Peanut components measured by ISAC: comparison with ImmunoCap and clinical relevance in peanut allergic children.

BACKGROUND: Specific IgE (sIgE) against the peanut component Arachis hypogaea (Ara h) 2 has been shown to be the most important allergen to discriminate between peanut allergy and peanut tolerance. Several studies determined sIgE cut off values for Ara h 2, determined by singleplex measurements. However, cut off values for Ara h 2 from multiplex arrays are less well defined. The aim of this study was to evaluate the correlation between Ara h 2 sIgE determined by singleplex versus multiplex measurements and to assess the diagnostic value of the different peanut components included in Immuno Solid-phase Allergen Chip (ISAC) multiplex analysis in children with a suspected peanut allergy. METHODS: In this retrospective study we analyzed Ara h 2 sIgE values with singleplex Fluorescence Enzyme Immunoassay (FEIA, ImmunoCap) and multiplex microarray (ISAC) measurements in 117 children with a suspected peanut allergy. Also, other peanut components measured by ISAC were analyzed. Double blinded placebo controlled oral food challenges were used as golden standard. RESULTS: Among all studied peanut components FEIA Ara h 2 sIgE showed the highest area under the curve (AUC, 0.922), followed by ISAC Ara h 6 and Ara h 2 sIgE with AUCs of respectively 0.906 and 0.902. Best cut off values to diagnose peanut allergy were 4.40 kU/l for FEIA Ara h 2 sIgE and, 7.43 ISU and 8.13 ISU for respectively Ara h 2 and Ara h 6 sIgE in ISAC microarray. Ara h 2 sIgE determined in FEIA and ISAC showed a good correlation (r = 0.88; p < 0.01). CONCLUSION: Ara h 6 and Ara h 2 sIgE in multiplex ISAC are both good predictors of clinical peanut allergy in Dutch children, and their performance is comparable to the use of Ara h 2 in singleplex FEIA. The simultaneous measurement of different peanut components using ISAC is an advantage and clinically useful to detect peanut allergic children that are Ara h 2 negative but sensitized to other peanut proteins such as Ara h 6.

Describing fluctuating indoor aerosol dust measurements with application to house dust mite allergens.

Measuring house dust mite aeroallergen concentrations is essential in understanding mite allergen exposure. Physically, the aerolized house dust mite faeces are part of indoor particulate matter. We studied the statistical ways of summarizing measurements of fluctuating mite aeroallergen exposure inside homes through indoor particulate matter. To study emissions from beddings, we measured the time-related airborne dust concentration after shaking a duvet. Analysis was performed both by a method based on the estimated mean and by a non-linear model. Twenty-eight studies reported a sum of concentrations; only one also reported the peak. In our four experiments on shaking a duvet (245 to 275 measurements each), the peak value was two to four times higher than the mean. The mean-based and non-linear models both predicted the sum of concentrations exactly. A 1% upper prediction bound and the non-linear model predicted the peak emission rate moderately well (64 to 92%, and 63 to 93%, respectively). Mean levels of indoor particulate matter measurements differ substantially from peak concentrations. The use of the mean is only sufficient to predict the sum of concentrations. We suggest that, mite aeroallergen measurements should include information on the peak as well as the mean.

Clinical trials in allergen immunotherapy in the age group of children and adolescents: current concepts and future needs.

Allergen immunotherapy (AIT) is the only treatment option available for allergic patients with disease-modifying intention. Both efficacy and safety has been demonstrated for multiple trials in children, adolescents and adults. Though regulatory requirements for marketing authorization have been clearly outlined and an increasing number of high quality trials has been initiated, multiple concepts and details in study design may be further elaborated, harmonized and improved. An international group of experts in the field of AIT has thoroughly reviewed and discussed current concepts and provided an outlook on further improvement especially in the age group of children and adolescents. Emphasis of the group's discussion as a basis for this article was put on (i) the regulatory background of marketing authorization of AIT products including the 'Pediatric Investigational Plan', (ii) patient reported outcomes and endpoints in AIT trials, (iii) considerations regarding the 'minimal clinically important difference', (iv) the role of placebo effects in AIT clinical trials and clinical routine and (v) the potential of mobile Health for future development of AIT. Current concepts in AIT have been optimized throughout the recent decades, but there remains room for improvement e.g., in the topics outlined in this article.

The association between allergic diseases and cancer: a systematic review of the literature.

INTRODUCTION: Atopic syndrome (allergic rhinitis, asthma and eczema) and food allergies are frequently reported, especially in developed countries. Studies have previously suggested an inverse association between allergic diseases and cancer. The aim of this study was to investigate the association between allergic diseases and different types of cancers by performing a systematic review of the literature. METHODS: A systematic literature search of Ovid Medline, Embase, Web of Science, Cochrane Library and Google Scholar was performed for studies on the association between allergic diseases and cancers. RESULTS: We identified a total of 5868 articles through our search, with 145 articles describing an association between allergic diseases and cancers. Allergies were associated with reduced risk of brain cancer, pancreatic cancer and melanoma and with possibly reduced risk of lymphatic and hematopoietic cancer, colorectal cancer, urogenital cancers of women and cancers in general. Asthma, but not atopy without asthma, was however associated with increased risk of lung cancer. There is possibly no association between allergic diseases and the risk of breast cancer and prostate cancer. CONCLUSION: Overall, allergic diseases are inversely associated with the risk of cancers.

The roadmap for the Allergology specialty and allergy care in Europe and adjacent countries. An EAACI position paper.

The high prevalence of allergic diseases warrants for sufficient health care provisions available to patients with allergic diseases. Allergy care should be delivered by well-trained specialists. However, the current status of allergy care is not well documented. For this reason a survey among European and a few non-European countries was launched by the National Allergy Society Committee from the European Academy of Allergy and Clinical Immunology and the Union Européenne des Médecins Spécialistes section and board of Allergology. The survey shows that in the vast majority of countries allergy care services are available. However, a substantial heterogeneity is reported regarding recognition of the full specialty, the number of practicing specialists or subspecialists, and training aspects. Growth but also decline of specialty and subspecialties is reported. In addition, the survey gives insight in strengths, weaknesses, opportunities and threats in this field. It appears that the recognition of the full specialty determines strength as well as weakness. Aging of specialists combined with a decline in the number of trainees form a major threat. Opportunities are seen in creating awareness for allergy, focus on attracting young physicians. The conclusion is that harmonization of allergy services across Europe is needed. Investment in young doctors, creating new opportunities and lobbying for the full specialty is required.

EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis.

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.

Challenges in the implementation of EAACI guidelines on allergen immunotherapy: A global perspective on the regulation of allergen products.

Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high-quality AIT products are inherently linked to each other. While allergen products are available in many countries across the globe, their regulation is very heterogeneous. First, we describe the regulatory systems applicable for AIT products in the European Union (EU) and in the United States (US). For Europe, a depiction of the different types of relevant procedures, as well as the committees involved, is provided and the fundamental role of national agencies of the EU member states in this complex and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, Japan, Russia, and Switzerland provided information on the system implemented in their countries for the regulation of allergen products. While AIT products are commonly classified as biological medicinal products, they are made available by varying types of procedures, most commonly either by obtaining a marketing authorization or by being distributed as named patient products. Exemptions from marketing authorizations in exceptional cases, as well as import of allergen products from other countries, are additional tools applied by countries to ensure availability of needed AIT products. Several challenges for AIT products are apparent from this analysis and will require further consideration.

Challenges in the implementation of the EAACI AIT guidelines: A situational analysis of current provision of allergen immunotherapy.

PURPOSE: The European Academy of Allergy and Clinical Immunology (EAACI) has produced Guidelines on Allergen Immunotherapy (AIT). We sought to gauge the preparedness of primary care to participate in the delivery of AIT in Europe. METHODS: We undertook a mixed-methods, situational analysis. This involved a purposeful literature search and two surveys: one to primary care clinicians and the other to a wider group of stakeholders across Europe. RESULTS: The 10 papers identified all pointed out gaps or deficiencies in allergy care provision in primary care. The surveys also highlighted similar concerns, particularly in relation to concerns about lack of knowledge, skills, infrastructural weaknesses, reimbursement policies and communication with specialists as barriers to evidence-based care. Almost all countries (92%) reported the availability of AIT. In spite of that, only 28% and 44% of the countries reported the availability of guidelines for primary care physicians and specialists, respectively. Agreed pathways between specialists and primary care physicians were reported as existing in 32%-48% of countries. Reimbursement appeared to be an important barrier as AIT was only fully reimbursed in 32% of countries. Additionally, 44% of respondents considered accessibility to AIT and 36% stating patient costs were barriers. CONCLUSIONS: Successful working with primary care providers is essential to scaling-up AIT provision in Europe, but to achieve this, the identified barriers must be overcome. Development of primary care interpretation of guidelines to aid patient selection, establishment of disease management pathways and collaboration with specialist groups are required as a matter of urgency.

Allergen manufacturing and quality aspects for allergen immunotherapy in Europe and the United States: An analysis from the EAACI AIT Guidelines Project.

Adequate quality is essential for any medicinal product to be eligible for marketing. Quality includes verification of the identity, content and purity of a medicinal product in combination with a specified production process and its control. Allergen products derived from natural sources require particular considerations to ensure adequate quality. Here, we describe key aspects of the documentation on manufacturing and quality aspects for allergen immunotherapy products in the European Union and the United States. In some key parts, requirements in these areas are harmonized while other fields are regulated separately between both regions. Essential differences are found in the use of Reference Preparations, or the requirement to apply standardized assays for potency determination. As the types of products available are different in specific regions, regulatory guidance for such products may also be available in one specific region only, such as for allergoids in the European Union. Region-specific issues and priorities are a result of this. As allergen products derived from natural sources are inherently variable in their qualitative and quantitative composition, these products present special challenges to balance the variability and ensuring batch-to-batch consistency. Advancements in scientific knowledge on specific allergens and their role in allergic disease will consequentially find representation in future regulatory guidelines.

The roadmap for allergology in Europe: The subspecialty of allergology as "stop-over" on the way to a full specialty. An EAACI position statement.

The vision of European Academy of Allergy and Clinical Immunology (EAACI) and the Union of European Medical Specialists Section and Board on allergology is to promote and to establish a full specialty of allergology in all European countries. In many European countries, a full specialty does not exist. In those countries, organ-based (sub)specialists or paediatricians and internists with an expertise in allergology may deliver allergy care. There are no generally accepted requirements for the training of subspecialists available. To fill the gap between the need and availability of experienced and accredited physicians who can deliver optimal care to the allergic patients, the EAACI Specialty Committee proposes the minimal requirements for training and certification of subspecialists in allergology. This paper describes the required theoretical knowledge, skills, competences and training facilities (staff and institution). The subspecialist as described in this paper should ideally show the necessary competence in providing good quality care to patients in an environment lacking those full specialists in allergology or tertiary care paediatric subspecialists in allergy.

Health economic analysis of allergen immunotherapy for the management of allergic rhinitis, asthma, food allergy and venom allergy: A systematic overview.

BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is developing guidelines for allergen immunotherapy (AIT) for the management of allergic rhinitis, allergic asthma, IgE-mediated food allergy and venom allergy. To inform the development of clinical recommendations, we undertook systematic reviews to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT for these conditions. This study focusses on synthesizing data and gaps in the evidence on the cost-effectiveness of AIT for these conditions. METHODS: We produced summaries of evidence in each domain, and then, synthesized findings on health economic data identified from four recent systematic reviews on allergic rhinitis, asthma, food allergy and venom allergy, respectively. The quality of these studies was independently assessed using the Critical Appraisal Skills Programme tool for health economic evaluations. RESULTS: Twenty-three studies satisfied our inclusion criteria. Of these, 19 studies investigated the cost-effectiveness of AIT in allergic rhinitis, of which seven were based on data from randomized controlled trials with economic evaluations conducted from a health system perspective. This body of evidence suggested that sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) would be considered cost-effective using the (English) National Institute for Health and Clinical Excellence (NICE) cost-effectiveness threshold of £20 000/quality-adjusted life year (QALY). However, the quality of the studies and the general lack of attention to characterizing uncertainty and handling missing data should be taken into account when interpreting these results. For asthma, there were three eligible studies, all of which had significant methodological limitations; these suggested that SLIT, when used in patients with both asthma and allergic rhinitis, may be cost-effective with an incremental cost-effectiveness ratio (ICER) of £10 726 per QALY. We found one economic modelling study for venom allergy which, despite being based largely on expert opinion and plausible assumptions, suggested that AIT for bee and wasp venom allergy is only likely to be cost-effective for very high-risk groups who may be exposed to multiple exposures to venom/year (eg bee keepers). We found no eligible studies investigating the cost-effectiveness of AIT for food allergy. CONCLUSIONS: Overall, the evidence to support the cost-effectiveness of AIT is limited and of low methodological quality, but suggests that AIT may be cost-effective for people with allergic rhinitis with or without asthma and in high-risk subgroups for venom allergy. We were unable to draw any conclusions on the cost-effectiveness of AIT for food allergy.

Routine abdominal ultrasonography has limited value in the care for patients with indolent systemic mastocytosis.

OBJECTIVES: Systemic mastocytosis (SM) is a myeloproliferative disease characterized by the accumulation of aberrant mast cells. Since advanced subtypes of SM can lead to organ dysfunction and shortened survival, timely recognition of progressive disease is important for the adequate treatment of SM patients. METHODS: Here, we report the results of our cohort study on the value of routine abdominal ultrasonography for the detection of progression of indolent systemic mastocytosis (ISM). RESULTS: We included 88 patients with ISM, of whom 9 developed new hepatosplenomegaly during follow-up. In this group, the median serum tryptase level increased by 11.60 µg/l, compared with a decrease of -0.20 µg/l in the 79 patients with unchanged ultrasonography results (p = 0.016). A change in liver and/or spleen size never led to a change in clinical classification, nor management. DISCUSSION: Based on the finding that a change in ultrasonography findings did not correlate to disease progression in general, it appears that isolated hepatosplenomegaly does not have prognostic implications in patients with ISM. CONCLUSIONS: Routine abdominal ultrasonography is redundant in the follow-up of patients with ISM. A combination of physical examination with serum tryptase levels can be used to screen for hepatosplenomegaly.

Low percentage of clinically relevant pistachio nut and mango co-sensitisation in cashew nut sensitised children.

BACKGROUND: Cashew nut, pistachio nut and mango belong to the Anacardiaceae family and are botanically related. Therefore, cashew nut sensitised children are frequently advised to eliminate cashew nuts and pistachio nuts from their diet. The 'Improvement of Diagnostic mEthods for ALlergy assessment (IDEAL trial number NTR3572) study showed that cashew nut sensitised children were co-sensitised to pistachio nut in 98% of cases and to mango in 21% of cases. The aim of this follow-up study to IDEAL is to assess the clinical relevance of co-sensitisation to pistachio nut and mango in cashew nut sensitised children. METHODS: Children were recruited from the study: 'Improvement of Diagnostic mEthods for ALlergy assessment (IDEAL trial number NTR3572). Inclusion criterion for the IDEAL study was sensitization to cashew nut as demonstrated by either SPT or sIgE, and a clinical history of reactions to cashew nuts or no previous (known) exposure. Sensitized children who were tolerant to cashew nuts were excluded. Inclusion criterion for this IDEAL follow-up study was co-sensitization to pistachio nut, regardless the result of the DBPCFC with cashew nut. In this follow-up study a double-blind placebo-controlled food challenge with pistachio nut and an open food challenge with mango were performed. RESULTS: Twenty-nine children (mean age of 11.6 years, 62% male) were included. Pistachio nut sensitisation was clinically relevant in only 34% of cashew-sensitised children and only 31% of cashew challenge positive children. None of the children was challenge positive to mango. CONCLUSION: Although co-sensitisation between cashew nut and pistachio nut was observed in 98%, pistachio nut sensitisation was only clinically relevant in 34% of the children. Therefore, a challenge test with pistachio nut is recommended in children with cashew nut and pistachio nut sensitisation. Trial registration The study was registered in the Dutch trial register (registration number 3572) on 10 August 2012 (retrospectively registered).

Allergen exposure chambers: harmonizing current concepts and projecting the needs for the future - an EAACI Position Paper.

BACKGROUND: Allergen exposure chambers (AECs) are clinical facilities allowing for controlled exposure of subjects to allergens in an enclosed environment. AECs have contributed towards characterizing the pathophysiology of respiratory allergic diseases and the pharmacological properties of new therapies. In addition, they are complementary to and offer some advantages over traditional multicentre field trials for evaluation of novel therapeutics. To date, AEC studies conducted have been monocentric and have followed protocols unique to each centre. Because there are technical differences among AECs, it may be necessary to define parameters to standardize the AECs so that studies may be extrapolated for driving basic immunological research and for marketing authorization purposes by regulatory authorities. METHODS: For this task force initiative of the European Academy of Allergy and Clinical Immunology (EAACI), experts from academia and regulatory agencies met with chamber operators to list technical, clinical and regulatory unmet needs as well as the prerequisites for clinical validation. RESULTS: The latter covered the validation process, standardization of challenges and outcomes, intra- and interchamber variability and reproducibility, in addition to comparability with field trials and specifics of paediatric trials and regulatory issues. CONCLUSION: This EAACI Position Paper aims to harmonize current concepts in AECs and to project unmet needs with the intent to enhance progress towards use of these facilities in determining safety and efficacy of new therapeutics in the future.

Use of the Control of Allergic Rhinitis and Asthma Test (CARATkids) in children and adolescents: Validation in Dutch.

BACKGROUND: Allergic rhinitis and asthma are common and closely related diseases. Recently, a Portuguese questionnaire has been developed 'The Control of Allergic Rhinitis and Asthma Test' (CARATkids) that measures disease control of both diseases in children. This study aims to validate the CARATkids in Dutch children and for the first time in adolescents and, in addition, to calculate the minimal clinically important difference (MCID). METHODS: A prospective observational study was conducted in an outpatient clinic. After translation of the CARATkids from Portuguese to Dutch, patients (6-18 years) with asthma or asthma and allergic rhinitis completed the CARATkids, Asthma Control Test, and visual analog scale questionnaire three times. Baseline characteristics, mean scores, internal consistency, test-retest reliability, cross-sectional and longitudinal validity, discriminative properties, responsiveness, and MCID of the CARATkids were assessed. RESULTS: A total of 111 patients were included. In total, 86% and 79%, respectively, completed the questionnaires at the second and third visits. All children had asthma, and 85% had concomitant allergic rhinitis. The internal consistency was good with all expected a priori correlations met. CARATkids scores were higher in patients with uncontrolled asthma and patients with moderate-severe rhinitis compared to better controlled subjects. Patients with a variable asthma control had significantly higher scores during periods of uncontrolled asthma. Also the Guyatt's responsiveness index was good. The MCID was 2.8. CONCLUSIONS: The CARATkids questionnaire is a reliable and valid tool to assess allergic rhinitis and asthma control among Dutch children. The tool can be used in adolescents.

Defining pollen exposure times for clinical trials of allergen immunotherapy for pollen-induced rhinoconjunctivitis - an EAACI position paper.

BACKGROUND: Clinical efficacy of pollen allergen immunotherapy (AIT) has been broadly documented in randomized controlled trials. The underlying clinical endpoints are analysed in seasonal time periods predefined based on the background pollen concentration. However, any validated or generally accepted definition from academia or regulatory authorities for this relevant pollen exposure intensity or period of time (season) is currently not available. Therefore, this Task Force initiative of the European Academy of Allergy and Clinical Immunology (EAACI) aimed to propose definitions based on expert consensus. METHODS: A Task Force of the Immunotherapy and Aerobiology and Pollution Interest Groups of the EAACI reviewed the literature on pollen exposure in the context of defining relevant time intervals for evaluation of efficacy in AIT trials. Underlying principles in measuring pollen exposure and associated methodological problems and limitations were considered to achieve a consensus. RESULTS: The Task Force achieved a comprehensive position in defining pollen exposure times for different pollen types. Definitions are presented for 'pollen season', 'high pollen season' (or 'peak pollen period') and 'high pollen days'. CONCLUSION: This EAACI position paper provides definitions of pollen exposures for different pollen types for use in AIT trials. Their validity as standards remains to be tested in future studies.

sIgE Ana o 1, 2 and 3 accurately distinguish tolerant from allergic children sensitized to cashew nuts.

BACKGROUND: The double-blind, placebo-controlled food challenge test (DBPCFC) is the gold standard in cashew nut allergy. This test is costly, time consuming and not without side effects. Analysis of IgE reactivity to cashew nut components may reduce the need for food challenge tests. METHODS: In a prospective and multicentre study, children with suspected cashew nut allergy underwent a DBPCFC with cashew nut. Specific IgE to cashew nut and to the components Ana o 1, 2 and 3 were determined. A skin prick test (SPT) with cashew nut extract was performed. The association between the outcome of the food challenge test and specific IgE to Ana o 1, 2 and 3 was assessed with logistic regression analyses, unadjusted and adjusted for other diagnostic variables. Discriminative ability was quantified with a concordance index (c). RESULTS: A total of 173 children (103 boys, 60%) with a median age of 9 years were included. About 79% had a positive challenge test outcome. A steep rise in the risk of a positive challenge was observed for specific IgE to each individual component Ana o 1, 2 and 3 with estimated risks up to approximately 100%. Median values of Ana o 1, 2, 3 were 1.29 kU/l (range 0-100 kU/l), 4.77 kU/l (range 0-100 kU/l) and 8.33 kU/l (range 0-100 kU/l) respectively and varied significantly (p < 0.001). Specific IgE to Ana o 1, 2 and 3 was better distinguished between cashew-allergic and tolerant children (c = 0.87, 0.85 and 0.89, respectively) than specific IgE to cashew nut or SPT (c = 0.76 and 0.83, respectively). CONCLUSION: The major cashew nut allergens Ana o 1, 2 and 3 are each individually predictive for the outcome of food challenge tests in cashew-allergic children.

Symptomatic treatment of pollen-related allergic rhinoconjunctivitis in children: randomized controlled trial.

BACKGROUND: About 12% of children are affected by allergic rhinoconjunctivitis (AR). Although the main symptomatic treatments are intranasal corticosteroids (INCS) (daily or on demand) and oral antihistamines, it remains unclear which treatment provides the best relief of symptoms. Therefore, this study examines whether daily use of INCS is superior to on-demand use or to oral antihistamines on demand. METHODS: A single-blinded randomized controlled trial in children (aged 6-18 years) with pollen-related AR. Patients received either INCS daily (fluticasone propionate), INCS on demand (fluticasone propionate) or oral antihistamine on demand (levocetirizine) for 3 months during the grass pollen season. A daily online symptom diary on both nose and eye symptoms was completed. The primary outcome was the percentage of symptom-free days. RESULTS: A total of 150 children were randomized. The percentage symptom-free days was in favour of INCS on demand (30%) compared with INCS daily (22%), that is 8% difference (95% CI -5 to +21%; not significant). The antihistamine on-demand group had 15% symptom-free days, that is 7% difference compared to INCS daily (95% CI -6 to +19%;, not significant). Patients in the INCS on-demand group used on average 61% less fluticasone than patients in the INCS daily group during the study period (P < 0.0001). CONCLUSIONS: This trial with three parallel treatment groups shows that INCS daily was not superior to INCS on demand or to antihistamine on demand regarding the number of symptom-free days. An on-demand INCS strategy has the advantage of a lower overall corticosteroid exposure and less costs.