Abstract
Despite the fact that the achievement of appropriate immunization coverage for routine vaccines is a priority for health authorities worldwide, vaccination delays or missed opportunities for immunization are common in children with chronic diseases. The main aim of this cross-sectional study was to evaluate immunization coverage and the timeliness of vaccination in children suffering from 3 different rare genetic diseases: Rubinstein-Taybi syndrome (RSTS), Sotos syndrome (SS), and Beckwith-Wiedemann syndrome (BWS). A total of 57 children with genetic diseases (15 with RSTS, 14 children with SS, and 28 with BWS) and 57 healthy controls with similar characteristics were enrolled. The coverage of all the recommended vaccines in children with genetic syndromes was significantly lower than that observed in healthy controls (p < 0.05 for all the comparisons). However, when vaccinated, all of the patients, independent of the genetic syndrome from which they suffer, were administered the primary series and the booster doses at a similar time to healthy controls. In comparison with parents of healthy controls, parents of children with genetic diseases were found to more frequently have negative attitudes toward vaccination (p < 0.05 for all the comparisons), mainly for fear of the emergence of adverse events or deterioration of the underlying disease. This study shows that vaccination coverage is poor in pediatric patients with RSTS, BWS, and SS and significantly lower than that observed in healthy children. These results highlight the need for educational programs specifically aimed at both parents and pediatricians to increase immunization coverage in children with these rare genetic diseases.
Introduction
Despite the fact that the achievement of appropriate immunization coverage for routine vaccines is a priority for health authorities worldwide, vaccination delays or missed opportunities for immunization are common in children with chronic diseases.Citation1-3 Falsely perceived contraindications, fear of reactivation of the underlying disease, and the different opinions of multiple specialists involved in the care of these children are the most common reasons that justify the refusal of vaccine administration by parents.Citation4 Urgent interventions are needed to address this problem. However, because adherence to the immunization schedule varies according to the underlying disease,Citation5 information on the existing coverage and delays for each chronic medical condition has to be collected before planning corrective methods to promote timely vaccination. Poor data are presently available regarding children with genetic disorders. Among them, only those with Down syndrome have been evaluated, showing relatively good coverage for both routine and recommended immunizations.Citation5 The main aim of this study was to evaluate immunization coverage and timeliness of vaccination in children suffering from different rare genetic diseases and the attitudes of their parents toward vaccination.
Materials and methods
This cross-sectional study, which was carried out between November 1, 2014, and April 30, 2015 and approved by the Ethics Committee of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (Milan, Italy), involved all of the children with Rubinstein-Taybi syndrome (RSTS), Sotos syndrome (SS), and Beckwith-Wiedemann syndrome (BWS) regularly followed up in the Pediatric Highly Intensive Care Unit of the University of Milan's Department of Pathophysiology and Transplantation. Written informed consent of a parent or legal guardian was required. The three considered genetic disorders are rare diseases with a prevalence of 1:125,000 for RSTS, 1:40,000 for SS, and 1:13,700 for BWS.Citation6-8 RSTS and SS are associated with psychomotor delay and intellectual disability, whereas psychomotor and intellectual development is normal in BWS. All three conditions are associated with an increased risk of cancer. RSTS is also characterized by postnatal growth retardation in height and weight, microcephaly, broad thumbs, big toes, and dysmorphic facial features;Citation6 SS presents with excessive physical growth during the first few years of life, macrocrania with a slightly protrusive forehead and pointed chin, large hands and feet, hypertelorism and down-slanting eyes;Citation7 BWS causes large body size, external ear abnormalities and low-set ears, large eyes and tongue, and mild microcephaly.Citation8 The diagnosis of each syndrome was based on clinical findings and genetic testing showing gene mutations specific to each of them.Citation6-8
As controls, a group of age- and sex-matched healthy children were enrolled. Healthy controls were randomly selected among those who attended the outpatient clinic of the same Department for minor surgical problems, who did not have any history of chronic underlying disease, and who lived in the same Regions of the patients. The vaccination status of both patients and controls was established by consulting the official vaccination chart, which was issued by the Vaccination Service of the regions in which the children lived. Data regarding diphtheria (D), tetanus (T), pertussis (P), polio (IPV), hepatitis B (HB), Haemophilus influenzae type b (Hib), pneumococcal conjugate (PC), meningococcus C (MC), and measles, mumps and rubella (MMR) vaccines were collected. All of the children were considered fully vaccinated when they had received the doses of each vaccine at the suggested time, according to the recommendations of the most recent edition of the National Immunization Plan.Citation9 Moreover, the parents were administered a questionnaire (which was created and revised after pilot testing) soliciting information regarding their opinion on vaccination and on who mainly influenced their decisions on vaccination. Specific questions about influenza vaccination, which is recommended by the National Immunization Plan for these genetic diseases,Citation9 were included.
Different genetic diseases were compared each with the others and then each of them was compared with healthy controls. A contingency table analysis using the chi-square test or Fisher's exact test, as appropriate, compared the differences between the groups. The ordered categorical data were compared using a Cochran-Armitage trend test. All tests were 2-tailed, and a p value <0.05 was considered statistically significant. The data were analyzed using SAS, version 9.2 software (SAS Institute, Cary, NC, USA).
Results
A total of 57 children with genetic disease and 57 healthy controls were enrolled. summarizes the demographic and socioeconomic characteristics of the enrolled population. Patients with genetic syndromes and healthy controls were similar for all the studied variables.
Table 1. Demographic and socioeconomic characteristics in children with rare genetic diseases and healthy controls.
shows the vaccination coverage for the studied vaccines and the timeliness of administration of each recommended dose in the enrolled population. Vaccination coverage of almost all of the recommended vaccines in children with genetic syndromes was significantly lower than that reported in healthy controls. Respectively, only 80.0%, 78.5%, and 71.4% of patients with RSTS, SS, and BWS, respectively, were found to be vaccinated with the hexavalent preparation containing D, T, P, IPV, HB, and Hib, and the booster with DTP-IPV was administered to 44.4%, 33.3%, and 33.3% of patients with RSTS, SS, and BWS, respectively. However, vaccination coverage of healthy controls was 91.2% with the hexavalent vaccine (p < 0.05 for all the comparisons) and 83.3% with the booster (p < 0.05 for all the comparisons). However, when vaccinated, all of the patients, independent of the genetic syndrome from which they suffered, were given the primary series and booster dose of the hexavalent preparation at a similar age to healthy controls. Similar results were demonstrated for PC, MC, and MMR vaccines. For PC vaccine, the coverage was 40.0%, 35.7%, and 46.4% in children with RSTS, SS, and BWS, respectively, and 75.4% in controls (p < 0.05 for all the comparisons), with no difference in timeliness of immunization between the groups. Coverage for MC was 42.5%, 42.8%, and 48.1% and that for MMR vaccine was 40.0%, 50.0% and 46.4% in patients with RSTS, SS, and BWS, respectively. In the controls, MC coverage was 75.4% and MMR coverage was 91.2% (p < 0.05 for all the comparisons). Also for MC and MMR vaccines, no significant differences in timeliness of immunization were observed between the different groups of subjects with genetic disorders and the controls. Influenza vaccination coverage was poor in all the studied children (40.0% in RSTS; 50% in SS; 14.3% in BWS; 30.0% in healthy subjects). Coverage in patients with BWS was lower than that observed in RSTS and SS (p < 0.05 vs children with other genetic diseases).
Table 2. Vaccination coverage and timeliness of vaccine administration in children with rare genetic diseases and healthy controls.
shows the attitudes of the parents of the studied children toward vaccination. In comparison with parents of healthy controls, parents of children with genetic diseases were found to more frequently have negative attitudes toward vaccination (p < 0.05 for all of the comparisons), mainly for fear of the emergence of adverse events or deterioration of the underlying disease. Parents of healthy children were compliant with official immunization recommendations in most of the cases because they were convinced by the primary care pediatrician (87.7%). This is in contrast with the majority of the parents of children with genetic disease who, independent of the type of underlying disease, vaccinated their child only because immunization was, at least for some vaccines, mandatory by law (46.7%, 57.1% and 32.1% for RSTS, SS, and BWS, respectively). Moreover, in healthy children, the primary care pediatrician had a major role in suggesting compliance with the immunization schedule (91.2%). However, for children with genetic diseases, a significant importance in supporting official recommendations was stressed by the pediatricians of the hospital where the patients were regularly followed-up. In patients with RSTS, SS, and BWS, pediatricians of the hospital centers recommended vaccine administration in 53.3%, 28.6%, and 25.0% of cases, respectively, whereas in no case did this occur among control patients (p < 0.05 for all the comparisons).
Table 3. Attitudes toward vaccines of parents of children with rare genetic diseases and healthy controls.
Finally, most of the parents were against influenza vaccination for their children (80.0% in RSTS syndrome; 71.4% in SS; 92.9% in BWS; 64.9% in healthy subjects), even when their children had an underlying disease for which influenza vaccination is recommended by health authorities. The main reasons for being against influenza vaccination were the belief that the child could not be considered at risk of severe influenza-related complications and the fear of adverse events.
Discussion
This study shows that vaccination coverage is poor in pediatric patients with RSTS, SS, and BWS and significantly lower than that observed in healthy children. This is surprising because RSTS, SS, and BWS are rare genetic diseases associated with malformations favoring infection and infection-related complications that could be prevented by vaccine administration.Citation6-8 However, although the possibility of humoral immune dysfunction has been described in RSTS and all these conditions are associated with an increased risk of cancer development,Citation6-8 immune functions in these syndromes seem adequate to permit the administration of routine vaccines without any significant risk to the patientsCitation10-11 and with the advantages associated with vaccines that are highly efficacious against the diseases that they attempt to prevent.Citation9
Fortunately, in children who had received the vaccines, the timeliness of administration was adequate and not substantially different from that suggested in the vaccination schedule.Citation9 This favorable finding is in contrast to reports by Pandolfi et al., who analyzed immunization coverage and timeliness of vaccination in a group of Italian children with underlying diseases living in another region (Lazio) and found that delays in vaccine administration were very common, mainly because of a concurrent disease at the time suggested for vaccine administration.Citation5 The presence of a greater number of patients at higher risk of infection, such as those with advanced HIV, among the children enrolled in the study conducted by Pandolfi et al.Citation5 could explain the different results.
Immunization hesitancy is a recognized phenomenon in children with underlying diseases,Citation1-3 independent of the disease characteristics. Previous studies have indicated that different problems lie outside of the limited coverage of many vaccines.Citation4 Barriers to vaccination may be related to the limitations of the health system, to provider knowledge of vaccine indications and contraindications and to parental negative attitudes toward vaccines, mainly for fear of adverse events.Citation4 In this study, both parental and provider's problems seem to reduce compliance because parents indicate fear of adverse events and the risk of deterioration of the underlying disease as the main causes leading to vaccine refusal. However, among those who have received the vaccines, a non-marginal portion followed their pediatrician's recommendations. The recommendations followed were given by the hospital pediatricians who followed up the children for the underlying disease in the case of patients with genetic disorder and by the primary care pediatricians in healthy children. These findings suggest that vaccination coverage is strictly dependent on the suggestions of the pediatrician who has the patient in their charge, and the lack of adequate sources of information does not permit the removal of misinformation that reduces parental acceptance of vaccines. Providers can explain all of the benefits and real risks of vaccines, acknowledging parental concerns and respectfully trying to correct any misconceptions. The importance of providers that regularly follow-up children for a specific clinical condition in favoring compliance with vaccine recommendations has been documented in studies involving children with different diseasesCitation13-15 and also seems evident in children with genetic disorders.
In conclusion, although the study population was quite small due to the rarity of the studied genetic diseases and the findings in terms of both coverage and potential delays may not be generalized to other genetic diseases or other populations, the results presented in this study highlight the need for educational programs specifically aimed at both parents and pediatricians to increase immunization coverage in children with RSTS, SS and BWS.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Funding
This study was supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009).
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