R E V I E W EUR ANN ALLERGY CLIN IMMUNOL VOL 51, N 2, 51-61, 2019 A. RADICE1, G. CARLI2, D. MACCHIA1, A. FARSI2 Allergic reactions after vaccination: translating guidelines into clinical practice 1SOS Allergologia e Immunologia, Firenze, Azienda USL Toscana Centro, Italy 2SOS Allergologia e Immunologia, Prato, Azienda USL Toscana Centro, Italy KEYWORDS Summary vaccine; vaccination; allergic reactions; Vaccination represents one of the most powerful medical interventions on global health. anaphylaxis; vaccine hesitancy; vaccine Despite being safe, sustainable, and effective against infectious and in some cases also components; desensitization non-infectious diseases, it’s nowadays facing general opinion’s hesitancy because of a false perceived risk of adverse events. Adverse reactions to vaccines are relatively rare, instead, and those recognizing a hypersensitivity mechanism are even rarer. Corresponding author The purpose of this review is to offer a practical approach to adverse events after vaccina- Anna Radice Ospedale San Giovanni di Dio tion, focusing on immune-mediated reactions with particular regard to their recognition, Via Torregalli 3, 50143 Firenze diagnosis and management. Phone: +39 055 6932304 According to clinical features, we propose an algorythm for allergologic work-up, which E-mail: [email protected] helps in confirming hypersensitivity to vaccine, nonetheless ensuring access to vaccination. Finally, a screening questionnaire is included, providing criteria for immunisation in spe- Doi cialized care settings. 10.23822/EurAnnACI.1764-1489.86 Introduction The gain from vaccination is not just about human health, but it is also a matter of financial resources for health systems. “Smallpox is dead” stated the magazine of the World Health It has been calculated that for every dollar spent in vaccines, Organisation (WHO) in 1980. It was the first time that a high 16 dollars (US $) are expected to be saved in healthcare costs, contagious and dangerous disease was globally eradicated. loss of productivity and incomes (7). Even before, several stud- And the credit went to an extensive worldwide immunisation ies had assessed the cost-benefits of immunisation (8). A loss campaign, begun in 1967, combined to highly organised pre- of more than 60 billion dollars (direct and indirect costs) has vention and surveillance measures. Once again, the vaccines been quantified in a hypothetical unvaccinated cohort of three showed their indisputable efficacy (1,2). million children in the US (9). Recently, after the introduction To date, vaccines are considered one of the most powerful of new expensive vaccines and the global financial crisis, a bet- public health interventions that have contributed to the dras- ter standardization in the scientific works regarding the topic tic reduction of the mortality and the morbidity of several in- “cost-benefits” has been advocated, since most of them differ fectious diseases (3). Moreover, vaccines have also demonstrat- in adopted methodologies (10,11). ed a primary role in preventing virus-associated malignancies, In 2018 the European Commission, in agreement with such as HPV-driven cervical cancer (4). WHO, has reiterated the importance of reaching and main- Vaccination saves between 1 and 3 million lives worldwide taining high level of coverage rate of vaccination. The pillars every year. According to the World Health Organisation, vac- of its proposal included a better financial sustainability and a cines will save 25 million more lives in the coming decade “tackling vaccine hesitancy” strategy (12,13). Vaccine hesitan- (adapted from: 5). One of the primary aims of WHO is giv- cy is a recent phenomenon, typical of Western countries, con- ing equitable access to vaccines, collected under the name of sisting in refusing or delaying an available vaccination (14), Global Vaccine Action Plan (GVAP) (6). that has led to an alarming reduction in coverage rate. The 52 A. Radice, G. Carli, D. Macchia, A. Farsi case of measles best resumes the consequence of the “vaccine allergic ones. Over the time, more and more knowledge has hesitancy”. In the European Vaccine Action Plan for 2015- been collected, and to date allergological diagnostic tests and 2020, WHO aimed at eradicating measles (15). However, the even desensitization protocols are available. Notwithstanding gradual decrease of vaccination against this infection resulted the rarity of allergic events following vaccination, they can be in a resurgence of measles with several outbreaks, 14,600 cases harmful for at least two reasons: first, severe allergic reactions and 37 deaths in the European area in 2017. The highest in- such as anaphylaxis could be life threatening; second, a real, cidence was observed in children aged < 4 years, especially ≤ 1 presumed or even feared allergy to vaccines limits or delays the year, and most of the cases occurred in unvaccinated subjects, accessibility to a regular immunisation program. reaching a rate of 96% in children aged ≤ 1 year (16). In De- Here we propose a practical approach to AEFI from an allergo- cember 2018 the European Centre for Disease Prevention and logical point of view aimed at identifying risk factors, diagnos- Control (ECDC) reported 34 fatalities due to measles in 2018 ing allergies and providing a framework to ensure vaccination, (17). Hence, the goal of the European Commission regarding according to the subjects’ risks, either in a standard care or in measles has now turned into “reaching at least a coverage rate specialized centres. A better selection of patients requiring an of 95%”. allergological in case of AEFI is necessary to properly address Although vaccine hesitancy is a multi-layered phenomenon, health resources. safety of vaccination is one of its most relevant cofactors. In- jecting a potentially dangerous organism in a healthy subject Definitions is intuitively experienced as a danger (14); that encourages distrust towards vaccines, especially if false or real claims of Adverse event following immunization (AEFI) is “any untow- adverse reactions are widespread. A striking example was that ard medical occurrence which follows immunization and which of Wakefield. His fraudaulent study supporting the associa- does not necessarily have a causal relationship with the usage of tion between measles-mumps-rubella vaccine and autism was the vaccine” (23). The Working Group on Vaccine Safety has definitively disproved with heavy consequences for the author, classified AEFI in 5 groups: but nevertheless this misinformation still troubles those skep- • vaccine product-related reactions: caused or precipitated by a tical towards vaccines (18). Moreover, unlike their parents and vaccine due to one or more of the inherent properties of the grandparents, new generations in Western countries have no vaccine product; confidence with epidemics and their potential consequenc- • vaccine quality defect-related reactions: caused or precipitat- es. And it has been demonstrated that perceiving more the ed by a vaccine due to one or more quality defects of the risks than the benefits of immunisation favours the reluctance vaccine product, including the administration device, as pro- against vaccines (19). vided by the manufacturer; Hence, it is necessary to reduce this false perception of unsafe- • immunization error-related reactions: caused by inappropri- ty and even uselessness regarding the immunisation. Also, the ate vaccine handling, prescribing or administration and that introduction of new vaccines has required better tools to anal- therefore, by its nature, is preventable; yse their real impact on subject’s health, as mentioned above. • anxiety-related reactions: arising from anxiety about the im- Scientific societies, drug agencies and major health organisa- munization; tions have created several active vaccine-pharmacovigilance • coincidental events: caused by something other than the vac- entities and working groups. The Vaccine Adverse Event Re- cine product, immunization error or immunization anxiety. porting System (VAERS) in the US (20) or pharmacovigilance section of EMA, for example, regularly collect reports and Vaccine product- and quality defect-related reactions are those cooperate with governments in the field of vaccination. The potentially involving immune system, summarized in table I “unmet needs” regarding vaccination is the field of interest of according to the latest document of CIOMS. the Working Group on Vaccine Safety (WG), a subgroup of Classification in systemic and local could help the physician the Council for International Organizations of Medical Sci- in a faster differential diagnosis between allergic and non-al- ences (CIOMS), an organization established by the WHO lergic reactions in daily-clinical practice (table II). The term and UNESCO in 1949 (21). There are several working groups “allergy” encompasses all 4 types of reactions according to dedicated to support research, produce guidelines, organise Gell and Coombs. (25). trainings and offer precise information (for example, the Vac- Classifying reactions according to timing is also extremely im- cines Working Party, VWP) (22). portant to better understand their nature: i) immediate type This has led to a better knowledge of the pathogenic mecha- occurs within minutes and usually no more than after 4 hours; nisms of the AEFI (Adverse Events Following Immunisation) ii) delayed type occurs hours to days (up to 2-3 weeks) after until the discover of immune-mediated reactions, including