Allergen-specific immunotherapy for respiratory allergies: From meta-analysis to registration and beyond

Article Outline

• Abstract
• Where are we now?
  • International recommendations
  • Registration of SIT products
  • Standardization of allergens
  • Subcutaneous immunotherapy
    • Efficacy
    • Safety
    • Indications
    • Impact of SCIT on the natural history of allergic disease
    • Economic evaluation of SCIT
  • Sublingual immunotherapy
    • Efficacy
    • Safety
    • Indications
    • Impact of SLIT on the natural history of allergic disease
    • Economic evaluation of SLIT
  • Comparison of sublingual and subcutaneous immunotherapies
• Where are we going?
  • International recommendations
  • Clinical trial reporting
  • Safety
  • Registration of SIT products
  • Standardization of allergens
  • Economic evaluation of SIT
  • Indications for SIT
• References
• Copyright

Allergen-specific immunotherapy (SIT) is an etiology-based treatment for respiratory and Hymenoptera-allergic diseases. Although introduced a century ago, SIT was not widely accepted for many years until its efficacy in the treatment of both allergic rhinoconjunctivitis and allergic asthma was demonstrated in appropriate double-blind, placebo-controlled trials and its mechanism of action was better understood. The indications for allergen-specific immunotherapy have been specified in consensus reports. Allergen-specific immunotherapy is primarily targeted to benefit patients with Hymenoptera allergy or severe upper and mild to moderate lower allergic respiratory diseases that are poorly controlled by pharmacologic treatments or who are unable or unwilling to use the latter. Several recent developments have helped to reinforce the position of SIT in the overall therapeutic management of respiratory allergies: (1) improvement in the quality of allergen extracts as a result of standardization, (2) better understanding of SIT's mechanism of action, (3) the introduction of sublingual tablets and their rigorous registration as pharmaceutical therapies by regulatory agencies, and (4) rationalization of prescribing patterns.

There is a requirement for additional well designed, well executed, randomized trials in adults and children with allergic rhinitis and asthma, with a special focus on optimal patient selection, dosage, and treatment duration.

In this review, the authors put into perspective current international expert recommendations on the use of SIT (in relation to levels of clinical evidence) and analyze what is needed for the future.

Key words: Specific immunotherapy, allergic rhinitis, allergic asthma, allergens

Abbreviations used: EMA, European Medicines Agency, IR, Index of reactivity, SCIT, Subcutaneous immunotherapy, SIT, Specific immunotherapy, SLIT, Sublingual immunotherapy, SQ-T, Standardized quality tablet, WHO, World Health Organization

Allergic diseases are now considered to result from a breakdown, probably T-regulated, in the immune tolerance we normally have to natural exposure to allergens. Specific immunotherapy (SIT) consists of repeatedly administering doses of an allergen to a subject with allergy to induce specific clinical and immunologic tolerance.¹ This will cause a clinical improvement in the symptoms and can alter the natural history of the disease.

The mechanisms of action of SIT are becoming better understood. Subcutaneous allergen immunotherapy (SCIT) reduces allergen-specific IgE production and increases the production of specific IgG (which acts as a “blocking” antibody).² Additional studies have indicated that the predominant mechanism depends on modification of the phenotype of allergen-specific T_H cells.³ The effect of SIT on these cells involves (1) immunologic deviation (stimulation of T_H0/T_H1 lymphocytes, with increased IFN-γ and IL-2 production), (2) specific T-lymphocyte anergy (a decrease in T_H2/T_H0 lymphocyte counts), or (3) induction of regulatory T-lymphocytes, which produce cytokines such as IL-10 and TGF-β. SCIT also reduces allergen-specific inflammation by decreasing inflammatory cell recruitment, activation, and mediator release (histamine, prostaglandin D₂, and eosinophil cationic protein).² All these effects contribute to immune tolerance and the long-lasting changes in the immune system even after treatment is discontinued. In sublingual specific allergen immunotherapy (SLIT), the mechanisms of action are not fully understood but seem to be similar to those of SCIT, with the particular involvement of mucosal dendritic cells.⁴

Since the inception of allergen therapy for treating seasonal allergic rhinitis to grass pollen (“hay fever”) by Noon and Freeman⁵ in 1911 in Europe and Lowdermilk⁶ in 1914 in the United States, SIT has remained the only etiology-based treatment for allergic diseases. Its use worldwide is mainly based on evidence of its clinical efficacy. However, the clinical evaluation of SIT must take into account specific critical issues regarding the high heterogeneity among studies.

In the current review, we put into perspective current international expert recommendations on the use of SIT for allergic rhinoconjunctivitis and asthma (in relation to the stated levels of clinical evidence) and offer suggestions on what is needed for the future.

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Where are we now? 

International recommendations 

Over the past few years, guidelines on the use of SIT in allergic respiratory diseases have been published by the European Academy of Allergy and Clinical Immunology,⁷ the International Consensus Report on Asthma,⁸ the International Consensus Report on Rhinitis,⁹ the Global Strategy for Treatment and Prevention of Asthma,¹⁰ Allergic Rhinitis and its Impact on Asthma,¹¹ the World Health Organization (WHO),¹ the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology,¹² the World Allergy Organization,¹³, ¹⁴ and the British Society for Allergy and Clinical Immunology.¹⁵

These guidelines are based on the published literature and have primarily focused on the efficacy and safety of SIT in allergic rhinitis and allergic asthma. Eight meta-analyses have included all of the publications published over the last 20 years: 2 for SCIT¹⁶, ¹⁷ and 6 for SLIT.¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³ The Allergic Rhinitis and its Impact on Asthma document, which is in collaboration with WHO,²⁴ gave SIT the highest level of evidence according to the grading system of Shekelle et al²⁵ (ie, level Ia). However, the various studies suffer from large clinical and methodologic heterogeneities,²⁶ including diverse sources and types of allergenic extracts, treatment durations, doses, outcome measures, symptom and outcome scoring systems, rhinitis and/or asthma of different severities, and population ages (ie, adults vs children). Most importantly, the population sizes in these studies were generally small. This is identified in recent reviews.²⁷, ²⁸ We consider that because of this high heterogeneity among studies, the results from meta-analyses should be viewed with caution.

Registration of SIT products 

In 2010, only 3 SIT products have been registered as pharmaceutical treatments by the European Medicines Agency (EMA): 2 SLIT and 1 SCIT grass pollen products for allergic rhinitis. There are other products registered at national levels (eg, in Germany). All other formulations worldwide are used as named-patient products.²⁹ In contrast to the situation in Europe, more than 95% of the final allergen extracts used in the United States are prepared in the physician's office.³⁰ In the United States, allergen extracts are regulated by the Food and Drug Administration's Center for Biologics Evaluation and Research but are not registered.²⁹ At the end of 2008, the EMA published a specific guideline on SIT therapeutic trials that are designed for product registration³¹ (Table I).

Table I. EMA recommendations for future registration of SIT products

Standardization of allergens 

High-quality allergen extracts are essential for both the diagnosis and treatment of respiratory allergic diseases.¹ Most of the common extracts used in the clinic are now available in standardized forms or are in the process of being standardized.

Allergenic extracts are labeled in biological units on the basis of skin tests.²⁹ A major difference in standardization between Europe and the United States is the use of skin prick tests and wheals (Europe) and intradermal skin tests and flare (United States). There are multiple allergen specific units and concentrations resulting in a variety of unrelated unit names among marketed products. These units are not comparable and extracts may have different potencies because of (1) differences between extracts, (2) differences in the sensitivity of the patient population chosen, (3) the relatively small number of patients tested, or (4) methodologic differences.²⁹, ³², ³³

In Europe, potency determination is based on comparison with in-house (manufacturer-specific) reference standards.³² As a consequence, each manufacturer defines its own specific units and concentrations. In the European Pharmacopoeia,³⁴ the allergen preparations for SIT may be (1) unmodified extracts (natural extracts), (2) chemically modified extracts, (3) extracts modified by adsorption (depot extracts), (4) modified and adsorbed extracts (allergoids), or (5) recombinant allergens (though none of the last are yet on the market). In the United States, potency determination is centralized and based on comparison with Center for Biologics Evaluation and Research reference samples.²⁹ The allergen extract types available are natural and alum-precipitated depot extracts.

The biological activity, composition, and stability of some allergen extracts have been documented. Composition can be categorized as follows²⁴: (1) extracts originating from a single raw material, (2) extracts containing mixtures of similar cross-reacting allergens (such grass pollens, tree pollens, ragweed pollens, or house dust mites) and (3) extracts containing mixtures of unrelated allergens (as long as data for stability and clinical efficacy are available). There are significant differences between Europe and the United States regarding the number of allergens that are used together in a named-patient preparation for SIT. In Europe, most formulations are single-allergen extracts, whereas most of the preparations in the United States contain an average of 8 different components.³⁰

Subcutaneous immunotherapy 

The clinical efficacy of SCIT in allergic rhinitis and asthma is well established, and Cochrane meta-analyses of the efficacy of this therapy in allergic rhinitis¹⁷ and asthma¹⁶ are available (Table II). However, dose-response issues complicate the position of SCIT. At a low dose, SCIT is ineffective. However, high doses of allergen extracts can give rise to an unacceptably high level of systemic reactions. Efforts have been made to define the “optimal monthly dose” (defined as the dose inducing an adequate clinical effect in the majority of patients without provoking undesirable side-effects) in biological units or as the weight of major allergen content. For most allergen extracts, this value corresponds to between 5 and 20 μg of major allergen per injection.¹

Table II. Summary of meta-analyses for SCIT and SLIT

HDM, House dust mite; I², I squared (for heterogeneity); NR, not reported; RCT, randomized controlled trial; SMD, standardized mean difference.

In allergic rhinitis, clinical efficacy (in terms of a reduction in symptoms and/or the need for additional medication) has been shown for grass, birch, ragweed and Parietaria pollens, house dust mite and cat dander. Only few studies clearly demonstrated that the clinical effect was dose-dependent.³⁵, ³⁶, ³⁷ SCIT studies have also shown improvement in patients' quality of life.³⁵, ³⁸ In allergic asthma, the clinical efficacy of SCIT was demonstrated by a Cochrane meta-analysis.¹⁶ The duration of SCIT needed to guarantee long-term efficacy after stopping the treatment is generally agreed to be 3 years.³⁹, ⁴⁰, ⁴¹

Only 2 published studies have found that extracts containing recombinant allergens were effective in reducing the symptoms of allergic rhinitis.⁴², ⁴³ New forms of SCIT using the adjuvant monophosphoryl lipid⁴⁴ and adjuvanted allergen extracts using oligodeoxyribonucleotide immunostimulatory sequence of DNA containing a CpG motif as immunostimulants⁴⁵, ⁴⁶ have been evaluated.

SCIT is associated with a risk of systemic side effects and anaphylaxis. Side effects may occur with all allergen preparations, whether they are standardized extracts, allergoids, or recombinant allergens. The risk is greater in subjects with asthma¹, ⁴⁷ and with accelerated dosing schedules. Using the European Academy of Allergy and Clinical Immunology classification for adverse events,⁸ a Cochrane meta-analysis of SCIT for seasonal allergic rhinitis¹⁷ found that 8% and 7% of patients in the treated groups experienced grade II and grade III systemic reactions, respectively. A small number of patients (0.72%; 3 in the treated group vs 1 in the placebo group) experienced grade IV reactions. Adrenaline/epinephrine was used in 0.13% of injections. Some patients had systemic side effects with injections containing 5 to 20 μg major allergens,³⁵ considered to be the “optimal dose” for most allergen extracts.¹ Pretreatment with oral H₁-antihistamines during the induction phase reduces the frequency and severity of systemic side effects.⁴⁸ Recent international efforts have aimed at standardizing the reporting and rapid treatment of postinjection adverse events.⁴⁹

International guidelines suggest the use of SCIT in pollinosis when (1) the condition is severe and/or prolonged, (2) it is poorly controlled by adequate pharmacological treatment, or (3) pharmacologic treatment is refused by the patient or leads to significant side effects. Furthermore, SCIT is particularly indicated when perennial allergic rhinitis is associated with mild or moderate asthma. The indications and contraindications for SIT are the same for children >5 years of age and for adults (Table III).

Table III. Indications for specific immunotherapy¹, ⁷, ²⁴

The clinical success of SCIT can be optimized if the patient fulfills a number of specific conditions assessed by the prescribing physician before SIT initiation (Table IV). Doctors, nurses, and health care personnel in general should be trained particularly in the surveillance and emergency treatment of anaphylactic reactions. A supply of adrenaline should be readily available in health care facilities in which SCIT is administered.

Table IV. Considerations for the initiation of immunotherapy¹, ⁷, ²⁴

Small size studies show that the efficacy of SCIT persists for some years after treatment is withdrawn.³⁹, ⁴⁰ SCIT may prevent the development of new sensitizations in house dust mite monosensitized children⁵⁰ and the appearance of allergic asthma in patients with grass and/or birch pollen induced-allergic rhinitis.⁴¹

The health economics of SCIT versus pharmacologic treatment for pollen and mite allergic rhinitis have been modeled for Germany,⁵¹ France,⁵² and the United States.⁵³ SCIT was found to be cost-effective on the basis of on this modeling.

Sublingual immunotherapy 

Sublingual immunotherapy is commercially available in several countries worldwide. The most recent SLIT extracts are standardized by using biological or immunologic methods, and the major allergen content is indicated in micrograms (using in-house manufacturer-specific assays and reference standards). Extracts can be administered as drops or fast-dissolving tablets.

In allergic rhinitis, the efficacy of SLIT has been shown in 4 meta-analyses¹⁸, ¹⁹, ²², ²³ (Table II). These meta-analyses have shown moderate to high heterogeneity in study designs; therefore, conclusions should be drawn with caution.²⁶, ²⁷, ²⁸ However, recent data from large phase III studies of SLIT tablets in grass pollen allergic rhinitis has enabled the assessment of efficacy and safety with more confidence⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹ (Table V). The quality of life of patients treated with SLIT is improved.⁵⁶, ⁶⁰ The size of these studies has allowed subgroup analyses showing, for example, that the beneficial effect does not vary according to the presence or absence of asthma and is similar in monosensitized and polysensitized patients.⁶¹ It is interesting to note that low doses (25,000 standardized quality tablet [SQ-T] and 100 index of reactivity [IR], equivalent to 5-7 μg allergen Phl p 5 per day, according to the manufacturers) are ineffective and that a daily dose of around 15 to 25 μg is required to obtain a statistically significant clinical improvement in symptom scores. One study showed that a higher dose (33-40 μg major allergen Phl p 5 per day) was no more effective than 15 to 25 μg.⁵⁶

Table V. Large randomized controlled studies on grass pollen SLIT tablets for seasonal allergic rhinitis

In allergic asthma, 4 meta-analyses with small number of studies have shown significant reduction on asthma symptoms and asthma medication use²⁰, ²¹, ²², ²³ (Table II). Here again, there was significant interstudy heterogeneity, so the results of ongoing large studies of allergic asthma with SLIT products are keenly awaited.

SLIT is well tolerated by adults and children in many different clinical trials using drops and tablets. In clinical trials, local side effects (notably mild itching and mild swelling of the lips and floor of the mouth) are typically observed in 60% to 85% of patients. These symptoms appear within minutes or hours after taking SLIT and are usually of short duration (less than 14 days). They do not require medical treatment or dose adjustment and often disappear during the course of treatment. Side effects are not necessarily more frequent in patients taking high doses.⁵⁵, ⁵⁶ The high incidence of local side effects had led to some concern about the inability to blind SLIT trials adequately.⁶²

Systemic reactions such as urticaria, angioedema, and asthma occur during dose escalation and maintenance phases. These reactions may be dose-dependent and allergen-dependent. Six clinical cases of anaphylaxis to SLIT have been published.⁶³, ⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷ These events have stressed the indication that the first dose of SLIT should be taken in a doctor's office with an observation period of at least 30 minutes; this advice is now clearly stated in the labeling of the SLIT tablet.

As SLIT is administered to patients in their home, the following precautions are recommended: (1) give the patient (or the parents, in the case of a child) clear and simple written instructions on the steps to take if an adverse event occurs, and (2) store the allergen tablets or drops in a secure place, out of the reach of children.²⁷

When nationally registered, SLIT is indicated in allergic rhinitis and asthma induced by pollens (birch, cypress, grasses, olive tree, Parietaria) or house dust mites as summarized in Table III.

SLIT may also have an effect on the natural course of the disease. A study published in 2010 demonstrated that 3 years of treatment with SLIT tablets resulted in consistent clinical improvement associated with immunologic changes that were sustained 1 year after treatment cessation.⁶⁸ It has been suggested that SLIT may prevent asthma in treated patients with allergic rhinitis⁶⁹ and may reduce the development of additional allergen sensitivities.⁷⁰ Additional data are needed to confirm these observations.

The health economics of SLIT versus pharmacologic treatment for pollen and mite allergic rhinitis in children and adults have been modeled in Europe.⁵², ⁷¹, ⁷² These analyses suggest that SLIT is cost-effective.

Comparison of sublingual and subcutaneous immunotherapies 

The comparative efficacy of SLIT and SCIT in patients with allergic respiratory diseases has been evaluated in several underpowered trials.⁷³, ⁷⁴, ⁷⁵, ⁷⁶ Allergic rhinoconjunctivitis was evaluated in all studies; in addition, 2 studies included mild-to-moderate allergic asthma.⁷³, ⁷⁵ Different allergens were evaluated, such as mixed grass pollens, birch pollen, house dust mite, and multiple allergen extracts. The published data show little or no statistical difference between SCIT and SLIT with respect to symptom scores and medication scores. The lack of significant difference between the 2 treatments does not indicate equivalent efficacy. To detect minor differences, larger groups are necessary. Moreover, we must consider that not all the studies had a double-blind double-dummy randomized design: some were open-label, whereas others were placebo-controlled and randomized. These differences limit interpretation of the data.

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Where are we going? 

International recommendations 

After reviewing published guidelines, we advocate a single international consensus statement based on large, well designed phase III studies with registered products. This guideline could then be adapted at regional and/or national levels. The role of an international organization is pivotal as it is conformed by panels of clinical and research experts who will reflect the regional needs, influenced by cultural, economic, environmental, and genetic differences.

Clinical trial reporting 

When researchers embark on a clinical trial, they make a commitment to perform the work and report the findings in accordance with basic ethical and study conduct principles, as outlined in the International Congress of Harmonization (ICH) guideline.⁷⁷ This should include maintaining the accuracy of the results and making both positive and negative findings publicly available. Unfortunately, a significant proportion of health care research remains unpublished or is published only in part. Selective reporting (for whatever reason) leads to an incomplete and potentially biased view of a trial and its results; this also explains why few “negative” studies are available for systematic review and meta-analysis.²⁶, ²⁸

We still consider that meta-analyses of SIT based on well performed systematic reviews represent the highest level of evidence (Table III). However, at this stage of evidence-based medicine, it is mandatory to report all negative and positive studies. In addition, studies included in meta-analyses should be carefully scrutinized for adequate design (including appropriate and well characterized subject populations, use of validated and standardized outcomes, and vigorous recording of concomitant and rescue medications). Finally, because of large discrepancies in the methodology followed by small and middle-sized studies, it is crucial to evaluate well powered, large clinical studies in both children and adults in SIT. Recommendations should be carried out by unbiased methodologists with the input of clinicians.

We support the recently developed Consolidated Standards of Reporting Trials statement for SIT,⁷⁸ which proposed a checklist in the context of performing and reporting trials in allergen SIT. Only randomized, blind (with respect to participants, care providers, and outcome assessors), placebo-controlled, phase III studies with explicit description of participant inclusion and exclusion criteria and identification of primary, secondary, and exploratory outcomes, involving standardized allergens and reporting adverse events in an ICH guidelines–based fashion, should be evaluated.⁷⁷, ⁷⁸ In this way, the discrepancy of data reported and published in peer-reviewed journals and data reported in regulatory agencies (see Table V) should eventually be eliminated.

Safety 

Safety of any treatment is fundamental. Evidence is required throughout the entire spectrum of the treatment life cycle, from the premarketing phase to the postmarketing phase.

The SIT safety and effectiveness also need to be assessed in the real world, where outcomes differ from those in controlled clinical trials, which provide premarket test results. Postmarketing safety surveillance is required for all marketed treatments including drugs, vaccines, and biologicals to evaluate a new treatment safety code. It usually relies on spontaneous adverse drug reaction reports and represents an important tool in monitoring the safety and in providing information on any required revision of the prescribing information. The classification and reporting methods should be standardized around the world. Although reporting is mandatory in many countries, underreporting exists primarily because of the general burden of reporting (time required to report, questions of privacy, confidentiality, liability, and so forth). Also, these reports can be limited by quality problems including incomplete data and difficulty in demonstrating a causal relationship between exposure and adverse events.

A universal terminology and grading system for SIT-related adverse events should be implemented by an independent multidisciplinary group of experts and promoted by international and local medical organizations.⁴⁹ However, currently, the Medical Dictionary for Regulatory Activities is the only internationally recognized system for the classification of adverse reactions in all studies, from phase I to postpharmacologic surveillance. The public should have access to the information on all SIT-related adverse reactions.

Registration of SIT products 

All the most relevant allergen extracts (in terms of public health issues in a particular country or region) should be registered. Such measures would directly benefit the health of the population affected and, in the long term, would be advantageous for the local or regional economy. We acknowledge that manufacturers cannot afford to execute the requisite registration procedures for the other allergen extracts they are producing. The less relevant allergen extracts could still be sold on a named-patient basis. There is also a need for standardizing and validating surrogate outcomes that could possibly replace the need for seasonal trials (exposure chambers, allergen challenges, and so forth).

Standardization of allergens 

Because allergen extracts are usually prepared from natural biological sources, standardization procedures are of crucial importance. No progress will occur if each manufacturer is using its own in-house standard. Currently, no standards for the measurement of allergen content are universally accepted. To address this issue, internationally standardized measurement of major allergens is a realistic and justifiable aim,²⁴ but other alternatives should be considered. To achieve this, the input of experts worldwide is needed. Allergen manufacturers should indicate the content of representative major allergens in their products in units of mass (μg/mL), even though direct comparisons between the various manufacturers would still be prevented by differences in the assays and analytical methods used.²⁴, ³³ Therefore, the use of standardized assays (provided by WHO), which can be used in an identical fashion, should be implemented. For allergen mixtures, the proportion of each component should be specified.

Economic evaluation of SIT 

Although few studies have compared the cost-effectiveness of SIT with that of standard pharmaceutical treatment, these 2 approaches are very difficult to compare in view of differing national health insurances, variable epidemiologic data, and the different prescription habits and outcome measures used.⁷⁹ Moreover, because these studies were based on modeling, it is important that prospective, randomized, cost-effectiveness trials are conducted. Evaluation with unified criteria and outcomes carried out by independent investigators is now mandatory, because the use of SIT is encouraged as a result of its long-term clinical benefits and potential to prevent the development of new sensitizations and asthma in severe high-risk populations.

Indications for SIT 

The WHO estimates that allergic rhinitis affects 600 million people worldwide, including 200 million with associated asthma.⁸⁰ Half of all adults with asthma and at least two thirds of children with asthma have allergies.¹⁰

Most people with allergic rhinitis have mild symptoms that do not affect their quality of life and/or that are satisfactorily controlled with readily available pharmacologic treatments (eg,. antihistamines and nasal corticosteroids).⁸¹ However, around 20% of these patients see little or no improvement with these treatments (because of the severity of their disease), whereas others wish to adopt a more curative approach to their illness. These patients can clearly benefit from SIT⁸² and should therefore be eligible and selected for allergen immunotherapy. Criteria selection of patients with asthma for SIT should be established.

Efforts should be made to (1) evaluate the usefulness of all registered SIT products in polysensitized patients, (2) consider the exact regimen (eg, coseasonal treatment vs year-round treatment), (3) assess treatment duration, and (4) evaluate early use of SIT in children to prevent asthma and reduce the development of additional allergen sensitivities. Preliminary studies are addressing these issues, but further data are required.⁸³, ⁸⁴, ⁸⁵, ⁸⁶

After almost a hundred years of clinical use of SIT for allergic rhinitis and asthma, tremendous progress has been achieved worldwide. In this review, we raise many relevant clinical and research issues that to be addressed need proper funding.

Currently, SCIT represents the most common administration route in allergen immunotherapy, and we believe that (1) large, well designed, randomized, controlled studies are needed for the most common allergens (house dust mite and grasses in both children and adults), (2) further economic evaluations and postmarketing surveillance studies are required, (3) objective evaluations of the effect of SCIT in monosensitized and polysensitized individuals should be established, (4) the use of multiple-allergen SCIT in polysensitized patients should be objectively evaluated and documented, and (5) SCIT's safety profile in high-risk groups (such as patients with moderate to severe asthma) should be specified and included in the guidelines.

Regarding SLIT, we suggest that (1) the clinical efficacy and safety for perennial allergens (mainly house dust mite) should be established in large, well designed, international clinical trials; (2) the treatment duration and optimal regimen (including data on coseasonal or continuous treatment for seasonal allergens) should be objectively evaluated; (3) the long-term effect after discontinuation should be clinically and immunologically documented; (4) given that SLIT is recommended for home use, the regular assessment and reporting of adverse events by the prescribing physician should be monitored (patients and doctors must be aware of the potential risk of very rare but potentially severe systemic reactions, including anaphylaxis); (5) clinical trials with other relevant pollens (such as tree pollens) should be encouraged; and (6) large, well designed, head-to-head SLIT versus SCIT comparisons are needed.

Finally, a number of future forms of immunotherapy may provide better alternatives to the currently available SCIT or SLIT, including combination of conventional SCIT with anti-IgE, allergen plus anti–IL-4 or Toll-like receptor 4 agonists, CpG (Toll-like receptor 9 agonists) oligonucleotides ± allergen, allergen coupled with viruslike particles, allergen/IgG chimeric proteins (in clinical trials soon), and recombinant allergens/peptides. Ultimately, these newer forms will provide information on the pathogenesis of allergic diseases and ideally will result in decreased symptoms and improved quality of life and profound immunomodulation, will be cost-effective, and will have favorable risk/benefit ratios.

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References 

1. Bousquet J, Lockey R, Malling HJ. WHO Panel Members. Allergen immunotherapy: therapeutic vaccines for allergic diseases: a WHO position paper. J Allergy Clin Immunol. 1998;102:558–562
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (53 KB)
   • CrossRef
2. James LK, Durham SR. Update on mechanisms of allergen injection immunotherapy. Clin Exp Allergy. 2008;38:1074–1088
   • View In Article
   • CrossRef
3. Akdis CA, Akdis M. Mechanisms and treatment of allergic disease in the big picture of regulatory T cells. J Allergy Clin Immunol. 2009;123:735–746
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (365 KB)
   • CrossRef
4. Scadding G, Durham SR. Mechanisms of sublingual immunotherapy. J Asthma. 2009;46:322–334
   • View In Article
   • CrossRef
5. Noon L. Prophylactic inoculation against hay fever. Lancet. 1911;i:1572–i:1573
   • View In Article
6. Lowdermilk RC. Hay fever. J Am Med Assoc. 1914;LXIII:141–142
   • View In Article
7. Malling H. Immunotherapy. Position paper of the EAACI. Allergy. 1988;43(suppl 6):9–33
   • View In Article
   • CrossRef
8. International Consensus Report on Diagnosis and Management of Asthma. International Asthma Management Project. Allergy. 1992;47(13 suppl):S1–S61
   • View In Article
9. International Consensus Report on Diagnosis and Management of Rhinitis. International Rhinitis Management Working Group. Allergy. 1994;49(19 suppl):S1–S34
   • View In Article
10. Global Strategy for Asthma Management and Prevention. WHO/NHLBI workshop report. National Institutes of Health, National Heart, Lung and Blood Institute; 1995;Publication no. 95-3659
    • View In Article
11. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108:S147–S334
    • View In Article
    • Full Text
    • Full-Text PDF (2098 KB)
    • CrossRef
12. Cox L, Li JT, Nelson H, Lockey R. Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol. 2007;120:S25–S85
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (3387 KB)
    • CrossRef
13. Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ, Lockey RF, Malling HJ, et al. Recommendations for standardisation of clinical trials with allergen specific immunotherapy for respiratory allergy: a statement of a World Allergy Organisation (WAO) Taskforce. Allergy. 2007;62:317–324
    • View In Article
    • MEDLINE
    • CrossRef
14. Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, et al. Sub-lingual immunotherapy: World Allergy Organization Position Paper 2009. Allergy. 2009;64:S1–S59
    • View In Article
15. Scadding GK, Durham SR, Mirakian R, Jones NS, Leech SC, Farooque S, et al. BSACI guidelines for the management of allergic and non-allergic rhinitis. Clin Exp Allergy. 2008;38:19–42
    • View In Article
    • CrossRef
16. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2003;(4):CD001186
    • View In Article
17. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham SR. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007;(1):CD001936
    • View In Article
18. Wilson DR, Lima MT, Durham ST. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy. 2005;60:4–12
    • View In Article
    • MEDLINE
    • CrossRef
19. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta R, Passalacqua G, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol. 2006;97:141–148
    • View In Article
    • Abstract
    • Full-Text PDF (518 KB)
    • CrossRef
20. Calamita Z, Saconato H, Pela AB, Attalah AN. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy. 2006;61:1162–1172
    • View In Article
    • MEDLINE
    • CrossRef
21. Penagos M, Passalaqua G, Compalati E, Baena-Cagnani CE, Orozco S, Pedroza A, et al. Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest. 2008;133:599–609
    • View In Article
    • CrossRef
22. Olaguíbel JM, Alvarez Puebla MJ. Efficacy of sublingual allergen vaccination for respiratory allergy in children: conclusions from one meta-analysis. J Investig Allergol Clin Immunol. 2005;15:9–16
    • View In Article
    • MEDLINE
23. Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy. 2009;64:1570–1579
    • View In Article
    • CrossRef
24. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organisation, GA²LEN and AllerGen). Allergy. 2008;63:S8–S160
    • View In Article
25. Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ. 1999;318:593–596
    • View In Article
    • MEDLINE
    • CrossRef
26. Calderon MA. Meta-analyses of specific immunotherapy trials. Drugs Today. 2008;44:S31–S34
    • View In Article
27. Calderon MA, Penagos M, Durham SR. Sublingual immunotherapy for allergic rhinoconjunctivitis, allergic asthma and prevention of allergic diseases. Clin Allergy Immunol. 2008;21:359–375
    • View In Article
28. Nieto A, Mazon A, Pamies R, Bruno L, Navarro M, Montanes A. Sublingual immunotherapy for allergic respiratory diseases: an evaluation of meta-analyses. J Allergy Clin Immunol. 2009;124:157–161
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (6974 KB)
    • CrossRef
29. Cox L, Jacobsen L. Comparison of allergen immunotherapy practice patterns in the United States and Europe. Ann Allergy Asthma Immunol. 2009;103:451–459
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (192 KB)
    • CrossRef
30. Esch RE. Specific immunotherapy in the U.S.A.: general concept and recent initiatives. Arb Paul Ehrlich Inst Bundesamt Sera Impfstoffe Frankf A M. 2003;94:17–23
    • View In Article
31. EMEA. Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases 2008. Available at: http://www.emea.europa.eu/pdfs/human/ewp. Accessed August 8, 2010.
    • View In Article
32. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR, Malling HJ, Valovirta E. Standards for practical allergen-specific immunotherapy. Allergy. 2006;61:S1–S20
    • View In Article
33. Sander I, Fleischer C, Meurer U, Brüning T, Raulf-Heimsoth M. Allergen content of grass pollen preparations for skin prick testing and sublingual immunotherapy. Allergy. 2009;64:1486–1492
    • View In Article
    • CrossRef
34. Allergen products (Producta allergenica). European Pharmacopeia. 1997;1063–1068
    • View In Article
35. Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117:319–325
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (201 KB)
    • CrossRef
36. Mirone C, Albert F, Tosi A, Mocchetti F, Mosca S, Giorgino M, et al. Efficacy and safety of subcutaneous immunotherapy with a biologically standardized extract of Ambrosia artemisiifolia pollen: a double-blind, placebo-controlled study. Clin Exp Allergy. 2004;34:1408–1414
    • View In Article
    • MEDLINE
    • CrossRef
37. Nanda A, O'Connor M, Anand M, Dreskin SC, Zhang L, Hines B, et al. Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract. J Allergy Clin Immunol. 2004;114:1339–1344
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (265 KB)
    • CrossRef
38. Corrigan CJ, Kettner J, Doemer C, Cromwell O, Narkus A. Efficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid. Allergy. 2005;60:801–807
    • View In Article
    • MEDLINE
    • CrossRef
39. Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999;341:468–475
    • View In Article
    • MEDLINE
    • CrossRef
40. Des-Roches A, Paradis L, Knani J, Bouges S, Daurès J-P, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract, V: duration of efficacy of immunotherapy after its cessation. Allergy. 1996;51:430–433
    • View In Article
    • MEDLINE
    • CrossRef
41. Niggemann B, Jacobsen L, Dreborg S, Ferdousi HA, Halken S, Host A, et al. Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy. 2006;61:855–859
    • View In Article
    • MEDLINE
    • CrossRef
42. Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol. 2005;116:608–613
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (219 KB)
    • CrossRef
43. 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;122:951–960
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (509 KB)
    • CrossRef
44. Patel P, Salapatek AM. Pollinex Quattro: a novel and well-tolerated, ultra short-course allergy vaccine. Expert Rev Vaccines. 2006;5:617–629
    • View In Article
    • CrossRef
45. 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;355:1445–1455
    • View In Article
    • CrossRef
46. Senti G, Johansen P, Haug S, Bull C, Gottschaller C, Muller P, et al. Use of A-type CpG oligodeoxynucleotides as an adjuvant in allergen-specific immunotherapy in humans: a phase I/IIa clinical trial. Clin Exp Allergy. 2009;39:562–570
    • View In Article
    • CrossRef
47. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol. 1987;79:660–677
    • View In Article
    • MEDLINE
    • CrossRef
48. Nielsen L, Johnsen C, Mosbech H, Poulsen L, Malling HJ. Antihistamine premedication in specific cluster immunotherapy: a double-blind, placebo-controlled study. J Allergy Clin Immunol. 1996;97:1207–1213
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (639 KB)
    • CrossRef
49. Cox L, Larenas-Linnemann D, Lockey R, Passalacqua G. Speaking the same language: the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol. 2010;125:569–574
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (136 KB)
    • CrossRef
50. Des-Roches A, Paradis L, Ménardo J-L, Bouges S, Daurès J-P, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract, VI: specific immunotherapy prevents the onset of new sensitisations in children. J Allergy Clin Immunol. 1997;99:450–453
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (391 KB)
    • CrossRef
51. Schadlich PK, Brecht JG. Economic evaluation of specific immunotherapy versus symptomatic treatment of allergic rhinitis in Germany. Pharmacoeconomics. 2000;17:37–52
    • View In Article
    • MEDLINE
    • CrossRef
52. Omnes LF, Bousquet J, Scheinmann P, Neukirch F, Jasso-Mosqueda G, Chicoye A, et al. Pharmacoeconomic assessment of specific immunotherapy versus current symptomatic treatment for allergic rhinitis and asthma in France. Eur Ann Allergy Clin Immunol. 2007;39:148–156
    • View In Article
53. Hankin CS, Cox L, Lang D, Levin A, Gross G, Eavy G, et al. Allergy immunotherapy among Medicaid enrolled children with allergic rhinitis: patterns of care, resource use, and costs. J Allergy Clin Immunol. 2008;121:227–232
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (177 KB)
    • CrossRef
54. Dahl R, Kapp A, Colombo G, de Monchy JGR, Rak S, Emminger W, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;118:434–440
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (185 KB)
    • CrossRef
55. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117:802–809
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (258 KB)
    • CrossRef
56. Didier A, Malling HJ, Worm M, Horak F, Jäger S, Montagut A, et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol. 2007;120:1338–1345
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (648 KB)
    • CrossRef
57. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M, Klimek L, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol. 2009;123:167–173
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (345 KB)
    • CrossRef
58. Wahn U, Tabar A, Kuna P, Halken S, Montagut A, de Beaumont O, et al. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2009;123:160–166
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (489 KB)
    • CrossRef
59. Didier A, Melac M, Montagut A, Lhéritier-Barrand M, Tabar A, Worm M. Agreement of efficacy assessments for five-grass pollen sublingual tablet immunotherapy. Allergy. 2009;64:166–171
    • View In Article
    • CrossRef
60. Rak S, Yang WH, Pedersen MR, Durham SR. Once-daily sublingual allergen-specific immunotherapy improves quality of life in patients with grass pollen-induced allergic rhinoconjunctivitis: a double-blind, randomised study. Qual Life Res. 2007;16:191–201
    • View In Article
    • MEDLINE
    • CrossRef
61. Malling HJ, Montagut A, Melac M, Patriarca G, Panzner P, Seberova E, et al. Efficacy and safety of 5-grass pollen sublingual immunotherapy tablets in patients with different clinical profiles of allergic rhinoconjunctivitis. Clin Exp Allergy. 2009;39:387–393
    • View In Article
    • CrossRef
62. Casale TB, Canonica GW, Bousquet J, Cox L, Lockey R, Nelson HS, et al. Recommendations for appropriate sublingual immunotherapy clinical trials. J Allergy Clin Immunol. 2009;124:665–670
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (180 KB)
    • CrossRef
63. Dunsky EH, Goldstein MF, Dvorin DJ, Belecanech GA. Anaphylaxis to sublingual immunotherapy. Allergy. 2006;61:1235
    • View In Article
    • MEDLINE
    • CrossRef
64. Antico A, Pagani M, Crema A. Anaphylaxis by latex sublingual immunotherapy. Allergy. 2006;61:1236–1237
    • View In Article
    • MEDLINE
    • CrossRef
65. Eifan AO, Keles S, Bahceciler NN, Barlan IB. Anaphylaxis to multiple pollen allergen sublingual immunotherapy. Allergy. 2007;62:567–568
    • View In Article
    • MEDLINE
    • CrossRef
66. Blazowski L. Anaphylactic shock because of sublingual immunotherapy overdose during third year of maintenance dose. Allergy. 2008;63:374
    • View In Article
    • CrossRef
67. de Groot H, Bijl A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet. Allergy. 2009;64:963–964
    • View In Article
    • CrossRef
68. Durham SR, Emminger W, Kapp A, Colombo G, de Monchy JG, Rak S, et al. Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J Allergy Clin Immunol. 2010;125:131–138
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (825 KB)
    • CrossRef
69. Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De Marco E, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2004;114:851–857
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (238 KB)
    • CrossRef
70. Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G. Randomized controlled open study of sublingual immunotherapy for respiratory allergy in real-life: clinical efficacy and more. Allergy. 2004;59:1205–1210
    • View In Article
    • MEDLINE
    • CrossRef
71. Berto P, Passalacqua G, Crimi N, Frati F, Ortolani C, Senna G, et al. Economic evaluation of sublingual immunotherapy versus symptomatic treatment in adults with pollen-induced respiratory allergy: the Sublingual Immunotherapy Pollen Allergy Italy (SPAI) study. Ann Allergy Asthma Immunol. 2006;97:615–621
    • View In Article
    • Abstract
    • Full-Text PDF (299 KB)
    • CrossRef
72. Bachert C, Vestenbaek U, Christensen J, Griffithsz UK, Poulsen PB. Cost-effectiveness of grass allergen tablet (GRAZAX) for the prevention of seasonal grass pollen induced rhinoconjunctivitis—a Northern European perspective. Clin Exp Allergy. 2007;37:772–779
    • View In Article
    • MEDLINE
    • CrossRef
73. Mungan D, Misirligil Z, Gurbuz L. Comparison of the efficacy of subcutaneous and sublingual immunotherapy in mite-sensitive patients with rhinitis and asthma—a placebo controlled study. Ann Allergy Asthma Immunol. 1999;82:485–490
    • View In Article
    • Abstract
    • Full-Text PDF (356 KB)
    • CrossRef
74. Khinchi MS, Poulsen MK, Carat F, André C, Hansen AB, Malling HJ. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy. 2004;59:45–53
    • View In Article
    • MEDLINE
    • CrossRef
75. Quirino T, Lemoli E, Sicilliani E, Parmiani S, Millazo F. Sublingual versus injective immunotherapy in grass pollen allergic patients: a double blind (double dummy) study. Clin Exp Allergy. 1996;26:1253–1261
    • View In Article
    • MEDLINE
    • CrossRef
76. Mauroa M, Russelloa M, Incorvaiab C, Gazzolaa GB, Di Carac G, Frati F. Comparison of efficacy, safety and immunologic effects of subcutaneous and sublingual immunotherapy in birch pollinosis: a randomized study. Allerg Immunol. 2007;39:119–122
    • View In Article
77. Structure and content of clinical study reports E3: ICH harmonized tripartite guidelines. November 1995. Available at: http://www.ich.org/cache/compo/276-254-1.html. Accessed August 8, 2010.
    • View In Article
78. Bousquet PJ, Brozek J, Bachert C, Bieber T, Bonini S, Burney P, et al. The CONSORT statement checklist in allergen-specific immunotherapy—a GA²LEN paper. Allergy. 2009;69:1737–1745
    • View In Article
79. Berto P, Frati F, Incorvaia C. Economic studies of immunotherapy: a review. Curr Opin Allergy Clin Immunol. 2008;8:585–589
    • View In Article
80. Bousquet J, Dahl R, Khaltaev N. Global alliance against chronic respiratory diseases. Eur Respir J. 2007;29:233–239
    • View In Article
    • MEDLINE
    • CrossRef
81. Demoly P, André C. Information and consent forms for sublingual immunotherapy. Clin Allergy Immunol. 2008;2:527–534
    • View In Article
82. Bousquet J, Bachert C, Canonica GW, Casale TB, Cruz AA, Lockey RJ, et al. Extended Global Allergy and Asthma European Network, World Allergy Organization and Allergic Rhinitis and its Impact on Asthma Study Group. Unmet needs in severe chronic upper airway disease (SCUAD). J Allergy Clin Immunol. 2009;124:428–433
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (113 KB)
    • CrossRef
83. Cox L, Cohn JR. Duration of allergen immunotherapy in respiratory allergy: when is enough, enough?. Ann Allergy Asthma Immunol. 2007;98:416–426
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (119 KB)
    • CrossRef
84. Horak F, Zieglmayer P, Zieglmayer R, Ing D, Lemell P, Devillier P, et al. Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. J Allergy Clin Immunol. 2009;124:471–477
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (344 KB)
    • CrossRef
85. Amar SM, Harbeck RJ, Sills M, Silveira LJ, O'Brien H, Nelson HS. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. J Allergy Clin Immunol. 2009;124:150–156
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (392 KB)
    • CrossRef
86. Nelson H. Multiallergen immunotherapy for allergic rhinitis and asthma. J Allergy Clinical Immunol. 2009;123:763–769
    • View In Article