Abstract
Background: The remarkable effectiveness of universal infantile hepatitis B (HB) vaccination is well documented in many countries. Nevertheless, the influence of insulin-dependent diabetes mellitus (IDDM) on the sero-protective level of antibody to hepatitis B surface antigen (anti-HBs) after HB vaccination has not been investigated in Egyptian children. The aim of this study was to investigate long-term anti-HBs sero-protective levels after infantile HB vaccination in Egyptian IDDM children.
Results: The mean age of the healthy children was 10.86 ± 1.21 y (range, 5.5–15 y); 49 (45.8%) were boys and 58 (54.2%) were girls. The mean age of the IDDM children was 10.29 ± 3.04 y (range, 4–17 y); 32 (50.8%) were boys and 31 (49.2%) were girls. There were no significant differences between the healthy and IDDM children with respect to age and sex (p > 0.05). Among the 107 healthy children, 43 (40%) did not have a protective anti-HBs level (anti-HBs < 10 IU/L) and 64 (60%) had a protective level (anti-HBs ≥ 10 IU/L). In contrast, among the IDDM children, 44 (69.8%) and 19 (30.2%) did not and did have protective anti-HBs levels, respectively. This difference in anti-HBs concentration between healthy and diabetic children was highly significant (p < 0.001). None of the vaccinated healthy or IDDM children was reactive to HBsAg or total anti-HBc.
Patients and Methods: A total of 170 children (81 boys, 89 girls) who had been routinely vaccinated against HB were included. Their mean age was 10 ± 2.1 y. The enrolled children were divided into healthy (n = 107) and IDDM (n = 63) cohorts. Body Mass Index and levels of hepatitis B surface antigen (HBsAg), total antibody to hepatitis B core antigen (anti-HBc), and anti-HBs were evaluated in all children. In addition, the duration of diabetes mellitus (DM) and levels of glycated hemoglobin (HbA1c) were measured in IDDM children.
Conclusion: Our results are alarming. It appears that the majority of Egyptian diabetic children vaccinated against HB may not have sufficient anti-HBs levels to protect them from HB. Moreover, this study emphasizes the need for a population-based strategy for the management of patients without an anti-HBs protective level after HB vaccination and justifies the need to elucidate the heritability of those children.
Introduction
Hepatitis B virus (HBV) infection is a global issue affecting 2 billion people in the world, with 360 million chronic carriers of hepatitis B surface antigen (HBsAg).Citation1 The prevalence of HBV is estimated to be 6.7% among the general population in Egypt.Citation2 Although it has been widely accepted that genotype D is the most prevalent among Egyptians, genotype C was recently detected among the majority of HBV-infected patients in the Ismailia governorate.Citation3
Diabetes is a marker for increased risk of HBV transmission through exposure to contaminated blood during diabetes care and monitoring. One study found that adults between 23 and 59 y of age with diabetes who lacked traditional risk factors for HBV infection had twice the odds of acquiring acute hepatitis B (HB) compared with adults without diabetes.Citation4 As well, children with insulin-dependent diabetes mellitus (IDDM) are at an increased risk of HBV infection.Citation5
The remarkable effectiveness of universal infantile HB vaccination is well documented in many countries.Citation6-Citation9 A significant reduction of HBV seroprevalence was recently reported in Egypt.Citation10 The frequency of HBV infection as a cause of symptomatic HB decreased from 43.4% in 1983 to 28.5% in 2002 and was largely attributed to the universal HB vaccination program.Citation11
Persons with IDDM have a compromised immune system, and their immunological response to the HB vaccine is less optimal than that of normal subjects.Citation12 This is probably a result of genetic factors, as genes present in the major histocompatibility complex play a central role in the modulation of the immune response to HBsAg.Citation13,Citation14
Recently, failures of HB vaccinations in children with IDDM were reported.Citation14 In spite of this, the influence of IDDM on the antibody to hepatitis B surface antigen (anti-HBs) sero-protective rate after HB vaccination has not yet been investigated in Egyptian children. The aim of this study, therefore, was to investigate the long-term anti-HBs sero-protective rate after infantile HB vaccination of Egyptian IDDM children.
Results
Demographic Data
Among the 170 patients included, the healthy group included 107 children with a mean age of 10.86 ± 1.21 y (range, 5.5–15 y). Forty-nine (45.8%) were boys and 58 (54.2%) were girls. The IDDM group included 63 children with IDDM with a mean age of 10.29 ± 3.04 y (range, 4–17 y). Thirty-two (50.8%) were boys and 31 (49.2%) were girls.
There were no significant differences between the healthy and the diabetic children with respect to age and sex (p > 0.05) (). The mean BMI of the diabetic children was significantly higher than the mean BMI of healthy children (p < 0.001) ().
Table 1. Clinical and laboratory characteristics of the studied children
The mean duration of IDDM in the diabetic children was 1.73 ± 1.96 y (range, 0.1–9 y). The mean HbA1c level was 6.78 ± 1.37.
Anti-HBs Levels
According to the quantification of the anti-HBs titer tests, 43 (40%) healthy children showed a non-protective anti-HBs response (anti-HBs < 10 IU/L) and 64 (60%) displayed a protective anti-HBs response (anti-HBs ≥ 10 IU/L). Among the 63 IDDM children, 44 (69.8%) showed a non-protective anti-HBs response (anti-HBs < 10 IU/L) and 19 (30.2%) had a protective anti-HBs response (anti-HBs > 10 IU/L). This difference in anti-HBs response between healthy and IDDM children was highly significant (p < 0.001) ().
Predictors of Anti-HBs Levels
Although 30% of vaccinated healthy children aged ≤ 10 y had non-protective levels of anti-HBs, 41.2% of those aged > 10 y showed non-protective anti-HBs levels. This difference was highly significant (p < 0.001) (). No significant correlation was found between anti-HBs levels and sex or BMI in healthy children (p > 0.05).
Table 2. Predictors of non-protective anti-HBs levels after hepatitis B vaccination in insulin dependent diabetes mellitus
When IDDM children with non-protective anti-HBs levels were compared with those with a protective anti-HBs response, no significant differences were found regarding age, sex, BMI, duration of IDDM, or HbA1c (p > 0.05) ().
HBV Diagnostic Seromarkers
None of the healthy or IDDM children showed evidence of the presence of HBsAg or anti-HBc.
Discussion
Children with IDDM are at an increased risk of HBV infection.Citation5 The HB vaccine is therefore recommended, at least in countries in which HBV is endemic, such as Egypt. Diabetic patients have a compromised immune system, and their immunological response to the HB vaccine is therefore frequently less optimal than that of non-diabetic individualsCitation12; nevertheless, the influence of this metabolic disease on the sero-protection rate after HB vaccination has not yet been investigated in Egyptian children.
In the current study, we showed that the long-term seroprotection rate after HB vaccination was significantly reduced in IDDM children. A meta-analysis of current literature addressing the role of DM in determining responses to the HB vaccine found a weaker response among diabetic patients.Citation15 Furthermore, it was recently reportedCitation16 that diabetic children display significantly decreased levels of anti-HBs (58.2%) in comparison to healthy control children (84%).
The poor immune response of IDDM patients to HB vaccination may be linked to defects in antigen uptake, processing, and presentation, as well as suppression of B-cell production of the anti-HBs. Human leukocyte antigen (HLA) is critical for control of the immune response. More than 90% of diabetic patients express one or both of the DR3/DQ2 and DR4/DQ8 haplotypes; this HLA profile could explain the unresponsiveness to the HB vaccine by diabetic patients.Citation17 Douvin et al. highlighted the relationship between HLA-DQ2 and a poor response to HB vaccine in IDDM patients.Citation18 This hypothesis was recently confirmed in a small cohort of patients.Citation16
It is not clear whether diabetic patients have a failure of induction of the antibody response needed for development of long-term immunity linked to metabolic control and duration of DM. Indeed, we could not find any significant relationship between metabolic control or duration of diabetes and a non-protective anti-HBs immune response. Schillie et al. reviewed the literature for a possible association between an impaired anti-HBs response and duration of DM as well as glycemic control; however, no association was demonstrated in the four studies included in the review.Citation19
In contrast with our results, other studies have reported a good response to the HB vaccine.Citation20,Citation21 Halota et al. suggested that patients with diabetes reacted to HB vaccination similarly to healthy subjects.Citation22 These contradictory results may be explained by differences in study designs, as well as ethnic and genetic variations in the studied populations.
Several studies have shown that the protective effects of HB vaccination can last for at least 10 y.Citation23-Citation27 Around 60% of healthy children displayed protective (> 10 IU/L) levels of anti-HBs in our study. The long-term immunity to HB following vaccination of healthy children has been assessed in different Egyptian studies. One study found that, 5 y after a full course of vaccination, 67% of Egyptian children maintained anti-HBs protective levels.Citation28 While one study found a protective rate of 39.4% among vaccinated Egyptian children aged 6 to 12 y,Citation29 another found it was 37.9% among vaccinated children aged 10 y.Citation30 Recently Abushady et al. reported that 65% of children aged 2 to 4 y and 20.5% of children aged 4 to 13 y had responded well to HB vaccination and showed protective anti-HBs levels.Citation31 Taken together, these results indicate a decrease in anti-HBs levels over time among Egyptian children and emphasize the need for further anti-HBs assessment among older Egyptian adolescents.
A significant reduction of HBV seroprevalence in Egypt was recently reported.Citation10 The frequency of acute HBV infection as a cause of symptomatic HB decreased from 43.4% in 1983 to 28.5% in 2002; this was largely attributed to the universal HB vaccination program.Citation11 The rate of HBsAg has been reported to range from 0% to 2% among vaccinated Egyptian children.Citation28-Citation31 In 2000 the frequency of HBV infection was profoundly reduced (0%) among Egyptian children < 9 y, compared with the rate (6.8%)Citation11 reported for a similar age group in 1983. Additionally, despite the low protective rate following HB vaccination in both healthy (60%) and diabetic children (31.2%), the frequency of HBV seromarkers was zero in our study population. There are no available data regarding the frequency of HBV seromarkers among vaccinated Egyptian children with IDDM; however, Salvatore et al. reported that HBsAg and anti-HBc were not detected among vaccinated children with IDDM.Citation16 Our data as well as those of Salvatore et al. hint that the immunological memory seems to persist after the vaccination of IDDM children, even in the absence of anti-HBs.
To date, there have been no protocols or guidelines for the management of non-responders to the HB vaccine. Intradermal administration of the vaccine could be an alternative strategy; patients with celiac disease showed a non-response to conventional intramuscular vaccination but not intradermal administration,Citation32 and the celiac non-responders display the same profile as those with DM. Also, administration of additional doses of HB vaccine improves the proportion of responders. Additional doses have not caused unusual adverse reactionsCitation33 and constitute an option for the management of non-responders. Another strategy that may improve the response of diabetic children to HB vaccine include modification of the vaccine schedule; for example, a longer interval between the final two doses was found to be associated with higher final anti-HBs levels.Citation34
The anti-HBs response to HB vaccine is usually tested within 2 to 6 mo after the last dose. Lower antibody levels assayed at later intervals may be a result of an absence of initial response or waning of antibody concentration after the initial satisfactory response. In our study, we evaluated the sero-protection rate at various intervals after vaccination. The lag time between the final vaccine doses and anti-HBs testing does not lend itself to simple interpretation about vaccination responsiveness and could represent an important limitation of our study.
Our results are alarming in that, in the current population, the majority of IDDM Egyptian children vaccinated against HB with a mean age around 10 y showed non-protective anti-HBs levels. Especially since adolescents with diabetes have several risk factors for HBV infection, including self-monitoring of blood glucose, intravenous and subcutaneous insulin injection, and repeated hospitalizations, additional studies are required in older adolescents with long-standing diabetes to establish the degree of loss of vaccine efficacy and identify the need for an ideal timing of booster doses. In addition, our results emphasize the need for a population-based strategy for management of patients without protective levels of anti-HBs after HB vaccination. Finally, further studies are needed to elucidate the heritability of Egyptian children with IDDM without anti-HBs protective levels.
Patients and Methods
Setting
This study was conducted at Al-Azhar University Hospital, Cairo, Egypt, from September 2012 to April 2013. All procedures were performed in accordance with the ethical standards of the Al-Azhar University committee on human experiments. Informed consent was obtained from all children’s parents.
Studied Children
A total of 170 children who had been routinely vaccinated against HB were included in the study. Their ages ranged from 4 to 17 y (mean, 10.6 ± 2.1 y); 81 were boys, and 89 were girls. All children were related to two different geographic regions in Egypt: the Cairo governorate (n = 70) and the Kafr Elsheikh governorate (n = 100). The children enrolled in the study were divided into healthy (n = 107) and IDDM (n = 63) cohorts.
Diabetic children were recruited consecutively as they were hospitalized or as they were followed up at an outpatient clinic. IDDM was diagnosed on the basis of hyperglycemia and absolute insulin dependence. All diabetic patients were receiving human insulin through two, three, or four injections daily. All patients were compliant with insulin therapy. Any diabetic patients with associated comorbidities or who were receiving immunosuppressive drugs were excluded from participation.
Vaccination Program
The universal HB vaccination program was initiated in Egypt in 1992. Three doses of recombinant vaccine had been administered to all participating children (n = 170) at 2, 4, and 6 mo of age, between 1996 and 2009, according to the vaccine schedule of the Egyptian Ministry of Health and Population. All included children had completed their HB vaccination schedule at least 3 y before the study began. All diabetic patients had been vaccinated before the onset of diabetes. Vaccination histories were obtained from the parents.
Methods
Body Mass Index (BMI) and serum levels of antibody to hepatitis B surface antigen (anti-HBs), HBsAg, and antibody to hepatitis B core antigen (anti-HBc) were measured in all children (n = 170). In addition, the duration of IDDM and glycated hemoglobin (HbA1c) levels were evaluated in all diabetic children (n = 63).
Blood samples
Five milliliters of venous peripheral blood were obtained from all children. Blood samples were centrifuged and then serum samples immediately stored at –21°C. To perform HbA1c testing, 1.5 mL of whole blood was further collected from the IDDM children into tubes with EDTA.
Serology tests
HBsAg (Murex Biotech Limited, 9F80–01/05), total anti-HBc (DiaSorin, N0137), and anti-HBs (DiaSorin, P001603) were measured by enzyme immunoassay, according to the manufacturers’ instructions. Anti-HBs titers were classified as undetectable (0), < 10 IU/L, 10–100 IU/L, or > 100 IU/L. An anti-HBs titer < 10 IU/L was considered a non-protective level (i.e., it provided insufficient protection against HBV), while an anti-HBs titer ≥ 10 IU/L indicated a protective level.
Statistical Analysis of Data
Differences in frequency between groups were compared with the chi-square test or the Fisher exact test. A P value < 0.05 was considered significant.
| Abbreviations: | ||
| HB | = | hepatitis B |
| IDDM | = | insulin-dependent diabetes mellitus |
| Anti-HBs | = | antibody to Hepatitis B surface antigen |
| HBsAg | = | Hepatitis B surface antigen |
| Anti-HBc | = | antibody to Hepatitis B core antigen |
| DM | = | diabetes mellitus |
| HbA1c | = | glycated hemoglobin |
| HBV | = | Hepatitis B virus |
| HLA | = | human leukocyte antigen |
| BMI | = | body mass index |
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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