Special Immunization Service: A 14-year experience in Italy
Special Immunization Service: A 14-year experience in Italy
Daniele Donà 0 1
Susanna Masiero 1
Sara Brisotto 1
Lorena Gottardello 1
Rebecca Lundin 1
Eleonora Borgia 1
Federica Visentin 1
Liviana Da Dalt 1
0 Division of Pediatric Infectious Diseases, Department for Woman and Child Health, University of Padua , Padua , Italy , 2 Pediatric Emergency Unit, Department for Woman and Child Health, University of Padua , Padua , Italy , 3 Department of Hygiene and Public Health, University of Padua , Padua, Italy, 4 PENTA Foundation, Padua , Italy
1 Editor: Francesco Pappalardo, Universita degli Studi di Catania , ITALY
Concerns regarding vaccine safety are increasing along with lack of compliance to vaccination schedules. This study aimed to assess vaccination-related risks and the impact of a Special Immunization Service (SIS) at the Pediatric Emergency Department (PED) of Padua on vaccination compliance among participants.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Materials and methods
This retrospective cohort study included all children attending the SIS from January 1st 2002
to December 31st 2015. The Service is divided into a clinic (SIS-C) where all referred
children undergo a pre-vaccination visit and an area within the Pediatric Emergency
Department (SIS-PED) where children are vaccinated if indicated. During each SIS-C visit, age,
gender, admission criteria and scheduled vaccinations were recorded, with any
vaccinerelated adverse events captured during SIS-PED visits. Follow-up was conducted to
evaluate vaccination plan completion.
359 children received 560 vaccine administrations (41.3% MMR/MMRV, 17.5% hexavalent)
at the SIS during the 14 year study. Admission criteria were adverse events after previous
vaccination (immediate, IgE/not IgE mediated, and late) in 27.2% of cases,
non-anaphylactic allergies (mostly egg allergy) in 42.7% and anaphylaxis in 10.3%. After vaccination, 15/
560 (2.7%) mild adverse events were observed. 96.3% of children vaccinated at least once
at the SIS-PED and available for follow-up completed their vaccination plan, in contrast to
55.5% of children referred to the SIS-C who were not vaccinated in SIS-PED.
For children referred to SIS-C and available for follow-up, vaccination in SIS-PED was
associated with more frequent completion of vaccination plans, indicating a benefit of the service
to vaccine coverage. The low number and mild severity of adverse events reported after
vaccination of high-risk children in SIS-PED attest to the safety of the service
Vaccine administration is one of the greatest achievements of biomedical science and public
health, and among the most effective medical procedures, preventing two to three million
deaths every year [
]. It also provides indirect protection or `herd immunity' to those who
cannot be vaccinated due to age or specific diseases or treatments [
The safety of vaccines in the pediatric population is of the utmost importance for parents
and healthcare workers, especially in countries in which vaccine-preventable diseases are rare
]. As with any medical procedure, some risks are involved; minor reactions are common,
while serious reactions are rare [
], with anaphylaxis occurring in one in a million vaccine
Some children are at higher risk of vaccine-related adverse events (AEs) due to reactions to
previous vaccinations, egg allergies, or anaphylaxis [
With vaccination increasingly questioned by concerned parents and compliance to
vaccination schedules falling [7±10], a Special Immunization Service (SIS) was established in 2002 at
the Pediatric Emergency Department (PED) in Padua to monitor and address immunization
SIS in other settings have played a central role in improving adherence to regional
vaccination plans and increasing immunization coverage [11±13].
The primary aim of this study is to describe SIS referrals and visits in Padua and AEs
observed after vaccinations over a 14-year period.
The secondary aim is to assess vaccination plan compliance after SIS attendance.
This is a retrospective cohort study including all referrals and visits to the Padua SIS from
January 1st 2002 to December 31st 2015.
The SIS, established on January 1st 2002 in the PED of Padua University Hospital, is divided
into a SIS-Clinic (SIS-C) in which a pre-vaccination evaluation takes place and an area within
the PED (SIS-PED) where vaccinations are administered when indicated.
Children are referred to our Service by primary care pediatricians or local Health Districts
of Padua if considered at high risk for vaccine-related AEs or for non-adherence to vaccination
schedules due to parental reluctance (Fig 1 section 1).
At the SIS-C, each child is seen by a pediatrician with sub-specialty training in
immunization techniques who determines, according to clinical history or diagnostic tests performed
(RAST, Prick test, Prick by Prick), whether to suspend the vaccination plan or to proceed.
Patients advised to continue their vaccination schedule may be vaccinated in the SIS-PED or
their local Health Districts according to their risk of AEs. Decisions are made following the
most recent Guidelines of the Italian Higher Institute of Health [
] and National Guidelines
for the immunization in a SIS [
], and taking into consideration parents' concerns (Fig 1
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Fig 1. Special Immunization service organization in Padua. population for primary aim of this study. Êpopulation
for secondary aim of this study.
In the SIS-PED, each child is evaluated by a pediatrician to exclude acute illness and
preparations are made to respond to possible AEs prior to vaccination. Afterwards, children remain
in the SIS-PED for a three-hour observation period, which can be extended as deemed
necessary by the attending pediatrician.
Following SIS-PED vaccination, each child is advised to complete their vaccination plan at
the SIS-PED or local Health District, or to suspend their vaccination plan on the basis of any
AE and accounting for parental preference (Fig 1 section 3).
Data were collected retrospectively and entered into an Excel database.
A unique survey code was assigned to each patient and all data were anonymized to
guarantee data privacy.
This study was approved by the Institutional Review Board of the Department for Woman
and Child Health at the University of Padua.
Primary aim. For all children vaccinated in SIS-PED the following data were collected:
- Motivation for referral to SIS-C, including:
· allergies: both anaphylactic and non-anaphylactic reactions (egg, dairy, drug, multiple
· AEs after previous vaccinations: immediate or delayed reactions and IgE mediated or not;
· other reasons: parents who chose not to vaccinate their children (until vaccination
became mandatory in 2007), chronic conditions such as hemophilia, cutaneous
mastocytosis, thrombocytopenia, epilepsy and rare genetic syndromes.
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- Type of vaccine(s) administered
- AEs occurring during post-vaccination observation period or reported by parents via
telephone after leaving SIS-PED.
Secondary aim. SIS-PED admissions and total vaccinations in the Padua urban area were
compared using the ULSS 6 EUGANEA Prevention Department database, where all
administered vaccinations in the metropolitan area are registered. This database was also used to
follow up all children visiting SIS-C regardless of whether they were subsequently seen in
Compliance was categorized as vaccination plan completed at the SIS, vaccination plan
completed at the Health District or vaccination plan not completed.
Vaccination plan completion was defined as the accumulation of the required number of
doses of all required immunizations by the specified age regardless of the timing of
administration. Current Italian vaccination schedule at time of follow-up was used to determine required
vaccines, doses and timelines (Table 1).
Influenza, rotavirus and Hepatitis A vaccination (HAV) vaccines were excluded in
assessment of vaccination completion as they are not actively offered and are not free of charge.
A descriptive analysis was performed to assess number of vaccines administered in SIS-PED
and overall in the Padua region, motivations for SIS-PED admission, vaccine type and any
associated acute adverse events. Time trends for the most requested vaccinations and related
reasons for referral were also assessed. Results are summarized using frequencies and
percentages for qualitative variables and median and standard deviation for continuous variables.
Comparisons of categorical variables over time or based on SIS-PED admission was carried
out using the chi-square test.
Vaccinations not actively offered and not free of charge
2 doses if not immunized before
2 doses from 1 year of age
Three-hundred and fifty-nine children attended the SIS-PED and 560 vaccine doses were
administered between 2002 and 2015. Comparing the number of vaccines administered at the
SIS-PED with those administered in the Padua Health District, SIS-PED vaccination was only
a small percentage of overall vaccination in the region (560/2,127,785 (0.03%)).
Allergies accounted for 53.0% (297/560) of SIS-PED admissions, 58/297 (19.5%) anaphylactic
reaction and 239/297 (80.5%) non-anaphylactic. 186/560 (33.2%) SIS-PED admissions and
166/239 (69.5%) of non-anaphylactic allergy related admissions were for egg allergy, 31/560
(5.5%) were related to dairy allergy, 11/560 (2.0%) to drug allergies, and 59/560 (10.5%) to
multiple allergies (Fig 2).
AEs after previous vaccinations accounted for 27.2% (152/560) of SIS-PED admissions. 58/
152 (38.2%) of these were immediate IgE mediated reactions, including important local
reactions (7/58, 12.1%), urticarial rash or other spread cutaneous reactions (37/58, 63.8%), and
bronchospasm (7/58, 12.1%); 16/152 (10.5%) were immediate non-IgE mediated reactions
such as vasovagal reactions (3/20, 15%) and hypotonic hypo-responsive episodes (13/20,
65.0%). 78/152 (51.3%) reactions occurred more than two hours after vaccination, most
commonly cutaneous reactions (37/74, 50.0%), irritability and/or drowsiness and hypotonia (16/
74, 21.6%), and febrile seizures (19/74, 25.6%).
Other reasons for referral accounted for 19.8% (111/560) of SIS-PED admissions. Included
in this group were parents who did not wish to vaccinate their children, and children with
particular diseases such as neuromuscular disorders, cutaneous mastocytosis, thrombocytopenia,
epilepsy, and rare genetic syndromes.
Fig 2. SIS-PED admissions for allergies.
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Fig 3. SIS-PED admission criteria for administration of MMR/MMRV vaccines.
From 2009, egg allergy was no longer considered an indication for referral to the SIS for
MMR/MMRV vaccination [
]. Accordingly, 70.0% (30/43) of SIS referrals were for
egg allergy in 2004, with only 20.0% (3/16) in 2015 (55.6% for period before 2008 vs 27.0%
for period after 2008, p<0.001). Over time the proportion of SIS referrals for anaphylactic
allergies remained stable (10.3% before 2008 vs. 11.8% after 2008, p = 0.7) and for AEs
increased (Fig 3).
The most requested vaccination in the SIS-PED was MMR/MMRV (231/560, 41.3%), followed
by hexavalent vaccine (98/560, 17.5%). Other vaccinations were requested at a significantly
lower rate (Fig 4).
No serious vaccine-related AEs were observed over 14-years, with 15 mild vaccine-related AEs
The vaccinations related to these mild AEs were MMR/MMRV (8/15, 53.3%), hexavalent
(3/15, 20.0%), influenza (3/15, 20.0%) and HPV (1/15, 6.7%).
Eight children experiencing mild adverse events after SIS-PED vaccination (8/15, 53.3%)
had been referred to the SIS for a previous vaccine-related AE, with six (6/15, 40.0%) referred
for allergies. No vaccine-related AEs were recorded among children referred to SIS for parental
concerns regarding vaccination.
Immunization coverage among referrals
All 417 children who attended a pre-vaccination visit at SIS-C were followed up for vaccine
schedule adherence, whether they had been admitted for immunization at the SIS-PED or not.
Fifty-eight children (58/417, 13.9%) attending SIS-C were not referred to SIS-PED: 13/417
(3.1%) following recommendation of SIS-C pediatrician to suspend the vaccine plan (11/13
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Fig 4. Types of vaccines administered at Padua SIS-PED, 2002±2015.
because of a neurologic disease under investigation and 2/13 for previous severe IgE mediated
reactions) and 45/417 (10.8%) following recommendation of SIS-C pediatrician to continue
vaccination plan with the Health District due to lack of identified risk for vaccine-related AEs.
In this case, 25/45 (55.5%) completed their immunization schedules and 20/45 (44.5%) did
Among patients vaccinated at SIS-PED, 65/359 (18.1%) continued the vaccination schedule
at the Service and 294/359 (81.9%) received only one vaccination at the SIS-PED.
Two-hundred eighty-three children (283/294, 96.3%) receiving a single vaccination at
SIS-PED completed their vaccination plan at the Local Health District, while 11/294 (3.7%)
interrupted the vaccinations for various reasons, including parental refusal. This percentage of
completed vaccination plans is significantly higher than the 55.6% (25/45) observed among
children receiving a SIS-C recommendation to continue their plan at the Local Health Districts
without receiving a single vaccination in SIS-PED (p<0.001) (Fig 5).
Concerns related to the safety of vaccines are increasing, and communication about relative
risks and benefits is needed when advising parents on childhood vaccinations. Parents of
children who experienced an AE after a previous vaccination, or who have a serious history of
anaphylaxis may have particular difficulty in making the decision to complete their child's
vaccination plan. There is a paucity of information about the risk of subsequent vaccine-related
AEs, and not all risk factors are completely understood. A SIS may help to address the need for
more information, as indicated by increasing participation during the first three years of our
service in Padua, Italy.
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Fig 5. Follow-up of vaccination plan of referrals to Padua SIS-PED, 2002±2015.
One important consideration is the feasibility of extending SIS services to a broader segment
of the population. From 2002 to 2014, 0.05% to 0.01% of vaccinations in the Padua Health
Districts and SIS combined were administered at SIS-PED due to strict admission criteria.
Although utilization of the SIS in Padua remained fairly constant during our study, reasons
for referrals to the service varied. Admissions for non-anaphylactic allergies decreased (from
54.5% before 2008 to 31.3% after 2010), likely due to changes in recommendations for children
with egg allergies, while admissions for anaphylaxis remained stable around 10%. Referrals for
a past history of AE following a previous immunization increased over time, reaching 62.5% in
We observed very few cases (86/560, 15.4%) of appropriate reason for referral to the SIS,
such as an immediate reaction to a previous dose of the same vaccine (presumably
IgE-mediated, non-anaphylactic) and a past medical history of anaphylaxis, but not related to any
component of the vaccine [
In our study, 38.8% of admissions with a past history of AE had an immediate IgE mediated
reaction, while 10.5% were referred after immediate non-IgE mediated event, such as
vasovagal reactions or hypotonic hyporesponsive episodes, and the remaining 51.3% after a delayed
reaction, which may be of immunological and non-immunological type [
]. In contrast, only
a small number of children were admitted for anaphylaxis. It is a rare event, as reported in a
study involving North American children and teenagers where the incidence of anaphylactic
reaction was 0.75 cases /1000 person years [
Only a few mild AEs after vaccination in SIS-PED were observed in our 14-year experience,
confirming the high safety profile of vaccines and the low risk for complications.
We observed a small number of children (2.7%) who experienced minor reactions to the
vaccine administration. All were local or systemic reactions and quickly resolved, and all
occurred among children referred to SIS for an appropriate reason. These types of
vaccinerelated AEs are well described in the immunization literature, with a reported incidence
around 10% for local reactions and around 5±15% for systemic ones. In addition, the incidence
of AEs after revaccination at our SIS-PED was similar to that reported in other studies [
The Padua SIS-PED may prove useful in assessing and ensuring post-marketing vaccine safety
among vaccination subsequent to a vaccine-related AE.
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The difference in the proportion of children who completed their vaccination plan at the
Health District after just a single vaccination at the SIS-PED (96.3%) and those who completed
the plan at the Health District after a SIS-C visit not followed by a SIS-PED admission (55.5%)
indicates a potential role of the SIS in promoting the immunization. The SIS addressed
understanding the needs of vaccine hesitant parents and improving communication skills and
interaction between parents and health care workers. Useful strategies from our SIS included
solicitation of questions about vaccines, establishment of a trusting relationship, and provision
of appropriate educational materials to parents [
The SIS became more important after Regional Decree n.7 of March 23rd 2007 suspended
mandatory vaccinations in the Veneto Region from 2008 onwards [
More and more frequently parents feel hesitant to vaccinate their children because of
conflicting information from media, internet and other sources and were constantly influenced by
their social group and anti-vaccination movements [
]. Subsequent increases in
vaccination refusal may have played a role in a recent measles outbreak in our country .
In response Italy's parliament has given final approval to a new program making
vaccinations compulsory for school children up to age 16 [
]. For this reason, especially in the
immediate future, a continuous updating of the medical staff involved in administering
immunizations would be useful to provide appropriate information to families, in order to increase
population awareness about this key topic of public health.
The high percentage of vaccination plans completed among children receiving at least one
immunization at the Padua SIS over 14 years suggests a positive influence of the service on
intention to vaccinate among concerned parents. A very small number of mild vaccine-related
AEs were observed, with no moderate or severe vaccine-related AEs, and all children with an
appropriate reason for SIS referral were successfully vaccinated. Specialized immunization
services show potential for improving vaccination compliance, increasing immunization coverage
and ensuring safe vaccination in high-risk children.
S1 File. Database.
Conceptualization: Daniele Donà, Susanna Masiero, Eleonora Borgia, Federica Visentin,
Liviana Da Dalt.
Data curation: Daniele Donà, Susanna Masiero, Sara Brisotto, Lorena Gottardello, Rebecca
Lundin, Eleonora Borgia, Federica Visentin.
Formal analysis: Daniele Donà, Sara Brisotto, Lorena Gottardello, Rebecca Lundin.
Methodology: Daniele Donà.
Project administration: Daniele Donà, Susanna Masiero, Liviana Da Dalt.
Resources: Daniele Donà, Sara Brisotto.
Software: Daniele Donà. Supervision: Daniele Donà, Susanna Masiero, Liviana Da Dalt.
9 / 11
Validation: Daniele Donà, Susanna Masiero, Eleonora Borgia, Federica Visentin, Liviana Da
Visualization: Daniele Donà, Susanna Masiero, Sara Brisotto, Eleonora Borgia, Federica
Writing ± original draft: Sara Brisotto.
Writing ± review & editing: Daniele Donà, Susanna Masiero, Sara Brisotto, Rebecca Lundin,
Eleonora Borgia, Federica Visentin, Liviana Da Dalt.
10 / 11
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