, 4%-17%).17,18,22–24,26,27 Regardless of the vaccine type, myalgia, arthralgia, fatigue, headache, chills, nausea, and fever were the most seen systemic adverse events (Figure 6). Myalgia was encountered in 5 studies, with a pooled incidence of 24% (95% CI, 9%-44%).17,18,21,22,26 Arthralgia was found in 3 studies, with a pooled incidence of 13% (95% CI, 0%-37%).17,18,22 Fatigue was seen in 9 studies, with a pooled incidence of 13% (95% CI, 6%-23%).17,18,21–24,26,28 Headache was found in 9 studies, with a pooled incidence of 12% (95% CI, 5%-20%)..17,18,21–23,25,26,28 Chills were reported in 3 studies, with a pooled incidence of 9% (95% CI, 1%-23%), whereas nausea (ref) and fever (refs) pooled incidences were 5% (95% CI, 1%-10%) and 3% (95% CI, 1%-6%), respectively. Overall, local adverse reactions were seen more commonly compared with systemic adverse events.
Meta-analysis of most commonly found local adverse events following immunization among patient with inflammatory bowel disease. Abbreviations: ES, effect size; CI, confidence interval; PPSV, pneumococcal polysaccharide vaccine; PCV, pneumococcal conjugate vaccine.
Meta-analysis of most commonly found systemic adverse events following immunization among patient with inflammatory bowel disease. Abbreviations: ES, effect size; CI, confidence interval; PPSV, pneumococcal polysaccharide vaccine; PCV, pneumococcal conjugate vaccine.
Discussion
We conducted a systematic review and several meta-analyses on AEFI and flares after immunization in patients with IBD. To our knowledge, this is the first systematic review that describes the safety profile of recommended vaccines in patients with IBD. In this systematic review and meta-analysis of 13 studies of 2116 participants, we found that vaccines are safe and well-tolerated, with the majority of AEFIs to be local or characterized as mildly systemic. Of note, no hospitalizations or deaths were reported following immunization. Moreover, vaccinations do not seem to result in a substantial increase of IBD activity.
An audit of 250 patients with IBD found that only 41.6% were immunized against influenza. Two main reasons for declining vaccination included concerns for AEFIs (39.6%) and fear of long-term AE (29.7%).30 In another study, compliance with all recommended vaccinations for VPD was reported in 45.3%, with fears of AEFIs remaining the main reason behind vaccine hesitance.14 Our results do not support these patient concerns. We did not encounter severe systemic AEFIs resulting in hospitalization or death. The majority of AEFIs were local or mild systemic. The frequencies of encountered AEFIs do not differ from the published data for the general population. For example, up to 65% of subjects in the general population experience pain at the immunization site with the influenza vaccine compared with 39% in our analysis.31 A recent study underlined the acceptable safety profile and rate of AEFIs for vaccines routinely recommended to the general US population, with the incidence of examined AEFI being infrequent, including arthritis or arthralgias.32 Additionally, lack of proper information regarding vaccination is a frequent reason for nonadherence. In a study with 153 patients with IBD, 58.4% of patients noncompliant with immunization reported poor knowledge as a main reason for declining vaccinations.33 Recommendation by health care providers has been cited as the most common reason for willingness to receive a vaccination. The consensus among studies indicate that a physician recommendation is the strongest independent predictor of vaccination completion.34
Fear of reactivation of IBD after immunization is an additional barrier to achieving high vaccine uptake.30 Our results demonstrate that the rate of increased activity of IBD after vaccination is low, with a pooled incidence of 2% (95% CI, 1%-4%) and the severity mild, with most of those events controlled with treatment adjustments. The highest rate (11%) was found in an influenza study in which all adult patients with IBD were included in the study regardless of the clinical state of their IBD.19 In this study, only 3% of patients required a change in medical therapy after vaccination. These rates are consistent with background rates of disease flare in patients with IBD.35 Apart from a single PCV13 vaccination study, no hospitalizations were recorded. During this study in which all adult patients with IBD were eligible for inclusion, 4 patients were hospitalized; 1 patient with CD on infliximab 21 days after immunization experienced bloody diarrhea, but it was controlled with infliximab infusion; 1 patient with CD who was not on any treatment was hospitalized for drainage of a peri-anal abscess 73 days after immunization and was treated with corticosteroids and infliximab; 1 CD patient on infliximab 70 days after immunization had surgical drainage a peri-anal abscess; and 1 patient treated with adalimumab was found with ileal stenosis 49 days following vaccination, requiring surgery.18 It is unlikely that these flares are due to the vaccination, as we would expect a strong immunologic effect of the vaccine and, as a result, an increased activity of IBD sooner than 3 weeks postimmunization. Three out of 4 patients in this study that were hospitalized were already on an anti-TNF, which could be a reason for this higher rate of increased activity of IBD due to aggressive IBD clinical status. Also, a control group was not used to assess more objectively the risk, as there is an inherent risk of flare in any patient with IBD.
Furthermore, a series of studies do not support association between immunization against VPD and development of IBD.36 A meta-analysis of studies between receipt of childhood vaccination, including Bacille Calmette-Guérin, diphtheria, tetanus, smallpox, poliomyelitis, measles, and H1N1 immunization in adults did not find an association between vaccination and development of IBD.37
The low rate of immunization is multifactorial and can be attributed both to patient-centered beliefs and factors associated with health care providers.38 A key for intervention is for physicians to be aware of who should receive the vaccination and when. Althoiugh primary care physicians are at the front line of health care maintenance for most patients, data show that only 30% of primary care physicians are confident coordinating vaccinations for patients with IBD.13 Thus, the responsibility of timely and appropriate vaccine administration falls on treating gastroenterologists. Unfortunately, studies have also shown that nearly one-third of gastroenterologists would incorrectly recommend live vaccines to immunocompromised patients, and up to a half would mistakenly withhold inactivated vaccines.9 Clinical guidelines suggest that specialists should have a more active role ensuring proper vaccination status, whereas studies have cited patients believe that specialists should be involved in discussions of immunization.39 Therefore, awareness of vaccination indications and safety profiles through standardized gastroenterology education is needed.
In addition, system-based changes could be another avenue towards increasing vaccination uptake. Utilization of electronic health records (EHRs) is pivotal in targeting how gastroenterologists address workflow of and access to information. Standardized documentation templates can aid gastroenterologists in obtaining detailed immunization history. Moreover, a recent study of patients with IBD demonstrated that utilization of automated messages within EHR patient portals led to an improvement in vaccination uptake.40,41
This is a timely study as we attempt to protect vulnerable patients with IBD from SARS-CoV-2 infection (COVID-19). Data suggest that COVID-19 infection in patients with active IBD is associated with worse outcomes, yet treatment with biologics and immunomodulatory agents may not be associated with worse prognosis.42 With the recent emergency use authorization of suitable COVID-19 vaccines, physicians will need to improve vaccination strategies to protect their patients against other VPDs, in addition to educating and helping patients dispel the hesitancy against vaccination. Continuing to foster a foundation towards positive immunization attitudes in IBD care is especially important at this time regarding how we will manage IBD preventative care during this pandemic. We hope that the positive results of this study will help guide physicians and further improve their immunization practices.
Limitations of this study come from the published literature. Many studies of vaccination of patients with IBD do not include complete data about increased activity of IBD or AEFIs or include only a specific AE. Therefore, some recommended vaccines were not analyzed, including the human papillomavirus vaccine. In addition, despite using a random effects model and subanalyses where feasible, we encountered high heterogeneity that could not be explained even when metaregression models were utilized (data not shown). We believe that this is at least partially explained by the inclusion of studies with different study designs, different follow-up times, and variable AE report systems. Moreover, because of the small number of studies, we could not analyze the incidence of AEFIs related to the time of the immunization. Most of the studies do not provide detailed definitions of AEFIs, and severity is not described in detail. Also, AEFIs were self-reported, but because the majority are local or mildly systemic, this is overall acceptable. Also, different activity scores were used. Nevertheless, all scores used are valid activity indexes. Finally, we could not perform subgroup analysis for patients using different medications against IBD like biologic and nonbiologic or between nonimmunosuppressed and immunosuppressed patients due to the low number of patients and incomplete data from the included studies.
Based on the available evidence, we conclude that the recommended vaccines we studied for patients with IBD are safe, and the majority of encountered AEFIs are local and/or mildly systemic. The risk of increased activity after immunizations is acceptably low. However, the available literature remains limited, and more studies to address this important topic are needed. The immunization rates for VPDs for patients with IBD are lower than expected, with the major explanations being the concerns about immunization safety and poor knowledge of vaccine profiles. We believe that our findings could improve and support the efforts to increase patient compliance with the recommended vaccines.
Funding
No funding was received for the completion of the study.
Conflicts of Interest
A.D, M.P, M.K, F.D, L.D, and G.K have no relevant financial or nonfinancial relationships to disclose. F.C has been a consultant for GSK, Takeda, Celgene and Arena Pharmaceuticals and received research support from Takeda Pharmaceuticals and Sanofi for work unrelated to the topic of this manuscript. F.A.F. is a consultant for BMS, Braintree labs, GSK, Innovation Pharmaceuticals, Iterative Scopes, Janssen, Pfizer, and Sebela and sits on a DSMB for Lilly and Theravance.
References
Author notes
Authors contributed to the manuscript equally.
