Background: Patients with inflammatory bowel disease (IBD) have a higher risk of infection and are frequently not up to date with their immunizations. Objectives: This study aims to review vaccination status and evaluate whether age, disease type, or treatment regimen could predict the absence of seroprotection against selected vaccine-preventable infection in adults with IBD. Methods: Cross-sectional study using questionnaire, immunization records review, and assessment of tetanus-specific, varicella-specific, and measles-specific immunoglobulin G concentrations. ClinicalTrials.gov: NCT01908283. Results: Among the 306 adults assessed (median age 42.7 years old, 70% with Crohn’s disease, 78% receiving immunosuppressive treatment), only 33% had an immunization record available. Absence of seroprotection against tetanus (6%) was associated with increasing age and absence of booster dose; absence of seroprotection against varicella (1%) or measles (3%) was exclusively observed in younger patients with Crohn’s disease. There was no statistically significant difference in immunoglobulin concentrations among treatment groups. Although vaccinations are strongly recommended in IBD patients, the frequencies of participants with at least 1 dose of vaccine recorded were low for nearly all antigens: tetanus 94%, diphtheria 87%, pertussis 54%, poliovirus 22%, measles-mumps-rubella 47%, varicella-zoster 0%, Streptococcus pneumoniae 5%, Neisseria meningitidis 12%, hepatitis A 41%, hepatitis B 48%, human papillomavirus 5%, and tick-borne encephalitis 6%. Conclusions: Although many guidelines recommend the vaccination of IBD patients, disease prevention through immunization is still often overlooked, including in Switzerland, increasing their risk of vaccine-preventable diseases. Serological testing should be standardized to monitor patients’ protection during follow-up as immunity may wane faster in this population.
As the immune system of patients with inflammatory bowel disease (IBD) is altered, their vulnerability to infections is greater [1-3]. Several international groups of experts have hence issued structured recommendations on vaccination in immunocompromised hosts and IBD patients [4-9], recently reviewed in this journal . Unfortunately, a number of studies have pointed out that the vaccination status of IBD patients is suboptimal [11-15], and that their immune responses to nearly all vaccinations can be impaired , in particular in those under immunosuppressive treatment . Our aim was to document the vaccination status in Swiss adults with IBD and identify whether age, disease type, or treatment regimen could predict the absence of seroprotection against selected vaccine-preventable infections.
Materials and Methods
This cross-sectional study was nested in a phase IV multicenter study evaluating the safety and immunogenicity of the 13-valent pneumococcal conjugate vaccine in 306 adults with IBD . Participants from 4 regions in Switzerland (Bern, Geneva, Neuchatel, and Vaud) were included as previously described and provided their written informed consent. Temporary exclusion criteria were pregnancy, current IBD flare pregnancy, pneumococcal immunization in the previous 5 years, and influenza immunization in the previous 4 weeks . The protocol was approved by the Ethics Committee of all participating institutions (CER 12-211), and the study was conducted in compliance with the Declaration of Helsinki.
Two questionnaires were completed at inclusion collecting details on participants’ disease and treatment (306 questionnaires completed) and querying previous history of vaccine-preventable infections and/or vaccinations (299 questionnaires completed), including review of immunization records (101 records available). Blood was collected from all 306 participants at inclusion; tetanus-specific, varicella-specific, and measles-specific immunoglobulin G (IgG) concentrations were measured using ELISA on the platform DSX® (Dynex® Technologies, Chantilly, VA, USA). The cutoffs for defining seroprotective concentration against tetanus, varicella, and measles were set as 100 IU/L, 50 IU/L, and 150 IU/L, respectively. These were experimentally defined as the lowest concentration associated with the presence of neutralizing antibodies in a series of independent sera from healthy subjects (unpublished data).
Mann-Whitney tests were used for comparison of IgG concentration among gender and diagnostic groups. Kruskal-Wallis tests were used for comparison among participants’ age (18–35 years old, 35–50 years old, 50–65 years old, and above 65 years old), region (Bern, Geneva, Neuchatel, and Vaud), and treatment groups (no immunosuppression, immunosuppression without anti-TNF, and immunosuppression with anti-TNF), followed by Mann-Whitney tests for comparisons between subgroups. All analyses were 2-sided and performed using Stata 13® (StataCorp, College Station, TX, USA), and p < 0.05 was considered statistically significant. Bonferroni adjustment was used for multiple comparisons. ClinicalTrials.gov identifier: NCT01908283.
A total of 306 participants aged 18.0–92.5 years (median 42.7) were assessed (Table 1). The majority had Crohn’s disease (70%) and was receiving an immunosuppressive treatment (78%), mostly anti-TNF agents (51%) . Only 101 participants had an immunization record available (Table 2); their status was compared to the Swiss recommendation (summarized in Table 3). According to the questionnaire, approximately a third of the cohort (112/299) had been immunized against influenza during the preceding winter and 61% (186/299) had received the influenza vaccine at least once in their life. Among those, nearly half (86/186) were immunized yearly.
Seroprotection rates against tetanus, varicella, and measles were high (Fig. 1). Nearly all participants (288/306, 94%) were seroprotected against tetanus. Tetanus-specific IgG concentration was the highest in the 35- to 50-year-old group (p = 0.003, compared with the rest) and the lowest in the >65-year-old group (p < 0.001, compared with the rest). Overall, tetanus-specific IgG concentrations were slightly lower in participants with Crohn’s disease (p = 0.09, compared with participants with ulcerative colitis). There was no difference among treatment and region groups; 5 of the 18 nonseroprotected participants were not receiving any immunosuppressive treatment. Among the 18 nonseroprotected participants, only 3 had an immunization record available, and their last tetanus doses documented were nearly 30 years before inclusion.
A quarter of the participants either did not recall previous history of chickenpox disease (19%) or believed they never had it before (9%). Nevertheless, 99% of participants were seroprotected against varicella. There was no statistically significant difference in varicella-specific IgG concentration between the gender, treatment, age, region, and disease groups. The 2 nonseroprotected participants were in their 30s and had Crohn’s disease.
Nearly all participants (97%) were seroprotected against measles. A third of the participants (32%) recalled having measles disease and had significantly higher IgG concentration. Higher measles-specific IgG concentration was associated with increasing age (Fig. 1); the level was the highest in the >65-year-old group (p < 0.001, compared with the rest). All the nonseroprotected participants were <30 years old and had Crohn’s disease; most of them (7/10) were receiving immunosuppressive treatment. Only 2 of them had an immunization record available, with 1–2 doses of measles-mumps-rubella documented. There was no statistically significant difference in measles-specific IgG concentration between the region groups.
Although numerous immunization guidelines exist [4-9], this cross-sectional study of over 300 adults with IBD suggests that there are many missed opportunities for disease prevention through vaccination, putting these patients at risk for infection. Only a third of the participants had an immunization record available, with low vaccination rates for nearly all pathogens, emphasizing the room for improvement. This is in line with previous reports in IBD patients from other regions, revealing that physicians’ and patients’ compliance with the published recommendations remains poor [19, 20]; vaccinations are indeed the least frequently followed quality of care recommendations for this population . This may be attributed to numerous factors [11-15], such as fear of vaccine-induced adverse events and/or of interference of treatment on vaccine responses [22, 23].
At least 1 dose of tetanus-containing vaccine was documented on nearly all vaccination records. However, most participants were not up to date, with insufficient number of doses, and long delays since the last vaccine dose recorded, whereas boosters are recommended every 10 years in immunocompromised patients . Eighteen participants had undetectable tetanus serology, in whom a soiled wound would carry significant risk. Our data suggest that this was probably due to waning immunity with age, in the absence of booster dose. However, both the disease and treatment likely had an impact as well, given the overall lower seroprotection rate and antitetanus IgG concentration compared to those reported in the healthy population . Interestingly, 5 nonseroprotected participants were not receiving any immunosuppressive treatment, highlighting the need for serological monitoring regardless of the treatment regimen.
An alarming low number of participants were vaccinated against hepatitis virus A and B; among them, a high proportion had received more vaccine doses than usually indicated, suggesting that they were probably “nonresponders.” Additionally, only few participants were vaccinated against the human papillomavirus, whereas this vaccine is highly recommended in this population, given their higher risk of HPV-related malignancy [7, 25]. Only 5% of the participants with an available vaccination record had received a pneumococcal vaccine. IBD patients have an increased risk of pneumococcal infection [2, 26-28]; the safety and immunogenicity of the pneumococcal conjugate vaccine have now been established in adults with IBD, regardless of their underlying treatment [18, 29], and therefore the use of this vaccine should be strongly promoted in this population. Annual vaccination against influenza virus is also highly recommended to prevent hospitalization and secondary infection with pneumococcus; however, less than half of the participants surveyed were following this recommendation. All those facts strongly advocate for systematically updating the IBD patients’ immunization status and emphasize the importance of monitoring vaccine responses in this population.
Varicella and measles infections have a higher risk of complications in immunocompromised patients , including those with IBD , with mortality rates up to 7% and 40–70%, respectively [32-34]; Janus kinase inhibitor in particular greatly increases the risk of herpes zoster [35, 36]. Guidelines recommend serological testing at IBD diagnosis, with immunization updating, and postexposure prophylaxis in case of contact . Our study shows that nearly all participants were seroprotected against both infections. In Switzerland, varicella vaccination is recommended in all individuals aged ≥11 years who never had chickenpox. As a result, the virus circulates in the community, enabling seroprotected individuals to boost their immunity regularly. This may explain why we found such high varicella-specific antibody concentration across all age groups. Our results may not be generalizable to populations with lower circulation rate of the varicella virus. Nevertheless, 2 participants were not seroprotected and were unaware of their risk of severe infection if exposed to varicella. Our results also confirm prior assumption that questioning patients on previous history of disease is not reliable enough  since a quarter of the seroprotected participants could not recall having had chickenpox previously. As for measles, universal vaccination started in the 1960s, and therefore nearly all individuals aged ≥50 had presumably been in contact with the virus during childhood. This might explain why in our study the individuals aged >65 years old had the highest anti-measles antibody concentration. All the nonseroprotected participants were <30 years old. Previous vaccination was documented in the 2 participants with an available vaccination record. Measles infections could potentially be fatal in these 10 nonseroprotected patients, most of them having immunosuppressive treatment. Our data, in line with previous studies from other regions [38, 39], suggest that serological testing should be standardized in all IBD patients.
In conclusion, disease prevention in immunocompromised patients through immunization is often overlooked, but is indeed needed; serological testing should be standardized to monitor patients’ protection during follow-up as immunity may wane faster in this population. Temporary withholding of immunomodulating treatment is recommended during an infectious illness, which could have an impact on disease activity. Therefore, by preventing infections, vaccines also indirectly spare IBD flaring [2, 7]. Awareness raising campaigns must be organized to promote the systematic monitoring of specific disease immunity status and subsequent vaccination strategies among the IBD population, regardless of the treatment regimen [19, 20]. Campaigns should convince physicians and patients that vaccines are safe even for patients with immune-mediated inflammatory diseases, in whom they do not trigger disease flare, and that protection is likely to be reached, especially when vaccination is performed during periods of reduced immune suppression , even if vaccine immunogenicity might be slightly attenuated due to immunosuppression [40-46].
This study was partly nested in the existing cohort of patients recruited into the Swiss IBD Cohort Study (SIBDCS). We gratefully thank the Platform of Clinical Research in Pediatrics of the Department of Pediatrics, Geneva University Hospitals, a Swiss-PedNet hub, for the logistic support and tremendous work. We also thank all the study participants and the investigators, particularly Katja Barahona, José Bengoa, Gianna Cadau, Philippe De Saussure, Suzanne Duperret, Christian Felley, Barbara Lemaitre, Cassandra Oropesa, Sophie Restellini, Maria Isabel Rodriguez, Carole Salomon, Alain Schoepfer, Paolo Valenti, and Christina Wylie. Special thanks to Natacha Noël for her substantial contribution to the enrollment of participants and data collection. We also thank the contributions of the Clinical Research Center of the Geneva University Hospitals and the Faculty of Medicine.
Statement of Ethics
This research complies with the guidelines for human studies and was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Subjects have given their written informed consent, and the study protocol was approved by the institute’s committee on human research of all participating sites (CER 12–211), by the Swiss Agency for Therapeutic Products (Swissmedic No. 2012DR2022), and by the SIBDCS scientific board (Project No. 2012-17).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
L.F.P. is supported by the Swiss National Science Foundation (Early Postdoc.Mobility Grant No. P2GEP3_178155). This work was supported by the Center for Vaccinology and Neonatal Immunology (University of Geneva), grants from The Swiss Inflammatory Bowel Disease Cohort Study, which is financially supported by the Swiss National Science Foundation since 2005 (Grant No. 33CS30-148422), grants from the Foundation for Liver and Gut Studies, and the Schweizerische Morbus Crohn/Colitis ulcerosa Vereinigung.
Study concept and design: L.F.P., C.M.V., K.M.P.B., and C.A.S.; obtained funding: L.F.P., K.M.P.B., and C.A.S.; enrollment of participants, acquisition of data, and administrative, technical, or material support: L.F.P., C.M.V., P.M., E.G., M.G., P.J., C.M., and M.H.M.; statistical analysis and drafting of the manuscript: L.F.P.; critical revision of the manuscript for important intellectual content and approval of the final draft submitted: C.M.V., P.M., E.G., M.G., P.J., C.M., M.H.M., K.M.P.B., and C.A.S.