Evaluation and validation of a bee venom sting challenge performed by a micro-syringe.

BACKGROUND: The honeybee sting challenge is considered a reliable procedure to evaluate the efficacy of specific immunotherapy, but it is difficult and unpractical to perform in clinical practice, because live insects are required. OBJECTIVE: To assess the feasibility and reliability of a challenge test using a micro-syringe, and compared the procedure with sting challenge. METHODS: Patients on bee venom immunotherapy and without systemic reactions at field sting were enrolled. They underwent a sting challenge with live bee, and large local reactions were assessed up to 48 hours. Those patients displaying systemic reactions at the sting challenge were excluded from the syringe challenge for ethical reasons. The syringe challenge was done by injecting 0.5 µL fresh unfiltered bee venom at 2 mm depth (the length of the sting left by a bee). The same follow-up as at the first challenge was performed. Bee-specific immunoglobulin E (IgE) and tryptase were measured after each challenge. RESULTS: Nineteen patients underwent the sting challenge with live bees. Four had immediate systemic reactions (urticaria or asthma) and were excluded from the second challenge. The remaining 15 patients with large local reaction underwent the syringe challenge. No significant difference was seen in the maximum area of the large local reactions between the challenge with live bees and the syringe challenge. Also, no change was seen in tryptase and specific antibodies. CONCLUSION: This preliminary study suggests that the micro-syringe challenge with honeybee venom is feasible and produces results indistinguishable from those of the traditional sting challenge.

Role of contact sensitization in chronic urticaria.

We tested the hypothesis that contact allergy plays a role in chronic urticaria, and included the Italian series of patch tests in the diagnostic workup. Of 121 patients with chronic urticaria, 50 (41%) tested positive to contact allergens. In all patients, avoidance measures led to a complete remission within 1 month. We suggest that testing for contact sensitization can be helpful in the management of chronic urticaria.

Allergen immunotherapy in asthma; what is new?

The use and role of allergen immunotherapy (AIT) in asthma is still a matter of debate, and no definite recommendation about this is made in guidelines, both for the subcutaneous and sublingual routes. This is essentially due to the fact that most controlled randomised trials were not specifically designed for asthma, and that objective measures of pulmonary function were only occasionally considered. Nonetheless, in many trials, favourable results in asthma (symptoms, medication usage, bronchial reactivity) were consistently reported. There are also several meta analyses in favour of AIT, although their validity is limited by a relevant methodological heterogeneity. In addition to the crude clinical effect, a disease modifying action of AIT (prevention of asthma onset and long-lasting effects) have been reported. The safety is an important aspect to consider in asthma. Fatalities were rare: in Europe no fatality was reported in the last three decades, as in the United States in the last 4 years. Based on previous surveys, and common sense, uncontrolled asthma is still recognized as the most important risk factor for severe adverse events. On the contrary, there is no evidence that AIT can worsen or induce asthma. According to the available evidence, AIT can be safely used as add-on treatment when asthma is associated with rhinitis (a frequent condition), provided that asthma is adequately controlled by pharmacotherapy. AIT cannot be recommended or suggested as single therapy. When asthma is the unique manifestation of respiratory allergy, its use should be evaluated case by case.

The relationship between allergen immunotherapy and omalizumab for treating asthma.

Allergen-specific immunotherapy (AIT) is considered the only treatment capable of modifying the natural history of allergic respiratory disorders. The possible adverse events related to AIT have, until now, limited its use to mild and controlled asthma. The pre-administration or concomitant treatment of AIT and omalizumab (an anti-IgE humanized antibody), recommended for the treatment of severe allergic asthma, could be useful in reducing the adverse events due to AIT and to allow its use in patients with more severe or uncontrolled asthma. AIT/omalizumab combination has been explored in a few trials on asthma patients and also in other allergic disorders, such as rhinitis, hymenoptera systemic reaction and food allergy with significant results. We are at the beginning a new era where phenotype/endotype-based treatment will be associated with drug mass therapy and/or nonpharmacological phenotype/endotype-driven treatment to optimize disease control and/or to make the use of other treatments safer.

Allergenius, an expert system for the interpretation of allergen microarray results.

BACKGROUND: An in vitro procedure based on a microarray containing many different allergen components has recently been introduced for use in allergy diagnosis. Recombinant and highly purified allergens belonging to different allergenic sources (inhalants, food, latex and hymenoptera) are present in the array. These components can either be genuine or cross-reactive, resistant or susceptible to heat and low pH, and innocuous or potentially dangerous. A large number of complex and heterogeneous relationships among these components has emerged, such that sometimes these interactions cannot be effectively managed by the allergist. In the 1960s, specialized languages and environments were developed to support the replacement of human experts with dedicated decision-making information systems. Currently, expert systems (ES) are advanced informatics tools that are widely used in medicine, engineering, finance and trading. METHODS: We developed an ES, named Allergenius ®, to support the interpretation of allergy tests based on microarray technology (ImmunoCAP ISAC ®). The ES was implemented using Flex, a LPA Win-Prolog shell. Rules representing the knowledge base (KB) were derived from the literature and specialized databases. The input data included the patient's ID and disease(s), the results of either a skin prick test or specific IgE assays and ISAC results. The output was a medical report. RESULTS: The ES was first validated using artificial and real life cases and passed all in silico validations. Then, the opinions of allergists with experience in molecular diagnostics were compared with the ES reports. The Allergenius reports included all of the allergists' opinions and considerations, as well as any additional information. CONCLUSIONS: Allergenius is a trustable ES dedicated to molecular tests for allergy. In the present version, it provides a powerful method to understand ISAC results and to obtain a comprehensive interpretation of the patient's IgE profiling.

Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations.

BACKGROUND: A preferential association between systemic mastocytosis (SM) and hymenoptera allergy (HVA) has been observed. Patients with both diseases are at risk for more severe reactions, and venom immunotherapy (VIT) may represent a life-saving treatment, but the use of VIT in such patients raised concerns about its safety. OBJECTIVE: We evaluated a large population of patients with SM and HVA who received VIT. METHODS: This prospective study was performed in Italy and Spain. A diagnosis of SM and HVA and a VIT prescription were made according to international recommendations. The patients were carefully followed up during VIT, with special attention to field stings. RESULTS: A total of 84 patients (70 men, 14 women; mean age 52.1 years) were included, 81% with grade IV reaction, 91% with indolent SM. No difference was seen between the Italian and Spanish patients. There were 10 adverse reactions during the induction phase: 3 with the conventional induction and 7 with the rush-modified induction, none resulted in epinephrine administration and/or hospitalization. Fifty patients had one or more field re-sting (95 episodes), none during induction. The time elapsed from starting VIT and first re-sting was 2 months to 7 years, and the number of re-stings per patient was 1-6. Of the 50 patients who were re-stung, 43 (86%) resulted in being fully protected. Seven patients had reactions, and the maintenance dose was safely increased to 200 mcg. The maintenance dose interval was not different between patients with and those without reactions at re-stings. CONCLUSION: VIT is well tolerated, safe, and effective in patients with SM.

Evidences of efficacy of allergen immunotherapy in atopic dermatitis: an updated review.

PURPOSE OF REVIEW: To update and assess the quality of the evidence concerning the efficacy of allergen immunotherapy for atopic eczema. Desensitization for eczema as a clinical manifestation of food allergy was not a target of this review. RECENT FINDINGS: In the past 5 years, from the last comprehensive systematic review of Bussmann et al., four controlled trials have been published on this topic, two using injection and two sublingual immunotherapy. The active treatment was compared with placebo, pharmacotherapy or different schedules of immunotherapy. The studies variably involved adults and children and showed an improvement of atopic dermatitis severity. Severe eczema seems less responsive to hyposensitization, and a minimal treatment duration of 9-12 months appears necessary. SUMMARY: The efficacy of immunotherapy in patients with atopic eczema has been poorly investigated in the past 5 years. The available trials have small dimension and some methodological shortcomings, in addition to incomplete reporting. Clinical and methodological interstudy heterogeneity is apparent. Only one study adopted a placebo control. The evidence of efficacy has not critically changed from previous systematic observations. No long-term studies have been conducted to determine the disease-modifying potential of specific immunotherapy in the context of the 'allergy march'.

Patients with asthma and comorbid allergic rhinitis: is optimal quality of life achievable in real life?

OBJECTIVES: Asthma trials suggest that patients reaching total disease control have an optimal Health Related Quality of Life (HRQoL). Moreover, rhinitis is present in almost 80% of asthmatics and impacts asthma control and patient HRQoL. We explored whether optimal HRQoL was reachable in a real-life setting, and evaluated the disease and patient related patterns associated to optimal HRQoL achievement. METHODS AND FINDINGS: Asthma and rhinitis HRQoL, illness perception, mood profiles, rhinitis symptoms and asthma control were assessed by means of validated tools in patients classified according to GINA and ARIA guidelines. Optimal HRQoL, identified by a Rhinasthma Global Summary (GS) score ≤20 (score ranging from 0 to 100, where 100 represents the worst possible HRQoL), was reached by 78/209 (37.32%). With the exception of age, no associations were found between clinical and demographic characteristics and optimal HRQoL achievement. Patients reaching an optimal HRQoL differed in disease perception and mood compared to those not reaching an optimal HRQoL. Asthma control was significantly associated with optimal HRQoL (χ(2) = 49.599; p<0.001) and well-controlled and totally controlled patients significantly differed in achieving optimal HRQoL (χ(2) = 7.617; p<0.006). CONCLUSION: Approximately one third of the patients in our survey were found to have an optimal HRQoL. While unsatisfactory disease control was the primary reason why the remainder failed to attain optimal HRQoL, it is clear that illness perception and mood also played parts. Therefore, therapeutic plans should be directed not only toward achieving the best possible clinical control of asthma and comorbid rhinitis, but also to incorporating individualized elements according to patient-related characteristics.

Eosinophilic esophagitis: which role for food and inhalant allergens?

Eosinophilic esophagitis is a chronic inflammatory disease of the esophagus, immune/antigens mediated, whose incidence is increasing both in adults and pediatric population. It is clinically characterised by symptoms related to esophageal dysfunction and associated with eosinophil-predominant esophageal inflammation. The role of atopy has been clearly demonstrated both in epidemiological and experimental studies and has important implications for diagnosis and therapy. In fact, many evidences show that food and inhalant allergens represent the most important factors involved in the progress of the disease. Several studies have reported that, in a range between 50 and 80%, patients with eosinophilic esophagitis have a prior history of atopy, and for them, the presence of allergic rhinitis, asthma or atopic dermatitis is frequent. Skin tests are able to identify in most patients the allergens involved, allowing a correct dietary approach in order to achieve the remission of symptoms and the biopsy normalization.

Effects of different up-dosing regimens for hymenoptera venom immunotherapy on serum CTLA-4 and IL-10.

BACKGROUND: Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is involved in the activation pathways of T lymphocytes. It has been shown that the circulating form of CTLA-4 is elevated in patients with hymenoptera allergy and can be down regulated by immunotherapy. OBJECTIVE: to assess the effects on CTLA-4 of venom immunotherapy, given with different induction protocols: conventional (6 weeks), rush (3 days) or ultra rush (1 day). METHODS: Sera from patients with hymenoptera allergy were collected at baseline and at the end of the induction phase. CTLA-4 and IL-10 were assayed in the same samples. A subset of patients were assayed also after 12 months of VIT maintenance. RESULTS: Ninety-four patients were studied. Of them, 50 underwent the conventional induction, 20 the rush and 24 the ultra-rush. Soluble CTLA-4 was detectable in all patients at baseline, and significantly decreased at the end of the induction, irrespective of its duration. Of note, a significant decrease of sCTLA-4 could be seen already at 24 hours. In parallel, IL-10 significantly increased at the end of the induction. At 12 months, sCTLA-4 remained low, whereas IL-10 returned to the baseline values. CONCLUSIONS: Serum CTLA4 is an early marker of the immunological effects of venom immunotherapy, and its changes persist after one year of maintenance treatment.

Persistent Allergic Rhinitis and the XPERT Study.

Allergic rhinitis (AR) is a chronic disease with an increasing trend in most of the Western Countries. It may significantly impair the individual quality of life (QoL) and also represents a social burden for its economic costs. Levocetirizine (XYZAL; UCB Pharma) as a second generation, nonsedating H1-antihistamine, has been shown to be clinically effective in patients with AR in different randomized controlled trials. The XPERT (XYZAL in Persistent Rhinitis Trial) is the first large, long-term clinical study involving patients with persistent rhinitis as defined by ARIA (Allergic Rhinitis and its Impact on Asthma). The XPERT was a 6-month double-blind, placebo-controlled, multicenter, multinational trial in 551 subjects. Adults with persistent rhinitis sensitized to both grass pollen and house dust mites were randomized to receive levocetirizine 5 mg/d or placebo. Two primary objectives were considered: comparison of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) overall score and Total 5 Symptoms Score (rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) (T5SS) between active and control group over a period of 4 weeks. As secondary endpoints, similar evaluations at 1 week and 3, 4, 5, and 6 months, summary scores for a general health status questionnaire (Medical Outcomes Survey Short Form 36), comorbidities, pharmacoeconomic and safety evaluations. Levocetirizine significantly improved both the RQLQ overall score and the T5SS from week 1 to 6 months (P <.001). Medical Outcomes Survey Short Form 36 summary scores were also improved in the group treated with levocetirizine with respect to placebo. Treatment cessation because of lack of efficacy, comorbidities, and overall costs of disease, and comorbidities per working patient per month (160.27 vs 108.18) were lower in the levocetirizine group. In conclusion, levocetirizine resulted to improve the quality of life and the symptoms related to AR and also to reduce the overall costs of the disease after 6 months treatment.

Emerging sublingual immunotherapy drugs.

IMPORTANCE OF THE FIELD: There is epidemiological evidence that respiratory allergy has reached epidemic proportions; owing to the related socio-economic impact, this topic deserves particular attention. An integrated approach involving pharmacotherapy and the immunomodulatory effect of immunotherapy is expected to optimize the management of respiratory allergy, reducing its clinical and economic burdens. Sublingual immunotherapy (SLIT) has gained increasing interest for its efficacy comparable to traditional subcutaneous immunotherapy and its good safety profile. AREAS COVERED IN THIS REVIEW: A review of the up-to-date state of the art concerning the key aspects of SLIT is provided; the critical issues are discussed in the light of the comprehensive revision of the recent World Allergy Organization position paper and the subsequent literature, paying particular attention to efficacy, safety, additional effects, adherence and clinical developments. WHAT THE READER WILL GAIN: The overview of current certainties and concerns, related to the use of SLIT, allows the reader's insight into the future directions of research and clinical applications of SLIT, aimed at covering current unmet needs. TAKE HOME MESSAGE: A large amount of experimental evidence sustains the use of SLIT, though some aspects still need to be clarified to provide clear, evidence-based recommendations. Unmet needs represent the basis for future research, while clinical hypotheses would open the search for new indications and modalities.

Levocetirizine in persistent allergic rhinitis: continuous or on-demand use? A pilot study.

BACKGROUND: Allergic rhinitis is a high-prevalence disease that affects quality of life (QOL), sleep quality and productivity of patients. According to the ARIA initiative, it is classified as intermittent and persistent, the latter being the most troublesome. METHODS: The aim of this randomized, open-label, 6-month, pilot study was to determine whether levocetirizine 5 mg administered continuously once daily in the morning was better than levocetirizine 5 mg on-demand in symptomatic subjects with persistent allergic rhinitis. Total and individual symptom scores were recorded in a diary card throughout the study. QOL, quality of sleep, nasal cytology, rate of drug intake, and safety were also assessed at pre-defined time-points. RESULTS: In all, adult patients (31 in each group) were enrolled, of whom 22 dropped out. Both treatment regimens considerably decreased the total and individual symptoms scores from baseline and achieved similar levels up to week 14. Continuous treatment was generally better than on-demand from week 15 onwards, reaching statistical significance from weeks 17 to 21 (from week 19 to 21 for nasal pruritus). Both regimens substantially improved QOL and sleep quality. Both treatments were well tolerated, although the on-demand group reported more adverse events. CONCLUSION: The present open label study in 62 patients indicates that levocetirizine 5 mg reliably controls persistent rhinitis over a period of 6 months, and shows a trend to be more effective in controlling the symptoms of rhinitis, improving QOL and decreasing nasal inflammation, when administered as long-term continuous therapy rather than as on-demand therapy.

Randomized open comparison of the safety of SLIT in a no-updosing and traditional updosing schedule in patients with Parietaria allergy.

BACKGROUND: Due to optimal safety of sublingual immunotherapy (SLIT), it was suggested that a slow up-dosing phase maybe not necessary, and therefore the treatment will be more patient-friendly, avoiding dosing mistakes. PATIENTS: Twenty adult patients suffering allergic rhinitis due to Parietaria, were enrolled. Half of them received the traditional schedule and the other half immediately started with 200 STU. RESULTS: No difference was observed between the traditional up-dosing treatment schedule and no-up-dosing treatment schedule in terms of side effects, even mild local side effects, even mild local side effects was greater with traditional regimen.

Comparison of the effects in the nose and skin of a single dose of desloratadine and levocetirizine over 24 hours.

BACKGROUND: Desloratadine (DL) and levocetirizine (LCZ) are the newest commercialized antihistamines. Pharmacokinetics, pharmacodynamics and clinical data are available for both drugs, but there is to date no direct comparison involving the nose and skin at the same time. We compared the effects of a single dose of the two drugs in the nose and skin over 24 h. METHODS: Twenty-three patients with symptomatic allergic rhinitis were enrolled in a randomized double-blind crossover administration of DL and LCZ. The histamine-induced wheal and flare was measured at baseline and 2 and 24 h after dosing. A reflective total symptom score (rTSS) for the previous 24 h was assessed before and after each dose. An instant symptom score was also measured at various time points after each drug. RESULTS: LCZ provided greater inhibition of the flare at 2 h (p = 0.05) and at 24 h (p = 0.007) and greater inhibition of the wheal only at 2 h (p = 0.02). The decrease in wheal and flare was significant versus baseline (p = 0.007) with both drugs. The rTSS of the previous 24 h decreased significantly with both LCZ (11.53 vs. 8.0; p < 0.05) and DL (11.3 vs. 7.9; p < 0.05). The instant TSS progressively decreased in parallel with both drugs, but a difference in favor of LCZ was seen 2 h after dosing. CONCLUSIONS: Single doses of DL and LCZ had a comparable effect on nasal symptoms, but LCZ was faster and displayed a greater effect on histamine wheal.