Epicutaneous immunotherapy in rhino-conjunctivitis and food allergies: a review of the literature.

BACKGROUND: Epicutaneous immunotherapy (EPIT) is a new way of allergen administration that has a high rate of adherence and safety. The aim of this manuscript is to review clinical trials on EPIT for respiratory and food allergies published in the last 10 years, taking into account how different variables (i.e., dose, patch application duration, skin preparation, and efficacy and safety evaluation) have influenced study results. MAIN BODY: From a review of the literature, we identified eight placebo-controlled, double-blind trials conducted on children and adults, including four studies on grass pollen rhino-conjunctivitis, one on cow's milk allergy and three on peanut allergy. Different methods for skin pre-treatment, such as skin abrasion and tape stripping or stratum corneous hydration by an occlusive system, different endpoints and cumulative allergen doses, and different durations of patch application and tape stripping, were used in the rhino-conjunctivitis studies. A visual analogue system was used for the efficacy evaluation. Several local skin reactions (eczema) and some systemic adverse reactions were reported at higher rates in the active group compared to placebo in one study, but this was not shown by other authors. Local eczema reactions were correlated to the times for applying the tape stripping, while systemic side effects were correlated to the deepness of scraping. In the food allergy trials, differences in the food challenge thresholds, endpoints and allergen sites of the cutaneous patch application influenced the study results. A slight dose-dependent efficacy was found in the peanut allergy studies, which was confirmed by a more significant increase in the following progressive open study. Few adverse events and high adherence in all of the food allergen trials were reported. CONCLUSIONS: Overall, the EPIT study results, even if they were affected by great heterogeneity among the methodologies applied, have shown not only the high safety and adherence with this kind of immunotherapy but also suggested the possibility for obtaining definitive evidence of the efficacy of EPIT, especially for food allergies.

Exhaled nitric oxide and nasal tryptase are associated with wheeze, rhinitis and nasal allergy in primary school children.

Rhinitis and asthma are the most common respiratory diseases in children. We assessed whether airway inflammation markers were associated with nasal allergies and self-reported symptoms of wheeze and rhinitis in 130 children 6-12 year old in an epidemiological context. Independent of sex and age, the fraction of exhaled nitric oxide (FeNO) and nasal mast cell (MC) activation (tryptase ≥ 5 ng/mL) were positively associated with wheeze, rhinitis and with nasal allergy. Nasal eosinophil cationic protein (ECP) and exhaled breath condensate (EBC) markers (pH, 8-isoprostane, interleukin-1ß) were not associated with symptoms or with nasal allergy. In conclusion, FeNO and nasal tryptase reflect allergic inflammation in the respiratory system.

Specific IgE response to different grass pollen allergen components in children undergoing sublingual immunotherapy.

BACKGROUND: Grass pollen is a major cause of respiratory allergy worldwide and contain a number of allergens, some of theme (Phl p 1, Phl p 2, Phl p 5, and Phl 6 from Phleum pratense, and their homologous in other grasses) are known as major allergens. The administration of grass pollen extracts by immunotherapy generally induces an initial rise in specific immunoglobulin E (sIgE) production followed by a progressive decline during the treatment. Some studies reported that immunotherapy is able to induce a de novo sensitisation to allergen component previously unrecognized. METHODS: We investigated in 30 children (19 males and 11 females, mean age 11.3 years), 19 treated with sublingual immunotherapy (SLIT) by a 5-grass extract and 11 untreated, the sIgE and sIgG4 response to the different allergen components. RESULTS: Significant increases (p < 0.001) were detected for Phl p 1, Phl p 2, Phl p 5, and Phl p 6, while sIgE levels induced in response to Phl p 7 and Phl p 12 were low or absent at baseline and unchanged following SLIT treatment; no new sensitisation was detected. As to IgG4, significant increases were found for Phl p2 and Phl p 5, while the increase for Phl p 12 was not significant. In the control group, no significant increase in sIgE for any single allergen component was found. CONCLUSIONS: These findings confirm that the initial phase of SLIT with a grass pollen extract enhances the sIgE synthesis and show that the sIgE response concerns the same allergen components which induce IgE reactivity during natural exposure.

Effects of sublingual immunotherapy on allergic inflammation: an update.

The most common allergic diseases, and especially the respiratory disorders such as rhinitis and asthma, are closely related to the allergic inflammation elicited by the causative allergen. This makes inflammation the main target of anti-allergic therapies. Among the available treatments, allergen specific immunotherapy (AIT) has a patent effect on allergic inflammation, which persists also after its discontinuation, and is the only therapy able to modify the natural history of allergy. The traditional, subcutaneous route of administration was demonstrated to modify the allergen presentation by dendritic cells (DCs) that in turn correct the phenotype of allergen-specific T cells, switching from the Th2-type response, typical of allergic inflammation and characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy of Th2 or to tolerance, the latter being related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual AIT with high allergen doses proved to be similar to subcutaneous immunotherapy. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa, with particular importance for mucosal DCs, plays a crucial role in inducing tolerance to the administered allergen.

Anti-inflammatory activity and clinical efficacy of a 3-month levocetirizine therapy in mite-allergic children.

The non-sedating third generation antihistamine levocetirizine has ample evidence of efficacy in allergic rhinitis. In vitro studies suggested that levocetirizine has anti-inflammatory properties not simply related to the antihistamine activity but also to regulation of eosinophils. We performed a double-blind placebo-controlled study in 40 children allergic to house dust mites with persistent rhinitis with the primary aim to evaluate the anti-inflammatory efficacy of levocetirizine measuring eosinophil-related parameters and exhaled nitric oxide (eNO). After one month of treatment, a significant improvement in nasal symptom-medication scores was observed in actively but not in placebo treated patients. After 3 months of treatment, a significant effect was detected on eosinophilic cationic protein (ECP) in nasal mucosa and on nasal eNO in active treated patients. This suggests that during treatment of mite-allergic children with levocetirizine the early improvement in nasal symptoms is due to the antihistamine activity, while more time is needed to achieve an effect on allergic inflammation.

Safety of sublingual immunotherapy started during the pollen season.

BACKGROUND: Sublingual immunotherapy (SLIT) is safer than subcutaneous immunotherapy (SCIT) and this has lead to the reconsideration of the use of ultra-rush schedules for SLIT. The aim of this study was to assess the safety of ultra-rush SLIT in pollen-allergic children according to different timing of administration in relation to the pollen season. METHODS: In total, 34 children with pollen-induced rhinitis and 36 with pollen-induced asthma and rhinitis, were enrolled and assigned to three study groups: group 1 (n = 17 patients): conventional pre-seasonal-SLIT treatment; group 2 (n = 23 patients), seasonal SLIT ended before the pollen seasonal peak; group 3 (n = 30 patients), SLIT began after the pollen seasonal peak and ended after the pollen season. SLIT was performed using extracts from Stallergenes (Antony, France) and following an ultra-rush schedule, consisting in four doses at a 30-min intervals, and maintenance treatment by administering the top dose three times a week. RESULTS: In all, 54 adverse events (AEs) were reported: 12 in nine patients in group 1 (9/17, 52.9%), 22 in 14 patients in group 2 (14/23, 60.9%), and 20 in 13 patients in group 3 (13/30, 43.3%). No statistically significant differences were found between the three groups. Local AEs (oral itching and burning) were short lasting and self-resolving. Systemic AEs were also mild, except for a case of asthma, which lasted 5 days, in a patient from group 1. There were no severe reactions, and none of the patients dropped out. CONCLUSIONS: This study suggests that SLIT with pollen extracts may be safely started at the beginning and also during the pollen season, with a tolerability profile comparable to the conventional pre-seasonal SLIT.

Effects of sublingual immunotherapy on allergic inflammation.

The clinical expression of the most common allergic diseases reflects allergic inflammation and underlines that inflammation is the main target of anti-allergic therapies. Allergen specific immunotherapy (AIT) has a recognized impact on allergic inflammation, which persists after its discontinuation, and is the only therapy able to modify the natural history of allergic march. The traditional, subcutaneous route of administration is effective in altering the phenotype of allergen-specific T cells, switching from a Th2-type response, characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy or tolerance of Th2, the latter related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual IT with high allergen doses proved to be similar compared to subcutaneous immunotherapy. Recent data obtained in biopsies clearly indicate that the pathophysiology of the oral mucosa, and in particular mucosal dendritic cells, plays a pivotal role in inducing tolerance to the administered allergen.

Mucosal immunization application to allergic disease: sublingual immunotherapy.

Sublingual immunotherapy (SLIT) is an effective and safe treatment for respiratory allergy, and its mechanism of action currently is investigated with increasing attention. Studies of pharmacokinetics showed that allergen extracts administered via the sublingual route are not directly absorbed by the oral mucosa but are long retained at mucosal level, where the allergen molecules are captured by dendritic cells and, following their migration in the draining lymph nodes, presented to T cells. This seems to be the pivotal factor underlying the mechanisms of action of SLIT, at least for the long-term effects, and for the short-term efficacy, observed with ultrarush or coseasonal treatment, a down-regulation of mast cells resulting in hyporeactivity at the peak of the pollen season may be suggested. Regarding the clinically established long-lasting effects, the core mechanism is likely to consist of T regulatory (Treg) cell activation. In particular, Treg cells differentiate from naive T cells after application of soluble antigens to the mucosae, a crucial factor being the tolerogenic function of dendritic cells, and exert a suppressive effect on both Th1 and Th2 responses. Moreover, at least for the type 1 cells (Treg1), a production of IL-10 with consequent down-modulation of the immune response has been reported. Another characteristic of sublingual immunization is the absence of effectors cells, viz., mast cells, basophils, and eosinophils, in the oral mucosa of allergic subjects, which account for the excellent tolerability of SLIT.

Allergic inflammation and the oral mucosa.

Allergic inflammation is initiated by the contact between allergen(s) and specific IgE antibodies, driven by regulatory cells such as antigen presenting cells and T lymphocytes, which orientate and orchestrate the response, and sustained by effector cells such as mast cells, basophils, and eosinophils. Among tissues and organs targeted by allergy, the nose, the lungs and the skin have the property to spread in distant sites the initially local reaction, thus resulting in systemic disease. By contrast, the oral mucosa seems to be a tolerogenic site regarding the immunologic response to allergens. This mucosa is characterized by abundance of dendritic cells, which are antigen presenting cells specialized in uptaking, processing and presenting the antigens to T cells, and particularly to T regulatory cells which in turn can downregulate Th1 and Th2 immune responses by direct cell contact or by production of immunosuppressive cytokines. The other important aspect of the oral mucosa is the negligible presence of effector inflammatory cells, namely mast cells and eosinophils, which accounts for the reportedly good safety of sublingual administration of allergen immunotherapy. These peculiar aspects and patents have important implications in treatment and prevention of allergic diseases.

Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years.

BACKGROUND: The minimum age to start specific immunotherapy with inhalant allergens in children has not been clearly established, and position papers discourage its use in children younger than 5 years. OBJECTIVE: To assess the safety of high-dose sublingual-swallow immunotherapy (SLIT) in a group of children younger than 5 years. METHODS: Sixty-five children (51 boys and 14 girls; age range, 38-80 months; mean +/- SD age, 60 +/- 10 years; median age, 60 months) were included in this observational study. They were treated with SLIT with a build-up phase of 11 days, culminating in a top dose of 300 IR (index of reactivity) and a maintenance phase of 300 IR 3 times a week. The allergens used were house dust mites in 42 patients, grass pollen in 11 patients, olive pollen in 5 patients, Parietaria pollen in 4 patients, and cypress pollen in 3 patients. All adverse reactions and changes in the treatment schedule were compared in 2 subgroups: children 38 to 60 months old and children 61. to 80 months old. RESULTS: The average cumulative dose of SLIT was 36,900 IR. Adverse reactions were observed in 11 children, none of them severe enough to require discontinuation of immunotherapy. Six reactions occurred in the 60 months or younger age group and 7 in the older than 60 months age group, with no differences between these 2 groups. CONCLUSION: High-dose immunotherapy in children younger than 5 years does not cause more adverse reactions than in children aged 5 to 7 years. There is no reason to forbear studies on safety and efficacy of these preparations in young children.