The risk of hepatitis B infection has been considered to be increased in patients with inflammatory bowel disease (IBD) (1–3). Patients with IBD often require immunosuppressive therapies, which can cause potentially fatal hepatitis B virus (HBV) reactivation, blood transfusions, and sometimes invasive procedures such as surgery and endoscopies. Thus, protection against vaccine-preventable diseases is important in patients with IBD. Screening for HBV and vaccination is recommended (4–13) and also response should be observed, as booster doses may be required.
There are few published studies on immunizations with hepatitis A and B vaccines in patients with IBD (13–18). In the present study, the rate of response to the hepatitis A and B vaccines and duration of protection against hepatitis A virus (HAV) and HBV were determined in pediatric patients with IBD and compared with healthy children.
Forty-seven children with IBD diagnosed and followed up between 2000 and 2012 at Division of Pediatric Gastroenterology of Sisli Etfal Training and Research Hospital (Istanbul, Turkey) and 50 healthy age- and sex-matched controls were evaluated prospectively. The patients and controls who had been vaccinated previously against HAV and HBV were excluded. The controls were recruited from our hospital clinics.
Baseline hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), total antibody to hepatitis B core antigen (anti-HBc), anti-HAV IgG, and IgM were examined in all patients and controls. The diagnosis of IBD was based on clinical, radiological, and histological criteria. Informed consents were obtained from all of the parents before the procedures and the study was approved by the hospital institutional review board.
All of the patients were evaluated by the same physician to assess their disease activity at baseline (before vaccination), 1 month after the last dose of primary vaccination, and 1 month after the booster dose. Pediatric Crohn Disease Activity Index (PCDAI) was used for patients with CD (19–21). The score was obtained from items, which included subjective reporting of the degree of abdominal pain, stool pattern, and general well-being; presence of extraintestinal manifestations, such as fever, arthritis, rash, and uveitis; physical examination findings; weight and height; and hematocrit, erythrocyte sedimentation rate, and serum albumin. Pediatric Ulcerative Colitis Activity Index (PUCAI) was used for patients with UC (22). It was determined by items including abdominal pain, rectal bleeding, stool consistency of most stools, number of stools per day, nocturnal stools, and activity level. For both patients with UC and patients with CD, an increase of score observed 4 weeks after vaccination was considered to be a clinical flare.
The treatment with 5-aminosalicylic acid was initiated in all patients after diagnosis. Thirteen patients required additional therapy with corticosteroid (prednisolone 1–2 mg · kg−1 · day−1, 60 mg maximal dose), and azathioprine (2 mg · kg−1 · day−1) was used in 8 patients who had steroid-dependent IBD.
When the patients and the controls were susceptible to HAV defined as a negative total HAV antibody, 2 doses of hepatitis A vaccine (720 ELISA units, in 0.5 mL, Havrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) were given 6 months apart intramuscularly into the deltoid muscle. When they were not immune for HBV, 3 doses of hepatitis B vaccine (20 μg, in 0.5 mL, Genhevac B, Sanofi Pasteur Diagnostic, Paris, France) were administered at months 0, 1, and 6 intramuscularly. None received the combined hepatitis A/B vaccine. Postvaccination serologic and virologic evaluation was performed 1 month after the last dose of vaccine. Seroconversion was considered if anti-HBs levels were ≥10 mIU/mL and anti-HAV IgG was positive. Those with anti-HBs <10 mIU/mL received a booster dose. Children were followed by testing anti-HAV antibodies, anti-HBs, and anti-HBc titers 1 month after the last dose of vaccinations, 1 month after the booster dose given to cases who did not respond to primary vaccination, and once every year during follow-up period.
Statistical analysis was performed using SPSS 11.0 software (SPSS Inc, Chicago, IL). Results were expressed as means ± SD for quantitative variables and proportions for categorical variables and percentage with 95% confidence interval (CI) was used to describe the prevalence. The analysis was conducted using Fisher exact test, χ2, and analysis of variance to analyze qualitative variables. P values of <0.05 were considered statistically significant.
The age of patients ranged from 3 to17 years (mean 11.06 ± 3.74), and male:female ratio was 1.13. None of the patients was vaccinated against HAV and HBV before the diagnosis of IBD. The control group consisted of 50 healthy children (17 girls and 33 boys, mean age 9.2 ± 1.7 years, range 1–17 years) with negative diagnostic tests for IBD.
Among 47 patients who had antibody testing, 24 (51%) had natural immunity for hepatitis A and 23 (48.9%) were susceptible to HAV. Fifteen (30%) of the controls had natural immunity for hepatitis A. All patients and controls were negative for HBsAg, anti-HBc, and anti-HBs before vaccination. Forty-seven patients without evidence of earlier exposure to hepatitis B received hepatitis B vaccine, whereas 23 (48.9%) of them negative for HAV antibodies received hepatitis A vaccine. All of the controls were vaccinated against HBV and 70% against HAV. The baseline demographic and clinical characteristics of the cases are shown in Table 1.
No severe adverse reactions or allergy to vaccine components were reported after any dose of the vaccines. Local adverse effects (erythema, pain at injection site, induration) were mild and systemic adverse effects such as flu-like syndrome and fever occurred several days following vaccines in only 3.5% of the cases in each group. No patients had an increased PCDAI/PUCAI score 4 weeks after completion of primary vaccination series and the booster dose; hence, the disease activity remained stable after vaccination.
All of the patients and 35 controls became positive for anti-HAV antibodies 1 month after hepatitis A vaccination (P = 1.00). 70.2% of the patients and 90% of the controls were anti-HBs–positive 1 month after the last dose of the vaccine (95% CI 0.71–0.87, P = 0.02). The anti-HBs–positive and –negative patients did not differ significantly in age, sex, body mass index (BMI), and IBD phenotype (P > 0.05). Healthy nonresponders to primary vaccination had achieved 60% (3/5) rate of seroconversion after a single booster (Table 2). Fourteen anti-HBs–negative patients with IBD received a booster dose, and only 7 (50%) became anti-HBs–positive afterward. When compared with IBD nonresponders (7/14), the difference was not statistically significant (95% CI 0.31–0.72, P = 0.67). The nonresponders after a booster dose did not differ significantly in age, sex, BMI, IBD phenotype, and the treatment given (P > 0.05). No patient who did not develop seroprotection against both HAV and HBV was observed.
Overall seroconversion rates after booster dose were 96% in controls and 85.1% in patients with IBD (95% CI 0.83–0.95, P = 0.08). All of the patients and controls except nonresponders had seroprotective titers of anti-HBs and anti-HAV IgG during the follow-up period after the administration of last doses of vaccines. The sustained response rates were also similar in hepatitis A and B vaccination in both groups (P > 0.05). None of the nonresponders became infected with HBV and HAV during follow-up period. All cases are still negative for anti-HAV IgM, HbsAg, and anti-HBc.
The patients with immune-mediated inflammatory diseases are at increased risk for infections, some of which are vaccine-preventable, partially because of the disease itself, but mostly immunomodulatory or immunosuppressive treatment (23). The consensus guidelines of the European Crohn's and Colitis Organization recommend serology testing for specific viruses and administration of a number of vaccinations shortly following the diagnosis of IBD, before the initiation of an immunosuppressive therapy, which may attenuate the response to vaccination (4). The reduced quality of the immune response in patients with IBD, especially in those under immunotherapy, may have a negative effect on antibody response and reduce the duration of protection provided by vaccination, thus requiring additional boosters.
Despite a routine childhood immunization program, including hepatitis B vaccination initiated in Turkey in 1998 (24), there are still unvaccinated children, especially in eastern part of our country because of low socioeconomic status, low parental education levels, parental attitudes, beliefs, and perceptions. According to the data given by Turkish Ministry of Health, the rate of hepatitis B immunization was 66% in 2000 and 77% in 2004. Only the patients who had been unvaccinated previously against HAV and HBV were included in the present study; therefore, the size of the sample was small.
Approximately 4% to 10% of healthy individuals do not develop an adequate immune response against the hepatitis B vaccine after the primary vaccination series (25,26) and nonresponsiveness was higher in patients with certain chronic illnesses such as chronic liver disease, celiac disease, and IBD (12,16–18,27–29). In our study, the seroconversion rate of patients with IBD was found lower after primary vaccination series when compared with healthy children (70.2% vs 90%, respectively), which is compatible with the studies reporting reduced vaccine immunogenicity in patients with IBD. The overall seroconversion rates 1 month after a single booster dose were 85.1% in patients with IBD and 96% in controls.
In our patient group, no significant differences were observed between antibody response and variables such as age, sex, BMI, and IBD phenotype. The lower response rate to hepatitis B vaccination in patients with IBD under immunotherapy has been reported (16). In our study, no correlation was established between initial vaccine response and the treatment given. Also, no reduction in antibody response was observed during treatment among patients with IBD.
Hepatitis A vaccine has been reported to be efficacious in healthy individuals and also in children with cancer, chronic liver disease, and IBD (30–32). The completion of the 2-dose vaccine induces 100% seropositivity (33,34) and nonresponse is extremely rare (35). There are only a few studies on immune response to hepatitis A vaccination in children with IBD (14,15). Hundred percent response to hepatitis A vaccine was obtained in our patients with IBD, which was not different from healthy controls.
The exact pathogenesis of unresponsiveness to hepatitis B vaccine still remains unknown. The response to HBV vaccine is associated with immunogenetical condition because of multiple-candidate genes (36). Some specific human leucocyte antigen haplotypes such as B8, DR3, and DQ2 are considered to be the most important genetic markers for nonresponders (36,37). The higher response rate to hepatitis A vaccine than hepatitis B vaccine may be explained by the role of human leucocyte antigen genotypes in unresponsiveness to the HBV vaccine.
Although hepatitis A and B vaccines show a good safety profile, to the best of our knowledge there is no reported study about assessing the effect of vaccination on IBD onset or course in pediatric patients with IBD by using pediatric disease activity indexes. In our study, all of the patients were evaluated by PUCAI and PCDAI at baseline, 1 month after the last dose of primary vaccination and 1 month after the booster dose. The disease activity or medication use did not significantly increase after vaccinations.
It is not known exactly how long the immunity of the vaccines lasts after primary immunization and whether low titers of antibodies provide sufficient protection against HAV and HBV in patients with IBD. Hepatitis B titers among patients with IBD should be assessed after the completion of primary vaccinations, and if seroconversion was not achieved, a booster dose must be applied. There is presently no consensus on the optimal schedule for anti-HBs testing. Regular annual testing for anti-HBs and administration of a booster dose when the titers fall below 10 mIU/mL is advisable. In view of the high seroconversion rates, postvaccination testing for anti-HAV antibodies may not be needed.
In conclusion, besides highly immunogenic hepatitis A vaccine, we established the low immunologic response of hepatitis B vaccine in pediatric patients with IBD similarly as reported in the literature. Further studies with larger study groups and longer duration of follow-up are required to clarify, in addition to antibody persistence, whether hepatitis A and B vaccinations also induce immune memory that could maintain antibody production and confer lifelong immunity in children with IBD and whether boosters in those with low titers are needed.
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