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RATE OF THE OCCURRENCE OF ADVERSE EVENTS IN PRESCHOOL CHILDREN AFTER VACCINATION AT THE HEALTH CARE CENTER IN INĐIJA

Introduction: An adverse event following immunization is any undesirable medical occurrence which follows immunization, and which does not necessarily have a causal relationship with the usage of the vaccine. The aim of this study was to determine the rate of occurrence of adverse events in preschool children, after vaccination at the Primary Health Care Center in Inđija. Material and methods: Data were used from the medical and administrative documentation of the Pediatrics Department in Inđija. The study covered a period of 11 years and during this period 4,273 children were vaccinated, and 70,558 doses of vaccines were administered. Results: 13 cases of severe adverse reactions to a vaccine were registered, with a rate of 18.4:100,000 vaccine doses. There were 6 severe adverse reactions to the DTP vaccine per 8,180 administered doses of this vaccine, which was a rate of 73.3:100,000 doses of the DTP vaccine. There were 7 cases of severe adverse reactions to the MMR vaccine per 8,505 administered doses of the MMR vaccine, which was a rate of 82.3:100,000 doses of MMR vaccine. The overall rate of adverse reactions in the form of mumps was 47.0:100,000 doses of the MMR vaccine, in the form of rubella rash it was 11.7:100,000 doses of the MMR vaccine and the rate of adverse allergic reactions to the MMR vaccine was 23.5:100,000 doses of the MMR vaccine. According to our results, there were two cases of adverse reactions in the form of allergic reaction, to all vaccines administered, which was the rate of 3:100,000. Conclusion: This study confirms the very rare occurrence of severe adverse reactions to vaccination and speaks in favor of a far greater benefit from vaccination as compared to the risk of an adverse reaction to vaccination.


INTRODUCTION
By decreasing morbidity and mortality from different pathogens, vaccines have a great influence on public health. Regular and comprehensive immunization programs have had great significance in the eradication of smallpox and the elimination of diphtheria in most countries of the world. Complications occurring during natural infection are 1,000 to 10,000 times more frequent and are accompanied by a more severe clinical presentation than the occurrence of complications after vaccination against the same disease [1].
Severe adverse events upon vaccination occur very rarely. Due to their low frequency, the limited number of registered test subjects and other limitations of studies, for certain adverse events, it is highly unlikely that they will be discovered during clinical testing before the issuance of permits for vaccine application. This is why monitoring adverse events after vaccination is necessary. The basis of monitoring the safety of vaccines is the review and analysis of spontaneously reported adverse events [2].
An adverse event following immunization is any undesirable medical occurrence which follows immunization, and which does not necessarily have a causal relationship with the usage of the vaccine. [3]. The Working Group on Vaccine Safety has categorized adverse events after immunization into 5 groups: 1) vaccine product-related reactions; 2) vaccine quality defect-related reactions; 3) immunization error-related reactions; 4) immunization anxiety-related reactions; 5) coincidental events -caused by something other than vaccine components [3].
The classification of postvaccine reactions by the time of occurrence is also of great significance for the understanding of their nature: 1) immediate type -occurs within several minutes to a maximum of 4 hours after vaccine administration; 2) delayed type -occurs a number of hours to several days (up to 2 -3 weeks) after vaccination [4].
Localized reactions at the vaccine injection site occur in 20 -50% of vaccinated individuals and mild systemic reactions are registered in around 50% of the vaccinated individuals [5].
The law stipulates mandatory reporting of adverse reactions upon immunization to the relevant expert team for permanent contraindications at the Institute of Public Health and to the Medicines and Medical Devices Agency, while the expert team is the one deciding on permanent contraindications of the given vaccine [6].
The aim of this study was to determine the rate of occurrence of adverse events after vaccination in preschool children immunized at the primary health care center in Inđija.

MATERIALS AND METHODS
Research was carried out in the form of a cross-sectional study, through the use of data from the medical documentation of the Pediatrics Department of the Health Care Center in Inđija. A record of vaccination is regularly kept at the Department for each patient. Data from special record protocols on adverse effects of vaccination were analyzed, as were the regular vaccination protocol and the vaccination reports for the period January 2009 -December 2019.
Active immunization of persons of a particular age is carried out at the Department of Pediatrics of the Health Care Center in Inđija, in keeping with the Rulebook on the Program of mandatory and recommended immunization of the population against certain infectious diseases, with the exception of those persons for whom permanent contraindications have been determined. Infectious diseases against which mandatory active immunization is carried out, in persons of a particular age, are the following: tuberculosis, diphtheria, tetanus, polio, whooping cough, measles, rubella, mumps, hepatitis B, diseases caused by Haemophilus influenzae bacterium type B, and diseases caused by Streptococcus pneumoniae [6].
This research encompassed the occurrence of severe adverse reactions to vaccines, without including postvaccine elevated temperature, swelling and/or hyperemia at the injection site, irritability, etc., which are categorized as mild postvaccine reactions and occur in more than 1 in 10 children receiving the vaccine.
Data were entered and grouped in Microsoft Word tables, while statistical processing was performed in the form of absolute and relative frequencies.

RESULTS
Our research covered the period from January 2009 to December 2019, and during that period a total of 4,273 preschool children were vaccinated. The total number of administered vaccine doses was 70,558. The scope of vaccination in the Municipality of Inđija fulfils the goals of the national immunization program, i.e., every year during this period the coverage was over 96%. Table 1 shows the number of children vaccinated with particular vaccines and the number of administered doses per type of vaccine in the period covered.
Reported severe adverse reactions to vaccines, recorded in our protocols, were the following: inconsolable crying lasting more than three hours, the occurrence of mumps symptoms, the occurrence of rubella, swelling, rash, and other.
Adverse reactions to immunization were reported after the application of the DTP and MMR vaccines and after booster shots of DT, OPV and MMR vaccines stopa pojave neželjenih događaja nakon vakcinacije kod predškolske dece u domu zdravlja u inđiji rate of the occurrence of adverse events in preschool children after vaccination at the health care center in inđija (Table 2). Severe adverse reactions to other mandatory vaccines were not recorded in these protocols.

DISCUSSION
Vaccination represents the most effective method of preventing infectious diseases. The adverse events that may occur after vaccination administration represent a potential risk to a child's health. Routine vaccination must offer significant protection against infectious diseases, and the risk of severe postvaccine adverse reactions must be minimal.
Through this research we identified 13 cases of adverse reactions to vaccination over a period of 11 years, in a sample of 4,273 children, i.e., in 70,558 administered vaccine doses, which in percentages amounts to 0.018%, i.e., 18.4 per 100,000 doses (1:5,555).
According to our research, the greatest number of children with an adverse reaction to vaccination was recorded in 2013, when children aged 2 -4 months were immunized with the first or second dose of DTP. This is a combined vaccine which consists of the concentrated and purified diphtheria toxoid, the concentrated and purified tetanus toxoid, and dead whole cells of the bacterium Bordetella pertussis, the causative agent of pertussis, adsorbed on a mineral carrier (aluminum phosphate);
Druga grupa sa najvećim brojem neželjenih postvakcinalnih reakcija je grupa dece koja je dobijala prvu dozu žive atenuisane vakcine prtiv morbila, rubele i mumpsa (Tabela 2) približno jednako u svim kalendarskim godinama u kojima smo sproveli istraživanje. Najveći broj dece je imao kliničku sliku postvakcinalnog parotitisa, potom jedan oblik postvakcinalne (nowadays an acellular vaccine against pertussis is administered). The reported adverse reaction was inconsolable crying lasting for more than three hours ( Table 2). There were 6 cases of adverse reactions to the DTP vaccine per 8,180 administered doses of the vaccine, which amounts to 73.3:100,000. The team for determining adverse events after vaccination recommended that each one of these children should continue their immunization by receiving the acellular booster shot of the vaccine against pertussis.
According to the data from literature, severe adverse events after DTP vaccination, such as inconsolable crying lasting more than three hours, occur in 1:100 of immunized children, while elevated body temperature > 40.5° C and febrile convulsions occur in 0.3 -1% of vaccinated children [5,7].
As of 2015, the pentavalent vaccine containing the acellular component against whooping cough, the inactivated component against polio, the conjugated vaccine against Haemophilus influenzae bacterium type B, and the anatoxic component against diphtheria and tetanus, is within the national program of mandatory immunization. According to the results of our research, this vaccine did not result in severe adverse reactions (Figure 1). Insight into the annual report of the Institute of Public Health of Vojvodina showed an almost twofold decrease in the number of reported adverse reactions to the DTP vaccine during 2016 and 2017 as compared to 2015 [8].
The group with the second highest number of postvaccine adverse events was the group of children who had been receiving their first dose of the live attenuated  (Table 2) approximately uniformly in all the calendar years for which the research was carried out. The greatest number of children had the clinical presentation of postvaccine parotitis; there was one case of postvaccine rubella; and there was one case of acute allergic reaction within half an hour of vaccine administration. Seven cases of adverse reactions after the administration of 8,505 doses of the MMR vaccine were noted, which was a rate of 82.3 per 100,000 doses of the vaccine. The total rate of postvaccine parotitis in our study was 47.0:100,000 doses of the vaccine; the total rate of postvaccine rubella was 11.7:100,000 doses of the vaccine; and the total rate of postvaccine mild allergic reaction was 23.5:100,000 doses of the vaccine, in the application of the trivalent MMR vaccine (one allergic reaction occurred in the application of the RV MMR, OPV and DT vaccines).
A study carried out in the Zhejiang Chinese province showed that the total rate of adverse events upon MMR vaccine administration was 34.3 per 100,000 doses, and the rate of severe adverse reactions was 5.6 per 100,000 doses [9].
National active monitoring in the United Kingdom determined a rate of 12 cases per 100,000 doses noted after the administration of a single-component vaccine against morbilli amongst children under 16 years old [10].
Allergic reactions to vaccines are extremely rare. In our study there were two cases of adverse reactions, in the form of allergic reactions, to the first dose of the MMR vaccine and after the administration of the RV MMR OPV DT, which was 3:100,000 (1:35,714). A recent report by the World Allergy Organization provided the data on the estimated rate of allergic reactions of 1:50,000 to 1:1,000,000 and of anaphylaxis of 1:100,000 to 1:1,000,000 administered vaccine doses [12]. Anaphylaxis upon immunization is very rare and a recent study by Su et al. reported a rate of 1.3 cases per 1 million received doses in USA [13].
In our study we did not detect a sex related predominance in the occurrence of adverse reactions to vaccination ( Table 2). In the analyses of McNeil et al. a predominance of the male sex was noted in those aged under 19 years and of the female sex in those aged over 19 years [14].

CONCLUSION
Adverse reactions upon vaccination, including allergic reactions, are very rare. Bearing in mind that there are postvaccine reactions of broad clinical presentation, it is very important to differentiate actual severe postvaccine reactions. In the occurrence of adverse reactions, including allergic reactions to a vaccine, clinical and allergological processing is necessary so as to prevent any delay or interruption in regular immunization. This study, just like many other studies related to this topic, confirm the very rare occurrence of severe adverse reactions to vaccination. Risks of adverse reactions to immunization are far lesser as compared to the benefits of comprehensive vaccination, both of an individual and of the entire community.

ACRONYMS AND ABBREVIATIONS
BCG -vaccine against tuberculosis DTP -vaccine against diphtheria, tetanus and pertussis OPV -oral polio vaccine Hib -vaccine against infections caused by the Haemophilus influenzae B bacterium Hep B -vaccine against hepatitis B BS -booster shot DT -vaccine against diphtheria and tetanus IPV -inactivated vaccine against poliomyelitis DT/IPV -vaccine against diphtheria, tetanus and poliomyelitis, inactivated MMR -vaccine against measles, rubella and mumps DtaP-IPV-Hib -combined vaccine against diphtheria, tetanus, acellular pertussis, poliomyelitis and infections caused by the Haemophilus influenzae B bacterium