Adherence to Recommended Immunization Schedules in Patients with Inﬂammatory Bowel Disease on Biologics and Small Molecule Therapies

: Introduction: Patients with inﬂammatory bowel disease (IBD) on biologic therapies are at increased risk of infections, emphasizing the importance of immunization. This study aimed to assess vaccination prevalence among patients with IBD on speciﬁc biologic therapies. Methods: A survey-based cross-sectional study was conducted at an IBD center, including patients receiving different biologic therapies from 1 January 2022 to the 30 April 2023. Demographic and vaccination data were collected using patient electronic records and patient interviews. Results: A total 394 patients (100%) received the measles, mumps, rubella (MMR), tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine. A total of 79 patients (20%) received the inﬂuenza vaccine, 40 patients (10.2%) were vaccinated against hepatitis A (HAV), and 34 patients (8.6%) received the pneumococcal vaccine. From the 103 female patients who are eligible to take human papillomavirus (HPV) vaccine, only 7 (6.8%) received it. Out of the 100 eligible patients above the age of 50, only 9 (9%) received the herpes zoster (HZ) vaccine. Conclusion: The uptake of certain vaccines such as Hepatitis B (HBV), seasonal inﬂuenza, HAV, pneumococcal, HZ and HPV vaccines among patients with IBD were below expectations. These ﬁndings highlight the need for interventions to improve patients’ awareness and adherence to prevent infectious complications in patients with IBD.


Introduction
Crohn's disease (CD) and ulcerative colitis (UC) are both subtypes of IBD, which is a chronic idiopathic inflammatory condition affecting the gastrointestinal tract.CD usually affects any part of the digestive system, whereas UC is associated with the colon and rectum.It is thought that an interaction between environmental factor such as diet, stress, and smoking [1] and immunoregulatory factors in genetically predisposed individuals triggers IBD [2].Although no known medical or surgical cure is available for IBD [3], induction and maintenance of remission can be achieved through medication, including anti-inflammatory drugs such as 5-aminosalicylates (5-ASA) in UC and corticosteroids in IBD [4,5].Immunomodulators such as azathioprine, mercaptopurine, and methotrexate are commonly used as maintenance therapy for mild to moderate disease in IBD.In addition, biologics such as infliximab, adalimumab, golimumab, and vedolizumab have been demonstrated to be effective for moderate to severe IBD [3,4].These medications aim to decrease intestinal inflammation, promote healing of fistulas, and minimize potential complications [6].
All of the previous medications except 5-ASA have immunosuppressive properties [7].Despite immunosuppressant exposure, all patients with IBD suffer from immune dysregulation [8].However, the main risk of infection is imposed by immunosuppressant therapy not to the disease itself but to the augmented vulnerability to a wide range of infectious agents, particularly during the first year of therapy [9,10].Thus, it is important to assess the immunologic and serologic status together with the presence of active or latent infections at diagnosis of IBD before starting immunosuppressants.An immunocompromised status predisposes patients to numerous infections, especially opportunistic infections, which are commonly correlated with remarkable morbidity and mortality that may decrease treatment effectiveness [11].Severe cases of pneumococcal infection, known as fulminant sepsis, have been reported [12][13][14].Additionally, pneumonia caused by the varicella zoster virus (VZ) [15,16] and reactivation of HBV have been described in multiple patients [17,18].In addition, significant number of cases with shingles have been found [19,20].Moreover, there is a risk of latent tuberculosis (TB) reactivation that may develop into serious infections such as meningitis, disseminated disease, and fulminant disease, especially if the patient is on combination therapy such as infliximab and azathioprine [21].Consequently, people with IBD may have poor quality of life and high risk of morbidity and mortality at a young age [1].Most infections, including those caused by opportunistic pathogens, can be prevented by appropriate vaccination programs [11].
According to the Canadian Association of Gastroenterology Clinical Practice Guideline for immunizations in IBD patients, three important practice statements involved reviewing vaccination status at diagnosis then regularly, giving appropriate vaccinations as soon as possible, and not delaying immunomodulators to provide vaccinations (especially if urgently needed).These vaccinations are important in optimizing patients' health outcome [22].A review of five international guidelines on IBD vaccination agreed on the importance of the following vaccines.Before starting immunosuppressive therapy, MMR vaccine, HZ, and varicella should be given as these live vaccines have the potential to replicate and cause harm [22].Other inactivated vaccines, which are recommended for most patients with IBD, involve HPV, tetanus-diphtheria, and pertussis (DTP), influenza, pneumococcus, meningococcus C, HBV, and HAV, and Coronavirus Disease-19 (COVID-19) [22,23].
There is a notable lack of research on vaccination uptake among patients with IBD residing in Kuwait.Kuwait exhibits a significantly higher prevalence of IBD compared to other Arabic countries, according to a study by Mosli et al., among seven Arabic nations, Kuwait demonstrates the highest incidence of IBD [2].This finding underscores the substantial burden of IBD within the Kuwaiti population.Therefore, this study aims to fill this knowledge gap by examining vaccination patterns in IBD patients in Kuwait.It focuses on assessing compliance rates to vaccination guidelines.The study's findings provide crucial information to healthcare providers, enabling them to understand the current vaccination status and enhance preventive care for this vulnerable population.Moreover, this study serves as an initial step that determine the proportion of IBD patients who are on biologics that received appropriate vaccinations based on international guidelines and protocols.

Materials and Methods
A cross-sectional study was conducted at the Haya AlHabeeb Gastroenterology Center in Kuwait to assess the prevalence of vaccination among patients with IBD.The study included 394 patients aged 18 years or older who had a confirmed diagnosis of IBD for at least six months and were currently receiving biologic therapies.Patients without a clinical diagnosis of IBD or those with confirmed IBD but not adhering to their prescribed biologics were excluded.Additionally, patients who declined participation were not included.Patients with missing data were also excluded.
To ensure internal validity, patients were contacted twice, with a minimum interval of eight weeks between phone calls.Data collection took place from 1 January 2022 to the 30 April 2023.Prior to the start of the study, healthcare providers educated patients about the importance of vaccination.The primary outcome of interest was to evaluate the percentage of IBD patients on biologic therapies who had received recommended vaccinations.The secondary outcome was whether vaccination status differ based on age, disease type (UC or CD), gender and nationality.The biologics and small molecule therapies under investigation included infliximab, ustekinumab, adalimumab, and vedolizumab, as well as golimumab upadacitinib and tofacitinib.Adherence to local vaccination schedule was performed by assessing the immunization status of our patients.
The study was performed and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, ensuring transparency and methodological rigor [25].
All collected data were compiled into a single Excel sheet for analysis.Quantitative variables were expressed as mean and standard deviation (SD), while qualitative variables were presented as percentages.χ2 tests were used to assess whether type of biologic therapy differed based on age, gender, and type of IBD (UC or CD).

Ethical Consideration
The study protocol was reviewed and approved by the standing committee for coordination of health and medical research at the Ministry of Health in Kuwait (IRB 2021/3613).Verbal and written informed consent have been obtained from all patients prior to the start of the study.

Results
Initially, a total of 520 patients with confirmed diagnoses of IBD were identified.Out of these, 394 patients met the eligibility criteria and were included in our study.Among the eligible participants, 235 (59.7%) were males and 159 (40.3%) were females.The mean age of the sample was 31.4 years.
The total number of IBD patients who were vaccinated are lower than expected with a percentage of 58.9%.Regarding vaccinations, all 394 patients (100%) received Bacille Calmette-Guérin (BCG) vaccine, MMR, DTP, and Tdap vaccine.Moreover, 391 patients (99.2%) were immunized against Hemophilus influenzae type B (Hib) in addition to receiving the DTP vaccine.Among the study participants, 385 patients (97.7%) received the meningococcal vaccine, while 352 patients (89.3%) received the HBVvaccine.A total of 343 patients (87%) were vaccinated against COVID-19, at least two doses.Furthermore, 79 patients (20%) received the seasonal influenza vaccine, 40 patients (10.2%) were vaccinated against HAV, and 34 patients (8.6%) received the pneumococcal vaccine.Among the 103 female patients aged between 27 and 45, who are eligible for the HPV vaccine, only 7 (6.9%) received it.Similarly, out of the 100 patients aging above the age of 50, who are eligible for HZ vaccine, only 9 (9%) received the vaccine (see Table 2 and Figure 1).The total number of patients who were below 50 years old was 332 (84.2%).Of these, only 193 (58.1%) patients took the recommended vaccines.Conversely, the total number of patients who were above 50 years old was 62 (16.1%), with only 43 (69.4%) of them reporting taking the recommended vaccinations.
Regarding gender differences, in our study, only 109 (46.4%) of male patients were immunized with the recommended vaccines, whereas a higher proportion of 127 (79.9%) female patients were immunized by taking the recommended vaccines.Unlike the observed difference stating that female patients were more likely to be vaccinated than male patients (p = 0.001), there was no significant association between vaccination status and patient age, disease type (UC or CD), and nationality (p = 0.6, p = 0.5, p = 0.8).
When considering the type of IBD, of the total patients diagnosed with CD, only 166 (58.2%) patients took the recommended vaccines.In contrast, among patients diagnosed with UC, the number was slightly higher, with 70 (64.2%)adhering to the recommended vaccines' schedule.
In terms of nationality, out of the total number of IBD patients, 180 (60.6%)Kuwaiti patients and 56 (57.7%) non-Kuwaiti patients were vaccinated with the recommended vaccines (Table 3).The total number of patients who were below 50 years old was 332 (84.2%).Of these, only 193 (58.1%) patients took the recommended vaccines.Conversely, the total number of patients who were above 50 years old was 62 (16.1%), with only 43 (69.4%) of them reporting taking the recommended vaccinations.
Regarding gender differences, in our study, only 109 (46.4%) of male patients were immunized with the recommended vaccines, whereas a higher proportion of 127 (79.9%) female patients were immunized by taking the recommended vaccines.Unlike the observed difference stating that female patients were more likely to be vaccinated than male patients (p = 0.001), there was no significant association between vaccination status and patient age, disease type (UC or CD), and nationality (p = 0.6, p = 0.5, p = 0.8).
When considering the type of IBD, of the total patients diagnosed with CD, only 166 (58.2%) patients took the recommended vaccines.In contrast, among patients diagnosed with UC, the number was slightly higher, with 70 (64.2%)adhering to the recommended vaccines' schedule.
In terms of nationality, out of the total number of IBD patients, 180 (60.6%)Kuwaiti patients and 56 (57.7%) non-Kuwaiti patients were vaccinated with the recommended vaccines (Table 3).

Discussion
Patients with IBD who are on biologic therapies are susceptible to opportunistic infections and its complications [22].These complications may happen due to the immunosuppressive treatments or to the IBD itself.Therefore, appropriate vaccination program is important to prevent such complications that may lead to increase morbidity and mortality rate [22,26].Failure to protect IBD patients with appropriate vaccines can have adverse consequences.For instance, an unvaccinated IBD patient receiving biologics may contract influenza, leading to severe respiratory complications, hospitalization, or even death [10].Similarly, a pneumococcal infection in an immunosuppressed IBD patient can result in life-threatening conditions such as sepsis or meningitis [10].Furthermore, IBD patients who are on single immunosuppression therapy such as infliximab or a combination therapy such as infliximab and azathioprine have increased risk of active tuberculosis [27].Furthermore, immunosuppressed individuals with IBD are susceptible to HBVinfection, particularly following procedures such as endoscopies and surgeries, owing to the nature of their disease course [11].Inadequate prevention of HBV in this population can lead to the development of chronic liver disease [11].
Guidelines from reputable organizations such as the American College of Gastroenterology (ACG), European Crohn's and Colitis Organization (ECCO) [26], and the British Society of Gastroenterology (BSG) [28] emphasize the importance of vaccinating patients with IBD before receiving biologics [29].However, there are three fundamental factors that must be considered.First, individuals with IBD should be aware and educated about the importance of the immunization program and implement shared decision making by the gastroenterologist team, primary care physician and the patient [30].Second, assessment of the vaccination statement as soon as diagnosis of IBD is confirmed with regular annual checkup [30].Third, immunization success rates may be affected by immunosuppression medication or by the disease itself.Therefore, serology checkup is important to ensure patients reached immunization status [26,30].
It was observed in our study that there was high compliance rate of 100% for MMR and Tdap vaccines in our sample, which significantly exceeded the rates reported in previous studies.Specifically, Malhi et al. documented that approximately 50% or more of their participants had received these vaccines, while Ford et al. reported a low immunity rate of 8.7% against MMR [31,32].Moreover, cross sectional study which was based in Brazil states that only 43.8% received MMR vaccine [33].While Ryu et al. reported low adherence to the MMR vaccine with a percentage of 18.1% and low Tdap uptake with a percentage of 13.6% [34].In line with our results, Ruiz et al. demonstrated a comparable percentage of immunization for measles (99.3%), although their assessment did not include Tdap [35].
It is also observed in our study that there is a 100% complete adherence to the BCG vaccine, which contracts with two previous studies conducted in Korea by Ryu et al. and in Brazil by Strasse KL, reporting adherence rates of 60.3% and 55.3%, respectively [33,34].Another study that noted lower BCG vaccine uptake was carried out in Australia on adolescent and children, and it states that only 8.7% received the vaccine [32].One of the probable reasons why there was complete adherence to the BCG vaccine in our study is due to its high TB prevalence in the Middle East and Asia [36].
In terms of DTP and Hib vaccines, our study showed adherence rate of 99.2% compared to a study on newly diagnosed children and adolescents, where lower rates of 18.8% and 24.6% were documented, respectively [32].Reduced uptake of DTP and Hib was also observed in another study with a percentage of 43% and 0.8% [33] Regarding the meningococcal C vaccine, our participants exhibited a significantly higher uptake rate of 97.7% compared to the rates mentioned in Malhi et al. (20.7%) and Wasan et al. (30%) [31,37].
One of the main reasons why there was a high vaccination uptake in the previous vaccinations mentioned is due to the fact that it is part of the national vaccination program in Kuwait, which is mandatory to attend school.However, post high school vaccinations become optional.
Furthermore, our sample demonstrated a high uptake rate of 87% for the COVID-19 vaccine, a survey of Chinese IBD patients revealed a minority receiving this vaccine [38].One of the reasons of this high uptake rate is awareness campaigns that was promoted during the pandemic.Medical health staff including preventative medicine, primary care physicians, and a gastroenterologist took full responsibility in promoting the safety of this vaccine.
Our findings highlighted a low adherence rate of 20% to the seasonal influenza vaccine, which is in line with another study carried out by Narula et al., showing 24.8% vaccination uptake [39].In addition, a Canadian study that reported significantly lower influenza vaccine uptake of only 4.7% among adults with IBD [30].These findings emphasize the need for targeted interventions to improve vaccination rates.In contrast to our study, seasonal influenza vaccine had higher uptake rates of 81.5%, 72.4%, and 61.3% observed in other studies [31,33,37].Moreover, a study revealed that there was moderate uptake of seasonal influenza vaccine with a percentage of 43.2% [34].
It was also noticed in our study that HAV vaccination levels was low (10.2%).This finding is consistent with Ford et al. and Ryu et al. observed vaccinated percentages of 8.7% and 13.2%, respectively [32,34].However, it is inconsistent with other studies reporting adherence percentages of 52% and 19.9% [37].
Moreover, our investigation revealed a notable deficiency in compliance with the pneumococcal vaccine, with a mere 8.6% of participants receiving the vaccination.This outcome is consistent with another study, where the uptake of the pneumococcal vaccine was reported to be 4.9 only [34].On the other hand, a different study showed a higher uptake rate of pneumococcal vaccine with a percentage of 42.6% [1].The uptake of the HPV vaccine among eligible females in our study was lower with a percentage of 6.8% similar to a study carried out in Brazil with a percentage of 3.4% [33].However, there were other studies reporting higher uptake rates of 50% [1] and 11% [38].Another study showed relatively higher uptake of the HPV with a percentage of 35% among female patient who were younger than 26 years old [34].Finally, the HZ vaccine was taken by 9% of the eligible sample in our investigation, whereas other studies reported a higher immunity rate of 33.3% [37].There was another study that showed higher uptake of HZ with percentage of 20% in patients aged more than 60 years [34].However, HZ uptake among our patients is higher than that found in Canada (5.3%) [31].
The variation in immunization compliance rates among patients with IBD who are on biologics can be attributed to several factors.First, patients might be presented with active cases of moderate to severe IBD as a first presentation and it would be difficult to give the recommended vaccination especially the live attenuated vaccines [8].Second, limited knowledge and awareness regarding the significant importance of vaccination among those suffering from IBD.A study conducted in Korea revealed that a majority of IBD patients reported not receiving education from their healthcare providers about the vaccination program [34].This lack of information and guidance from doctors may contribute to suboptimal immunization rates in this population.Addressing this knowledge gap and enhancing healthcare provider-patient communication regarding vaccinations is crucial for improving immunization compliance among individuals with IBD since some patients prefer to have a direct consultation with their gastroenterologists [40].In addition, there is limited collaboration between gastroenterologists, primary healthcare providers, and the department of preventive medicine.As it was shown in different studies that primary care providers are not comfortable to hold responsibility of immunizing patients with IBD, gastroenterologist believe preventive medicine falls under the job description for primary care [37,40].
It is crucial to recognize that patient may refuse vaccinations to several reasons.Patients with IBD undergoing biologic therapy may harbor fears regarding vaccination, driven by misconception that even inactivated vaccines may provoke infections.moreover, misinformation propagated by media and the internet has been identified as a significant influencer, contributing to reduced vaccination rates [41].Cultural factors also play a role, with some individuals with IBD turning to complementary and alternative medicine, perceiving it as a safer alternative [42].Doubts and apprehensions surrounding vaccine safety and potential adverse effects present additional barriers, impacting vaccination decision [37,39].Furthermore, some patients harbor misconceptions and doubts about the vaccines' side effects, efficacy, and potential deterioration of their condition [37].In addition, some patient may suffer from trypanophobia which make them refuse taking the recommended vaccinations [8].Therefore, it is important to address and encourage of obtaining the recommended vaccinations as it prevents patients from conducting serious infection while they are on biologics or combination therapy.Addressing these factors and providing accurate, evidence-based information is crucial in dispelling misconceptions, fostering trust, and encouraging vaccination uptake in the IBD population.This can be accomplished by having educational brochures to promote vaccination uptake such as influenza and pneumococcal vaccines [8].In addition, digital health records which are used in clinics and hospitals can aid physicians in vaccines administration and notify them if vaccines are contraindicated in immunosuppressive patients [43].
The prevalence of HPV-related diseases is relatively low in Kuwait and other Middle Eastern countries, leading to a perception of low risk.However, complacency towards HPV and low intentions to receive vaccination are observed [44].Despite evidence indicating the public health significance of HPV-related cancers, challenges remain in the region, including lack of awareness, safety concerns, low vaccine uptake, hesitancy towards vaccination, and affordability concerns.The cost of the HPV vaccine is a major barrier, even in high-income countries such as Kuwait, where it is not included in routine immunization programs [44].Furthermore, the Middle East has witnessed the embrace of conspiratorial ideas about vaccination, including among educated groups, and misinformation plays a crucial role in shaping negative attitudes [44].These facts together could be the reason behind the low HPV vaccine uptake shown in our sample.
In our cohort, 87% of participants received at least two doses of the COVID-19 vaccine, indicating a substantial uptake.One of the key drivers behind this reasonable uptake could be attributed to government regulations that enforce vaccination and restrict travel for non-vaccinated individuals [45].
However, our study shed light on a noteworthy finding, revealing some hesitancy among patients with IBD on biologic therapies to receive the COVID-19 vaccine or a booster dose.This hesitancy warrants attention to ensure equitable protection for all vulnerable populations [45].
In line with our findings, other studies have also identified specific factors influencing COVID-19 vaccination rates in IBD patients.Female patients, those above the age of 50, and expatriates were more likely to receive COVID-19 vaccines [46,47].Similarly, a study by Kwon et al. observed higher vaccination uptake among IBD patients who were on biologics and of white or Asian race.Additionally, older age and female gender were associated with increased COVID-19 vaccine acceptance [47].
Furthermore, regular clinic visits during acute flares and follow-ups correlated with higher COVID-19 vaccine uptake among IBD patients [47].These findings underscore the significance of healthcare provider engagement and patient education in fostering vaccine acceptance.
Reassuringly, evidence has demonstrated the safety of vaccinating patients with IBD [48], offering essential reassurance to hesitant individuals within this patient population.
The cross-sectional design gives a realistic portrayal of clinical practice adding to the strength of this study.No previous studies in the region explored this issue, indicating the need for such important information.The study included most important vaccinations that are recommended and focused on an important immunocompromised population who are hesitant to vaccinate.In addition, the data were collected in two separate occasions to ensure accuracy and validity.
Limitations of our study include its moderate sample size and use of a single center to recruit patients.In addition, vaccination status was obtained by self-report, which is subject to recall bias, inability to distinguish which vaccine was received, and is not as accurate as serologic tests.Our findings pave the way for further investigation of reasons behind vaccine-uptake patterns to plan the basis for an intervention enhancing patient awareness and adherence to vaccination guidelines.Moreover, our study was a descriptive study with no control group to compare if rates between patients with IBD vs healthy individuals vary.

Conclusions
In our study, we found that the uptake of certain vaccines such as HBV seasonal influenza, HAV, pneumococcal, HZ and HPV vaccines among patients with IBD were below expectations compared to other studies.These findings highlight the need for interventions to improve patients' awareness and adherence to prevent infectious complications in patients with IBD.

Figure 1 .
Figure 1.Percentages of adherence to recommended vaccines.

Figure 1 .
Figure 1.Percentages of adherence to recommended vaccines.

Table 1 .
Baseline characteristics of included patients.

Table 2 .
Percentages of adherence to recommended vaccines.

Table 3 .
Demographics of the vaccinated patients.

Table 3 .
Demographics of the vaccinated patients.