At present, the standard of care for food allergy is a strict elimination diet,12,13 which carries the potential risk of experiencing accidental reactions requiring safe and effective medical treatment. There have been important advances in the management of anaphylaxis, such as the development of adrenaline auto-injectors in the 1980s, which has facilitated immediate treatment outside the hospital (for example, at school, home or restaurants).

In 1908, researchers reported for the first time the successful ingestion of progressively increasing doses of hen's egg to an adolescent with a previous history of anaphylaxis. Since then, allergen-specific immunotherapy (AIT) has been at the core of research efforts on the subject. Although the underlying mechanism is not fully understood, there is evidence that AIT leads to immunomodulation decreasing basophils and mast cells activation, increasing levels of specific IgG4, reducing levels of allergen-specific IgE and generating regulatory T and B cells.14,15 In general, for both food and respiratory allergens, AIT consists of administration of gradually increasing doses of the culprit allergen (food, standardised allergen extracts) during induction until a specific maintenance dose is reached.16

One of the goals of AIT for IgE-mediated food allergy is desensitization,12 or increasing the response threshold to an allergen, which is achieved in 60%–90% of cases.13,17,18 A more desirable outcome is the absence of reactivity on treatment discontinuation, what is known as sustained unresponsiveness. Sustained unresponsiveness has been described in 27.5%–50% of patients after 2–4 years of treatment.17

The oral route of administration is the most thoroughly investigated to date, mainly for cow’s milk, eggs and peanuts,19 and less frequently for fish, hazelnuts, peach20 and other allergens.13,16,17 Oral immunotherapy is associated with stronger immune response and higher rates of remission.17 Some of the adverse effects described with oral allergen administration are mild allergic reactions, anaphylaxis (6.7%–30.8%)15 and eosinophilic esophagitis (2.7%).15,17

The sublingual route (of which the prime example is immunotherapy for peach allergy) and the epicutaneous route are potential alternatives for allergen administration, with adverse effects that are most frequently local.16,19 However, the safety and effectiveness of these routes in the paediatric population are still under investigation (Fig. 3).

Figure 3.

Allergen-specific immunotherapy (AIT). The figure presents the main clinical and immunological effects of AIT. It also shows the different routes of administration used to deliver AIT for treatment of both respiratory allergies and food allergies.

(0.3MB).

In 2017, the European Academy of Allergy and Clinical Immunology (EAACI) published guidelines on AIT for food allergies, recommending its prescription in patients aged at least 4–5 years for treatment of persistent IgE-mediated allergy to eggs, cow’s milk or peanuts.21 Other scientific societies have also developed clinical practice guidelines to promote a standardised and safe practice of AIT.15,22

In recent years, research in the medical and pharmaceutical fields has focused on innovations in food allergy therapeutics with promising results,23 using modified forms of allergens (powder, high-temperature , food matrix, delivery vehicle) and improving safety and adherence. One important step forward is the authorization by regulatory agencies (Food and Drug Agency [FDA] and the European Medicines Agency [EMA]) of the first standardised product for treatment of peanut allergy (Palforzia®, AR101®).24,25 Also, an epicutaneous patch with peanut, milk and egg (Viaskin®) has been developed and awaits authorization for its commercial distribution.12,17 Research on other strategies is underway (chemical modification of allergens, bacterial plasmid-based DNA vaccines, peptides, alternative routes of administration, probiotics, biologic agents) and at different stages of development.17,26,27

The management of respiratory allergies mainly consists of allergen exposure avoidance measures and pharmacotherapy to control symptoms and underlying inflammation.14,28 However, a significant proportion of patients continue to experience symptoms in spite of receiving the standard of care.28,29

Inhalant allergen immunotherapy was a pioneering empirical treatment first introduced by Noon more than 100 years ago. Since its initial description, specific treatments have been developed, and inhalant AIT is the only disease-modifying treatment available for respiratory allergies.14,29,30 There is significant evidence of its effectiveness in improving AR and allergic asthma in patients aged more than 5 years.14,30,31 Inhalant AIT promotes allergen desensitization, which in turn results in a reduction in both, symptoms and the need for rescue medication.

Its use is currently endorsed by international guidelines in cases of moderate to severe AR and also mild cases to modify the course of the disease (e.g. progression to asthma)28 and for treatment of dust mite-driven asthma32,33 with a duration of 3 years.23,28,30,32,34,35 The subcutaneous and sublingual routes are used most frequently and have exhibited adequate effectiveness and safety (Fig. 3).

Recent advances have produced new modalities of treatment aimed at improving adherence, with a higher effectiveness and safety, through allergen modification (allergoids, recombinant hypoallergenic derivatives), the fusion of allergens with immunomodulators and the creation of peptide transport proteins. Another promising strategy is the use of adjuvants to enhance immunogenicity, of which aluminium hydroxide is used most commonly, although other novel adjuvants can also be used (monophosphoryl lipid A, microcrystalline tyrosine).14,36 Research is also being conducted on alternative routes of administration for which the evidence is still insufficient (intralymphatic and epicutaneous).30

Although many questions remain unresolved, AIT is proving to be a very useful tool.

Advances in the understanding of the underlying pathophysiology and the phenotype and endotype of allergic diseases have allowed the development of new therapeutic options.

Biologic agents have opened up a novel therapeutic approach,37 chiefly in patients with a poor response to conventional treatment. Initially, biologic agents were used as adjuvant treatment for refractory asthma, since up to 4.5% of children with asthma develop severe disease.37 The evidence of its efficacy in the treatment of other allergic diseases continues to grow.

These agents have a high molecular weight and bind specific molecules (cytokines, receptors), exerting their effects through the modification of activation and signalling pathways of different proteins involved in allergic diseases.

Since biologic agents are selective, they are ideal for the practice of personalised and precision medicine.38 A thorough knowledge of the pathophysiology of the disease to be treated is required to maximise the benefits of these therapies.38

One of the most commonly used biologic agents, omalizumab, has exhibited an adequate effectiveness and safety profile, and proven to be cost-effective compared to the isolated use of conventional medication.38 It was first authorised by the FDA in 2003 and by the EMA in 2005 for use in adults and adolescents aged more than 12 years with persistent severe allergic asthma. The indication for treatment of paediatric patients (age ≥ 6 years) was authorised by the EMA in 2009 and by the FDA in 2016.

Multiple studies have demonstrated that omalizumab achieves a decrease in the use of both inhaled corticosteroids and rescue medication, in emergency department visits and in hospital admissions in addition to improvement in the quality of life of patients with severe asthma.38 It has also been used in combination with AIT, improving the safety of immunotherapy, especially in high-risk cases.

Recent evidence has shown that omalizumab can be useful as adjuvant therapy in patients with severe food allergies undergoing AIT, helping the achievement of desensitization.38 There is also evidence on the benefits in disease activity in moderate to severe chronic spontaneous or inducible urticaria, refractory to the standard first-line treatment, therefore its use is recommended in international guidelines as third-line treatment for this disease.

The first biologic agents approved for children aged more than 6 years were omalizumab and mepolizumab.37 Recently, dupilumab has also been approved for treatment of atopic dermatitis.

Table 1 lists the biologic agents and their corresponding therapeutic indications in allergic diseases.

Mepolizumab for treatment of atopic dermatitis is currently being investigated, with evidence of only a modest improvement to date, so its use should be reserved for cases refractory to conventional treatment. There have also been promising results with the use of dupilumab for treatment of allergic asthma, with randomised controlled trials showing that it is effective in reducing the incidence of severe exacerbations, improving lung function and controlling asthma in patients receiving inhaled steroids at moderate-to-high doses.

There is no question that biologic therapy has advanced the management of allergic diseases, with an impact not only on the outcomes of disease but also on the quality of life of patients.

Each new advance confirms that in the future, the indication for a biologic agent will also be determined based on biomarkers, endotypes and genetic factors. The integration of these elements in the clinical characterization of patients will result in an increased use of biologic agents, possibly changing traditional management algorithms.38 Other therapies aimed at modifying the different Th2 pathways of the immune system are currently being investigated.