Ann Allergy Asthma Immunol xxx (2016) 1e5

Contents lists available at ScienceDirect

Review

Orphan immunotherapies for allergic diseases Erminia Ridolo, MD *; Marcello Montagni, MD *; Cristoforo Incorvaia, MD y; Gianenrico Senna, MD z; Giovanni Passalacqua, MD x * Department

of Clinical and Experimental Medicine, University of Parma, Parma, Italy Allergy/Pulmonary Rehabilitation, ICP Hospital, Milan, Italy z Allergy Unit, Verona University Hospital, Verona, Italy x Allergy and Respiratory Diseases, IRCCS San Martino-IST-University of Genoa, Genoa, Italy y

A R T I C L E

I N F O

Article history: Received for publication August 18, 2015. Received in revised form December 28, 2015. Accepted for publication December 30, 2015.

A B S T R A C T

Objective: As confirmed by systematic reviews and meta-analyses, allergen immunotherapy is clinically effective in the treatment of allergic diseases. In particular, subcutaneous immunotherapy is a pivotal treatment in patients with severe reactions to Hymenoptera venom, whereas subcutaneous immunotherapy and sublingual immunotherapy are indicated in the treatment of allergic rhinitis and asthma by inhalant allergens. Other allergies related to animal dander (other than cat, which is the most studied), such as dog, molds, occupational allergens, and insects, have also been recognized. For these allergens, immunotherapy is poorly studied and often unavailable. Thus, use of the term orphan immunotherapies is appropriate. Data Sources: We used MEDLINE to search the medical literature for English-language articles. Study Selection: Randomized, controlled, masked studies for orphan immunotherapies were selected. In the remaining cases, the available reports were described. Results: The literature on food desensitization is abundant, but for other orphan allergens, such as mosquito, Argas reflexus, dog, or occupational allergens, there are only a few studies, and most are small studies or case reports. Conclusion: Orphan immunotherapy is associated with insufficient evidence of efficacy from controlled trials, an erroneous belief of the limited importance of some allergen sources, and the unlikelihood for producers to have a profit in making commercially available extracts (with an expensive process for registration) to be used in few patients. It should be taken into consideration that adequate preparations should be available also for orphan allergens. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction Allergen immunotherapy (AIT) is the only disease-modifying treatment for allergy because of its ability to affect the TH2-biased immune response, whereas pharmacotherapy acts only on mediator- or receptor-related symptoms.1 AIT was introduced more than a century ago for the treatment of pollen allergy.2,3 Its effectiveness has been experimentally demonstrated since 1954, when the first controlled trial was published.4 In subsequent years, the efficacy and safety of AIT were clearly confirmed in patients with allergic rhinitis and asthma and for the treatment of Hymenoptera venom allergy.5e7 In addition, the understanding of the immunologic mechanism of AIT rapidly improved.8 Currently, the routes of administration available in clinical practice are subcutaneous and sublingual. In sublingual immunotherapy (SLIT), the allergen Reprints: Giovanni Passalacqua, MD, Allergy and Respiratory Diseases, IRCCS San Martino-IST-University of Genoa, Pad.Maragliano, L.go R.Benzi 10, 16133 Genoa, Italy; E-mail: [email protected]. Disclosures: Authors have nothing to disclose.

(tablet or drops) must be kept under the tongue for 1 to 2 minutes and then swallowed. In addition to these traditional routes, other modalities of administration, such as the epicutaneous and intralymphatic, have been developed for a future use.9,10 These characteristics make AIT a cornerstone of therapy for patients with respiratory allergy and insect venom allergy and allow us to hypothesize a role for other forms of allergic diseases. Because of its importance in the treatment of allergic diseases, numerous scientific societies have developed guidelines on AIT.11e15 AIT remains formally indicated when an IgE-mediated mechanism is clearly demonstrated; therefore, in patients with proven IgE sensitization to allergens with a clinical significance, AIT is indicated. AIT is currently used in clinical practice to treat respiratory allergy due to pollens, dust mites, or Hymenoptera venom allergy, but for other less frequently studied allergens, the clinical efficacy has not been fully proven. These less frequently studied allergens include aeroallergens such as animal dander other than cat, molds, and occupational allergens. In IgE-mediated food allergy, immunotherapy seems to be a promising therapeutic approach. In this

http://dx.doi.org/10.1016/j.anai.2015.12.031 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

2

E. Ridolo et al. / Ann Allergy Asthma Immunol xxx (2016) 1e5

field, numerous trials are available; therefore, AIT for the treatment of food allergy is be considered as an orphan immunotherapy. The aim of this review is to summarize the studies published to date on the use of orphan immunotherapy, considering the rarity of allergenic sources and the paucity of controlled trials. Food Allergy One of the major public health concerns that heavily affects the quality of life is food allergy.16 Because of the lack of approved treatment for patients with food allergies, the only standard of care is a strict dietary avoidance of the properly diagnosed food allergens. Moreover, access to emergency medications, such as selfinjectable epinephrine, systemic steroids, and antihistamines, in the case of ingestion of those allergens is mandatory. Milk, egg, peanut, tree nuts, wheat, soy, fish, and shellfish are the most common food allergens that elicit IgE-mediated reactions. In the case of food allergy, AIT should not be strictly considered an orphan immunotherapy because the literature is abundant on milk, egg, and peanut allergies.17e19 Overall, the clinical results are favorable because tolerance can be achieved in most patients, although the desensitization procedure is time-consuming, and adverse events (systemic and severe) are relatively frequent. In addition, it is not still clear whether the tolerance induction obtained with SLIT or oral desensitization is permanent or transient and whether these procedures can be considered AIT in the classic sense. For these reasons, desensitization to foods remains an experimental approach and is not recommended for clinical practice. Animal Allergy (Other Than Cat) Respiratory allergic diseases due to the sensitization to animal allergens are common. The responsible allergens can be present in the urine, saliva, and secretions of the animals or dried on fur, bedding, or other vectors so that the antigen can become airborne via different size particles. To date, clear evidence of the efficacy of AIT is available only for cat, for which a clear dose-response effect has been demonstrated,20 whereas for other culprit animal allergens, the clinical efficacy is not sufficiently proven.12e15 For instance, although dog is a relatively common allergenic source, there is only one randomized clinical trial available.21 Laboratory animal allergy is an important occupational health problem that affects basic research, pharmaceutical, and toxicologic sectors and may have a serious effect on workers.21 An open-label study was performed in 23 patients with laboratory animal allergy: 11 received AIT with different laboratory animal allergen extracts (5 mouse, 6 rat, 1 rabbit) and were matched to 12 untreated patients. Nine of 11 patients subjectively improved with AIT.22 More recently, Hansen et al23 treated patient with respiratory allergy due to rat epithelium with severe rhinoconjunctivitis and bronchial asthma with AIT for 18 months. The patients had a significant improvement of symptoms and a decrease of specific IgE toward rat epithelium (after 18 months of treatment, specific IgE against rat epithelium was undetectable). Horse dander may cause severe respiratory allergy and anaphylaxis.24 A noncontrolled study by Fernández-Távora et al25 was performed on 24 horse allergic patients, revealing the safety and efficacy of horse AIT. All these patients had asthma and rhinoconjunctivitis with or without skin symptoms. A purified extract was used for immunotherapy in a cluster (87%) or conventional (13%) schedule. Then maintenance doses were administered up to 5 years (median, 7.4 months; range, 5e63 months). Five adverse reactions were observed in 4 patients. Conjunctivitis symptoms were reduced in all patients, rhinitis symptoms in 93% of patient, asthmatic symptoms in 90% of patients, and cutaneous symptoms in 87% of patients.

Dog immunotherapy based on the use of natural extracts was reported as less efficacious compared with cat immunotherapy.26 However, a great variability in the quality of commercial dog dander extracts was also reported.27 Recently, a tetrameric molecule, comprising the 4 dog lipocalin allergens Can f 1, Can f 2, Can f 4, and Can f 6, with the specific folds of the 4 allergens conserved, was constructed.28 This multimeric allergen induced high concentrations of dog allergenespecific blocking IgG antibodies and reduced IgE specific production compared with the mix of dog allergens. However, no trial on this preparation is currently available. Mosquito Allergy Allergic reactions to mosquito bites are not uncommon and may cause systemic reactions, such as generalized urticaria, angioedema, wheezing, or anaphylaxis.29e31 Moreover, mosquitoderived airborne allergens might be relevant inhalant allergens in allergic respiratory diseases.32 Reactions to mosquito bites can be immune mediated because of specific IgE sensitization to the mosquito salivary proteins, which are significantly increased in individuals with systemic allergic reactions.33 In addition, IgG- and T-lymphocyteemediated reactions can be involved.31,33 To date, only a few attempts have been made to treat this form of allergy with AIT.34e36 In a pilot study, 2 patients who experienced systemic anaphylaxis from mosquito bites received AIT based on whole-body mosquito extracts (Aedes aegypti). Complete disappearance of the adverse reactions to mosquito bites was observed in one patient, whereas the other reported only a partial improvement.34 Ariano et al35 treated 20 mosquito allergic individuals with large local reactions and rhinitis after mosquito bites, using an Aedes communis whole-body extract by the subcutaneous route for 18 months. All individuals reported the disappearance of the severe local reactions and rhinitis, which were statistically correlated with an improvement in symptom and medication scores and a decreased allergic reactivity on nasal provocation tests with mosquito extract.35 In a randomized, double-blind, placebo-controlled trial, 40 patients with asthma, rhinitis, or both were treated with a Culex quinquefasciatus extract for 1 year, achieving a significant improvement in skin reactivity, symptom scores (rhinitis and asthma), and forced expiratory volume in 1 second.36 Moreover, in the active group, the serologic analysis revealed a slight reduction in IgE levels (P ¼ .02) and a significant increase in IgG4 (P ¼ .001), with a significant decrease in the IgE/IgG4 ratio (P ¼ .001). No change was statistically significant in the placebo group. It must be underlined that in the aforementioned trials that an IgE-mediated mechanism was not always clearly proven. Allergy to Tick Bites The bite of the European pigeon tick (Argas reflexus) can cause local inflammatory reactions and anaphylaxis. A reflexus is a soft tick with a lifetime of up to 10 years that feeds on blood only once or twice yearly. Without eating, it can survive up to 9 years (more commonly, 3e5 years). Because of the increasing number of domestic pigeons in Middle and Southern Europe, infestations of pigeon-breeding sites by A reflexus are becoming a relevant problem. Removing pigeons from houses and buildings is difficult because A reflexus seeks and accepts human beings as substitute hosts.37 Allergic reactions to A reflexus are uncommon but not particularly rare. A previous immunologic study38 of 13 patients with anaphylactic reactions constructed a complementary DNA expression library to identify the lipocalin Arg r 1 as the major allergen. Thus far, the only attempts to perform AIT were based on whole-body A reflexus extracts from which the major allergen could be extracted,39 which may not ensure sufficient content of the major allergen for immunotherapy and diagnosis of allergy.37

E. Ridolo et al. / Ann Allergy Asthma Immunol xxx (2016) 1e5

Fungal Allergy Sensitization to fungi is relatively frequent in asthmatic patients. and it has been suggested that fungal sensitivity might be a risk factor for severe asthma.40 Overall, 107 allergens from 28 fungal genus have been approved by the International Allergen Nomenclature Subcommittee.41 However, only a few species were investigated thus far. The clinical spectrum of hypersensitivity reactions elicited by fungi is broad and includes IgE-mediated type 1 allergy.42,43 Besides asthma, specific IgE antibodies against fungi can be detected in patients with rhinosinusitis, allergic bronchopulmonary aspergillosis, and atopic dermatitis. A small number of studies evaluated the role and efficacy of AIT with fungal extracts in patients with IgE-mediated respiratory allergy44e52 (Table 1). The fungal species mostly investigated are Alternaria and Cladosporium

3

(1 single study44), particularly in patients with asthma. Horst et al45 conducted a double-blind, placebo-controlled trial of subcutaneous immunotherapy (SCIT) in patients monosensitized to Alternaria, starting the treatment with a 2-day rush protocol and continuing with maintenance injections, which were administered for 1 year. At the end of the study, global symptom-medication scores, including asthma and rhinoconjunctivitis, were significantly lower in the actively treated group. In patients with allergic fungal sinusitis, the role of AIT was evaluated only in small open-label studies.46,47 In these studies, all based on SCIT, the treatment with fungal extract seemed to be effective in reducing symptoms and the use of steroids, and a good safety profile was documented. A recent article reviewed the cases of allergic fungal sinusitis treated with SLIT from 2007 to 2011. Decreases in clinical symptoms and serum IgE levels, accompanied by a good safety profile,

Table 1 Available controlled trials with orphan immunotherapy Source

Route

Design

Cladosporium Dreborg et al44

SCIT

RDBPC

Alternaria Cantani et al49

SCIT

Horst et al45

No. of patients

Duration

Main results

30

10 mo

Medication scores were significantly lower in the active group (P < .01), whereas bronchial (P < .01) and conjunctival sensitivity (P ¼ .01) were significantly reduced in the Cladosporium-treated group but not in the placebo group after 10 months of treatment.

Prospective case-control

39

3y

SCIT

RDBPC

24

1 year

Melzer et al48

SLIT

Retrospective

10

4y

Tabar et al50

SCIT

Retrospective

129

Tabar et al51

SCIT

RDBPC

28

1y

Cortellini et al52

SLIT

RDBPC

27

10 mo

After 3 years, all patients in the active group reported clinical a improvement, whereas symptoms worsened in 87.5% of the control patients. Symptom-medication scores, including asthma and rhinoconjunctivitis, were significantly lower in the active group (P < .005). Specific IgG increased significantly in the active group. Decreases in subjective symptoms, examination findings, Lund-McKay scores, and serum IgE levels. Risk of adverse reactions significantly higher in children, patients with asthma, and during the initial phase of treatment. Patients with adverse reactions had higher levels of total and specific IgE. Significant improvement found in respiratory symptoms in the active group. Peak expiratory flow increased significantly only in the active group. Asthma severity decreased in the active treatment group. Patients undergoing active SLIT had a significant improvement in symptoms and a reduction in medication intake vs placebo and vs the runin season. No change in the placebo group. Skin prick test reactivity significantly decreased only in the SLIT group. No change in specific IgG4 in both groups. Alt a 1 specific IgE significantly increased in the active group.

Dog Hedlin et al26

SCIT

RDBPC

Mosquito Srivastava et al36

SCIT

RDBPC

Wheat Flour Armentia et al54

SCIT

RDBPC

32 (14 cat, 11 dog. all placebo switched to active

>1 y

3y

In the dog-allergen treated group, 5 of 11 patients had fewer symptoms when they were exposed to dogs. Symptoms of bronchial hyperresponsiveness decreased in 3 and increased in 1 patient. In the dog allergen treated group, there was no significant change of PC.

40

1y

Significant decrease in intradermal reactivity, symptom scores. and nonspecific bronchial reactivity. Significant increase in IgG4.

30

20 mo

Significant decrease in hyperresponsiveness to methacholine (P < .001), skin sensitivity (P ¼ .002), and specific IgE to wheat flour (P < .005).

Abbreviations: PC, placebo controlled; RDBPC, randomized, double-blind, placebo-controlled; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy.

4

E. Ridolo et al. / Ann Allergy Asthma Immunol xxx (2016) 1e5

were observed, leading the authors to conclude that SLIT appears to be a safe adjunct to the management of allergic fungal sinusitis that may improve patient outcomes.48 In an observational study, Tabar at al50 described an overall symptomatic improvement despite adverse events occurring in approximately 35% of patients. These events were mostly systemic (rhinitis, asthma, urticaria) but were mild in severity, and no anaphylaxis occurred. The same authors51 in a randomized clinical trial reported an improvement with Alternaria SCIT for rhinitis symptoms only. Cortellini et al52 performed a double-blind, placebo-controlled SLIT trial in 27 patients with respiratory allergy to Alternaria. After treatment, those patients receiving active treatment had a significant improvement in symptoms and a reduction in medication use, whereas no change was found in the placebo group.

Aspergillum, and Cladosporium, is still low, and the lack of diagnosis obviously prevents AIT. The same is true for occupational allergies, which, although relatively rare, can pose important ethical and medicolegal problems.60 On the contrary, in allergies that are easily recognized, such as baker’s asthma, which is one of the leading causes of occupational asthma, no standardized treatment products are available to date. On the basis of the ongoing identification of the major allergens of cereal allergens.61 adequate preparations will need to be produced for selected patients. In general, the rarity of some allergic diseases (and allergenic sources) makes it difficult to develop large clinical trials62 and resources to standardize extracts that would be used in a limited number of patients (Table 1). Nonetheless, orphan immunotherapy should always be taken into account for rare allergies.

Cereal Flour Allergy Respiratory allergies are common among bakery workers. Wheat is the most frequently responsible allergenic source, although other cereals, such as rye, barley, rice, maize, and oat, may be involved. Baker’s asthma is one of the most common types of occupational allergy, and its prevalence does not seem to decrease.53 The demonstration of the efficacy of AIT in treating baker’s asthma is essentially based only on older studies. The only double-blind, placebo-trial conducted to date54 was performed on 30 asthmatic patients treated with an aqueous wheat flour extract for up to 20 months (20 patients received SCIT and 10 received placebo). After the AIT course, actively treated patients had a significant clinical improvement, a decrease in bronchial hyperresponsiveness (increase in the methacholine threshold provocative dose), and a decrease in specific skin reactivity. Some case reports and a retrospective study seemed to confirm the efficacy of AIT in baker’s asthma.55,56 However, the lack of standardized extracts is the main drawback of immunotherapy in baker’s asthma, which reflects the uncertainty of the role of the different wheat proteins in causing occupational diseases. In 2007, the case of a patient with asthma from flour inhalation and gastrointestinal symptoms from cereal-based foods who was successfully treated with SLIT by a 4-cereal mix (wheat, rye, barley, and oats) commercially available in the array of grass allergens was reported. Starting 6 months after SLIT initiation, the patient had an increasing tolerance to ingestion of cereals and respiratory exposure to flour. After 1 year he had no more flour-induced asthma and was able to eat small amounts of bread and pasta without gastrointestinal symptoms. After 2 years, he could eat normal servings of any bakery product. One may argue that in a single case the clinical improvement may be spontaneous, but the remarkable decrease of cereal specific IgE supports the immunologic aspect. In fact, the level changed from 38.7 to 9.2 kU/L for wheat, 40.1 to 8.2 kU/L for barley, 29.2 to 6.6 kU/L for rye, and greater than 100 to 43.4 kU/L for oats.57 These findings suggest that the effectiveness of the 4-cereal mix should be investigated in randomized clinical studies. Conclusions There is insufficient evidence from controlled trials of the efficacy of orphan immunotherapy. Another issue regarding orphan immunotherapy is the erroneous belief of a limited importance for some allergen sources, which is the case for fungal allergy. It is apparent that most physician are not informed about the increasingly important role of molds as a cause of allergy and particularly asthma exacerbations.58 As indicated by the findings of epidemiologic studies, the presence of dampness and molds in the human environment is frequent, being traced in 18% to 50% of buildings, and the risk of allergic sensitization is much higher in damp dwellings.59 Awareness of the importance of fungal allergy, including the most clinically relevant species, Alternaria,

References [1] Jutel M, Akdis CA. Immunological mechanisms of allergen-specific immunotherapy. Allergy. 2011;66:725e732. [2] Noon L, Cantab BC, Eng FR. Prophylactic inoculation against hay fever. Lancet. 1911;177:1572e1573. [3] Frati F, Incorvaia C, Lombardi C, Senna G. Allergen immunotherapy: 100 years, but it does not look like. Eur Ann Allergy Clin Immunol. 2012;44:99e106. [4] Frankland A, Augustin R. Prophylaxis of summer hay fever and asthma: a controlled trial comparing crude grass pollen extract with the isolated main protein components. Lancet. 1954;266:1055e1058. [5] Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007;1:CD001936. [6] Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;4:CD001186. [7] Boyle RJ, Elremeli M, Hockenhull J, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev. 2012; 10:CD008838. [8] Akdis M, Akdis CA. Therapeutic manipulation of immune tolerance in allergic disease. Nat Rev Drug Discov. 2009;8:645e660. [9] Senti G, Graf N, Haug S, Rüedi N, et al. Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy. J Allergy Clin Immunol. 2009;124:997e1002. [10] Senti G, Prinz Vavricka BM, Erdmann I, et al. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci U S A. 2008;105:17908e17912. [11] Zuberbier T, Bachert C, Bousquet PJ, et al. J. GA2LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis and asthma. Allergy. 2010;65:1525e1530. [12] Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 suppl):S1eS55. [13] Jutel M, Agache I, Bonini S, et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015;136:556e568. [14] Walker SM, Durham SR, Till SJ, et al; British Society for Allergy and Clinical Immunology. Immunotherapy for allergic rhinitis. Clin Exp Allergy. 2011;41: 1177e1200. [15] Canonica GW, Bousquet J, Casale T, et al. Sub-lingual immunotherapy: World Allergy Organization position paper 2009. World Allergy Organ J. 2009;2: 233e281. [16] Muraro A, Werfel T, Hoffmann-Sommergruber K, et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy. 2014;69:1008e1025. [17] Passalacqua G, Landi M, Pajno G. Oral immunotherapy in cow milk allergy. Curr Opin Allergy Immunol. 2012;12:271e277. [18] Romantsik O, Bruschettini M, Tosca MA, et al. Oral and sublingual immunotherapy for egg allergy. Cochrane Database Syst Rev. 2014;11:CD010638. [19] Anagnostou K, Clark A. Peanut immunotherapy. Clin Transl Allergy. 2014;4:30. [20] Nanda A, O’connor M, Anand M, et al. Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract. J Allergy Clin Immunol. 2004;114:1339e1344. [21] Crivellaro M, Senna G, Marcer G, Passalacqua G. Immunological treatments for occupational allergy. Int J Immunopathol Pharmacol. 2013;26:579e584. [22] Wahn U, Siraganian RP. Efficacy and specificity of immunotherapy with laboratory animal allergen extracts. J Allergy Clin Immunol. 1980;65:413e421. [23] Hansen I, Hörmann K, Klimek L. Specific immunotherapy in inhalative allergy to rat epithelium. Laryngorhinootologie. 2004;83:512e515. [24] Gawlik R, Pitsch T, Dubuske L. Anaphylaxis as a manifestation of horse allergy. World Allergy Organ J. 2009;2:185e189. [25] Fernández-Távora L, Rico P, Martín S. Clinical experience with specific immunotherapy to horse dander. J Investig Allergol Clin Immunol. 2002;12: 29e33. [26] Hedlin G, Graff-Lonnevig V, Heilborn H, et al. Immunotherapy with cat- and dog-dander extracts, V: effects of 3 years of treatment. J Allergy Clin Immunol. 1991;87:955e964.

E. Ridolo et al. / Ann Allergy Asthma Immunol xxx (2016) 1e5 [27] Curin M, Reininger R, Swoboda I, Focke M, Valenta R, Spitzauer S. Skin prick test extracts for dog allergy diagnosis show considerable variations regarding the content of major and minor dog allergens. Int Arch Allergy Immunol. 2011;154:258e263. [28] Nilsson OB, Neimert-Andersson T, Bronge M, et al. Designing a multimer allergen for diagnosis and immunotherapy of dog allergic patients. PLoS One. 2014;9:e111041. [29] Peng Z, Simons FE. Advances in mosquito allergy. Curr Opin Allergy Clin Immunol. 2007;7:350e354. [30] Reiter N, Reiter M, Altrichter S, et al. Anaphylaxis caused by mosquito allergy in systemic mastocytosis. Lancet. 2013;382:1380. [31] Peng Z, Beckett AN, Engler RJ, Hoffman DR, Ott NL, Simons FE. Immune responses to mosquito saliva in 14 individuals with acute systemic allergic reactions to mosquito bites. J Allergy Clin Immunol. 2004;114:1189e1194. [32] Kausar MA, Vijayan VK, Bansal SK, Menon BK, Vermani M, Agarwal MK. Mosquitoes as sources of inhalant allergens: clinicoimmunologic and biochemical studies. J Allergy Clin Immunol. 2007;120:1219e1221. [33] Peng Z, Simons FE. Mosquito allergy: immune mechanisms and recombinant salivary allergens. Int Arch Allergy Immunol. 2004;133:198e209. [34] McCormack DR, Salata KF, Hershey JN, et al. Mosquito bite anaphylaxis: immunotherapy with whole body extracts. Ann Allergy Asthma Immunol. 1995;74:39e44. [35] Ariano R, Panzani RC. Efficacy and safety of specific immunotherapy to mosquito bites. Allerg Immunol (Paris). 2004;36:131e138. [36] Srivastava D, Singh BP, Sudha VT, Arora N, Gaur SN. Immunotherapy with mosquito (Culex quinquefasciatus) extract: a double-blind, placebocontrolled study. Ann Allergy Asthma Immunol. 2007;99:273e280. [37] Kleine-Tebbe J, Heinatz A, Gräser I, et al. Bites of the European pigeon tick (Argas reflexus): risk of IgE-mediated sensitizations and anaphylactic reactions. J Allergy Clin Immunol. 2006;117:190e195. [38] Hilger C, Bessot JC, Hutt N, et al. IgE-mediated anaphylaxis caused by bites of the pigeon tick Argas reflexus: cloning and expression of the major allergen Arg r 1. J Allergy Clin Immunol. 2005;115:617e622. [39] Rolla G, Nebiolo F, Marsico P, et al. Allergy to pigeon tick (Argas reflexus): demonstration of specific IgE-binding components. Int Arch Allergy Immunol. 2004;135:293e295. [40] Neukirch C, Henry C, Leynaert B, et al. Is sensitization to Alternaria alternata a risk factor for severe asthma? a population-based study. J Allergy Clin Immunol. 1999;103:709e711. [41] Twaroch TE, Curin M, Valenta R, et al. Mold allergens in respiratory allergy: from structure to therapy. Allergy Asthma Immunol Res. 2015;7:205e220. [42] Crameri R, Garbani M, Rhyner C, Huitema C. Fungi: the neglected allergenic sources. Allergy. 2014;69:176e185. [43] Coop CA. Immunotherapy for mold allergy. Clin Rev Allergy Immunol. 2014;47: 289e298. [44] Dreborg S, Agrell B, Foucard T, et al. A double-blind, multicenter immunotherapy trial in children, using a purified and standardized Cladosporium herbarum preparation. Allergy. 1986;41:131e140.

5

[45] Horst M, Hejjaoui A, Horst V, Michel FB, Bousquet J. Double blind, placebo controlled rush immunotherapy with a standardized Alternaria extract. J Allergy Clin Immunol. 1990;85:460e472. [46] Mabry RL, Marple BF, Folker RJ. Immunotherapy for allergic fungal sinusitis: three years’ experience. Otolaryngol Head Neck Surg. 1998;119:648e651. [47] Greenhaw B, deShazo RD, Arnold J, et al. Fungal immunotherapy in patients with allergic fungal sinusitis. Ann Allergy Asthma Immunol. 2001;107: 432e436. [48] Melzer JM, Driskill BR, Clenney TL, et al. Sublingual immunotherapy for allergic fungal sinusitis. Ann Otol Rhinol Laryngol. 2015;124:782e787. [49] Cantani A, Businco E, Maglio A. Alternaria allergy: A three-year controlled study in children treated with immunotherapy. Allergol Immunopathol. 1988; 16:1e4. [50] Tabar AI, Lizaso MT, Garcia BE, Echechipía S, Olaguibel JM, Rodríguez A. Tolerance of immunotherapy with a standardized extract of Alternaria tenuis in patients with rhinitis and bronchial astma. J Investig AIlergol Clin Immunol. 2000;10:327e333. [51] Tabar AI, Lizaso MT, García BE, et al. Double-blind, placebo-controlled study of Alternaria alternata immunotherapy: clinical efficacy and safety. Pediatr Allergy Immunol. 2008;19:67e75. [52] Cortellini G, Spadolini I, Patella V, et al. Sublingual immunotherapy for Alternaria-induced allergic rhinitis: a randomized placebo-controlled trial. Ann Allergy Asthma Immunol. 2010;105:382e386. [53] Malo JL, Chan-Yeung M. Agents causing occupational asthma. J Allergy Clin Immunol. 2009;123:545e550. [54] Armentia A, Martin-Santos JM, Quintero A. Baker’s asthma: prevalence and evaluation of immunotherapy with a wheat flour extract. Ann Allergy. 1990; 65:265e272. [55] Swaminathan S, Heddle RJ. Wheat flour immunotherapy in baker’s asthma. Intern Med J. 2007;37:663e664. [56] Cirla AM, Lorenzini MA, Cirla PE. Specific immunotherapy and relocation in occupational allergic bakers. Gior It Med Lav Ergon. 2007;29:443e445. [57] Incorvaia C, Riario-Sforza GG, Mauro M, et al. A case for treatment with sublingual immunotherapy in asthma and food allergy to cereals. Allergy. 2007;62(suppl 83):263e264. [58] Incorvaia C, Ridolo E. In the strategies to prevent asthma exacerbations, allergic asthma needs specific treatment. Curr Med Res Opin. 2015;31: 821e823. [59] Quansah R, Jaakkola MS, Hugg TT, et al. Residential dampness and molds and the risk of developing asthma: a systematic review and meta-analysis. PLoS One. 2012;7:e47526. [60] Moscato G, Rolla G, Siracusa A. Occupational rhinitis: consensus on diagnosis and medicolegal implications. Curr Opin Otolaryngol Head Neck Surg. 2011;19: 36e42. [61] Brant A. Baker’s asthma. Curr Opin Allergy Clin Immunol. 2007;7:152e155. [62] Kaul S, May S, Lüttkopf D, Vieths S. Regulatory environment for allergenspecific immunotherapy. Allergy. 2011;66:753e764.