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The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials. ispartof: ALLERGY vol:76 issue:3 pages:629-647 ispartof: location:Denmark status: published

Placebo effects are common in medicine. Randomised clinical trials help us to understand their magnitude in different therapies. There are particular problems with placebo effects in allergen immunotherapy (AIT) as it is difficult to blind the active treatment and the endpoints are largely subjective. This may explain why large placebo effects are often found in AIT trials. Patients receiving open label AIT get the benefit of the active and placebo components but it can be difficult to say how much benefit is due to the active component. The use of active placebos has been proposed but brings its own problems (ethical and scientific). An EAACI Task Force has been established to address these issues. Here we review the current literature on the placebo effect in general, with a special focus on AIT trials, and indicate what we believe to be important considerations and unmet needs in AIT trial design.

Reanalysis of UK22 subcutaneous immunotherapy trial according to WAO/EAACI recommendations revealed clinically relevant improvements at both doses. Starting at the lower dose should enable efficacy with lower risk of adverse events.

Background: Our understanding of factors which affect adherence to health sustaining self-care behaviours in adolescents with food allergy is limited. This study used the Health Belief Model to explore the relationship between food allergic adolescents’ health beliefs, demographic, structural and social psychological factors with adherence to self-care behaviours, including allergen avoidance and carrying emergency medication.\ud Methods: A cross-sectional study of 188 13- to 19- olds identified from hospital prescribed auto-injectable epinephrine for food allergy. Data were collected on\ud demographics, structural factors, social psychological factors, health beliefs and current adherence behaviour using a postal questionnaire.\ud Results: Full adherence was reported by 16% of participants. Multivariate analysis indicated that adherence was more likely to be reported if the adolescents belonged to a support group (OR = 2.54, (1.04, 6.20) 95% CI), had an anaphylaxis management plan (OR = 3.22, (1.18, 8.81) 95% CI), perceived their food allergy to be more severe (OR = 1.24, (1.01, 1.52) 95% CI) and perceived fewer barriers to disease management (OR = 0.87, (0.79, 0.96) 95% CI).\ud Conclusions: Membership of a patient support group and having an anaphylaxis management plan were associated with good adherence to self-care behaviours in adolescents with food allergy. Our results suggest that interventions to improve provision and utilisation of management plans, address adolescents’ perceptions of the severity of anaphylaxis and reduce barriers to disease management may facilitate good adherence behaviours than focussing on knowledge-based interventions.

Allergic rhinitis is common and not always well controlled by standard drug therapies. Allergen-specific immunotherapy (SIT) is an effective treatment for allergic rhinitis and allergic asthma but to achieve maximum efficacy, several years' treatment is needed. SIT was first developed in the first decade of the 20th century, before the discovery of the underlying mechanisms of allergic disease. Nonetheless, the principles of SIT remain valid today. SIT is known to induce changes in allergen-specific T cells, leading to a decreased responsiveness to allergen exposure. Symptoms following natural exposure to allergens are reduced, but not abolished. The clinical benefits of SIT persist after it is discontinued. There is some evidence that SIT alters the course of allergic disease, which may lead to wider use of SIT in children in years to come. Several approaches have been tried to improve the safety and convenience of SIT. Sublingual SIT is increasingly popular and carries some benefits in terms of safety and convenience compared with injection SIT.

Asthma is a heterogeneous disease with symptoms that fluctuate in scale and severity throughout life. Whilst allergic triggers have been implicated in both its development and subsequent exacerbations, there is no conclusive evidence that allergen avoidance in infancy prevents subsequent development of asthma. Recent studies suggest that allergen avoidance is not an important management strategy in established asthma.

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Background:\ud \ud It is widely believed that for allergic rhinitis and asthma, avoidance of specific triggers can improve symptom control. Whilst many children with asthma or rhinitis are sensitised to airborne allergens, primary care diagnostic and management decisions are often made without a detailed history of the allergic triggers or allergy testing. Thus, treatment decisions are empirical and allergen avoidance advice is either not given or, if given, not tailored to the child’s sensitivities.\ud \ud Objective:\ud \ud To ascertain whether allergy assessment and tailored advice in General Practice enhances outcomes of children with asthma and rhinitis.\ud \ud Method:\ud \ud Pragmatic RCT of allergy intervention (structured allergy history, skin prick testing and appropriate allergy avoidance advice) versus usual care in children with asthma and/or rhino-conjunctivitis. A blinded observer assessed outcomes at 12 months. Main outcome measures were symptom scores and disease-specific health-related QoL. Secondary outcomes were health care utilisation, days unable to pursue usual activities, and self-rated improvement.\ud \ud Results:\ud \ud 335 participants were randomised to formal allergy assessment or normal care. There were no differences in participants’ demographic or clinical characteristics at baseline (all p>.05). At 12 months, participants receiving the allergy intervention had fewer rhinitis symptoms (MD -3.14, 95% CI -6.01, -0.81) and an improvement in QoL (MD -0.50, 95% CI 0.32, 0.68). There were no significant changes in asthma symptoms, health care utilisation or number of days unable to pursue usual activities.\ud \ud Conclusion:\ud \ud Amongst children with known asthma and/or rhinitis in primary care, taking a structured allergy history with skin prick testing and tailored advice on allergy avoidance resulted in reduced symptoms of rhinitis and improved QoL.

Background: The concept of a General Practitioner with Special Interest (GPwSI) was first proposed in the 2000 National Health Service Plan, as a way of providing specialised treatment closer to the patient’s home and reducing hospital waiting times. Given the patchy and inadequate provision of allergy services in the UK the introduction of GPwSIs might reduce the pressure on existing specialist services. Objectives: This study assessed what proportion of referrals to a specialist allergy clinic could be managed in a GPwSI allergy service with a predefined range of facilities and expertise (accurate diagnosis and management of allergy; skin prick testing; provision of advice on allergen avoidance; ability to assess suitability for desensitisation). Methods: 100 consecutive GP referrals to a hospital allergy clinic were reviewed to determine whether patients could be seen in a community-based clinic led by a general practitioner with special interest (GPwSI) allergy. The documentation relating to each referral was independently assessed by three allergy specialists. The referrals were judged initially on the referral letter alone and then re-assessed with the benefit of information summarised in the clinic letter, to determine whether appropriate triage decisions could be made prospectively. The proportion of referrals suitable for a GPwSI was calculated and their referral characteristics identified. Results: 29 % referrals were judged unanimously appropriate for management by a GPwSI and an additional 30 % by 2 of the 3 reviewers. 18 % referrals were unsuitable for a GPwSI service because of the complexity of the presenting problem, patient co-morbidity or the need for specialist knowledge or facilities. Conclusions and clinical relevance: At least a quarter, and possibly half, of allergy referrals to our hospital-based service could be dealt with in a GPwSI clinic, thereby diversifying the patient pathway, allowing specialist services to focus on more complex cases and reducing the waiting time for first appointments.

To cite this article: Shamji MH, Ljorring C, Francis JN, Calderon MA, Larche M, Kimber I, Frew AJ, Ipsen H, Lund K, Wurtzen PA, Durham SR. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy 2012; 67: 217–226. Abstract Background: Induction of allergen-specific IgG4 antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG4 antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG4 titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG–associated inhibitory activity such as inhibition of IgE–allergen interactions (IgE-blocking factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response. Methods: In an 8-month dose–response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100 000 SQ-U, 10 000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG4 titres and IgG-associated inhibitory activity were evaluated. Results: A time- and dose-dependent increase in serum inhibitory activity for both the IgE-blocking factor and IgE-FAB was observed, which paralleled increases in grass pollen–specific IgG4 antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom–rescue medication scores (IgE-FAB: r = −0.25, P = 0.0002; IgE-blocking factor: r = −0.28, P

This guidance for the management of patients with hymenoptera venom allergy has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and pediatricians practising allergy. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are epidemiology, risk factors, clinical features, diagnostic tests, natural history of hymenoptera venom allergy and guidance on undertaking venom immunotherapy (VIT). There are also separate sections on children, elevated baseline tryptase and mastocytosis and mechanisms underlying VIT. Finally, we have made recommendations for potential areas of future research.

Specific immunotherapy is a well-established treatment for allergic rhinoconjunctivitis; conventional regimens are lengthy, however, reducing convenience and cost-effectiveness. This study evaluated the efficacy and safety of an ultrashort course (four doses) of the immunotherapy Grass Modified Allergen Tyrosine Adsorbate (Allergy Therapeutics, Worthing, U.K.) monophosphoryl lipid A (MATA MPL). Subjects were randomized to receive four injections of either Grass MATA MPL (n 514; 300-2000 standardized units/injection) or placebo (n 514) before the grass pollen season. They used electronic diaries to record allergy symptoms and medication use during the pollen season. The primary end point was the difference between the mean combined symptom and medication scores in the Grass MATA MPL and placebo groups during the 4 local peak pollen weeks. The injection course was completed by 95.3 and 97.7% of the Grass MATA MPL and placebo groups, respectively, and was well tolerated. Grass MATA MPL treatment afforded a 13.6% benefit over placebo in the 4 peak pollen weeks (p 0.0038). The benefit in subjects with 28 complete diary entries during the 4 peak pollen weeks was 24.3% (p 0.0031). Significant benefits over placebo were observed in subjects with severe symptoms (16.6%; p 0.0023), in those who had a history of allergic rhinoconjunctivitis for up to 35 years (up to 31%; p 0.0059) and at sites with a higher burden of disease (31%; p 0.0001). The ultrashort course of Grass MATA MPL was well tolerated and provided a significant benefit over placebo in relieving allergy symptoms. (Allergy Asthma Proc 32:239–247, 2011; doi: 10.2500/aap.2011.32.3453)

Adverse reactions to medication are common. Some are predictable side-effects of the drug, others involve individual sensitivity to the drug. Allergic reactions are an important subset of these, but other specific sensitivities are caused by variations in the metabolism or mode of action of the drug. Patients who have experienced adverse reactions to medication will often refer to themselves as being allergic to the drug, regardless of the actual mechanism that caused the reaction. Consequently, anyone taking a history of ‘drug allergy’ needs to keep an open mind about the mechanism that may have been involved. Fortunately, most idiosyncratic reactions are minor, but some are severe, or even life-threatening. In most situations, there are satisfactory alternatives for the drug in question, but sometimes it is necessary to investigate and get an accurate diagnosis. The over-riding priority is to distinguish anaphylactic, potentially life-threatening reactions from other types of drug reaction, which are generally more protracted, less dangerous and usually managed by simple avoidance. While all doctors need to understand the underlying principles, drug challenges should only be undertaken by clinicians experienced in this area.

Anaphylaxis is a systemic allergic reaction that often involves respiratory symptoms and cardiovascular collapse, which are potentially life-threatening if not treated promptly with intramuscular adrenaline. Owing to the unpredictable nature of anaphylaxis and accidental exposure to allergens (such as peanuts and shellfish), patients should be prescribed intramuscular adrenaline auto-injectors and carry these with them at all times. Patients also need to be able to use their auto-injectors correctly while under high stress, when an anaphylactic attack occurs. Despite this, an alarming number of patients fail to carry their auto-injectors and many patients, carers of children with known anaphylaxis and healthcare professionals do not know how to use the device correctly, despite having had training. Currently available auto-injector devices have various limitations that may impede their use in the management of anaphylaxis. There is also a lack of validated assessment criteria and regulatory requirements for new devices. This review describes the different delivery systems used in currently available auto-injectors and discusses the key barriers to the use of adrenaline auto-injectors, with the goal of identifying the 'ideal' features/characteristics of such devices in the emergency treatment of anaphylaxis that will ensure ease of use, portability and accurate delivery of a life-saving drug.

Asthmatics are recognised to be more susceptible than healthy individuals to adverse health effects caused by exposure to the common air pollutant ozone. Ozone has been reported to induce airway neutrophilia in mild asthmatics, but little is known about how it affects the airways of asthmatic subjects on inhaled corticosteroids. We hypothesised that ozone exposure would exacerbate the pre-existent asthmatic airway inflammation despite regular inhaled corticosteroid treatment. Therefore, we exposed subjects with persistent asthma on inhaled corticosteroid therapy to 0.2 ppm ozone or filtered air for 2 h, on 2 separate occasions. Lung function was evaluated before and immediately after exposure, while bronchoscopy was performed 18 h post exposure. Compared to filtered air, ozone exposure increased airway resistance. Ozone significantly enhanced neutrophil numbers and myeloperoxidase levels in airway lavages, and induced a fourfold increase in bronchial mucosal mast cell numbers. The present findings indicate that ozone worsened asthmatic airway inflammation and offer a possible biological explanation for the epidemiological findings of increased need for rescue medication and hospitalisation in asthmatic people following exposure to ambient ozone.

Exposure to elevated concentrations of ozone, a common air pollutant, has been associated with numerous adverse health effects. We have previously reported the time-course of ozone-induced airway inflammation, demonstrating an early up-regulation of vascular endothelial adhesion molecules in bronchial mucosa at 1.5 hours, followed by a neutrophilic infiltration 6 hours after exposure to 0.2 ppm ozone. We hypothesized that the neutrophilic infiltration in the bronchial mucosa would reflect an early increase in bronchial epithelial expression of redox-sensitive transcription factors and kinases regulating neutrophil chemoattractant expression. To test this hypothesis, endobronchial biopsies were obtained from healthy human subjects (n = 11) 1.5 hours after 0.2 ppm of ozone and filtered air exposures (lasting for 2 hours) and stained for mitogen-activated protein kinases (MAPKs), transcription factors, and neutrophil chemoattractants. Total epithelial staining was quantified, as well as the extent of nuclear translocation. Contrary to expectation, ozone significantly suppressed total and nuclear expression of nuclear factor kappaB (NFkappaB) in bronchial epithelial cells (p = 0.02 and p = 0.003 respectively). Similarly, the total staining for phosphorylated C-jun was suppressed (p = 0.021). Expression of interleukin 8 (IL-8) in the bronchial epithelium was likewise decreased after ozone (p = 0.018), while GRO-alpha, ENA-78, C-fos, p-p38, p-JNK, and p-ERK stainings were unchanged. These data suggest that the redox-sensitive NFkappaB and activator protein 1 (AP-1) pathways within the human bronchial epithelium do not seem to be involved in the early inflammatory cell recruitment pathways in healthy subjects exposed to ozone.

Background Many United Kingdom patients with asthma and rhinitis are allergic, but in primary care few diagnostic and management decisions are made with formal allergy assessment. Arguably, knowing a patient's atopic status might be helpful in distinguishing the cause of disease and in selecting appropriate treatments. Objectives Our objective was to estimate the extent to which a formal allergy assessment (a structured allergy history and skin prick tests to 5 common aeroallergens) would improve the precision of allergy diagnosis compared with a patient's self-report or the structured allergy history alone. Methods One hundred twenty-seven patients with asthma, rhinitis, or both were recruited from 4 general practices in Wessex, United Kingdom. Allergy status based on the patient's opinion and on structured allergy history alone was compared with formal allergy assessment. Assessments were validated by an independent allergy specialist reviewing the files. Patients were given written advice specific to their allergies and followed up 3 months later to assess satisfaction, recall, and effect on health and behavior. Results Self-reporting misclassified allergic status in many patients. A structured allergy history alone was little better and resulted in false-positive rates for cat allergy of 32%, grass pollen of 48%, house dust mite of 75%, tree pollen of 54%, and dog of 27% compared with formal allergy assessment. Skin prick testing combined with a structured history was essential to reach a correct causative diagnosis. Three months later, 41% patients had made changes to lifestyle, medications, or both, and 18% reported clinical improvement. Conclusions Skin prick testing improves the accuracy of an assessment of allergic status based on patient opinion or a structured allergy history alone.

BackgroundEpidemiological evidence demonstrates that exposure to traffic-derived pollution worsens respiratory symptoms in asthmatics, but controlled human exposure studies have failed to provide a mechanism for this effect. Here we investigated whether diesel exhaust (DE) would induce apoptosis or proliferation in the bronchial epithelium in vivo and thus contribute to respiratory symptoms.MethodsModerate (n?=?16) and mild (n?=?16) asthmatics, atopic non-asthmatic controls (rhinitics) (n?=?13) and healthy controls (n?=?21) were exposed to filtered air or DE (100 ?g/m 3 ) for 2 h, on two separate occasions. Bronchial biopsies were taken 18 h post-exposure and immunohistochemically analysed for pro-apoptotic and anti-apoptotic proteins (Bad, Bak, p85 PARP, Fas, Bcl-2) and a marker of proliferation (Ki67). Positive staining was assessed within the epithelium using computerized image analysis.ResultsNo evidence of epithelial apoptosis or proliferation was observed in healthy, allergic or asthmatic airways following DE challenge.ConclusionIn the present study, we investigated whether DE exposure would affect markers of proliferation and apoptosis in the bronchial epithelium of asthmatics, rhinitics and healthy controls, providing a mechanistic basis for the reported increased airway sensitivity in asthmatics to air pollutants. In this first in vivo exposure investigation, we found no evidence of diesel exhaust-induced effects on these processes in the subject groups investigated.

Objectives: Asthma is a chronic condition affecting 300 million people worldwide. Management involves adherence to pharmacological treatments such as corticosteroids and β-agonists, but residual symptoms persist. As asthma symptoms are exacerbated by stress, one possible adjunct to pharmacological treatment is expressive writing (EW). EW involves the disclosure of traumatic experiences which is thought to facilitate cognitive and emotional processing, helping to reduce physiological stress associated with inhibiting emotions. A previous trial reported short-term improvements in lung function. This study aimed to assess whether EW can improve lung function, quality of life, symptoms, and medication use in patients with asthma. Methods: Adults (18–45 years) diagnosed as having asthma requiring regular inhaled corticosteroids were recruited from 28 general practices in South East England (n = 146). In this double-blind randomized controlled trial, participants were allocated either EW or nonemotional writing instructions and asked to write for 20 minutes for 3 consecutive days. Lung function (forced expired volume in 1 second [FEV1]% predicted), quality of life (Mark's Asthma Quality of Life Questionnaire), asthma symptoms (Wasserfallen Symptom Score Questionnaire), and medication use (inhaled corticosteroids and β-agonist) were recorded at baseline, 1, 3, 6, and 12 months. Results: Hierarchical linear modeling indicated no significant main effects between time and condition on any outcomes. Post hoc analyses revealed that EW improved lung function by 14% for 12 months for participants with less than 80% FEV1% predicted at baseline (β = 0.93, p = .002) whereas no improvement was observed in the control condition (β = 0.10, p = .667). Conclusions: EW seems to be beneficial for patients with moderate asthma (

Objective:Patient information leaflets (PILs) are widely used to reinforce or illustrate health information and to complement verbal consultation. The objectives of the study were to assess the readability and presentation of PILs published by Allergy UK, and to conduct a longitudinal assessment to evaluate the impact of leaflet amendment and revision on readability. Methods:Readability of Allergy UK leaflets available in 2013 was assessed using Simple Measure of Gobbledegook (SMOG) and Flesch-Kincaid Reading Grade Formula. Leaflet presentation was evaluated using the Clear Print Guidelines of the Royal National Institute of Blind People (RNIB) and the Patient Information Appraisal System developed by the British Medical Association (BMA). Changes in the leaflets’ readability scores over five years were investigated. Results:108 leaflets, covering a wide range of allergic conditions and treatment options, were assessed. The leaflets had average SMOG and Flesch-Kincaid scores of 13.9 (range 11-18, SD 1.2) and 10.9 (range 5-17, SD 2.1) respectively. All leaflets met the RNIB Clear Print guidelines, with the exception of font size which was universally inadequate. The leaflets scored on average 10 (median 10, range 7-15) out of a maximum of 27 on the BMA checklist. The overall average SMOG score of 31 leaflets available in both 2008 and 2013 had not changed significantly. The process of leaflet revision resulted in 1% change in readability scores overall, with a predominantly upward trend with six leaflets increasing their readability score by >10% and only three decreasing by >10%. Conclusion:Allergy-related patient information leaflets are well presented but have readability levels that are higher than those recommended for health information. Involving service users in the process of leaflet design, together with systematic pre-publication screening of readability would enhance the accessibility and comprehensibility of written information for people with allergy and their careers.

Specific immunotherapy is widely used to treat allergic rhinitis, but few large-scale clinical trials have been performed.We sought to assess the efficacy and safety of specific immunotherapy with 2 doses of Alutard grass pollen in patients with moderately severe seasonal allergic rhinitis inadequately controlled with standard drug therapy.We performed a double-blind, randomized, placebo-controlled study of 410 subjects (203 randomized to 100,000 standardized quality units [SQ-U] maintenance, 104 to 10,000 SQ-U, and 103 to placebo). Three hundred forty-seven (85%) completed treatment. Groups were well matched for demographics and symptoms.Across the whole pollen season, mean symptom and medication scores were 29% and 32% lower, respectively, in the 100,000-SQ-U group compared with those in the placebo group (both P.001). Over the peak pollen season, mean symptom and medication scores were 32% and 41% lower, respectively, than those in the placebo group. The 10,000-SQ-U group had 22% less symptoms than the placebo group over the whole season (P.01), but medication scores reduced by only 16% (P = .16). Quality-of-life measures confirmed the superiority of both doses to placebo. Local and delayed side effects were common but generally mild. Clinically significant early and delayed systemic side effects were confined to the 100,000-SQ-U group, but no life-threatening reactions occurred.One season of immunotherapy with Alutard grass pollen reduced symptoms and medication use and improved the quality of life of subjects with moderately severe hay fever. The 100,000-SQ-U regimen was more effective, but the 10,000-SQ-U regimen caused fewer side effects.

In 2004 the World Allergy Organization’s Specialty and Training Council conducted a survey of World Allergy Organization (WAO) member societies to obtain information about the status of the specialty of allergy worldwide. Responses were received from 33 countries, representing a population of 1.39 billion people, of whom it was estimated that 22% may suffer from some form of allergic disease. Allergy was reported by 23 respondents to be a certified or accredited specialty in their country, and the number of certified allergists per head of population ranged from 1:25 million to 1:16,000. Allergists were ranked as the fifth most likely clinicians to see cases of allergic asthma, third most likely to see allergic rhinitis, and fourth most likely to see eczema or sinusitis. Nine countries only reported that children with allergic diseases would be seen by a pediatrician with appropriate training. The survey results highlight a pressing need for the development of allergy services worldwide.

Diesel exhaust (DE) is a major component of airborne particulate matter. In previous studies we have described the acute inflammatory response of the human airway to inhaled DE. This was characterized by neutrophil, mast cell, and lymphocyte infiltration into the bronchial mucosa with enhanced epithelial expression of IL-8, Gro-α, and IL-13. In the present study, we investigated whether redox-sensitive transcription factors were activated as a consequence of DE exposure, consistent with oxidative stress triggering airway inflammation. In archived biopsies from 15 healthy subjects exposed to DE [particulates with a mass median diameter of 3] and air, immunohistochemical staining was used to quantify the expression of the transcription factors NF-κB (p65) and AP-1 (c-jun and c-fos), as well their upstream MAPKs, p38 and JNK, in the bronchial epithelium. In addition, phosphorylation of tyrosine residues was examined. DE induced a significant increase in the nuclear translocation of NF-κB ( P = 0.02), AP-1 ( P = 0.02), phosphorylated JNK ( P = 0.04), and phosphorylated p38 ( P = 0.01), as well as an increase in total (cytoplasmic + nuclear) immunostaining of phosphorylated p38 ( P = 0.03). A significant increase in nuclear phosphorylated tyrosine was also observed ( P

Background: Drug allergy is an increasingly important clinical problem. About 5-10% of patients consulting allergy centers have some form of drug allergy or pseudo allergy. At present there is no consensus concerning the best way to study and diagnose hypersensitivity reactions to drugs. This leads both to practical difficulties in diagnosing individual patients and to more general problems in comparing protocols and results from different centers. Methods/Data base: The European Network for Drug Allergy (ENDA) Drug Ambassador Project aimed to collect information on the ways that different European centers approach these patients. Results: The present report summarizes data collected during this project, focussing on the organization of drug allergy consultations, diagnostic protocols and the various in vitro and in vivo investigation procedures in current use. The study revealed wide variation in the diagnostic procedures used for drug allergy in clinical practice, despite the apparent consensus achieved in recommendations and position papers. Conclusion: Reciprocal exchange of information and discussions based on these observations may help to achieve standardization and harmonization in this sector with significant potential benefits for patients with drug allergies.

The past year has seen a welcome increase in the number of articles published in the Journal on environmental and occupational disorders. Some of the major themes have been risk factors for allergic sensitization, the measurement and containment of domestic allergens (especially cockroach but also house dust mite), and risk factors for occupational allergy and asthma. Some important articles were also presented on mechanisms of occupational and environmental asthma.

The role of these co-factors in promoting anaphylaxis in food-dependent exerciseinduced anaphylaxis is not entirely clear, but several models have been proposed. One theory argues that blood is diverted from the gut during exercise, causing relative ischaemia which increases gut permeability and thus the delivery of food allergens into the circulation (Matsuo et al, 2005). Palosuo et al (2003) proposed that exercise activates the gut enzyme tissue transglutaminase which aggregates with omega-5-gliadin to form a high molecular weight complex that binds to immunoglobulin E with high affinity. Finally, exercise-associated changes in blood pH and osmolality could directly reduce the threshold for mast cell and basophil degranulation (Cooper et al, 2007). The diagnosis of food-dependent exerciseinduced anaphylaxis is largely clinical, based on the recognition of systemic anaphylaxis following exposure to a particular food allergen in association with specific cofactors. It is important to know that food and exercise are independently tolerated. The clinical features of anaphylaxis including urticaria, angioedema, breathing difficulties and collapse each have a wide differential diagnosis, and a diagnosis of ‘allergic reaction’ made in the emergency department is frequently revised in clinic. For example, urticaria may be spontaneous (often having an autoimmune aetiology), physical (resulting from mast cell degranulation in response to physical stimuli), drug-induced in a non-specific manner or associated with

Objective: To review the clinical features and underlying mechanisms of occupational asthma in an attempt to glean insights into various other forms of asthma. Data Sources: Published literature, including consensus guidelines on diagnosis and management of occupational asthma. Study Selection: This article represents a synthesis of these data sources and the opinion of the author. Results: Occupational asthma may be caused by a variety of mechanisms, including both IgE-dependent and non-IgE-dependent immunological processes. IgE-dependent mechanisms are responsible for reactions to all high-molecular-weight occupational antigens and to some but not all low-molecular-weight antigens. Factors in sensitization and onset include the general genetic predisposition to make IgE and the specific responsiveness of the individual to particular allergens. Once sensitized, the main factor that influences the onset of symptoms is the degree of exposure. In general, the higher the level of exposure, the more likely the sensitized person is to develop asthma. Conclusions: Occupational asthma can be induced by a variety of agents that appear to use different mechanisms to affect the airway. Studies of the remission of occupational asthma indicate that resolution is a slow process. However, the study of occupational asthma may eventually allow us to identify treatments that will accelerate remission or induce remission in other forms of asthma.

The environment plays a crucial role in determining the development and expression of allergic disorders. Epidemiologic studies allow us to understand risk factors for allergic disease, which may lead to interventional studies to provide the evidence base for our clinical advice. Articles published in The Journal of Allergy and Clinical Immunology last year highlighted the relevance of mold exposure and environmental tobacco smoke as risk factors for the development of asthma and the expression of symptoms. The role of fitted carpets as a reservoir for house dust allergens was also challenged by data arising from this work. Occupational allergy is an important clinical and socioeconomic problem. A large body of work on latex allergy has been reported in the past year, demonstrating the impact of containment strategies on exposure to latex and the incidence of sensitization to latex. Other articles have explored the range of latex allergens to which patients are sensitized and the HLA associations of latex allergy. Two models of isocyanate sensitization were reported, providing some insight into possible mechanisms of isocyanate asthma and some clues for understanding nonallergic asthma. Environmental and occupational disorders are highly relevant to our readership, and the new Editorial Board hopes to encourage submission and publication of relevant articles in this area.

BackgroundThere is no longer any doubt that the past 30–40yearshave witnessed an increase in the prevalence and inci-dence of asthma and other allergic diseases (1,74).Epidemiological data indicate that this rise has beenmost marked in affluent westernised countries, althoughthereisalsodatasuggestiveofaparallelincreaseinlessdeveloped parts of the world including parts of Africawhere the nature and degree of affluence is different.Although atopy and asthma both have a significantgeneticcomponent,thereisnoreasontothinktherehasbeenashiftinthegenepooloverasinglegeneration.Thismeansthatwemustseekoutoneormoreaspectsofthewestern lifestyle which may have interacted with asusceptible subgroup who now show asthma and aller-gies, whereas they would not have been affected if theyhad been born 50years ago. In thinking about this wemustalwaysrememberthatthereisalsoasubgroupwhohaveasthmanowandwouldstillhavehaditeveniftheyhadbeenborn50yearsago.Clinicaldatashowthatpatientswithasthmaaremorevulnerable to the effects of air pollution than normalhealthyindividuals.Thiscanbeseenwithdirecteffectsonlung function, increased rates of symptomatic episodesand increased rates of hospital admissions for asthmaduringepisodes ofozoneorparticulatepollution. How-ever, it is less clear whether air pollutants affect theprocessofallergicsensitizationortheinitialdevelopmentofasthma,asopposedtoexacerbatingtheconditiononceithasarisenforotherreasons.In broad terms, the affluent west has seen a dramaticreductionintraditionalformsofpollution,suchasblacksmokeandSO

SUMMARYT cells are thought to play an important regulatory role in atopic asthma. We hypothesized that human blood and BAL T cell subsets bearing various TCR-Vβ genes might show selective differences in their cytokine profile. Peripheral blood (PB) and bronchoalveolar lavage (BAL) T cells from seven atopic asthmatic and six non-atopic non-asthmatic subjects were stimulated with PMA and ionomycin in the presence of monensin and analysed for TCR-Vβ expression and production of cytokines at the single cell level. The percentage of IFN-γ- and IL-2-producing BAL T cells was elevated compared with PB T cells from both the asthmatic subjects and the non-atopic, non-asthmatic controls. A small percentage of PB and BAL T cells produced IL-4 and IL-5, in asthmatic and normal subjects. In peripheral blood, the percentage of T cells expressing each cytokine was similar in the various TCR-Vβ subsets and in total CD3+ T cells in all normal and six of seven asthmatic subjects. However, there was a substantial degree of heterogeneity in the cytokine profile of BAL TCR-Vβ subsets compared with the total CD3+ T cells. This was more obvious in the asthmatic subjects with a reduction in the percentage of IFN-γ- and IL-2-expressing T cells (five of seven asthmatic subjects) and an increase in the percentage of IL-4- and IL-5-expressing T cells (two of seven asthmatic subjects). These data confirm previous findings of an elevated proportion of IFN-γ- and IL-2-producing BAL T cells while only a small proportion of PB and BAL T cells produce IL-4 and IL-5. Moreover, subsets of BAL T cells, defined by their TCR-Vβ usage, may differ in their cytokine profile compared with the total CD3+ T cells, implying that T cells expressing different Vβ elements may play different roles in regulating the airway inflammation in asthma.

Allergic diseases are quite prevalent worldwide, and the incidence of allergy is increasing everywhere [1-7]. Because allergic and immunologic processes overlap all organ systems, allergy is not always taught in medical schools as a separate subject. Indeed, lack of recognition of the specialty and of the need to teach about allergic and immunologic diseases results in allergy not being included at all in some medical school curricula [8]. With an estimated 22% of the global population experiencing allergic and immunologic diseases, it is time to recognize and strengthen education in allergy and immunology [8]. The World Allergy Organization (WAO), an alliance of 74 national and regional allergy societies, created this consensus document to establish educational guidelines for worldwide application to help identify and correct allergy education and training deficiencies and to define appropriate competencies. In creating this consensus, it is recognized that each country has its own principles and goals in medical education at the undergraduate and postgraduate levels. This document defines what WAO considers medical practitioners should know to care appropriately for allergic patients.

Background Diesel exhaust is associated with cardiovascular and respiratory mortality and morbidity. Acute exposure leads to increased IL-8 expression and airway neutrophilia, however the mechanism of this response is unknown. Objectives: As cigarette smoke-induced IL-8 expression by epithelial cells involves transactivation of the epidermal growth factor receptor (EGFR), we studied the effects of diesel exhaust particles (DEP) on IL-8 release and the role of the EGFR. Methods Primary bronchial epithelial cells (PBEC) were exposed to DEPs or carbon black. IL-8 and EGFR ligand expression (transforming growth factor alpha (TGFα), heparin-binding EGF-like growth factor, and amphiregulin (AR)) were assessed by quantitative RT-PCR and ELISA. Results DEP, but not carbon black, caused a dose-dependent increase in mitogen-activated protein kinase (MAPK) activation and IL-8 expression, however above 50 μg/ml there was an increase in cytotoxicity. At 50 μg/ml, DEPs stimulated transcription and release of IL-8 and EGFR ligands. IL-8 release was blocked by EGFR neutralizing antibodies, an EGFR-selective tyrosine kinase inhibitor and by the metalloprotease inhibitor, GM6001, which blocks EGFR ligand shedding. Neutralizing antibodies to AR, TGFα and heparin-binding (HB)-EGF reduced DEP-induced IL-8 by >50%. Conclusion Expression of IL-8 in response to DEPs is dependent on EGFR activation and that autocrine production of EGFR ligands makes a substantial contribution to this response. Capsule Summary: This study identifies a mechanism whereby diesel particles stimulates IL-8 release from bronchial epithelial cells. This mechanism may help to explain the recruitment of neutrophils into the airways of people exposed to particulate air pollution.

Learning Objectives: The purpose of this review is to objectively critique available data regarding the role of diesel exhaust particles (DEPs) in allergic disease. Readers of this review should understand the ways in which diesel particulates can affect human airways and the extent of the scientific data which are currently available. Data Sources: Data were obtained from published studies and reviews. Study Selection: The specific reviewed studies selected for this review met the following criteria: human and animal in vivo, in vitro, and pulmonary dosimetry studies, as well as epidemiologic studies to examine the role of DEPs and particulates on the airways. Results: The results of the published studies show that although DEPs may play a role in the increased levels of allergic disorders through a number of immunologic mechanisms, it remains to be proven whether it is responsible for the recent rise in the prevalence of asthma and other allergic disorders. Conclusions: Further studies in humans are needed to elucidate the mechanisms by which DEPs may be responsible for the increased prevalence of allergic disorders.

Glucocorticosteroids are the backbone of asthma therapy and are administered mainly by the inhaled route. Patients with "difficult" asthma are not a single homogeneous group. Some are stable on high-dose steroid therapy but experience unacceptable side effects; others remain unstable despite receiving high doses of inhaled or oral steroids. Several different steroid-sparing and alternative agents have been tried, with varying degrees of success. Some success has been achieved with conventional immunosuppressants such as methotrexate, gold, and cyclosporin A, but these agents can be justified only in a limited range of cases. Leukotriene receptor antagonists have proved a useful addition to asthma therapy and have been shown to have a modest steroid-sparing effect. Although the existing range of alternative agents has not proved to be particularly effective, several new therapeutic agents have been developed to target specific components of the inflammatory process in asthma. These include IgE antibodies, cytokines, chemokines, and vascular adhesion molecules. Future developments might include better forms of immunotherapy and strategies targeting the remodeling of structural elements of the airways.

Airway remodeling in asthma refers to a collection of chronic structural changes including subepithelial fibrosis, airway smooth muscle hypertrophy/hyperplasia, and possibly angiogenesis. The mechanisms leading to remodeling are not well defined. One molecule of possible relevance is basic fibroblast growth factor (bFGF), which is a potent mitogen for fibro-blasts, airway smooth muscle cells, and endothelial cells. To test the hypothesis that bFGF expression is increased in asthma, we measured levels of the growth factor in bronchoalveolar lavage (BAL) fluid. Basally, BAL fluid bFGF concentrations were significantly higher in subjects with atopic asthma than in control subjects without asthma (median 0.22 vs 0.06 pg/mL, P = .003). The effect of acute allergen exposure was examined with a segmental bronchoprovocation model in a separate group of subjects with atopic asthma. Ten minutes after segmental bronchoprovocation there was a 5-fold increase in bFGF levels in BAL fluid recovered from allergen-challenged sites compared with control saline-challenged sites (1.52 vs 0.30 pg/mL, P < .002). We conclude that basal levels of BAL fluid bFGF are increased in atopic asthma and that a further increase occurs in response to acute allergen exposure. These findings lend support to the hypothesis that bFGF is implicated in airway remodeling in asthma.