Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

Abstract The specialties of allergy and clinical immunology have entered the era of precision medicine with the stratification of diseases into distinct disease subsets, specific diagnoses, and targeted treatment options, including biologicals and small molecules. This article reviews recent developments in research and patient care and future trends in the discipline. The section on basic mechanisms of allergic diseases summarizes the current status and defines research needs in structural biology, type 2 inflammation, immune tolerance, neuroimmune mechanisms, role of the microbiome and diet, environmental factors, and respiratory viral infections. In the section on diagnostic challenges, clinical trials, precision medicine and immune monitoring of allergic diseases, asthma, allergic and nonallergic rhinitis, and new approaches to the diagnosis and treatment of drug hypersensitivity reactions are discussed in further detail. In the third section, unmet needs and future research areas for the treatment of allergic diseases are highlighted with topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease. Unknowns and future research needs are discussed at the end of each subsection.


| INTRODUC TI ON
The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals.
After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding of endotypes and phenotypes of allergic diseases, asthma, allergic and chronic rhinosinusitis ± nasal polyps, chronic obstructive pulmonary disease, and on the development of biomarkers including novel interleukins and microRNAs that regulate their expression to stratify patients. [16][17][18]

| Structural and functional biology of allergenswhere are we at?
Cloning of allergen cDNAs and sequencing of purified natural aller-  19 Structural data of allergens allow the study of of allergic diseases, asthma, allergic and nonallergic rhinitis, and new approaches to the diagnosis and treatment of drug hypersensitivity reactions are discussed in further detail. In the third section, unmet needs and future research areas for the treatment of allergic diseases are highlighted with topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen-specific immunotherapy for airway disease. Unknowns and future research needs are discussed at the end of each subsection.

K E Y W O R D S
allergy, exposome, microbiome, neuroimmune, respiratory viral infections How to expand the understanding of allergens and allergic sensitization? • Define "susceptibility to allergic sensitization" at the molecular and mechanistic level cross-reactivities between related allergens, 20 or the design of allergens with altered IgE epitopes as vaccine candidates for AIT. 21 The location of IgE-binding epitopes can be determined based on allergen structures and experimental data. 22 Various technologies exist for mapping conformational IgE epitopes. 23 X-ray crystallography of an allergen-antibody complex allows the most precise identification of conformational epitopes. To date, only two structures of cocrystals of IgE and allergen are available, Bos d 5 24 and Phl p 2, 25 both complexed with an IgE Fab. Sequence and structural data have revealed that allergens are members of a limited number of protein families (http://www.medun iwien.ac.at/allfa m/). This insight has now become mainstream knowledge and indicates that the biological functions of allergens might be linked to their allergenicity. 26 Various explanations for the existence of the allergic immune response have been brought forward including the toxin hypothesis, 27,28 the danger theory, 29 and the allergic host defense model. 30 Unequivocally, these authors [27][28][29][30] argue that it is a common misconception to regard allergens as generally harmless environmental substances. Allergens interact with innate immune receptors (eg, TLR4, 31 protease-activated receptor-2, 32 dectin-1 33 ), disrupt the integrity of membranes (eg, phospholipase A2, 34,35 defensins 36,37 ), or degrade connective tissues (eg, hyaluronidases 38 ). However, very few studies on why only susceptible individuals raise an allergic immune response have come forward. They indicate that genetic susceptibility is based on altered signal processing 39 and mutations of pattern recognition receptors. 33 F I G U R E 1 Molecular mechanisms in allergic inflammation. Epithelial leakiness and activation and their proinflammatory cytokine and chemokine (TNF-α, IL-13, TSLP, IL-25, IL-33) production induce inflammation and contribute to the Th2 response. Highly activated epithelial cells undergo apoptosis and shedding takes place. Chemokines are essential players for the recruitment of inflammatory cells followed by survival and reactivation of migrating inflammatory cells and their interaction with resident tissue cells and other inflammatory cells. Innate lymphoid cells (ILC2) play a role in T-and B-cell activation and recruitment and are early providers of type 2 cytokines and T-cell recruitment-related chemokines. The Th2 type of an immune microenvironment is characterized by IL-4, IL-5, IL-9, IL-13, IL-25, IL-33 production by Th2 cells, ILCs, mast cells, and tissue cells. Eosinophilia is induced by IL-5, IL-25, and IL-33. Local and systemic IgE production takes place in allergic patients with the involvement of IL-4 and IL-13. Other effector T-cell subsets, such as Th9, Th17, and Th22 cells, also play partial roles in inflammation, mucus production, and tissue healing. Smooth muscle, myofibroblast activation, and bronchial hyperreactivity are related to IL-4, IL-9, IL-13, IL-25, and IL-33. Several chemokines, and arachidonic acid pathway molecules and other small molecules play roles in the inflammatory cell recruitment and further augmentation of the inflammatory cascades. Treg and Breg cells play a role on control of inflammation and extensive cellular activation by using IL-10 and TGF-β as well as many other suppressive mechanisms 2.2 | Mechanisms of type 2 inflammation and immune tolerance to allergens

| Type 2 immune response
Since the discovery of T-helper (Th) subsets, it was demonstrated in the last three decades that almost all immune cells display functional subsets characterized by distinct signature cytokines and surface receptors. Generally, it is considered that a type 2 immune response is the main player in the pathogenesis of eosinophilic asthma, allergic rhinitis, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and extrinsic atopic dermatitis. 40 The type 2 immune response is an immune response to environmental noninfectious proteins and helminths, and involves Th2 cells, type 2 B cells, group 2 innate lymphoid cells, type 2 macrophages, a small fraction of IL-4secreting NK cells, IL-4-secreting NK-T cells, basophils, eosinophils, and mast cells. 41,42 From a complex network of cytokines, IL-4, IL-5, IL-9, IL-13, and IL-31 are mainly secreted from immune system cells and IL-25, IL-33, and TSLP from tissue cells, particularly epithelial cells. 43,44 (Figure 1) GATA3 is the key transcription factor for the induction of this response. 45 Both the innate and the adaptive immune response contribute to type 2 immune response. Among these cytokines, IL-4 and IL-13 play roles in production of allergen-specific IgE, IL-5 in eosinophilia, 46,47 IL-9 and IL-13 in mucus production, IL-4 and IL-13 in tissue migration of Th2 cells and eosinophils, and IL-4 and IL-13 in regulation of tight junctions and epithelial barrier integrity. 48 Type 1, type 17, type 22, and immune regulatory responses, and nonallergic mechanisms such as environmental factors, psycho-social stress, activation of metabolic pathways, resident cells in the remodeled phenotype, or epithelial barrier dysfunction further modulate the profile of type 2-driven inflammation. In addition, type 2-driven inflammation is characterized by a high cellular plasticity that enables the cells to adapt to a specific inflammatory milieu. Several subendotypes might exist within the type 2 immune response complex endotype such as the IL-5-high, IL-13-high, or IgE-high endotype, and their dominance differs between allergic diseases ( Figure 1).
Omalizumab targeting IgE, mepolizumab, reslizumab targeting IL-5, benralizumab targeting the IL-5 receptor, and dupilumab targeting the IL-4 and IL-13 common receptor alpha chain are some of the biologicals currently available to control type 2 inflammation.

| T-regulatory and B-regulatory cells
Immune regulation is an important function of the immune system to tolerate self-tissues and non-self-environmental allergens. Tregulatory (Treg) cell subsets have distinct phenotypes and include constitutive and inducible subsets of CD4 + CD25 + Forkhead box P3 (FOXP3) + Treg cells and type 1 Treg cells (Tr1). As a second major player in immune regulation, IL-10-producing B-regulatory (Breg) cells have also been demonstrated to suppress allergen-specific responses and promote IgG4 isotype antibodies. 49 Allergen tolerance in high-dose-exposed individuals such as beekeepers and cat own- identify their regulation and in vivo relevance. 53 T-and B-regulatory cells suppress many functions of type 2 inflammation including type 2 innate lymphoid cells. 54 Extensive research is ongoing in this area.
To date, there are no biologicals that induce T-and B-regulatory responses in patients; however, various modes of AIT represent major stimulators of these cells in an allergen-specific manner in vivo.

| Neuroimmune mechanisms in allergic inflammation
It is becoming increasingly clear that immune cells do not act alone and that cross talk and reciprocal regulation between neural and immune systems are essential in the pathophysiology of allergic diseases including allergic asthma, atopic dermatitis, and food allergies. 55 In addition to mediating allergic responses via immune responses, these proinflammatory mediators also directly activate sensory neurons that regulate itch, cough, sneezing, bronchoconstriction, and alterations in gastrointestinal motility. 59 On stimulation, sensory and autonomic neurons release neuropeptides and neurotransmitters such as substance P, neurokinin A, neuromedin U (NMU), calcitonin gene-related peptide, vasoactive intestinal peptide, acetylcholine, and norepinephrine that signal immune cells. 55 In the airways, calcitonin gene-related peptide is released by sensory nerves, which has been shown to inhibit dendritic cell maturation and allergen-specific T-cell responses. 61 In the gut, ILC2 cells were shown to express Nmur1, a receptor for the neuropeptide NMU. ILC2s live in close proximity to NMU-producing nerve F I G U R E 2 The exposome: The exposome includes the entire environmental exposures of an individual from conception throughout the whole life. Early-life events such as mode of delivery, breastfeeding, mother's diet, lifestyle and health status, antibiotics, and other drug usage in pregnancy and early childhood, early-life environment (ie, siblings, pets at home, proximity to farm animals and green areas, usage of primary farm products) can significantly influence the epigenetic regulation of immune system and tissue cells cells and become proinflammatory when exposed to NMU. NMU signaling can significantly amplify allergic inflammation when high levels of IL-25, IL-33, and TSLP are present. 62 In a mouse model of allergic asthma, norepinephrine was found to stimulate IgE production on binding β2-adrenergic receptors and activating B cells. 63,64 A positive feedback loop between neurotransmitters and neuropeptides and immune cells exists. However, our understanding of these interactions and the signals that mediate their responses to the ever-changing physiological and pathological conditions is still very limited.

| Exposome, environmental factors and allergy
The rising trend in allergies is associated with changes in lifestyle and the control of infections which, taken together, seem to result in an "under-challenged" immune system. 65

| Role of the microbiome and diet in immune responses
Enormous varieties of microbes colonize the skin and mucosal body surfaces. These microbes are organized within complex community structures, whose composition is dependent on the specific body site examined. It is increasingly appreciated that the microbiome interacts intimately with mucosal immune processes and disrupted communication between the microbiome and the host due to altered microbiome composition and/or metabolism is thought to negatively influence immune homeostatic networks and may play a role in immune hypersensitivity to environmental exposures, such as allergens. 75 A number of studies have consistently demonstrated that an altered gut, lung, nasal, or skin microbiome is associated with, and sometimes precedes, allergic sensitization and inflammation. 76,77 In particular, early-life events such as mode of delivery, breastfeeding, mother's diet and health status, antibiotics, and other drug usage in pregnancy and early childhood, early-life environment (ie, siblings, pets at home, proximity to farm animals and green areas, usage of primary farm products) can significantly influence the timing of bacterial colonization and establishment. [78][79][80] However, one of the most potent modulators of microbiota composition is diet, as consumed foods provide the fuel for microbial metabolic activities. 81 For example, microbiota-accessible carbohydrates (MAC) are complex carbohydrates found in dietary fibers that contribute to microbial diversity and generation of metabolites, such as short-chain fatty acids (SCFAs). 82 SCFAs promote regulatory immune responses, and high SCFA levels early in life are associated with protection from atopic sensitization. 83 In contrast, a high-fat diet is associated with negative effects on microbiota composition and metabolism.
Despite increasing awareness of the importance of microbiome-diet interactions in health and disease, the molecular basis for these multidirectional functional interactions is only beginning to be Hot spots in environmental health research   102 This translates into rapid monocyte, NK-cell, and innate T-cell (MAIT and γδ T cells) activation, evident with CD38+ and/or CD69+ upregulation. 102 Therefore, an understanding of the predominant type and underlying mechanisms of mucosal inflammation triggered by common viral infections will allow identification of targets for better management of chronic airway inflammatory diseases.

| Precision medicine and immune monitoring of allergic diseases
Precision medicine (providing the right treatment to the right patient and the right dose at the right time) requires an accurate diagnosis and monitoring of the treatment response. While precision medicine has been practiced in allergology for over a century since the advent  111 it currently infers (often synonymous with "personalized medicine") use of the new "omics" technologies to identify genes or biomarkers for diagnosis or monitoring of treatment efficacy ( Figure 3). 13,112 The "omics" revolution is based on platform technologies in genomics (by far the most robust), metabolomics, proteomics, epigenomics, transcriptomics, lipidomics, and microbiomics to generate vast global datasets, and advanced bioinformatics to interrogate and interpret the datasets using machine learning and artificial intelligence ( Figure 4). 113 Such analysis of population-based datasets can reveal novel insights to underpin therapeutic selection from an expanded range of precise biologicals. 114 Examples are emerging from patients with inborn errors of immunity (IEI) in whom the genetically defined defect can be specifically targeted with therapeutics. 115,116 The functional utility of data from the omics platforms will be further enhanced by the public release of omics datasets including Genotype-Tissue Expression (GTEx) 117 and Encyclopaedia of DNA Elements (ENCODE). 118 Technological advances in immune monitoring capability are augmented by highly standardized or chimeric recombinant allergens and peptides (B-and T-cell epitope-based). Exponential advances in microarrays, time-of-flight mass cytometry (CyTOF), basophil activation tests, next-generation gene sequencing, and RNA-seq are generating huge enabling datasets. 15,115,116,[119][120][121][122][123] The risk that small

| Allergic rhinitis and nonallergic rhinitis
Chronic rhinitis (CR) is one of the most common diseases globally, with a considerable financial burden. 126,127 At present, CR is Unmet needs in precision medicine F I G U R E 4 Omics: The omics revolution was one of the major driving forces of recent developments that enabled investigation of almost everything at the molecular level of proteins, lipids, and small molecules including innumerable DNA and RNA sequencings with a hypothesis-free approach simplistically subclassified as allergic rhinitis (AR) and nonallergic rhinitis (NAR). 128 Although phenotyping of rhinitis has important consequences in the treatment of the entity, 129 the presently employed phenotypes cannot meet the needs of precision medicine; suggesting an urgent need for the CR phenotypes to be updated with the progress of diagnostic methods. In this regard, Meng and colleagues have recently investigated the phenotypes of CR based on a cluster analysis of 12 clinical variables. 130 In this study, AR was subclassified as allergic rhinitis with or without asthma, while NAR was subclassified as nonallergic rhinitis with eosinophilia syndrome (NARES) without asthma, NARES with asthma, local allergic rhinitis (LAR), and idiopathic rhinitis. The finding of the LAR cluster was interesting because none of these patients had a history of asthma, but demonstrated high levels of local eosinophils and local production of specific IgE (local IgE), of which the latter has been used in studies of LAR over the last few years. [131][132][133] Indeed, another study by Meng and colleagues has suggested that local IgE is a reliable noninvasive alternative to serum IgE for the diagnosis of AR, 134 and there is emerging evidence that local IgE could also be used instead of nasal allergen provocation test (NAPT) for the diagnosis of LAR. Besides local IgE, nasal cytology has also been shown to be useful in the diagnosis of CR A recent study by She and colleagues assessed nasal cytology in chronic sinusitis patients with rhinitis, using the liquid-based ThinPrep Cytology Test (TCT) and demonstrated that this technique has higher sensitivity, specificity, and positive predictive value for inflammation in the inferior turbinates than for inflammation in the maxillary sinus. 135 Thus, the TCT might also be used in the studies on CR, especially NARES.
In conclusion, there is increasing evidence that local IgE and nasal cytology are useful clinical diagnostic markers in CR and might represent the way forward especially for studies differentiating the endotypes of AR and NAR in the future.

| New approaches to the diagnosis and treatment of drug hypersensitivity reactions
Drug hypersensitivity reactions (DHRs) are defined as adverse effects of pharmaceutical formulations that clinically resemble allergy. Drug allergies are defined as DHRs for which a definite immunological mechanism, IgE-or T cell-mediated, is demonstrated. 136 DHRs constitute an important health problem, affecting more than 7% of the population, 137 for whom drugs, such as beta-lactam antibiotics and nonsteroidal anti-inflammatory drugs, are essential for treatment of common diseases. 138,139 Based on the clinical characteristics of DHRs, different phenotypes have been identified, 137 although the lack in understanding the underlying mechanisms of many DHRs has hampered the definition of endotypes and identification of biomarkers. 140,141 The classification of DHRs based on the time elapsed between drug administration and development of symptoms is still a matter of debate, because it is difficult to establish a cutoff point to distinguish between immediate and nonimmediate DHRs. 13,136,141 These data are relevant for defining phenotypes and establishing an accurate diagnosis and specific treatment. An important recent advance has been the inclusion of "Drug hypersensitivity" as a subsection in the International Classification of Diseases (ICD)-11. 140 The diagnosis of DHR is mainly based on skin tests and drug provocation tests, methods that are not free of risk, still lack standardization, and differ depending on the drug, mechanisms, and even the health system. [142][143][144] There is an urgent need for developing new in vitro diagnostic tests or improving those already existing, 138 such as basophil activation test, 145,146 to improve the diagnostic workup.
The complexity of DHR diagnosis and its lack of optimal specificity lead to an over-diagnosis. This is an important problem, as patients "labeled" as allergic receive alternative treatments that are usually less effective and more toxic, so "de-labeling" constitutes a public health measure. 147 Primary care physicians are often the first point of contact for patients with DHRs; thus, they have a key role in diagnosis and need specific training. 148 Although the specific treatment of DHRs is avoiding the drug involved and those chemically related, desensitization is nowadays a frequent option. [149][150][151] In that sense, rapid drug desensitization is a cost-effective technique that activates inhibitory mechanisms and permits patients to receive the first-choice medications to which they are allergic. 149,150 Research needs for DHRs • Could nasal cytology be used in the study of chronic rhinitis, especially for the differential diagnosis of chronic rhinitis?
• Can we provide the diagnostic standard of local IgE determination for allergic rhinitis and local allergic rhinitis?
• Can we provide the diagnostic standard of nasal eosinophil count for nonallergic rhinitis with eosinophilia syndrome?

| How to treat food allergy in the future: new developments and concepts
We are observing a pandemic increase in food allergy and approaching an era of efficient treatments. In peanut allergy oral immunotherapy (OIT), phase III studies on AR101 152 in peanut allergic patients and phase II(b) and III studies on epicutaneous immunotherapy (EPIT) for milk and peanut 153,154 have been conducted. The FDA application for AR101 is submitted, while peanut EPIT submission has been retracted to provide additional technical information.
Different ways of application differ with regard to efficacy of desensitization; however, all current applications are linked to an avoidance regimen and it is unclear how long the individual treatment needs to be applied. Consistent data from conventional high-dose milk, peanut, and egg OIT report good efficacy with regard to desensitization. 155,156 Therefore, in addition to these highly standardized products, OIT using conventional food sources may become a more frequent treatment offered by clinicians in the community as a result of excessive demand in the absence of guidelines and recommendations. As a first step, the European Academy of Allergy and Clinical Immunology (EAACI) stated to consider OIT for these three foods in settings with the appropriate infrastructure and experience. 155 The major issues in treating food allergy by immunotherapy are safety, the low rate of tolerance induction, 155 76,166 ; (e) the application of biologics either alone 167,168 or as adjuvants of OIT 169,170 ; (g) very low dose OIT 171,172 ; and (h) sublingual OIT.
Recent methodological developments on cloning and antibody generation from single-cell sorting of allergen-specific B cells will allow novel insights on the nature of peanut-specific B-cell responses and may give rise to novel high-affinity blocking antibody treatments. 173

| Treatment of allergic diseases with biologics
Molecular mechanisms of type 2 inflammation in allergic disease are discussed above. Treatment of allergic disease with biologicals particularly targets type 2 inflammation. For several years, omalizumab was the only broadly applied biological in allergic diseases in childhood and adult asthma 174 and chronic urticaria. 8,175 Recently, phase III trials demonstrated efficacy by blocking the IL-4/IL-13 pathway in glucocorticoid-dependent severe asthma, moderate-to-severe uncontrolled asthma, 176,177 CRSwNP, 178 and atopic dermatitis 179 (dupilumab), by blocking IL-5 in severe eosinophilic asthma (mepolizumab, 180 reslizumab 181 ) and CRSwNP and severe uncontrolled asthma by blocking the IL-5 receptor (benralizumab 182,183 ). 184 FDA and EMA approved mepolizumab, reslizumab, and benralizumab for adult uncontrolled asthma and dupilumab for atopic dermatitis in adolescents and adults, and these biologics are integrated in current guidelines and position papers. 12,175,185,186 New indications for these biologicals can be expected in the near future. 184,187 Novel data arising from a long pipeline of cytokine and chemokine receptor targeting drugs will lead to additional treatment options and change the landscape of therapeutics in other atopic diseases including food allergy, chronic rhinosinusitis with nasal polyps, 12,188 and systemic mastocytosis. 189 Biologics may also increase efficacy and safety of AIT.
Phase II trials of biologics targeting type-2 pathways beyond IL-4, IL-5, and IL-13 are encouraging. Tezepelumab blocking the TSLP receptor showed efficacy in uncontrolled asthma independent of eosinophil counts. 190 Nemolizumab blocks the IL-31R-alpha and reduces pruritus and to a certain extent also dermatitis severity. 191

It
Unknowns in the treatment of food allergy • Which markers predict treatment response?
• Which markers can be used to monitor tolerance development?
• What is the optimal dose and time of treatment?
• Is there a role for biologics to improve safety and efficacy of immunotherapeutic approaches?
• What is the best route to apply immunotherapy?
• How can we implement oral immunotherapy safely in a community setting?
• How to modify allergen formulations for tolerance induction?
Gaps in the treatment of allergic disease with biologics • How to predict treatment response?
• Will new biologics help to promote tolerance induction?
• How to define precision medicine approaches to treat severe and complex atopic phenotypes?
• Long-term side effects of biologics?
• Safety and efficacy of biologics in childhood, in pregnancy, and in elderly?
• Novel biomarkers and sets of biomarkers will be needed.
• Treatment algorithms and guidelines for biologics usage are needed.
is a good example for biologicals with the potential to be combined with a second to achieve better disease control. Another important group of emerging biologics will address mucosal inflammation 44,192 and upstream events which are key for innate lymphoid cells such as anti-IL-25 and anti-IL-33.
Costs are an important factor when prescribing biologics.
Currently, direct treatment expenses only partially contribute to the overall disease-associated financial burden. 193,194 Thus, costs related to comorbidities 195 and the impact of biologics on these factors will be key. The development of biomarkers, prediction models, 5,196 the design of trials comparing different biologics and the implementation of strategies to investigate the safety, function, and efficacy in children, the elderly, and pregnant women represent additional crucial challenges that need to be answered in the near future.

| Small molecules for the treatment of allergic asthma
Several targeted therapeutic options for asthma and related con-

| Novel therapeutic concepts in AIT for airway disease
Allergen-specific immunotherapy not only reduces symptoms in patients with AR, 106 LAR, 1 and asthma, 106,210 but there is also evidence that AIT can reduce the development of asthma and new sensitizations, [210][211][212] thus being the only available disease-modifying treatment. Altogether, albeit not all of the highest quality, there is evidence that AIT can halt the allergic march in patients with AR. 213 Moreover, there is some evidence that AIT is cost-effective in AR with or without asthma. 214 Allergen-specific immunotherapy is usually given as subcutaneous injections 215,216 or sublingually, 217-219 but novel treatment forms such as peptide immunotherapy, 11,220 intralymphatic immunotherapy 11,220 and use of recombinant allergens, and immune-modulating adjuvants and nanoparticles 21,220,221 are under development.
Despite this positive profile, AIT is only used for highly selected patient groups in most countries in Europe. 109 The reasons for this limited penetration are multifold 16,103,222 but the long duration of the treatment, the potential side effects especially in groups that could most benefit from AIT, and the inability to predict development of allergic disease and response to AIT treatment are among the most important ones. Recently, EAACI has been very active in providing guidelines for immunotherapy 109,223 to help physicians and patients in their decisions. However, for further expansion of AIT, we must influence the balance between allergenicity and immunogenicity, which can improve both duration of treatment and create a better side effect profile. Furthermore, we need greater understanding of the molecular mechanisms underlying the development Research needs for treatment with novel small molecules • Sensitive and reliable point-of-care biomarkers to identify potential responders and to monitor (long-term) effects of anti-lipid mediator small molecules (LM, LTRA, CRTH2 antagonists).
• Combining LTRA and CRTH2 antagonists may be beneficial in patients with type 2 inflammatory conditions and, hence, warrants further clinical investigation.
• Since both DP2/CRTH2 receptors and CysLT1 receptors are present on both immune/inflammatory and structural cells, apart from anti-inflammatory activity, blocking these receptors may potentially have disease-modifying effects ("anti-remodeling"). of respiratory allergic disease and of AIT at the level of the individual patient, facilitating better patient stratification for AIT to further improve optimal personalized treatment. 16