- Open Access
The future outlook on allergen immunotherapy in children: 2018 and beyond
Italian Journal of Pediatrics volume 44, Article number: 80 (2018)
Allergen immunotherapy (AIT) is the only currently available immune-modifying and aetiological treatment for patients suffering from IgE-mediated diseases. In childhood, it represents a suitable therapeutic option to intervene during the early phases of respiratory allergic diseases such as rhino-conjunctivitis and asthma, which is when their progression may be more easily influenced. A growing body of evidence shows that oral immunotherapy represents a promising treatment option in children with persistent IgE- mediated food allergy. The efficacy of AIT is under investigation also in patients with extrinsic atopic dermatitis, currently with controversial results. Furthermore, AIT might be a strategy to prevent the development of a new sensitization or of a (new) allergic disease. However, there are still some methodological criticisms, such as: a) the regimen of administration and the amount of the maintenance dose are both largely variable; b) the protocols of administration are not standardized; c) the description and classification of side effects is variable among studies and needs to be standardized; d) quality of life and evaluation of health economics are overall missing. All these aspects make difficult to compare each study with another. In addition, the content of major allergen(s) remains largely variable among manufacturers and the availability of AIT products differences among countries. The interest and the attention to AIT treatment are currently fervent and increasing. Well-designed studies are awaited in the near future in order to overcome the current gaps in the evidence and furtherly promote implementation strategies.
It is estimated that more than one third of population all over the world is currently suffering from at least one allergic disease . In particular, allergic rhinitis, asthma, and food allergy represent major disorders. Their incidence is increasing especially in children and young adults, who are bearing the greatest burden of these trends together with their families and health services . Nowadays, most patients have good disease control and acceptable quality of life through avoidance strategies and symptomatic drug therapy. However, a minority still have persistent symptoms or remain at risk of life-threatening allergic reactions. Allergen-specific immunotherapy (AIT) is currently recognized as the only clinically effective treatment capable of a disease-modifying effect for IgE-mediated allergic diseases [1,2,3,4,5,6,7,8]. AIT may not only desensitize a patient -including who is not responsive to avoidance strategies or pharmacotherapy- thereby ameliorating symptoms while on treatment, but also deliver long-term clinical benefits that may persist for years post-AIT discontinuation. Since the first description of the clinical efficacy of subcutaneous injections of a pollen extract in hay-fever, reported by Leonard Noon in 1911 , AIT has been performed (Fig. 1). Typically the subcutaneous, sublingual or oral routes are used. Others, such as the epicutaneous and the intra-lymphatic ones are under investigation. In the early years, allergenic extracts of poor quality and definition were used. Substantial progress in understanding the patho-mechanisms of allergic reactions has led to improve both safety and efficacy profile of AIT in clinical practice. Currently, AIT is accepted and routinely prescribed worldwide in the pediatric population for respiratory allergies and more and more in food allergies. However, there are still several gaps to be filled, particularly around AIT long-term benefit and its use in children. The efficacy of AIT is under investigation also in patients with extrinsic atopic dermatitis, currently with controversial results [10, 11]. A better understanding in mechanisms of action of AIT might improve both the clinical efficacy of the treatment – while permitting shorter, safer and more convenient strategies for the patient- and the early or even preliminary recognition of AIT-responders. Well-designed large scale studies are still needed in order to make AIT a precision medicine, targeted to the patient.
In the text below, we preliminary synthesize the current knowledge of the mechanisms of action of AIT. Afterwards, we describe the current evidence on AIT in terms of prevention, allergic rhinitis and food allergy. Finally, the current gaps and plans to address them will be discussed.
Mechanisms of action of AIT and predictive biomarkers
AIT works through several immunological pathways [12, 13]. The mechanisms of action include the induction of very early desensitization of mast cells and basophils [14, 15]; generation of specific regulatory T and regulatory B cell responses [16, 17]; regulation of allergen specific IgE, IgG4 and IgA [18,19,20,21]; decreases in numbers and activity of effector cells in mucosal of target organs, including mast cells , basophils , eosinophils , and type 2 innate lymphoid cells ; and decreases in the activity of basophils in circulation  (Fig. 2). However, a detailed knowledge of the mechanism involved in effective AIT is still missing. Furthermore, it is not clear whether the altered long-term memory resides within the T-cell or the B-cell compartment. Understanding mechanisms underlying induction and persistence of tolerance is a key point in order both to identify novel and more effective strategies tailored on the individual pattern and to establish predictive biomarkers of clinical response. So far, several biomarkers candidates have been investigated: IgE [total IgE, specific IgE (sIgE) and sIgE/Total IgE ratio); IgG-subclasses (sIgG1, sIgG4 including sIgE/IgG4 ratio); serum inhibitory activity for IgE (IgE-FAB and IgE-BF); basophil activation; cytokines and chemokines; cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and in vivo biomarkers (e.g. provocation tests) . In particolar, IgE specific activity (ratio specific IgE/total IgE) and serum IgE-FAB are currently considered as potential surrogate candidate biomarkers; however data are discordant . To explore the use of allergen-specific IgG4 is recommended as a biomarker for compliance. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are still needed.
Status of the art, unmet needs and future perspectives
Several studies have investigated the efficacy and safety of AIT [5,6,7]. However, to interprete the current evidence remains challenging for the deep heterogeneity among studies. For instance, they are evaluating different populations. It is known that atopic heredity play a role in the risk of developping allergic disease(s). Furthermore, children with atopic sensitization and/or early manifestations of atopic diseases (such as atopic dermatitis and food allergy) have a higher risk for development of other allergic manifestations (e.g. asthma) [27,28,29]. The age of the population is also a pivotal factor as the phenotypic expression may change with age and some manifestations may even disappear spontaneously [27,28,29]. The results of individual studies are difficult to compare because studies have used not only different populations, but also different methods (e.g. diagnostic criteria; allergens, formulation, and strength of products used; schedules; dose; route of administration; duration of the intervention) and outcomes. Additionally, many studies have small sample size and missing adjustment for confounders. Furthermore, not all AIT products used provide sufficient data to support their efficacy in clinical practice. Therefore, an individual product-based evaluation of the evidence for efficacy is strongly recommended before treatment with a specific product is initiated [5,6,7]. The identification of the gaps in the current evidence is a preliminary and mandatory phase in order to stimulate in the near future the development of longitudinal, prospective, well-designed studies with the final goal of a “precision medicine/prevention”, tailored on each individual.
Prevention is one of the major concerns, above all in pediatrics. Furthermore, it is known that the clinical expression of respiratory allergies tends to change over time, according to a “natural history”, the so-called “atopic march”. In the typical sequence, allergic rhinitis often precedes the onset of asthma and, therefore, it can be considered a risk factor for the development of allergic asthma [27,28,29]. In addition, there is often the tendency to develop new sensitivities along time: the natural history of sensitizations begins usually with foods, continues with environmental allergens (usually dust mites) and ends with pollens. However, some individuals begin their march only with sensitization to mites, pollens or molds without food allergens . Furthermore, molecular-based diagnostics showed that in most children the IgE response to a single allergenic source evolves over time, becoming more and more complex: the serum concentration of IgE antibodies rises progressively, both for an increase sensitizing molecules, and for a rising concentration of IgE antibodies directed against any individual allergenic molecule (the so-called phenomenon of “molecular spreading”) . Interestingly, a ‘pre-clinical’ IgE sensitization has been shown already years before (up to 5 years before) the development of seasonal allergic rhinitis, initially characterized by weak and simple IgE responses, progressively increasing in concentration and molecular complexity [30, 31]. Therefore, as AIT is the only disease-modifying treatment in allergic diseases the potential preventing effects of AIT have been suggested and investigated for the prevention not only of the development of allergic comorbidities in patients with established allergic diseases, but also the development of first allergic disease in not-sensitized children (“primary immune-prophylaxis”) and in still healthy children with specific IgE antibodies (“secondary immune-prophylaxis”) and allergic sensitization in patients with other allergic conditions (“tertiary immune-prophylaxis of atopy”) . Certainly, alongside efficacy, another pivotal issue to be considered is the safety profile, especially in the context of prevention in healthy individuals.
The current evidence suggests that a three-year-long course of subcutaneous or sublingual AIT can be recommended for children and adolescents with moderate to severe AR due to grass or birch pollen in order to prevent the onset of allergic asthma for up to 2 years post-AIT cessation in addition to its sustained effect on AR symptoms and medication [4, 32,33,34,35,36,37]. However, the strength of this recommendation is moderate as based on significant results from two moderate [33, 35] and two high risk of bias [32, 34] RCTs and some controlled before and after (CBA) studies. A few trials suggest a preventive effect on the onset of asthma symptoms and medication use longer than 2 years post-AIT [34, 35]. However, there is lack of evidence for AR triggered by house dust mites or other allergens different from grass/birch [4, 34, 38]. Overall, because of inconsistent results, AIT cannot currently be recommended for the prevention of new sensitizations, nor in patients with allergic rhinitis and/or asthma nor in healthy individuals [4, 34, 39,40,41]. For lack of evidence, no recommendation can be made in favor or against AIT in individuals with early life atopic manifestation, such as atopic eczema and food allergy nor in healthy subjects -with or without atopic sensitization- for the prevention of onset of allergic diseases [4, 42]. Therefore, though there is evidence for the preventive potential of AIT as disease modifying treatment, further well-designed clinical trials are needed to confirm the possible value of AIT in prevention of allergic diseases. They should consider the safety profile, the health-economic aspects, and the quality of life, too (Table 1). Additionally, strategies need to be targeted to different scenarios, e.g. women planning pregnancy to take preventive measures such as AIT to reduce the risk that their child will develop allergies, healthy infants and young children with atopic dermatitis and food allergy, older children with AR, healthy (with or without atopic sensitization) adolescents/adults and adolescents/adults with established allergic disease.
AIT is a therapeutic option in patients suffering from allergic rhinitis/rhino-conjunctivitis with/without allergic asthma with an evidence of specific IgE-sensitization towards clinically relevant inhalant allergen(s) [2, 5, 43]. It is indicated in the presence of moderate to severe symptoms interfering with usual daily activities or sleep (e.g. Allergic Rhinitis and its Impact on Asthma, ARIA)  despite avoidance measures and pharmacotherapy [2, 5].
Since AIT is allergen-specific, its efficacy and effectiveness depends on a proper identification of the triggering allergen(s). This concept fits into the perspective of a “precision medicine” and implies a proper recording of the clinical history and ascertainment of environmental exposure , confirmed by diagnostic tests . Before prescribing AIT, any specific patient-related (e.g. uncontrolled or severe asthma and adherence to the treatment) and product-specific absolute or relative contraindications should be considered.
Sublingual (SLIT) and subcutaneous (SCIT) allergen immunotherapy constitutes the preferred route of administration of AIT for respiratory allergies. Alternative modalities of delivery [such as epicutaneous , intradermal  and intralymphatic routes ] have been recently under investigation, however with currently modest body of evidence . In general, the current evidence suggests that both SCIT and SLIT are effective for AR [2, 5]. Both route of administration were associated with reductions in symptoms and with medication use. The strength of evidence is high in adult patients but moderate in pediatric patients for lack of data [2, 5]. In particular, in children suffering from moderate to severe seasonal AR, both continuous and pre- (i.e. AIT started at least 2, preferable 4 months before the pollen season) and pre−/co-seasonal AIT are currently recommended for clinical benefit during the AIT treatment [2, 5, 50,51,52,53,54,55,56,57]. Overall, there are insufficient data to determine which of SCIT and SLIT is the most effective [2, 5]. Concerning perennial AR due to house dust mites, there is evidence for efficacy of continuous AIT (both SCIT and SLIT, the latter in form of tablet but not in aqueous solution) during the AIT treatment [2, 5, 58, 59]. The evidence for clinical benefit to pediatric patient for at least 1 year after cessation of the AIT course (the so-called “long-term efficacy”) nowadays is limited to continuous grass pollen AIT (both SLIT -tablet or solution- and SCIT) performed for a minimum of 3 years in seasonal AR due to grass pollen [2, 5, 50, 60]. No study to our knowledge have investigated the long-term efficacy of AIT in perennial AR in children however there is evidence for continuous therapy with SLIT tablet in adults with AR to house dust mite . In addition, evidence to support SLIT in children with asthma due to HDM is still scarce . Many factors may affect the efficacy of AIT. Some factors are related to the patient, including poly-sensitization, co-existing asthma and specific issues in pre-school age. Other factors are related to the allergen(s), such as: the standardization of allergen extracts (including common allergens- whose characterization is still missing in many commercial products and/or lacking stability, e.g. molds- and “orphan allergen”, affecting a few patients); the formulation of SLIT preparation and allergen mixtures (some allergens with enzymatic activity, such as HDM, may affect the efficacy of SLIT drops). A careful evaluation of the indications to AIT and individual product-based evaluation of the evidence for efficacy is pivotal before prescribing a specific AIT product. Standardized AIT products with documented clinical evidence of efficacy should be used when available [2, 5]. Unfortunately, among the published data there is a substantial heterogeneity in terms of the study design (particularly the different outcomes used), study population and the products evaluated. This heterogeneity -as discussed above- hampers the meta-analyses and comparison among the available data [2, 5].
Many gaps are still unmet (Table 2): more prospective multi-centre controlled trials using standardized products are awaited in order to address them. New combined approaches have been suggested and experimented in order to improve adherence and quality of life with shorter courses, whilst reducing the risk of adverse reactions and improving the effectiveness . For instance, adjuvants have been added to AIT extracts [e.g. TLR-4 agonists [64,65,66,67], TLR-9 agonists ] with promising results in adults. Anti-IgE injections have been combined with AIT schedules with safer profile and maintained effectiveness also in children. However, this approach is expensive and there is no agreement on timing and mode of anti-IgE discontinuation when AIT maintenance is achieved [69, 70]. Another attractive approaches lies on the use of recombinant AIT as it allows accurate standardization of allergen products, and potentially a personalized treatment based on the individual allergic sensitization(s) . Further studies are awaited to further investigate these interesting approaches.
IgE-mediated food allergy (FA) is a potentially life-threatening condition , with a negative impact on the quality of life of patients and their family [73, 74]. The current standard approach consists of the strict avoidance of the culprit food and rescue medication in the event of an allergic reaction occurs . However, an elimination diet may be difficult and frustrating in patients with persistent FA, above all for those foods (e.g. cow’s milk, CM, and hen’s egg, HE) that are central in the common diet . Nevertheless, despite efforts to comply with this diet, accidental exposures leading to adverse reactions are frequent [76, 77]. In this context, considering the potential desensitizing effects of allergen administration, AIT has been investigated. The most frequent route of administration consists of the immediate swallowing of the allergen (oral immunotherapy, OIT). On the basis of the current body of evidence, OIT is performed more and more in clinical practice, though still in a few rate of eligible patients. OIT involves the administration of increasing doses of the culprit allergen until the food is tolerated at usually dietary doses. This approach can confer protection against accidental allergic reactions and contribute to improve nutritional status and quality of life of the affected patients . Many clinical trials performed with cow’s milk, hen’s egg and peanuts consistently show that an effective increase of the threshold of reaction while on OIT (desensitization) can be obtained, and therefore recommended, in children with persistent FAs, from around 4–5 years of age as most patients overcome their FAs to CM and HE spontaneously. However, it is not clearly defined if when desensitization has been achieved, a permanent tolerance persists, independent of the regular assumption of the responsible food [3, 6, 78, 79]. Adverse events may occur but most of them are not severe . It can be performed only in highly specialized centers and under strict medical supervision after the informed consent has been obtained from parents [3, 6, 80,81,82]. Other routes of administration have been investigated (e.g. sublingual, subcutaneous and epicutaneous ones) [83,84,85,86] as well as adjunctive treatments (such as omalizumab and probiotics) [87,88,89]. Though AIT represents an emerging reality as an active treatment for IgE-mediated food allergies, many issues remain unanswered. Clinical trials for OIT so far conducted are extremely heterogeneous and therefore their results are not comparable. Differences encompass dosage, amount and frequency, duration of build-up and maintenance phases, type of allergen used, patient characteristics, reporting in adverse events and adjuvant therapies (Table 3) . Much larger, longitudinal and well-designed studies using more homogenous protocols are needed in order to standardize products and to validate protocols (optimal doses and schedule), to assess the sustainability of the desensitization process, to improve the effectiveness after AIT discontinuation, the safety, and the impact on quality of life, and to identify the role of adjunctive therapies (such as omalizumab and probiotics) .
Through an overview of the up-to-date evidence in terms of mechanisms of action, efficacy and safety of AIT for prevention, allergic rhinitis and food allergy, this rostrum sought to gauge the main needs currently unmet in AIT in order to stimulate in the near future the development of longitudinal, prospective, well-designed studies with the final goal of a “precision medicine” tailored on each single eligible subject [90, 91]. A deep understanding of mechanisms of action will improve the current strategies and provide new ones for immune intervention, which will likely include targeting of the molecular mechanisms of allergen tolerance and reciprocal regulation of effector and regulatory T cell subsets. The molecular-based diagnostics would certainly improve the accuracy in AIT prescription, allowing to dissect the genuine sensitizations and the cross-reactions due to pan-allergens . Mobile health technologies might establish a cause-effect relationship between exposure to the pollen recognized by the patient’s IgE sensitization pattern and the patient’s symptoms and precisely assess the degree of severity of the patient’s symptoms, as AIT should be administered primarily to patients with moderate-severe rhinitis . An integrated approach combining different available diagnostic tools might achieve a more precise etiological diagnosis for a better AIT prescription. However, to our best knowledge, no informatics tool dedicated to support the implementation of internationally validated algorithm is so far available. Furthermore, the development of integrated care pathways incorporating (educating and training) primary and secondary care, as well as the availability of high quality AIT products, individual product-based evaluation of the evidence, and global actions aimed to develop a harmonized international approach to regulate AIT products are awaited in order to implement AIT in clinical practice. The interest and the attention to AIT treatment are currently fervent and increasing. Well-designed studies are awaited in the near future in order to overcome the current gaps in the evidence and furtherly promote implementation strategies.
Controlled before and after study
House Dust Mite
Randomized controlled trial
Pawankar R, Canonica GW, Holgate ST, Lockey RF, Blaiss M. The WAO White book on allergy (update 2013). 2013.
Roberts G, Pfaar O, Akdis CA, Ansotegui IJ, Durham SR, Gerth van Wijk R, et al. EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy. 2017; https://doi.org/10.1111/all.13317. [Epub ahead of print].
Pajno GB, Fernandez-Rivas M, Arasi S, Roberts G, Akdis CA, Alvaro-Lozano M, et al. EAACI guidelines on allergen immunotherapy: IgE-mediated food allergy. Allergy. 2017; https://doi.org/10.1111/all.13319. [Epub ahead of print].
Halken S, Larenas-Linnemann D, Roberts G, Calderón MA, Angier E, Pfaar O, et al. EAACI guidelines on allergen immunotherapy: prevention of allergy. Pediatr Allergy Immunol. 2017; https://doi.org/10.1111/pai.12807. [Epub ahead of print].
Dhami S, Nurmatov U, Arasi S, Khan T, Asaria M, Zaman H, et al. Allergen immunotherapy for allergic rhinoconjunctivitis: a systematic review and meta-analysis. Allergy. 2017;72:1597–631.
Nurmatov U, Dhami S, Arasi S, Pajno GB, Fernandez-Rivas M, Muraro A, et al. Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis. Allergy. 2017;72:1133–47.
Kristiansen M, Dhami S, Netuveli G, Halken S, Muraro A, Roberts G, et al. Allergen immunotherapy for the prevention of allergy: a systematic review and metaanalysis. Pediatr Allergy Immunol. 2017;28:18–29.
Sturm GJ, Varga EM, Roberts G, Mosbech H, Bilò MB, Akdis CA, et al. EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy. Allergy. 2017; https://doi.org/10.1111/all.13262. [Epub ahead of print]
Noon L. Prophylactic inoculation against hay fever. Lancet. 1911;177:1572–3.
Galli E, Neri I, Ricci G, Baldo E, Barone M, Belloni Fortina A, et al. Consensus conference on clinical management of pediatric atopic dermatitis. Ital J Pediatr. 2016;42:26.
Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, European Dermatology Forum (EDF), the European Academy of Dermatology and Venereology (EADV), the European Academy of Allergy and Clinical Immunology (EAACI), the European Task Force on Atopic Dermatitis (ETFAD), European Federation of Allergy and Airways Diseases Patients’ Associations (EFA), the European Society for Dermatology and Psychiatry (ESDaP), the European Society of Pediatric Dermatology (ESPD), Global Allergy and Asthma European Network (GA2LEN) and the European Union of Medical Specialists (UEMS), et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. J Eur Acad Dermatol Venereol. 2018;32:657–82.
Shamji MH, Durham SR. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J Allergy Clin Immunol. 2017;140:1485–98.
Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol. 2014;133:621–31.
Romano A, et al. Diagnosis and management of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127:S67–73.
Novak N, Mete N, Bussmann C, Maintz L, Bieber T, Akdis M, et al. Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2. J Allergy Clin Immunol. 2012;130:1153–8.
van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Sollner S, Akdis DG, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013;131:1204–12.
Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis M. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med. 2008;205:2887–98.
Scadding GW, Calderon MA, Shamji MH, Eifan AO, Penagos M, Dumitru F, et al. Effect of 2 years of treatment with sublingual grass pollen immunotherapy on nasal response to allergen challenge at 3 years among patients with moderate to severe seasonal allergic rhinitis: the GRASS randomized clinical trial. JAMA. 2017;317:615–25.
James LK, Shamji MH, Walker SM, Wilson DR, Wachholz PA, Francis JN, et al. Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. J Allergy Clin Immunol. 2011;127:509–16, e1–5. 50.
Renand A, Archila LD, McGinty J, Wambre E, Robinson D, Hales BJ, et al. Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization. J Allergy Clin Immunol. 2015;136:1627–35.e13. 51.
Pilette C, Nouri-Aria KT, Jacobson MR, Wilcock LK, Detry B, Walker SM, et al. Grass pollen immunotherapy induces an allergen-specific IgA2 antibody response associated with mucosal TGF-beta expression. J Immunol. 2007;178:4658–66.
Nouri-Aria KT, Pilette C, Jacobson MR, Watanabe H, Durham SR. IL-9 and c-kit1 mast cells in allergic rhinitis during seasonal allergen exposure: effect of immunotherapy. J Allergy Clin Immunol. 2005;116:73–9.
Passalacqua G, Albano M, Fregonese L, Riccio A, Pronzato C, Mela GS, et al. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis. Lancet. 1998;351:629–32.
Wilson DR, Nouri-Aria KT, Walker SM, Pajno GB, O’Brien F, Jacobson MR, et al. Grass pollen immunotherapy: symptomatic improvement correlates with reductions in eosinophils and IL-5 mRNA expression in the nasal mucosa during the pollen season. J Allergy Clin Immunol. 2001;107:971–6.
Lao-Araya M, Steveling E, Scadding GW, Durham SR, Shamji MH. Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol. 2014;134:1193–5.e4.
Shamji MH, Kappen JH, Akdis M, Jensen-Jarolim E, Knol EF, Kleine-Tebbe J, et al. Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI position paper. Allergy. 2017;72:1156–73.
Shaabban R, Zureik M, Soussan D, et al. Rhinitis and onset of asthma: a longitudinal-population based study. Lancet. 2008;372:1049–57.
Tran MM, Lefebvre DL, Dharma C, Dai D, Lou WYW, Subbarao P, et al. Predicting the atopic march: Results from the Canadian Healthy Infant Longitudinal Development Study. J Allergy Clin Immunol. 2018;141:601–7.e8.
Khan SJ, Dharmage SC, Matheson MC, Gurrin LC. Is the atopic march related to confounding by genetics and early-life environment? A systematic review of sibship and twin data. Allergy. 2017; https://doi.org/10.1111/all.13228. [Epub ahead of print].
Hatzler L, Panetta V, Lau S, et al. Molecular spreading and predictive value of preclinical IgE response to Phleum pratense in children with hay fever. J Allergy Clin Immunol. 2012;130:894–901.
Matricardi PM. Allergen-specific immunoprophylaxis: toward secondary prevention of allergic rhinitis? Pediatr Allergy Immunol. 2014;25:15–8.
Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, Jacobsen L, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol. 2002;109:251–6.
Moller C, Dreborg S, Lanner A, Bjorksten B. Oral immunotherapy of children with rhinoconjunctivitis due to birch pollen allergy. A double blind study. Allergy. 1986;41:271–9.
Marogna M, Tomassetti D, Bernasconi A, Colombo F, Massolo A, Businco AD, et al. Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study. Ann Allergy Asthma Immunol. 2008;101:206–11.
Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De ME, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2004;114:851–7.
Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Host A, et al. Specific immunotherapy has longterm preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007;62:943–8.
Valovirta E, Petersen TH, Piotrowska T, Laursen MK, Andersen JS, Sørensen HF, et al. Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. J Allergy Clin Immunol. 2018;141:529–38.
Grembiale RD, Camporota L, Naty S, Tranfa CM, Djukanovic R, Marsico SA. Effects of specific immunotherapy in allergic rhinitic individuals with bronchial hyperresponsiveness. Am J Respir Crit Care Med. 2000;162:2048–52.
Zolkipli Z, Roberts G, Cornelius V, Clayton B, Pearson S, Michaelis L, et al. Randomized controlled trial of primary prevention of atopy using house dust mite allergen oral immunotherapy in early childhood. J Allergy Clin Immunol. 2015;136:1541–7.
Garcia BE, Gonzalez-Mancebo E, Barber D, Martin S, Tabar AI, Diaz de Durana AM, et al. Sublingual immunotherapy in peach allergy: monitoring molecular sensitizations and reactivity to apple fruit and Platanus pollen. J Investig Allergol Clin Immunol. 2010;20:514–20.
Szepfalusi Z, Bannert C, Ronceray L, Mayer E, Hassler M, Wissmann E, et al. Preventive sublingual immunotherapy in preschool children: first evidence for safety and protolerogenic effects. Pediatr Allergy Immunol. 2014;25:788–95.
Holt PG, Sly PD, Sampson HA, Robinson P, Loh R, Lowenstein H, et al. Prophylactic use of sublingual allergen immunotherapy in high-risk children: a pilot study. J Allergy Clin Immunol. 2013;132:991–3.
Pajno GB, Bernardini R, Peroni D, Arasi S, Martelli A, Landi M, Allergen-specific immunotherapy panel of the Italian Society of Pediatric Allergy and Immunology (SIAIP), et al. Clinical practice recommendations for allergen-specific immunotherapy in children: the Italian consensus report. Ital J Pediatr. 2017;43:13.
Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, et al. Allergic rhinitis and its impact on asthma (ARIA) guidelines; 2010 revision. J Allergy Clin Immunol. 2010;126:466–76.
Bianchi A, Tsilochristou O, Gabrielli F, Tripodi S, Matricardi PM. TheSmartphone: a novel diagnostic tool in pollen allergy? J Investig Allergol Clin Immunol. 2016;26(3):204–7.
Stringari G, Tripodi S, Caffarelli C, Dondi A, Asero R, Di Rienzo BA, Bianchi A, et al. Italian pediatric allergy network (I-PAN). The effect of component-resolved diagnosis on specific immunotherapy prescription in children with hay fever. J Allergy Clin Immunol. 2014;134:75–81.
Senti G, von Moos S, Tay F, Graf N, Sonderegger T, Johansen P, et al. Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced rhinoconjunctivitis: a double-blind, placebo-controlled dose escalation study. J Allergy Clin Immunol. 2012;129:128–35.
Slovick A, Douiri A, Muir R, Guerra A, Tsioulos K, Hay E, et al. Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms. J Allergy Clin Immunol. 2017;139:1830–9.
Patterson AM, Bonny AE, Shiels WE, Erwin EA. Three-injection intralymphatic immunotherapy in adolescents and young adults with grass pollen rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2016;116:168–70.
Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Høst A, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma;10-year follow-up on the PAT study. Allergy. 2007;62:943–8.
Weyer A, Donat N, L’Heritier C, Juilliard F, Pauli G, Soufflet B, et al. Grass pollen hyposensitization versus placebo therapy. I. Clinical effectiveness and methodological aspects of a pre-seasonal course of desensitization with a four-grass pollen extract. Allergy. 1981;36:309–17.
Caffarelli C, Sensi LG, Marcucci F, Cavagni G. Preseasonal local allergoid immunotherapy to grass pollen in children: a double-blind, placebo-controlled, randomized trial. Allergy. 2000;55:1142–7.
Pajno GB, Vita D, Parmiani S, Caminiti L, La Grutta S, Barberio G. Impact of sublingual immunotherapy on seasonal asthma and skin reactivity in children allergic to Parietaria pollen treated with inhaled fluticasone propionate. Clin Exp Allergy. 2003;33:1641–7.
Valovirta E, Petersen TH, Piotrowska T, Laursen MK, Andersen JS, Sørensen HF, et al. Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. J Allergy Clin Immunol. 2017;S0091-6749(17):31088–6.
Wahn U, Tabar A, Kuna P, Halken S, Montagut A, de Beaumont O, et al. Efficacy and safety of 5-grasspollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2009;123:160–166.e3.
Roberts G, Hurley C, Turcanu V, Lack G. Grass pollen immunotherapy as an effective therapy for childhood seasonal allergic asthma. J Allergy Clin Immunol. 2006;117:263–8.
Stelmach I, Kaluzińska-Parzyszek I, Jerzynska J, Stelmach P, Stelmach W, Majak P. Comparative effect of pre-coseasonal and continuous grass sublingual immunotherapy in children. Allergy. 2012;67:312–20.
Nolte H, Bernstein DI, Nelson HS, Kleine-Tebbe J, Sussman GL, Seitzberg D, et al. Efficacy of house dust mite sublingual immunotherapy tablet in north American adolescents and adults in a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2016;138:1631–8.
Okubo K, Masuyama K, Imai T, Okamiya K, Stage BS, Seitzberg D, et al. Efficacy and safety of the SQ house dust mite sublingual immunotherapy tablet in Japanese adults and adolescents with house dust mite-induced allergic rhinitis. J Allergy Clin Immunol. 2017;139:1840–1848.e10.
Ott H, Sieber J, Brehler R, Fölster-Holst R, Kapp A, Klimek L, et al. Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study. Allergy. 2009;64:1394–401.
Bergmann KC, Demoly P, Worm M, Fokkens WJ, Carrillo T, Tabar AI, et al. Efficacy and safety of sublingual tablets of house dust mite allergen extracts in adults with allergic rhinitis. J Allergy Clin Immunol. 2014;133:1608–1614.e6.
Rice JL, Diette GB, Suarez-Cuervo C, Brigham EP, Lin SY, Ramanathan M Jr, et al. Allergen-Specific Immunotherapy in the Treatment of Pediatric Asthma: A Systematic Review. Pediatr. 2018;141(5) https://doi.org/10.1542/peds.2017-3833.
Tripodi S, Comberiati P, Di Rienzo Businco A. A web-based tool for improving adherence to sublingual immunotherapy. Pediatr Allergy Immunol. 2014;25:611–2.
Drachenberg KJ, Wheeler AW, Stuebner P, Horak F. A well-tolerated grass pollen specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid a, reduces allergic symptoms after only four preseasonal injections. Allergy. 2001;56:498–505.
DuBuske L, Frew A, Horak F, Keith P, Corrigan C, Aberer W. Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. Allergy Asthma Proc. 2011;32:239–47.
Patel P, Holdich T, von Weikersthal-Drachenberg KJ, Huber B. Efficacy of a short course of specific immunotherapy in patients with allergic rhinoconjunctivitis to ragweed pollen. J Allergy Clin Immunol. 2014;133:121–9.
Drachenberg K, Heinzkill M, Urban E. Short-term immunotherapy with tree pollen allergoids and the adjuvant monophosphoryl lipid-a - results from a multicentre, placebo-controlled, randomised, double blind study. [Kurzzeit-Immuntherapie mit Baumpollen- Allergoiden und dem Adjuvans Monophosphoryl lipid-a]. Allergologie. 2002;9:466–74.
Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006;355:1445–55.
Rolinck-Werninghaus C, Hamelmann E, Keil T, Kulig M, Koetz K, Gerstner B, et al. The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children. Allergy. 2004;59:973–9.
Larenas-Linnemann D, Wahn U, Kopp M. Use of omalizumab to improve desensitization safety in allergen immunotherapy. J Allergy Clin Immunol. 2014;133:937.
Pauli G, Larsen TH, Rak S, Horak F, Pastorello E, Valenta R, et al. Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2008;122:951–60.
Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133:291–307.
Cummings AJ, Knibb RC, King RM, Lucas JS. The psychosocial impact of food allergy and food hypersensitivity in children, adolescents and their families: a review. Allergy. 2010;65:933–45.
Arasi S, Otani IM, Klingbeil E, Bégin P, Kearney C, Dominguez TL, et al. Two year effects of food allergen immunotherapy on quality of life in caregivers of children with food allergies. Allergy Asthma Clin Immunol. 2014;10:57.
Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C, et al. EAACI food allergy and anaphylaxis guidelines group. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy. 2014;69:1008–25.
Ford LS, Taylor SL, Pacenza R, Niemann LM, Lambrecht DM, Sicherer SH. Food allergen advisory labeling and product contamination with egg, milk, and peanut. J Allergy Clin Immunol. 2010;126:384–5.
Boyano-Martínez T, García-Ara C, Pedrosa M, Díaz-Pena JM, Quirce S. Accidental allergic reactions in children allergic to cow's milk proteins. J Allergy Clin Immunol. 2009;123:883–8.
Arasi S, Pajno GB. Evidence gaps in oral immunotherapy for food allergy. Curr Treat Options Allergy. 2017;4:458–68. https://doi.org/10.1007/s40521-017-0146-0.
Jones SM, Burks AW, Keet C, Vickery BP, Scurlock AM, Wood RA, et al. Long-term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy. J Allergy Clin Immunol. 2016;137:1117–27.
Longo G, Barbi E, Berti I, Meneghetti R, Pittalis A, Ronfani L, et al. Specific oral tolerance induction in children with very severe cow’s milk-induced reactions. J Allergy Clin Immunol. 2008;121:343–7.
Pajno G, Caminiti L, Ruggeri P, de Luca R, Vita D, La Rosa M, et al. Oral immunotherapy for cow’s milk allergy with a weekly up-dosing regimen: a randomized singleblind controlled study. Ann Allergy Asthma Immunol. 2010;105:376–81.
Caminiti L, Pajno GB, Crisafulli G, Chiera F, Collura M, Panasci G, et al. Oral immunotherapy for egg allergy: a double blind placebo controlled study, with postdesensitization followup. J Allergy Clin Immunol Practice. 2015;70:99.
Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella R, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005;116:1073–9.
Kim EH, Bird JA, Kulis M, Laubach S, Pons L, Shreffler W, et al. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol. 2011;127:640–646.e1.
Zuidmeer-Jongean L, Huber H, Swoboda I, Rigby N, Versteeg S, Jensen BM, et al. Development of a hypoallergenic recombinant parvalbumin for first in man subcutaneous immunotherapy of fish allergy. Int Arch Allergy Immunol. 2015;166:41–51.
Jones SM, Sicherer SH, Burks W, Leung DYM, Lindblad RW, Dawson P, et al. Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults. J Allergy Clin Immunol. 2017;139:1242–52.
Wood RA, Kim JS, Lindblad R, Nadeau K, Henning AK, Dawson P, et al. A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow’s milk allergy. J Allergy Clin Immunol. 2016;137:1103–10.
Pajno GB, Nadeau KC, Passalacqua G, Caminiti L, Hobson B, Jay DC, et al. The evolution of allergen and non-specific immunotherapy: past achievements, current applications and future outlook. Expert Rev Clin Immunol. 2015;11:141–54.
MacGinnitie AJ, Rachid R, Gragg H, Little SV, Lakin P, Cianferoni A, et al. Omalizumab facilitates rapid oral desensitization for peanut allergy. J Allergy Clin Immunol. 2017;139:873–81.
Bonertz A, Roberts G, Slater JE, Bridgewater J, Rabin RL, Hoefnagel M, et al. Allergen manufacturing and quality aspects for allergen immunotherapy in Europe and the United States: an analysis from the EAACI AIT guidelines project. Allergy. 2017; https://doi.org/10.1111/all.13357. [Epub ahead of print].
Ryan D, Gerth van Wijk R, Angier E, Kristiansen M, Zaman H, Sheikh A, et al. Challenges in the implementation of the EAACI AIT guidelines: a situational analysis of current provision of allergen immunotherapy. Allergy. 2017; https://doi.org/10.1111/all.13264. [Epub ahead of print].
Asero R, Tripodi S, Dondi A, Di Rienzo Businco A, Sfika I, Bianchi A, et al. Prevalence and clinical relevance of IgE sensitization to profilin in childhood: a multicenter study. Int Arch Allergy Immunol. 2015;168:25–31.
We thank allergic children and their families who during many years took part in the AIT pediatric trials with commitment, patience, and kindness.
Availability of data and materials
A comprehensive search of the main medical electronic bibliographic databases was carried out.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Arasi, S., Corsello, G., Villani, A. et al. The future outlook on allergen immunotherapy in children: 2018 and beyond. Ital J Pediatr 44, 80 (2018). https://doi.org/10.1186/s13052-018-0519-4
- Allergen-specific immunotherapy
- Allergic rhinitis
- Food allergy
- IgE-mediated allergic diseases
- Oral immunotherapy
- Sub-lingual immunotherapy
- Sub-cutaneous immunotherapy