Vaccination strategies for Korean patients with inflammatory bowel disease

Yoo Jin Lee; Eun Soo Kim

doi:10.3904/kjim.2022.149

Korean J Intern Med > Volume 37(5); 2022 > Article

Lee and Kim: Vaccination strategies for Korean patients with inflammatory bowel disease

Review

The Korean Journal of Internal Medicine 2022;37(5):920-930.

Published online: August 8, 2022

DOI: https://doi.org/10.3904/kjim.2022.149

Vaccination strategies for Korean patients with inflammatory bowel disease

Yoo Jin Lee¹, Eun Soo Kim²

¹Department of Internal Medicine, School of Medicine & Institute for Medical Science, Keimyung University, Daegu, Korea

²Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea

Correspondence to: Eun Soo Kim, M.D. Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Kyungpook National University, 130 Dongdeokro, Jung-gu, Daegu 41944, Korea, Tel: +82-53-200-5362, Fax: +82-53-200-5879, E-mail: dandy813@hanmail.net

This manuscript was contributed by Korean Association for the Study of Intestinal Diseases.

Received April 18, 2022 Accepted July 10, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Patients with inflammatory bowel disease (IBD) are vulnerable to vaccine-preventable infectious diseases. Immunosuppressive drugs, which are often used to manage IBD, may increase this vulnerability and attenuate vaccine efficacy. Thus, healthcare providers should understand infectious diseases and schedule vaccinations for them to reduce the infection-related burden of patients with IBD. All patients with IBD should be assessed in terms of immunity to vaccine-preventable diseases at the time of IBD diagnosis, and be vaccinated appropriately. Vaccination is becoming more important because of the unprecedented coronavirus disease 2019 (COVID-19) global health crisis. This review focuses on recent updates to vaccination strategies for Korean patients with IBD.

Keywords: Vaccination; Inflammatory bowel diseases; COVID-19

INTRODUCTION

The incidence of inflammatory bowel disease (IBD) is increasing rapidly in many Asian countries [1–3]. Because IBD is an immune-mediated chronic disease, the majority of patients require lifelong treatment with immunosuppressive agents, such as thiopurines, methotrexate, biologics, and small molecule agents [4]. In line with the treat-to-target concept now being emphasized, these immunosuppressive agents are being widely used at an early stage, and for long-term maintenance [5–9]. However, this treatment strategy carries an increased risk of opportunistic infections [10–12]. Accordingly, appropriate screening and vaccination programs are needed for patients with IBD [13–16]. However, as vaccination is not always well-conducted in clinical practice [17], many IBD patients are vulnerable to vaccine-preventable diseases. Vaccination has become one of the most important health maintenance strategies for IBD patients during the coronavirus disease 2019 (COVID-19) pandemic. In this review, we discuss recent updates to vaccination strategies for patients with IBD in Korea.

INITIAL ASSESSMENT OF IMMUNE STATUS

Healthcare providers should ascertain patients’ immunity to vaccine-preventable diseases at the time of IBD diagnosis [13,16,18]. Vaccination and infectious disease history data should be obtained [13,16]. Detailed records of immunizations are important, particularly for children with IBD [19]. In addition, the immune status should be regularly determined during follow-up because vaccination recommendations vary depending on age, immunosuppressive therapy, and the patient’s medical condition [13,18]. If a patient does not have vaccine-induced immunity or any history of previous infection, serologic testing can be used to check the immunity status [13,15]. Table 1 presents the serological tests used to evaluate immune status in patients with IBD. Note that vaccination history is more important than serological screening because vaccine-induced antibodies may not reflect the patient’s actual vaccine-induced immunity [16]. If there is no immunity, all appropriate vaccinations should be administered promptly [13,16].

TWO MAIN TYPES OF VACCINES

The classification of inactivated and live attenuated vaccines is presented in Table 2. Inactivated vaccines, also known as killed vaccines, use dead virus or bacterium to stimulate antibody production by triggering an immune response [20]. Inactivated vaccines are safe regardless of immunosuppression status [21]. However, it is recommended that administration be completed at least 2 weeks before initiating immunosuppressive therapy to maximize the effect of the vaccination [14]. Inactivated vaccines generally provide weaker immunity than live vaccines, so subsequent booster shots are often required [22]. Live attenuated vaccines, including measles, mumps, and rubella (MMR), herpes zoster (HZ), and varicella vaccines should not be administered to patients undergoing immunosuppressive treatment due to the risk of developing the disease thereafter due to uncontrolled replication of the virus [20,21]. Live vaccines should be administered at least 4 weeks before starting immunosuppressive therapy. Patients already on immunosuppressive medications should stop at least 3 months before receiving a live vaccine [4]. Recent evidence suggests that live vaccines may be safely administered to a subset of immunocompromised patients [23]. However, further research is needed on this issue. Additionally, the administration of a live vaccine can depend on the definition of immunosuppression being used; this is described in more detail below.

DEGREE OF IMMUNOSUPPRESSION

Patients with IBD should ideally be vaccinated before commencing any immunosuppressive therapy, to achieve effective immunogenicity to the vaccine. Live attenuated vaccines should not be given during immunosuppressive therapy, particularly to a patient exhibiting a high level of immunosuppression [4,13]. However, vaccination should not delay immunosuppressive therapy in patients who urgently needs treatment for IBD [4,13]. Definitions of immunosuppression are presented in Table 3 [13,21,24,25]. If a live vaccine must be administered to a highly immunosuppressed patient, the immunosuppressive therapy should be discontinued 3 months before administering the vaccine [16]. However, certain live vaccines, such as travel vaccines, may be considered if the benefits outweigh the risks in a patient with a low level of immunosuppression [16]. Hence, the degree of immunosuppression of the patient and their medical condition should be considered together to ensure appropriate timing of vaccination. A summary of the recommendations for vaccines in patients with IBD is presented in Table 4 [16,26–30].

INACTIVATED VACCINES

Influenza vaccine

Patients with IBD have an increased risk of influenza and are more likely to be hospitalized compared with the general population [31]. Many studies have reported that appropriate immunological responses can be achieved in patients with IBD after inactivated influenza vaccination, although the response can be blunted in patients undergoing immunosuppressive therapy [32,33]. Antigenic drift or a mutation in surface hemagglutinin or neuraminidase proteins, which are involved in the host recognition of viral particles, often occur. Thus, seasonal influenza viruses tend to be quite different from each other and can overcome host immunity [34]. Therefore, all guidelines recommend that the influenza vaccine be administered annually [14,15,25]. The importance of influenza vaccination was emphasized during the COVID-19 pandemic given the clinical similarity between COVID-19 and influenza [15,34,35]. Caution should be exercised when using a live attenuated intranasal formulation, which is contraindicated in pregnant, critically ill, and immunocompromised patients [21]. In addition, other members’ of IBD patients’ households should receive the influenza vaccination every year [25].

Pneumococcal vaccine

Patients with IBD have an increased risk of invasive pneumococcal disease (IPD) [36,37]. This increased risk is observed even before IBD diagnosis or initiation of immunosuppressive therapy, implicating an underlying immunological change related to the pathogenesis of IBD in the higher risk of IPD [37]. However, 1-year mortality rates were significantly lower among pneumococcal-vaccinated than-unvaccinated IBD patients [38]. The immune response to pneumococcal vaccination in IBD patients is comparable to that of the general population, but immunosuppressive therapy may impair immunogenicity [39,40]. Guidelines recommend pneumococcal vaccination for all adult patients with IBD who are receiving or scheduled for immunosuppressive therapy [14,25]. A pneumococcal vaccine should ideally be provided at the time of IBD diagnosis, or before initiating immunosuppressive therapy, to achieve a higher level of seroprotection and greater immune response [16]. The recommended vaccination regimen is as follows: a single dose of 13-valent pneumococcal conjugate vaccine followed by a single dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23), at least 8 weeks apart. An additional PPSV23 dose is recommended at least 5 years after the first PPSV23 dose.

Hepatitis B vaccine

South Korea is a hepatitis B virus (HBV)-endemic area; however, the prevalence of HBV has decreased substantially since a nationwide vaccination program was implemented in 1995 [41]. Although patients with IBD may be more likely to be exposed to HBV infection due to frequent invasive procedures and blood transfusions [4], IBD is no longer a risk factor for HBV infection even in HBV-endemic areas [42–45]. Interestingly, the frequency of non-immunity against HBV is high among younger IBD patients in Korea [46,47]. Furthermore, immunosuppressive therapy in hepatitis B surface antigen-positive patients may reactivate HBV, which can be fatal [48,49]. Therefore, HBV immune status should be determined, particularly at IBD diagnosis, and any non-immunized patient with IBD should be vaccinated, particularly before initiating biologics or oral cytokine inhibitor treatment [24,50].

The standard regimen for vaccination against HBV in patients with IBD is the same as that for the general population: three doses at 0, 1, and 6 months [50]. However, an adequate immune response to the HBV vaccine is not achieved in a considerable number of IBD patients [51]. A recent meta-analysis including 1,688 IBD patients from 13 studies reported a response rate to HBV vaccination (defined as an hepatitis B surface antibodies [anti-HBs] titer > 10 mIU/mL) of only 61% [52]. Young age and vaccination during remission predicted an immune response, while patients prescribed immunosuppressive therapy had a lower likelihood of responding [53]. Therefore, although healthy individuals do not require routine follow-up serological tests after HBV vaccination, serological titers should be evaluated 1–3 months after the last HBV vaccination in immunocompromised patients to ensure a response [50]. Although further research is needed [14], experts recommend performing additional reactivation cycles (at 0, 2, and 6 months) if seroprotection is not achieved [15,50].

Hepatitis A vaccine

The hepatitis A vaccine (HAV) is recommended for IBD patients, given that they are more likely to undergo long-term immunosuppressive therapy [50]. Vaccination for HAV has been mandatory in South Korea since 2015. However, a recent study showed that many young IBD patients are not immune to HAV [54]. Thus, it is necessary to check whether a patient has immunity to HAV at IBD diagnosis. If a patient with IBD is not immune to HAV (i.e., is negative for anti-HAV immunoglobulin G [IgG] Ab), they should receive two doses of the HAV vaccine, at 0 and 6–18 months. As with other vaccines, the optimal time to vaccinate is at IBD diagnosis or before the start of immunosuppressive therapy [50].

Human papillomavirus vaccine

The association between IBD and cervical dysplasia/cancer is uncertain. However, the risk seems to increase in patients undergoing immunosuppressive therapy, such as those taking corticosteroids, immunomodulators, or anti-tumor necrosis factor (TNF) agents [14,25]. Many guidelines recommend the human papillomavirus vaccine (HPV) for all males and females aged 18 to 26 years [15,55], which also applies to same-aged patients with IBD [14]. Although recently published Canadian guidelines do not recommend HPV vaccination for individuals aged 27 to 45 years, it should be considered depending on the patient’s risk factors (possibility of a new sex partner or future immunosuppressive therapy) and preferences [14,16,56]. In a small study, HPV vaccination resulted in favorable immunogenicity and no serious adverse events in female patients undergoing immunosuppressive therapy [57].

Tetanus, diphtheria, and pertussis vaccine

The risk of diphtheria, tetanus, and pertussis (DTP) infection in patients with IBD is unknown. Guidelines recommend age-appropriate vaccination for DTP, including booster doses as needed, in patients with IBD, regardless of their immune status [14,15,25]. Several studies have reported an impaired immunological response to DTP vaccination, particularly among patients undergoing immunosuppressive therapy [52,58].

Meningococcal vaccine

The prevalence and risk of meningococcal infection in patients with IBD are unknown. Meningococcal disease is rare, but can lead to sepsis, meningitis, and death [25]. Vaccination for meningococcus is recommended in IBD patients with the following risk factors; anatomic or functional asplenia, complement and antibody deficiencies, human immunodeficiency virus infection, traveling to areas with high rates of endemic meningococcal disease or transmission, risk of occupational exposure to Neisseria meningitides, exposure to a confirmed case or outbreak situation, and serving in the military [14]. The benefit of meningococcal vaccination for all IBD patients without risk factors appears to be uncertain given the low incidence of meningococcal disease [14].

LIVE ATTENUATED VACCINES

Measles, mumps, and rubella vaccine

Limited data exist regarding vaccination against MMR in patients with IBD. A recent retrospective cohort in Korea demonstrated that the seropositivity rates of measles and rubella in patients with IBD are generally similar to those of the general population [54]. Vaccination for MMR is recommended for patients with IBD when it is unclear whether two doses of vaccine have been taken [16]. If the individual is not immune according to a serological test for MMR (Table 1), two doses at least 4 weeks apart if not previously vaccinated with the MMR vaccine, or one dose if previously vaccinated, should be administered [13,15,16]. The MMR vaccine should be avoided in patients undergoing immunosuppressive therapy, as this is a live attenuated vaccine [13].

Varicella vaccine

Primary varicella infection is more likely to be fatal in patients with IBD, particularly those treated with immunosuppressive therapy [59–61]. Guidelines recommend screening for previous infection or vaccine history-taking at the initial visit, and vaccination if patients are naïve [13,25]. The vaccine can be administered to IBD patients following the principle of live vaccination. However, it should be avoided in patients currently undergoing immunosuppressive therapy [13,62].

Herpes zoster vaccine

HZ, also called shingles, is caused by reactivation of the latent varicella-zoster virus. Previous studies have shown that patients with IBD have an increased risk of HZ compared to the general population [26,63–65]. The risk of HZ is even greater in IBD patients undergoing immunosuppressive therapy with thiopurines, corticosteroids, or anti-TNF agents compared to those who are not and the general population [26,64]. Among the new drugs, tofacitinib [66], an oral Janus kinase inhibitor, is associated with an increased risk of HZ, while ustekinumab [67] and vedolizumab are not [68].

Guidelines recommend HZ vaccines for patients ≥ 50 years with IBD. There are two types of HZ vaccines, live attenuated (Zostavax, Merck & Co. Inc., Kenilworth, NJ, USA) and inactivated adjuvant recombinant zoster vaccine (RZV, Shingrix, GlaxoSmithKline plc, London, England); the latter is preferred because of its superior efficacy and safety. Moreover, it significantly reduces the risk of HZ (by > 90%) [69]. RZV was approved for use in Korea in September 2021. This inactivated vaccine can be safely administered to immune-compromised patients and evokes a good immunogenic response [70,71]. IBD patients aged < 50 years may benefit from RZV [16]. RZV is also recommended for those who have already been vaccinated with the live attenuated vaccine [72]. However, long-term data on the durability of the RZV in patients < 50 years are lacking, so it is necessary to discuss its use in IBD patients aged < 50 years [14].

COVID-19 VACCINE

IBD patients are concerned about the effects of their disease, and associated medications, on the risk of contracting COVID-19 [73]. However, patients with IBD do not have an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [74], and COVID-19 outcomes do not seem to be worse in IBD patients except in cases with recent steroid use [75]. COVID-19 symptoms in patients with IBD are similar to those of the general population [76]. The SARS-CoV-2 virus binds to the angiotensin-converting enzyme II receptor and causes gastrointestinal symptoms [77]. Thus, caution is required because it is challenging to distinguish COVD-19 gastrointestinal symptoms from an IBD flare-up [78].

All guidelines recommend COVID-19 vaccination for IBD patients at the earliest opportunity [35,78,79]. All currently authorized COVID-19 vaccines are available for patients with IBD because they are non-live vaccines [35]. Adverse events associated with the COVID-19 vaccine occur at a similar (or lower) rate in IBD patients and the general population [80]. The COVID-19 vaccine is not related to disease flare-up in patients with IBD [81]. Patients with IBD should keep taking their medications at the time of COVID-19 vaccination, even if they are on an immunomodulatory regimen [35,78,79]. For patients taking high-dose systemic corticosteroids, as it is important to achieve an adequate immune response to the COVID-19 vaccine, the timing should be discussed with the healthcare provider [35,79].

Recent data demonstrate that IBD patients taking an anti-TNF agent or immunosuppressant can achieve immunity following the second dose of vaccine, while the immune response is blunted following a single dose [82]. However, waning of the immune response over time in infliximab-treated patients following two doses of the vaccine emphasizes the need for a third dose [83]. Based on the latest evidence (from April 5, 2022), healthcare providers should recommend the primary series and a booster vaccine for patients with IBD.

In early 2022, a fourth dose of the vaccine was authorized and implemented for elderly and immunocompromised people in some countries [84]. Thus, a second booster vaccine is available in a subset of patients with IBD (i.e., those treated with high-dose corticosteroids [equivalent to ≥ 20 mg prednisolone per day], anti-TNF or other biologics). However, additional data are needed to determine whether the second booster is appropriate for IBD patients.

CONCLUSIONS

As treatments for IBD continue to evolve, healthcare providers need to maintain an up-to-date understanding of potential health issues affecting patients’ daily lives. Vaccination is one of the most important healthcare interventions for patients with IBD. This review will help healthcare providers recognize the importance of vaccination, such that patients will be more likely to receive safe and effective vaccinations.

Acknowledgments

This work is supported by the research promoting grant from the Keimyung University Dongsan Medical Center in 2019.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Table 1

Suggested serological tests before immunization

Virus	Serologic test
MMR^a	Measles virus IgG, Mumps virus IgG, Rubella virus IgG
Varicella^a	Varicella-Zoster virus IgG
Hepatitis A^a	Anti-HAV IgG
Hepatitis B	HBsAg/anti-HBs/anti-HBc IgG

MMR, measles, mumps, and rubella; IgG, immunoglobulin G; HAV, hepatitis A vaccine; HBsAg, hepatitis B surface antigen; anti-HBs, hepatitis B surface antibody; anti-HBc, hepatitis B core antibody.

^a Serologic test is recommended only in the absence of age-appropriate vaccines or prior infection documentation.

Table 2

Definitions of inactivated and attenuated vaccines

Inactivated (killed) vaccines	Live attenuated vaccines
Td/Tdap	MMR (measles, mumps, rubella)
Hepatitis A & B	Varicella (chicken pox)
Pneumococcal	BCG
Meningococcal	Yellow fever
HPV
Herpes zoster (inactivated/ recombinant)	Herpes zoster (live)
Rabies virus	Rotavirus
Influenza (injectable)	Influenza (intranasal)
Japanese encephalitis virus	Japanese encephalitis virus
Polio (injectable)	Polio (oral)
Typhoid (injectable)	Typhoid (oral)

Td, tetanus-diphtheria; Tdap, tetanus-diphtheria-pertusis; BCG, Bacillus Calmette–Guérin; HPV, human papilloma virus.

Table 3

Definition of the immunosuppressed state

High level immunosuppression^a

Taking daily systemic corticosteroids for ≥ 14 days (prednisone ≥ 20 mg/day equivalent) and within 3 months of stopping

Treatment with immunomodulatory agents (methotrexate > 0.4 mg/kg/week, azathioprine > 3.0 mg/kg/day, or 6-mercaptopurine > 1.5 mg/kg/day) and within 3 months of stopping

Treatment with biologics agents (anti-tumor necrosis factor, ustekinumab) or tofacitinib and within 3 months of stopping

Low level immunosuppression

Taking daily systemic corticosteroids for ≥ 14 days (prednisone < 20 mg/day equivalent) and within 3 months of stopping

Treatment with immunomodulatory agents (methotrexate ≤ 0.4 mg/kg/week, azathioprine ≤ 3 mg/kg/day, or 6-mercaptopurine ≤ 1.5 mg/kg/ day) and within 3 months of stopping Vedolizumab

^a Protein calorie malnutrition can be included in immunosuppression status [25].

Table 4

Summary of vaccine recommendations for IBD patients

Vaccine	Target population	Recommendations	Considerations
Inactivated influenza	All patients	1 dose annually immunization with inactivated influenza vaccine Pregnant women and families of IBD patients are also recommended to vaccinate.	Live attenuated intra-nasal formulation is contraindicated in immunocompromised patients.
Pneumococcal^a	All patients	For vaccine-naïve patients, a single dose of PCV13 followed by PPSV23 at least 8 weeks apart. Repeat PPSV23 at least 5 years after the first PPSV23 dose. For patients previously vaccinated with PPSV23, one dose of PCV13 at least 5 years after the previous PPSV23
Hepatitis B virus^a	All patients	Check immune status 3 doses at 0, 1 and 6 months; check titers 1–2 month after the last dose; if anti-HBsAb titer < 10 mIU/mL, revaccinate
Hepatitis A virus^a	All patients	Check immune status 2 doses at 0 and 6–18 months
Human Papiolloma virus	Female and male patients aged 15–26 years	3 doses 0, 1–2, and 6-month	For patients aged 27–45 years, shared decision making regarding vaccination is needed considering patient’s risks and preference.
Tetanus, diphtheria, and pertussis	All patients	For patients previously vaccinated, 1 dose Tdap, then Td booster every 10 years For vaccine-naïve patients, uncertain history or birth before 1958, 3 doses 0 (Tdap) → 4–8 weeks (Td) → 6–12 months (Td). Then Td booster every 10 years
Meningococcal disease	High risk patients^b	Generally, 1 dose In HIV infected patients, complement deficiency, splenectomy or spleen hypofunction patients, 2 doses at an interval of 12 weeks	If the risk persists, revaccination is required every 5 years.
Measles, mumps, rubella	Patients with unknown vaccination history	Check immune status For vaccine naïve patients, 2-dose at least 4 weeks apart For previously vaccinated patients, 1 dose	Live vaccine Contraindicated in patients on immunosuppressive therapy^c
Varicella zoster	Patients with unknown vaccination history	Check immune status 2 doses 4–6 weeks apart	Live vaccine Contraindicated in patients on immunosuppressive therapy^c Women planning to become pregnant should use birth control for at least 1 month after vaccination.
Herpes zoster	All patients ≥ 50 years	Two types of vaccines present 1) Live attenuated zoster vaccine: 1 dose 2) RZV: 2 doses, 2–6 month apart	Live vaccine is contraindicated in patients on immunosuppressive therapy.^c RZV is more preferred than live zoster vaccine. RZV can be considered in patients age 19–49 year with risk factors.^d
Coronavirus disease 2019	All patients	1–2 doses (depending on the type of vaccine), followed by booster dose	Non-live vaccine Second booster vaccine is available in a subset of patients.

IBD, inflammatory bowel disease; PCV13, 13 valent pneumococcal conjugate vaccine; PPSV23, 23 valent pneumococcal polysaccharide vaccine; Tdap, tetanus, diphtheria, and pertussis vaccine; Td, tetanus and diphtheria vaccine; HIV, human immunodeficiency virus; RZV, recombinant zoster vaccine.

^a As of writing this review (May 2022), two new pneumococcal conjugate vaccines (PCV15 and PCV20) and hepatitis A and hepatitis B (recombinant) combination vaccine have not yet been available in Korea; therefore, we will not discuss them in this review.

^b High risk includes anatomic or functional asplenia, complement and antibody deficiencies, human immunodeficiency virus infection, travel to areas with high rates of endemic meningococcal disease or transmission, risk of occupational exposure to Neisseria meningitidis, exposure to a confirmed case or during disease outbreak, and military personnel. College students living in residential housing may also consider menincococcal vaccination.

^c In patients with immunosuppressive therapy, administration of live vaccines should be completed at least 4 weeks prior to immunosuppressive treatment, and considered at least 3 months after discontinuation of immunosuppressive treatment.

^d Risk factors include history of zoster, repeated corticosteroid therapy, immunosuppressant combination therapy, and tofacitinib.

REFERENCES

1. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017;390:2769–2778.

2. Ng WK, Wong SH, Ng SC. Changing epidemiological trends of inflammatory bowel disease in Asia. Intest Res 2016;14:111–119.

3. Low D, Swarup N, Okada T, Mizoguchi E. Landscape of inflammatory bowel disease in Singapore. Intest Res 2022;20:291–296.

4. Manser CN, Maillard MH, Rogler G, et al. Vaccination in patients with inflammatory bowel diseases. Digestion 2020;101(Suppl 1):58–68.

5. Im JP, Ye BD, Kim YS, Kim JS. Changing treatment paradigms for the management of inflammatory bowel disease. Korean J Intern Med 2018;33:28–35.

6. Jung YS, Han M, Park S, Cheon JH. Impact of early anti-TNF use on clinical outcomes in Crohn’s disease: a nationwide population-based study. Korean J Intern Med 2020;35:1104–1113.

7. Lee HS, Park SK, Park DI. Novel treatments for inflammatory bowel disease. Korean J Intern Med 2018;33:20–27.

8. Hong SW, Park J, Yoon H, et al. Comparison of loss of response between anti-tumor necrosis factor alone and combined use with immunomodulators in patients with inflammatory bowel disease. Korean J Intern Med 2021;36(Suppl 1):S9–S17.

9. Torres J, Bonovas S, Doherty G, et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis 2020;14:4–22.

10. Park J. Which biologic agents increase perioperative complications in patients with inflammatory bowel disease? Intest Res 2022;20:1–2.

11. Singh A, Mahajan R, Kedia S, et al. Use of thiopurines in inflammatory bowel disease: an update. Intest Res 2022;20:11–30.

12. Matsuoka K, Togo K, Yoshii N, Hoshi M, Arai S. Incidence rates for hospitalized infections, herpes zoster, and malignancies in patients with ulcerative colitis in Japan: an administrative health claims database analysis. Intest Res 2022;Mar. 11. [Epub]. https://doi.org/10.5217/ir.2021.00154 .

13. Benchimol EI, Tse F, Carroll MW, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for immunizations in patients with inflammatory bowel disease (IBD)-Part 1: live vaccines. Gastroenterology 2021;161:669–680.

14. Jones JL, Tse F, Carroll MW, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for immunizations in patients with inflammatory bowel disease (IBD)-Part 2: inactivated vaccines. Gastroenterology 2021;161:681–700.

15. Kucharzik T, Ellul P, Greuter T, et al. ECCO guidelines on the prevention, diagnosis, and management of infections in inflammatory bowel disease. J Crohns Colitis 2021;15:879–913.

16. Caldera F, Hayney MS, Farraye FA. Vaccination in patients with inflammatory bowel disease. Am J Gastroenterol 2020;115:1356–1361.

17. Wasan SK, Calderwood AH, Long MD, Kappelman MD, Sandler RS, Farraye FA. Immunization rates and vaccine beliefs among patients with inflammatory bowel disease: an opportunity for improvement. Inflamm Bowel Dis 2014;20:246–250.

18. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019;68(Suppl 3):s1–s106.

19. Tan B, Ong D. Pediatric to adult inflammatory bowel disease transition: the Asian experience. Intest Res 2020;18:11–17.

20. Horton HA, Kim H, Melmed GY. Vaccinations and immunoprophylaxis in gastrointestinal and liver disorders. In: McNally PR, ed. GI/Liver Secrets Plus. 5th ed. Philadelphia (PA): Elseviser, 2015;155–160.

21. Zullow S, Farraye FA. Updates on vaccinating the inflammatory bowel disease patient. Expert Rev Gastroenterol Hepatol 2019;13:229–239.

22. Petrovsky N, Aguilar JC. Vaccine adjuvants: current state and future trends. Immunol Cell Biol 2004;82:488–496.

23. Croce E, Hatz C, Jonker EF, Visser LG, Jaeger VK, Buhler S. Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation: a systematic review of randomized trials, observational studies and case reports. Vaccine 2017;35:1216–1226.

24. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58:309–318.

25. Farraye FA, Melmed GY, Lichtenstein GR, Kane SV. ACG clinical guideline: preventive care in inflammatory bowel disease. Am J Gastroenterol 2017;112:241–258.

26. Khan N, Patel D, Trivedi C, et al. Overall and comparative risk of herpes zoster with pharmacotherapy for inflammatory bowel diseases: a nationwide cohort study. Clin Gastroenterol Hepatol 2018;16:1919–1927.

27. The Korean Society of Infectious Diseases. Vaccinations for Adults. 3rd ed. Seoul (KR): Koonja Publishing Inc, 2019.

28. Korean Association for the Study of Intestinal Diseases. IBD care vaccination check list [Internet] Seoul (KR): KASID, 2022. [cited 2022 Jul 19]. Available from: https://www.kasid.org/sub07/checklist.html# .

29. Long MD, Martin C, Sandler RS, Kappelman MD. Increased risk of herpes zoster among 108 604 patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;37:420–429.

30. Caldera F, Hayney MS, Cross RK. Using number needed to harm to put the risk of herpes zoster from tofacitinib in perspective. Inflamm Bowel Dis 2019;25:955–957.

31. Tinsley A, Navabi S, Williams ED, et al. Increased risk of influenza and influenza-related complications among 140,480 patients with inflammatory bowel disease. Inflamm Bowel Dis 2019;25:369–376.

32. Hagihara Y, Ohfuji S, Watanabe K, et al. Infliximab and/or immunomodulators inhibit immune responses to trivalent influenza vaccination in adults with inflammatory bowel disease. J Crohns Colitis 2014;8:223–233.

33. Launay O, Abitbol V, Krivine A, et al. Immunogenicity and safety of influenza vaccine in inflammatory bowel disease patients treated or not with immunomodulators and/or biologics: a two-year prospective study. J Crohns Colitis 2015;9:1096–1107.

34. Melmed GY, Rubin DT, McGovern DP. Winter is coming!: clinical, immunologic, and practical considerations for vaccinating patients with inflammatory bowel disease during the coronavirus disease-2019 pandemic. Gastroenterology 2021;160:639–644.

35. Lee YJ, Kim SE, Park YE, et al. SARS-CoV-2 vaccination for adult patients with inflammatory bowel disease: expert consensus statement by KASID. Intest Res 2022;20:171–183.

36. Long MD, Martin C, Sandler RS, Kappelman MD. Increased risk of pneumonia among patients with inflammatory bowel disease. Am J Gastroenterol 2013;108:240–248.

37. Kantso B, Simonsen J, Hoffmann S, Valentiner-Branth P, Petersen AM, Jess T. Inflammatory bowel disease patients are at increased risk of invasive pneumococcal disease: a nationwide Danish cohort study 1977–2013. Am J Gastroenterol 2015;110:1582–1587.

38. Case DJ, Copeland LA, Stock EM, Herrera HR, Pfanner TP. Pneumococcal vaccination rates in VHA patients with inflammatory bowel disease. Medicine (Baltimore) 2015;94:e417.

39. Melmed GY, Agarwal N, Frenck RW, et al. Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease. Am J Gastroenterol 2010;105:148–154.

40. Dotan I, Werner L, Vigodman S, et al. Normal response to vaccines in inflammatory bowel disease patients treated with thiopurines. Inflamm Bowel Dis 2012;18:261–268.

41. Yim SY, Kim JH. The epidemiology of hepatitis B virus infection in Korea. Korean J Intern Med 2019;34:945–953.

42. Papa A, Felice C, Marzo M, et al. Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-α agents. J Crohns Colitis 2013;7:113–119.

43. Loras C, Saro C, Gonzalez-Huix F, et al. Prevalence and factors related to hepatitis B and C in inflammatory bowel disease patients in Spain: a nationwide, multicenter study. Am J Gastroenterol 2009;104:57–63.

44. Harsh P, Gupta V, Kedia S, et al. Prevalence of hepatitis B, hepatitis C and human immunodeficiency viral infections in patients with inflammatory bowel disease in north India. Intest Res 2017;15:97–102.

45. Kim ES. Inflammatory bowel disease is no longer a risk factor of viral hepatitis infection in Asia. Intest Res 2017;15:5–6.

46. Yeo SJ, Lee HS, Jang BI, et al. Nonimmunity against hepatitis B virus infection in patients newly diagnosed with inflammatory bowel disease. Intest Res 2018;16:400–408.

47. Kim ES, Cho KB, Park KS, et al. Prevalence of hepatitis-B viral markers in patients with inflammatory bowel disease in a hepatitis-B-endemic area: inadequate protective antibody levels in young patients. J Clin Gastroenterol 2014;48:553–558.

48. Loras C, Gisbert JP, Minguez M, et al. Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy. Gut 2010;59:1340–1346.

49. Lee JM, Wei SC, Lee KM, et al. Clinical course of hepatitis B viral infection in patients undergoing anti-tumor necrosis factor α therapy for inflammatory bowel disease. Gut Liver 2022;16:396–403.

50. Park SK, Choi CH, Chun J, et al. Prevention and management of viral hepatitis in inflammatory bowel disease: a clinical practice guideline by the Korean Association for the Study of Intestinal Diseases. Intest Res 2020;18:18–33.

51. Vida Perez L, Gomez Camacho F, Garcia Sanchez V, et al. Adequate rate of response to hepatitis B virus vaccination in patients with inflammatory bowel disease. Med Clin (Barc) 2009;132:331–335.

52. Caldera F, Saha S, Wald A, et al. Lower sustained diphtheria and pertussis antibody concentrations in inflammatory bowel disease patients. Dig Dis Sci 2018;63:1532–1540.

53. Jiang HY, Wang SY, Deng M, et al. Immune response to hepatitis B vaccination among people with inflammatory bowel diseases: a systematic review and meta-analysis. Vaccine 2017;35:2633–2641.

54. Hong HS, Jung J, Park SH, et al. Seroprevalence of viral infectious diseases and associated factors in Korean patients with inflammatory bowel diseases. Korean J Intern Med 2022;37:73–84.

55. Meites E, Szilagyi PG, Chesson HW, Unger ER, Romero JR, Markowitz LE. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2019;68:698–702.

56. Crosby S, Schuh MJ, Caldera F, Farraye FA. Vaccination of patients with inflammatory bowel disease during the COVID-19 pandemic. Gastroenterol Hepatol (N Y) 2021;17:18–30.

57. Jacobson DL, Bousvaros A, Ashworth L, et al. Immunogenicity and tolerability to human papillomavirus-like particle vaccine in girls and young women with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:1441–1449.

58. Dezfoli S, Horton HA, Thepyasuwan N, et al. Combined immunosuppression impairs immunogenicity to tetanus and pertussis vaccination among patients with inflammatory bowel disease. Inflamm Bowel Dis 2015;21:1754–1760.

59. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflamm Bowel Dis 2012;18:2392–2403.

60. Leung VS, Nguyen MT, Bush TM. Disseminated primary varicella after initiation of infliximab for Crohn’s disease. Am J Gastroenterol 2004;99:2503–2504.

61. Marin AC, Gisbert JP, Chaparro M. Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease. World J Gastroenterol 2015;21:11273–11281.

62. Freedman M, Kroger A, Hunter P, Ault KA, Advisory Committee on Immunization Practices. Recommended adult immunization schedule, United States, 2020. Ann Intern Med 2020;172:337–347.

63. Nugent Z, Singh H, Targownik LE, Bernstein CN. Herpes zoster infection and herpes zoster vaccination in a population-based sample of persons with IBD: is there still an unmet need? Inflamm Bowel Dis 2019;25:532–540.

64. Chang K, Lee HS, Kim YJ, et al. Increased risk of herpes zoster infection in patients with inflammatory bowel diseases in Korea. Clin Gastroenterol Hepatol 2018;16:1928–1936.

65. Soh H, Chun J, Han K, et al. Increased risk of herpes zoster in young and metabolically healthy patients with inflammatory bowel disease: a nationwide population-based study. Gut Liver 2019;13:333–341.

66. Winthrop KL, Melmed GY, Vermeire S, et al. Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib. Inflamm Bowel Dis 2018;24:2258–2265.

67. Hanauer SB, Sandborn WJ, Feagan BG, et al. IM-UNITI: three-year efficacy, safety, and immunogenicity of ustekinumab treatment of Crohn’s disease. J Crohns Colitis 2020;14:23–32.

68. Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut 2017;66:839–851.

69. James SF, Chahine EB, Sucher AJ, Hanna C. Shingrix: the new adjuvanted recombinant herpes zoster vaccine. Ann Pharmacother 2018;52:673–680.

70. Berkowitz EM, Moyle G, Stellbrink HJ, et al. Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: a phase 1/2a randomized, placebo-controlled study. J Infect Dis 2015;211:1279–1287.

71. Vink P, Ramon Torrell JM, Sanchez Fructuoso A, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in chronically immunosuppressed adults following renal transplant: a phase 3, randomized clinical trial. Clin Infect Dis 2020;70:181–190.

72. Centers for Disease Control and Prevention. Shingrix Recommendations [Internet] Atlanta (GA): CDC, 2022. [cited 2022 Jul 19]. Available from: https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/recommendations.html .

73. Lee YJ, Kim KO, Kim MC, et al. Perceptions and behaviors of patients with inflammatory bowel disease during the COVID-19 crisis. Gut Liver 2022;16:81–91.

74. Kim KO, Jang BI. Management of inflammatory bowel disease in the COVID-19 era. Intest Res 2022;20:3–10.

75. Hadi Y, Dulai PS, Kupec J, et al. Incidence, outcomes, and impact of COVID-19 on inflammatory bowel disease: propensity matched research network analysis. Aliment Pharmacol Ther 2022;55:191–200.

76. Singh AK, Jena A, Kumar-M P, Jha DK, Sharma V. Clinical presentation of COVID-19 in patients with inflammatory bowel disease: a systematic review and meta-analysis. Intest Res 2022;20:134–143.

77. Barbosa da Luz B, de Oliveira NM, Franca Dos Santos IW, et al. An overview of the gut side of the SARS-CoV-2 infection. Intest Res 2021;19:379–385.

78. Alexander JL, Moran GW, Gaya DR, et al. SARS-CoV-2 vaccination for patients with inflammatory bowel disease: a British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group position statement. Lancet Gastroenterol Hepatol 2021;6:218–224.

79. Siegel CA, Melmed GY, McGovern DP, et al. SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting. Gut 2021;70:635–640.

80. Botwin GJ, Li D, Figueiredo J, et al. Adverse events after SARSCoV-2 mRNA vaccination among patients with inflammatory bowel disease. Am J Gastroenterol 2021;116:1746–1751.

81. Lev-Tzion R, Focht G, Lujan R, et al. COVID-19 vaccine is effective in inflammatory bowel disease patients and is not associated with disease exacerbation. Clin Gastroenterol Hepatol 2022;20:e1263–e1282.

82. Kennedy NA, Lin S, Goodhand JR, et al. Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAd-Ox1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD. Gut 2021;70:1884–1893.

83. Lin S, Kennedy NA, Saifuddin A, et al. Antibody decay, T cell immunity and breakthrough infections following two SARSCoV- 2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab. Nat Commun 2022;13:1379.

84. Centers for Disease Control and Prevention. COVID-19 Vaccines for Moderately or Severely Immunocompromised People [Internet] Atlanta (GA): CDC, 2022. [cited 2022 Jul 19]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html?s_cid=10483:immunocompromised%20covid%20vaccine:sem.ga:p:RG:GM:-gen:PTN:FY21 .