Allergic rhinitis and asthma are prevalent diseases that share a type-2 inflammation caused by specific and functional defects in regulatory T cells. Allergen immunotherapy (AIT) is a unique causal therapy, specifically dampening type-2 immunity and restoring physiologic regulatory mechanisms.¹

For the first time, 15 years ago, tablet AIT (T-AIT) formulations were approved by regulatory agencies for treating allergic rhinitis because of grass pollen allergy in adults and children aged >5 years.² Consequently, presently, T-AIT is a drug, so safety constitutes a compelling issue.

Extensive evidences, provided by pivotal trials, exist that T-AIT is effective and usually safe.³ However, the safety profile is particularly relevant, mainly in children. Generally, T-AIT may cause local reactions, mostly in the oral cavity (similar to sublingual drops), that are usually mild to moderate and often self-resolving.⁴ However, systemic allergic reactions are also possible with T-AIT. Concerning this issue, anaphylaxis represents the most fearsome adverse event.

The term “anaphylaxis” is derived from the old Greek words ἀνά (over) and φύλαξις (defense); therefore, it means a reaction of excessive response toward allergens. Namely, anaphylaxis is a relevant clinical event that may evolve toward a life-threatening condition requiring immediate identification and treatment, as stated by the updated European Academy of Allergy and Clinical Immunology (EAACI) guidelines.⁵ However, there are different definitions and criteria for diagnosing anaphylaxis.⁶ Nevertheless, an immediate and severe multi-organ involvement represents a shared definition of anaphylaxis. In other words, at least two systems must be affected to define anaphylaxis.

Allergen immunotherapy through sublingual route may induce an anaphylactic reaction in susceptible individuals who are usually very sensitive to a causal allergen. It is well-known fact that allergic patients, depending on different immunological and clinical characteristics, significantly differ from one another.⁷ In particular, there are allergy patients who may tolerate very low doses of an allergen, while others can tolerate very high doses of the same allergen. In addition, some subjects are only sensitized but not allergic.⁸ Thus, the spectrum of the degree of allergy and immunization varies. Several factors influence these different phenotypes, such as subject’s age, duration of allergic disease, organs involved (e.g., rhinitis only or rhinitis with asthma), comorbidities, intercurrent illnesses, medications used, physical exertion, and hormonal factors, such as menstrual cycle.⁹ Therefore, in allergic patients, anaphylactic reaction could be triggered even with a low dose of an allergen. Paradigmatic examples are food, drug, and hymenoptera venom allergies.¹⁰ In fact, once the ingested allergen is exposed to immunoglobulin E (IgE) expressed on the surface of mast cells, it causes a massive and rapid release of preformed mediators (especially histamines) that, once released into the circulation, cause clinical manifestations typical of anaphylaxis.¹¹ It must be noted that anaphylactic reactions are usually unpredictable and not necessarily dose-dependent.

Anaphylaxis represents an exceptionally high risk during AIT, mainly considering that it could occur in a patient, primarily a child, treated for allergic rhinitis, such as a common and trivial disease. For this reason, it is essential to know the number of anaphylaxis patients reported during T-AIT in literature. Therefore, we conducted a literature search, consulting PubMed and Scopus, for pediatric (aged < 18 years) and adult (aged ≥ 18 years) patients reporting anaphylaxis because of T-AIT.

Some patients of anaphylactic reactions are reported in the literature (Table 1). In particular, T-AIT with pollen extracts caused anaphylaxis in 11 children and 13 adults. However, T-AIT with house dust mite extracts caused anaphylaxis in four adults, not in children.

Considering the frequency of anaphylaxis, we stratified the reported cases by the type of allergen extracts and the age. The proportion of anaphylaxis caused by five-grass-pollen products ranged from 0.01% to 0.32% in the pediatric population. The proportion of anaphylaxis caused by Timothy grass (Phleum pratense of the Pooideae family) extract ranged from 0.6% to 3.03% in children. In the adult population, the five-grass-pollen product had an anaphylaxis proportion of 0.01%–0.36%. The Phleum pratense extract caused a rate ranging from 0.17% to 1.23% in adults. T-AIT with dust mite showed a proportion of 0.26% in the adult population. These data emphasized the relevance of allergen extract used for AIT, that is, pollens were more frequently a cause of anaphylaxis than mites. It depends on the biological and immunological characteristics of different allergens. In this regard, a previous study showed that response to allergen nasal challenge significantly differed depending on single allergen.¹² In particular, each single allergen caused different immunological, inflammatory, functional, and clinical responses.

In addition, comparing the pediatric and adult population data, the prevalence was slightly more in children as reported in Table 2. However, the calculation of proportions deserves particular caution in interpretation, as the frequencies are obviously a function of the number of cases studied as well as the type of studies. Indeed, the studies conducted for regulatory purposes resulted in a higher frequency of anaphylaxis cases than the real-life studies.

This discrepancy was derived due to intentness to adverse events in the registration studies and the selected case series regarding the severity of allergic diseases. Furthermore, this literature review could not exclude the cases of anaphylaxis that were not published in literature.

Remarkably, no death has been reported with T-AIT up to now. This outcome is essential as it underscores the safety of T-AIT. However, T-AIT deserves careful attention, mainly in the pediatric population. In this regard, after the first reported instance of anaphylactic reaction following the first administration of T-AIT, manufacturers recommended that the first dose must be administered in a medical facility with the staff experienced in managing anaphylaxis, and the patient should be observed for at least 30 min.

Interestingly, anaphylactic reactions in children were due to grass pollen extracts only; no reaction has been reported regarding other allergen extracts at present. Moreover, it is relevant to note that in recent past, no anaphylactic reactions are reported because of T-AIT. This confirmed the substantial safety of T-AIT in children.

Conclusion

T-AIT very rarely determined an anaphylactic reaction and never caused a death. However, care is always required for T-AIT management, and the first dose of T-AIT must be administered in a medical setting. It would be even more prudent, at least in the pediatric population, to administer the second and third dose in a protected environment. In addition, a close contact must be ensured with the referral center through telemedicine, considering that T-AIT management is managed typically at home. Finally, as a good procedural principle, the patient should always be in good/optimal health, with a forced expiratory volume in 1 s (FEV₁) being within the normal range (spirometry must be conducted, especially in case of asthmatic patients) at the beginning of the treatment as well as in general, thus avoiding administration of the product in a condition of poor symptomatology in spite of controlling intercurrent facts.