Specific immunotherapy in grass pollen allergy

Abstract

Since its description by Noon in 1911, desensitization, or allergen specific immunotherapy (SIT), has been largely used in respiratory allergic diseases treatment. It remains the only etiologic treatment for allergic diseases. The development of the sublingual route and new forms of medication, as an alternative to subcutaneous injection, has led to large scale clinical trials. Many of them had been performed with allergen tablets, particularly in the field of pollen allergy. These studies have confirmed that SIT is efficient in reducing all respiratory allergic symptoms. Data on long-term benefits and sustained efficacy after stopping treatment have also been published. These show an impact on natural history of allergic disease, in particular, a reduction in the risk of asthma in desensitized rhinitic subjects and in the acquisition of new sensitivities. The basic mechanisms of immunotherapy are becoming better understood and allow us to envisage improvements in this therapeutic method in the future. The sublingual route appears to be safer with a better safety profile. This may lead to an extension of allergen specific immunotherapy indications in patients with respiratory allergic diseases.

Keywords: :

• pollen allergy
• rhinoconjunctivitis
• specific immunotherapy
• sublingual immunotherapy
• allergen tablets

Introduction

Allergen specific immunotherapy is currently the only etiologic treatment for grass pollen allergy. In recent years, new approaches in form and administration route have been developed. This development has been associated with large scale clinical trials in children and adults.

Administration Route

SIT was first developed using the subcutaneous route. As early as 1911, Noon first described the technique still used nowadays.¹ At this time, pollen extract was obtained using freezing and heating techniques, than injected in increasing concentrations. In this historic publication, efficacy was evaluated by a conjunctival provocation test with pollen instillation in the eye.

The subcutaneous route was the only mode of administration for more than 70 y. During this time, a lot of efforts were made to improve quality and standardization of allergen extracts.

The sublingual route was developed in the 90s with standardized allergen solutions. Drops of solution are placed under the tongue and kept in mouth for 2 min and then swallowed. In 2010, almost 100 y after Noon’s discovery, grass pollen tablets have been commercialized in Europe; one specialty contains 5 grass pollens (cocksfoot [Dactylis glomerata], meadow grass [Poa pratensis], rye grass [Lolium perenne], sweet vernal grass [Anthoxanthum odoratum], and Timothy grass [Phleum pratense]),² the other one contains only one species (Timothy grass pollen).³

Some other routes have been explored: The bronchial route was abandoned due to the frequency of local and systemic symptoms⁴; The intranasal route has been tried since the late 90s by Italian teams,^5,6 has been marketed in this country and still appears in a recent Taiwanese publication⁷; the oral route failed to demonstrate efficacy in respiratory allergies but seems promising in food allergy treatment;⁸the epicutaneous route, using patch tests (applied on the skin for a period of one to several days) was studied with grass pollens in one publication where efficacy in lowering allergic rhinitis symptoms was demonstrated.⁹

Finally, a new promising route of administration has been recently explored with intralymphatic allergen injections.¹⁰ In humans, 3 injections in a lymph node seems to be as efficient on rhinoconjunctivitis symptoms as 3 y of subcutaneous immunotherapy.¹¹

Mechanisms

It is now admitted that efficacy of SIT is related to the induction of a switch from Th2 system toward Th1.¹²

Several mechanisms have been proposed to explain the beneficial effects of SIT. Several cellular and molecular mechanisms have been demonstrated in various clinical trials: induction of CD4+ CD25+ FOXP3+ T regulatory cells, increase in IL10 secreting type 1 T regulatory cells, suppression of eosinophils, mast cells and basophils and an Ab isotype change from IgE to IgG4.¹²

Efficacy

Efficacy on rhinoconjunctivitis

Efficacy is most often evaluated by symptom scores and medication consumption scores. The daily symptom score (DSS)³ and the Rhinoconjunctivitis total symptom score (RTSS)² are the most widely used. They measure the intensity of nasal and ocular symptoms quantified by the patient: sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus, and watery eyes. For medication, the Rescue Medication Score (RMS) is frequently determined, giving each type of rescue medication a numeric value.²

A Cochrane meta-analysis performed on 51 studies has confirmed that subcutaneous SIT is efficient on both symptom and medication scores in patients with a pollen allergy.¹³

For sublingual SIT, a meta-analysis of 21 studies performed since 2003 showed a significant efficacy of sublingual grass pollen immunotherapy on symptoms and on rescue medication consumption.¹⁴ A most recent systematic review has included more than 4500 patients from 60 studies of sublingual SIT.¹⁵ Twenty-three of them concerned grass pollen allergic patients. In these studies, sublingual SIT induced significant reduction of the symptom scores in the treated patients compared with the placebo (standardized mean difference (SMD) -0.35; p < 0.00001). In 17 studies that evaluated medication consumption, the SMD was -0.23 (p = 0.0008) in the treated patients in comparison with the placebo. A Cochrane review specifically assessed the efficacy of sublingual SIT with seasonal allergens (n = 30). Significant reduction on total ocular symptom scores compared with a placebo was established (SMD -0.38; 95%CI: -0.50 to -0.25).¹⁶

The development of sublingual tablets for pollen SIT has led to large scale clinical trials in adult^17,18 and pediatric^19-21 populations. These studies have confirmed the efficacy of the treatment for the first pollen season. Some of them confirmed that the effect was sustained for several seasons under treatment.^2,22

Efficacy on allergic asthma

A meta-analysis of 75 trials (including more than 3,500 asthmatic patients) with subcutaneous SIT in which 18 were performed with grass pollen extracts demonstrated efficacy on clinical symptoms, specific and non-specific bronchial hyperresponsiveness and medication consumption.²³ There was no effect on lung function parameters.

For sublingual immunotherapy, a meta-analysis of 25 studies was first published by Calamita et al.²⁴ This meta-analysis is in favor of the treatment for several criteria: asthma symptoms, bronchial hyperresponsiveness, medication consumption reduction, FEV1 improvement. These results were confirmed in another meta-analysis focused on pediatric trials with sublingual SIT.²⁵

Alteration of the natural course of allergic disease

Some recent data showed that SIT is likely to influence the natural history of allergy.

Long-term efficacy after stopping SIT

Durham et al. showed that, after the third year of grass pollen subcutaneous SIT, efficacy on pollen allergy symptoms remained comparable in patients who stopped SIT and in subjects who maintained injections.²⁶ Moreover, the two active groups were significantly less symptomatic during the grass pollen season than patients from a control group.

A long-lasting study was performed in 13 children desensitized with subcutaneous grass pollen extract.²⁷ Efficacy evaluation (symptoms and rescue medication intake) was done 6 and 12 y after stopping SIT. This group was compared with a non-desensitized control group. Although the methodological quality of this trial remains questionable, this study showed that efficacy persists after 6 and 12 y in the treated group.

With the sublingual route, a large study has been conducted in more than 200 patients suffering from grass pollen allergic rhinitis. Treatment was given following a co-seasonal protocol for three consecutive years with grass pollen extract.²⁸ This study confirmed a significant improvement of a symptom/medication combined score during the three years of treatment compared with a placebo group. Finally, the clinical data recently published with tablet SIT administered with a perennial protocol, demonstrated a long-term effect in the treated group compared with placebo group, one and two years after stopping SIT.^3,29

Asthma risk reduction in patients desensitized for allergic rhinitis

Few studies have explored this complex question. The PAT Study has considered 205 children (6 to 14 y old) suffering from allergic rhinitis without asthma at inclusion.³⁰ After three years of grass or birch pollen subcutaneous SIT, less children in the treated arm had asthma than in the control group (odd ratio 2.52; p < 0.05). For 147 children an evaluation was also performed seven years after SIT discontinuation.³¹ The effect on asthma prevention was still persistent at this time.

Comparison of subcutaneous and sublingual routes

Only five trials have assessed this question.^32-36 Three of them have been performed with pollen allergens.^32,34,35 All of them are of weak methodology and all but one demonstrated a similar efficacy of the two routes of administration.

SIT Side Effects

Subcutaneous SIT might induce adverse events. Local reactions at the injection site are frequent and benign. Subcutaneous specific immunotherapy is burdened with a risk of systemic side effects: when treating rhinitis patients, the risk of serious anaphylactic reactions is rather limited but the risk increases in asthmatic patients. In most of the recently published studies, systemic side effects were still noticed either using standardized extracts, allergoids or recombinant allergens.³⁷

For sublingual SIT, local side effects have been frequently described in clinical trials. These include itching and swelling of the lips and under the tongue. These side-effects are often well tolerated, and require no medication or dosage alteration. They usually resolve with continued treatment. In a few clinical trials, systemic reactions such as urticaria and asthma have been observed, all of them self-limiting. No anaphylaxis was reported during clinical trials with sublingual SIT. Outside clinical trials, some case-reports of severe reactions can be found in the literature.¹⁵ They always concern allergens that are not recommended in the guidelines of good practice of SIT.

Indications and Contraindications

In adults

The presence of an IgE-mediated disease by positive skin tests and/or serum-specific IgE to grass pollens needs to be confirmed in a patient suffering from seasonal rhinitis.³⁷ Severity and duration of symptoms, tolerance of symptomatic medications must be evaluated. SIT is indicated in patients insufficiently controlled by conventional pharmacotherapy or when these medications induce undesirable effects. If asthma is associated, it needs to be controlled before SIT initiation.

Contraindications for grass pollens subcutaneous SIT are: treatment with β-blockers, other immunologic disease, inability of patient to comply with the treatment, starting immunotherapy with inhalant allergens during known pregnancy.³⁷

In children

Indications and contraindications for subcutaneous and sublingual grass pollens SIT are the same for children over the age of 5 y as for adults.³⁷ Sublingual SIT should be preferred since it is less invasive than subcutaneous SIT.

Perspectives

Forms

Allergen solutions, first for subcutaneous SIT, then for sublingual route were used for many years. A major advance in the last five years was the introduction of tablets for SIT. They are already commercialized in Europe for grass pollen SIT. Clinical development is still ongoing for other important allergens (birch pollen, house dust mites). However, because of development costs, the tablet form may never be developed for less frequent allergens.

For sublingual route, using adjuvants or other substances to enhance the contact of the allergens with the oral mucosal might be of interest to improve the treatment efficacy.³⁸

Modified allergens (allergoids)

Allergens can be modified with glutaraldehyde or formaldehyde. Theoretically this treatment decreases the number of epitopes that induce IgE response but leave T epitopes intact.⁴ Clinical trials in adult and children with grass pollen allergoïds have shown a benefit on symptom and medication scores and on conjunctival provocation test. Pollinex Quatro® (Allergy Therapeutics) contains an addition of the TLR-4 agonist monophosphoryl lipid, Allergovit^® (Allergopharma KG) is an aluminum hydroxide–adsorbed depot allergoid preparation of 6 grass pollen allergens. The real immunogenic potential of these low allergenic substances is not totally evaluated. Allergens modifications were also studied on birch pollen or hymenoptera allergens⁴

Adjuvants

Clinical trials have explored the association of immunomodulators with SIT.³⁹ Anti-IgE antibodies like omalizumab, an humanized, monoclonal anti-IgE antibody that binds exclusively to circulating IgE molecules, thus interrupting the allergic cascade administered in patients following subcutaneous SIT may improve SIT safety and efficacy on the control of pollen allergy symptoms. However, immunological mechanisms of this effect remain unknown.

Recombinant allergens and peptides

Recombinant allergens are purified allergens produced by DNA recombinant technology using the allergen’s known molecular, immunologic, and biological characteristics.⁴ The allergens produced mimic the properties of the natural allergen. Recombinant allergens can also be manipulated to reduce allergenic activity, increase immunogenicity, or both.

One study has used subcutaneous injections of a mixture of five different recombinant allergens of Timothy grass pollen, compared with placebo injections.⁴⁰ Efficacy on quality of life score was demonstrated but 1% of grass pollen injections led to systemic reactions.⁴⁰

Conclusion

SIT with grass pollens extracts has been used for more than 100 years as an etiologic treatment of allergic rhinitis and asthma. New routes of administration have been developed and new forms of treatment are now commercialized in Europe, using tablets of grass pollen extracts. The clinical efficacy of subcutaneous SIT is well established for both rhinitis and asthma. Sublingual SIT is safe and effective using allergens solutions and allergen tablets in adults and children. Adjuvants and allergen modifications offer new perspectives on obtaining more immunogenic and less allergenic vaccines.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.