Hans-Jørgen Malling

Consensus statement on the treatment of allergic rhinitis.

Allergic rhinitis (AR) is a high-prevalence disease in many developed countries, affecting about 10±20% of the general population (1±5). Several studies based on questionnaire and objective testing or medical examination indicate an increasing prevalence of AR in European countries over the last decades (6, 7). AR is characterized by nasal itching, sneezing, watery rhinorrhoea, and nasal obstruction. Additional symptoms such as headache, impaired smell, and conjunctival symptoms can be associated. According to the time of exposure, AR can be subdivided into perennial, seasonal, and occupational disease. Perennial AR (PAR) is most frequently caused by dust mites and animal dander. Seasonal AR (SAR) is related to a wide variety of pollen allergens including grasses, Parietaria, Ambrosia, Artemisia, birch, olive, hazelnut, and cypress. The morbidity of SAR obviously depends on the geographic region, the pollen season of the plants, and the local climate. Several other conditions can cause similar symptoms and are referred to as nonallergic (noninfectious) rhinitis: NARES (nonallergic rhinitis with eosinophilia syndrome); aspirin sensitivity; endocrine, occupational, postinfectious, and side-effects of systemic drugs; abuse of topical decongestants (rhinitis medicamentosa); and idiopathic rhinitis. Furthermore, diseases such as nasal polyposis, chronic sinusitis, cystic ®brosis, Wegeners disease, benign or malignant tumours, etc. have to be excluded carefully. Therefore, current guidelines (4) emphasize the importance of an accurate diagnosis of patients presenting with rhinitis symptoms. In fact, several causes may commonly coexist in the same *European Academy of Allergology and Clinical Immunology. Allergy 2000: 55: 116±134 Printed in UK. All rights reserved Copyright # Munksgaard 2000

Clinical efficacy of sublingual and subcutaneous birch pollen allergen‐specific immunotherapy: a randomized, placebo‐controlled, double‐blind, double‐dummy study

Background:  Both sublingual allergen‐specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed.

Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis

BACKGROUND Recombinant DNA technology has the potential to produce allergen-specific immunotherapy vaccines with defined composition. OBJECTIVE To evaluate the effectiveness of a new recombinant birch pollen allergen vaccine in patients with birch pollen allergy. METHODS A multicenter, randomized, double-blind, placebo-controlled trial was undertaken to compare the following 3 vaccines in 134 adults with birch pollen allergy: recombinant birch pollen allergen vaccine (rBet v 1a), licensed birch pollen extract, natural purified birch pollen allergen (nBet v 1), and placebo. Patients received 12 weekly injections followed by monthly injections of the maintenance dose containing 15 microg Bet v 1 for 2 years. RESULTS Significant reductions (about 50%) in rhinoconjunctivitis symptoms (rBet v 1, P = .0002; nBet v 1, P = .0006; birch extract, P = .0024), rescue medication (rBet v 1, P = .0011; nBet v 1, P = .0025; birch extract, P = .0063), and skin sensitivities (P < .0001) were observed in the 3 actively treated groups compared with placebo during 2 consecutive pollen seasons. Clinical improvement was accompanied by marked increases in Bet v 1-specific IgG levels, which were higher in the rBet v 1-treated group than in the birch and nBet v 1-treated groups. New IgE specificities were induced in 3 of 29 patients treated with birch pollen extract, but in none of the 32 rBet v 1-treated or 29 nBet v 1-treated patients. No severe systemic adverse events were observed in the rBet v 1-treated group. CONCLUSION The rBet v 1-based vaccine was safe and effective in treating birch pollen allergy, and induced a highly specific immune response.

Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile

To cite this article: Calderón MA, Simons FER, Malling H‐J, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67: 302–311.

CXCR3 Expression and Activation of Eosinophils: Role of IFN-γ-Inducible Protein-10 and Monokine Induced by IFN-γ

CXC chemokine receptor 3 (CXCR3), predominately expressed on memory/activated T lymphocytes, is a receptor for both IFN-γ-inducible protein-10 (γ IP-10) and monokine induced by IFN-γ (Mig). We report a novel finding that CXCR3 is also expressed on eosinophils. γ IP-10 and Mig induce eosinophil chemotaxis via CXCR3, as documented by the fact that anti-CXCR3 mAb blocks γ IP-10- and Mig-induced eosinophil chemotaxis. γ IP-10- and Mig-induced eosinophil chemotaxis are up- and down-regulated by IL-2 and IL-10, respectively. Correspondingly, CXCR3 protein and mRNA expressions in eosinophils are up- and down-regulated by IL-2 and IL-10, respectively, as detected using flow cytometry, immunocytochemical assay, and a real-time quantitative RT-PCR technique. γ IP-10 and Mig act eosinophils to induce chemotaxis via the cAMP-dependent protein kinase A signaling pathways. The fact that γ IP-10 and Mig induce an increase in intracellular calcium in eosinophils confirms that CXCR3 exists on eosinophils. Besides induction to chemotaxis, γ IP-10 and Mig also activate eosinophils to eosinophil cationic protein release. These results indicate that CXCR3-γ IP-10 and -Mig receptor-ligand pairs as well as the effects of IL-2 and IL-10 on them may be especially important in the cytokine/chemokine environment for the pathophysiologic events of allergic inflammation, including initiation, progression, and termination in the processes.

Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis.

BACKGROUND Seasonal allergic rhinoconjunctivitis affects millions of persons. The efficacy of allergen sublingual immunotherapy (SLIT) was demonstrated in previous short-term studies. OBJECTIVES We sought to evaluate the sustained efficacy of 2 dosing regimens of a pre- and coseasonal treatment with 300 IR (index of reactivity) 5-grass-pollen SLIT tablets (Oralair) compared with placebo assessed by using the average adjusted symptom score (AAdSS) at season 3 in adults with grass pollen-induced rhinoconjunctivitis. METHODS Six hundred thirty-three patients were treated for either 2 or 4 months before and then during the grass pollen season with active or placebo treatment for 3 consecutive seasons. The primary outcome was the AAdSS, a symptom score adjusted for rescue medication use, after 3 consecutive treatment seasons. Secondary outcomes were symptoms and rescue medication score, quality-of-life, and safety assessments. RESULTS The mean AAdSS was reduced by 36.0% and 34.5% at season 3 in the 2- and 4-month pre- and coseasonal active treatment groups, respectively, compared with that in the placebo group (P < .0001 for both). Reductions were observed in total symptom scores and ISSs and the medication score, with a marked improvement in quality of life for both active groups compared with the placebo group at season 3. Most treatment-emergent adverse events were local reactions expected with SLIT, decreasing in number and intensity in each treatment season. CONCLUSIONS Sustained efficacy of 2- and 4-month pre- and coseasonal treatment with the 300 IR tablet over 3 pollen seasons was demonstrated, with reduction in symptoms and rescue medication use. The treatment was well tolerated. Adverse events decreased in number and intensity over the 3 seasons.

Diagnosis and immunotherapy of mould allergy. V: Clinical efficacy and side effects of immunotherapy with Cladosporium herbarum

A placebo‐controlled, double‐blind study of immunotherapy with the mould species Cladosporium was performed in 22 adult asthmatics. The diagnosis of Cladosporium allergy was based on a combination of bronchial provocation test and daily symptom score in the Cladosporium season. An aqueous preparation of a potent, biologically standardized and purified extract was used in a clustered dose‐increase regimen. The clinical efficacy was evaluated by a combination of symptoms (asthma score + peak flow) and consumption of antiasthmatic medication. The mean changes in symptoms and medication consumption over a 10–week registration period (peak Cladosporium season) in 1982 after 5–7 months of immunotherapy were compared with the corresponding 1981 pretreatment 10‐week period A significant (P= 0.03) difference in terms of “improved”, “unchanged” and “deteriorated” patients in favour of Cladosporium treatment was found. Approximately 80% in the Cladosporium group showed improved/unchanged symptoms contrary to 30% of the placebo treated. Side effects were observed frequently but only in the Cladosporium‐treated. About 70% experienced a large local reaction and 100% had episodes of asthma during dose‐increase phase. Only a few severe systemic reactions occurred. Based on the clinical efficacy of the treatment we consider immunotherapy with Cladosporium feasible for highly specialized clinics.

Side-effects of allergen-specific immunotherapy. A prospective multi-centre study

Background and objective The safety of allergen‐specific immunotherapy (SIT) is a parameter of great interest in the overall assessment of the treatment. A clinical database was developed in order to obtain early warnings of changes in the frequency and severity of side‐effects and sufficient data for the evaluation of possible risk factors.

Antihistamine premedication in specific cluster immunotherapy: A double-blind, placebo-controlled study

BACKGROUND Specific immunotherapy treatment in allergic diseases involves a risk of systemic side effects. A double-blind, placebo-controlled study was performed in 45 patients allergic to pollen to determine whether pretreatment with loratadine could reduce the number and severity of systemic reactions during the dose-increase phase of cluster immunotherapy. METHODS The patients received cluster immunotherapy with a standardized birch (Betula verrucosa) or grass (Phleum pratense) pollen extract adsorbed to aluminum hydroxide. The immunotherapy schedule involved seven visits and 14 injections to reach a maintenance dose of 100,000 standardized quality units. Loratadine, 10 mg, or placebo tablets were administered 2 hours before the first injection at each visit. RESULTS A total of 720 injections were given (309 injections in 21 patients receiving loratadine and 411 injections in 24 patients receiving placebo). The median numbers of injections to reach maintenance dose were 15 (range, 14 to 18) in the loratadine group and 16 (range, 14 to 23) in the placebo group (p = 0.037). The numbers of patients with systemic reactions were seven (33%) and 19 (79%) in the loratadine and placebo groups, respectively (p = 0.002). Twenty-five reductions caused by systemic reactions were observed in the placebo group in contrast to nine in the loratadine group (p = 0.047). No life-threatening systemic reactions were observed in either group. Systemic reactions were, however, more severe in the placebo group, mainly because of a significantly higher incidence of urticaria (10 vs 1, p = 0.022). CONCLUSION Pretreatment with loratadine seems to reduce both the number and severity of systemic reactions in specific cluster immunotherapy.

Immunotherapy with Hymenoptera venoms. Position paper of the Working Group on Immunotherapy of the European Academy of Allergy and Clinical Immunology.

Immunotherapy with Hymenoptera venoms is widely used throughout the world and is accepted as an effective treatment for most patients with Hymenoptera venom allergy. There are, however, still some unresolved problems with this form of treatment. At present there is no definite test which makes it possible to identify patients at risk ‐ and thus candidates for immunotherapy ‐ unequivocally. On the basis of prospective studies on the natural history of Hymenoptera allergy, venom immunotherapy is indicated in adults with severe systemic anaphylaxis. It is usually not necessary in patients with large local reactions only. Children with mild systemic reactions, e.g. urticaria, will need immunotherapy only in case of repeated reactions and/or a high risk of re‐exposure. The selection of venoms for immunotherapy may lead to some confusion owing to common antigenic determinants shared by venoms of various Hymenoptera species. Many different regimens for immunotherapy have been proposed. At present, the three main are: rush, stepwise or clustered and classical. The maintenance dose of 100 μg usually protects from life‐threatening reactions. However, in some patients 200 μg are necessary for complete protection. The usual interval between maintenance injections is 4 to 6 weeks. In many patients a strong increase of venom specific serum IgG‐antibodies usually parallels clinical protection induced by venom immunotherapy, although many exceptions have been reported. Allergic side effects of venom immunotherapy are not rare, especially with honey bee venom and during the initial phase of dose increase. The question of the duration of venom immunotherapy is handled differently: although some authors recommend treatment for life, most suggest treating patients until skin tests and RAST become negative.