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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.

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.

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.

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.

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.

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.

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

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.

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.

We have previously demonstrated that short-term exposure to diesel exhaust (DE) for 1 h induced a marked leukocytic infiltration in the airways of healthy human volunteers involving neutrophils, lymphocytes, and mast cells along with increases in several inflammatory mediators. We hypothesized that the leukocyte infiltration and the various inflammatory responses induced by DE were mediated by enhanced chemokine and cytokine production by resident cells of the airway tissue and lumen. To investigate this, 15 healthy human volunteers were exposed to diluted DE and air on two separate occasions for 1 h each in an exposure chamber. Fiberoptic bronchoscopy was performed 6 h after each exposure to obtain endobronchial biopsies and bronchial wash (BW) cells. Using reverse transcriptase/polymerase chain reaction enzyme-linked immunosorbent assay (RT-PCR ELISA), a novel and sensitive technique to quantify relative amounts of cytokine mRNA gene transcripts, and immunohistochemical staining with computer-assisted image analysis to quantify expression of cytokine protein in the bronchial tissue, we have demonstrated that DE enhanced gene transcription of interleukin-8 (IL-8) in the bronchial tissue and BW cells along with increases in IL-8 and growth-regulated oncogene-alpha (GRO-alpha) protein expression in the bronchial epithelium, and an accompanying trend toward an increase in IL-5 mRNA gene transcripts in the bronchial tissue. There were no significant changes in the gene transcript levels of interleukin-1B (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and granulocyte macrophage colony-stimulating factor (GM-CSF) either in the bronchial tissue or BW cells after DE exposure at this time point. These observations suggest an underlying mechanism for DE-induced airway leukocyte infiltration and offer a possible explanation for the association observed between ambient levels of particulate matter and various respiratory health outcome indices noted in epidemiological studies.

This study sought to clarify the early events occurring within the airways of healthy human subjects performing moderate intermittent exercise following ozone challenge. Thirteen healthy nonsmoking subjects were exposed in a single blinded, crossover control fashion to 0.2 parts per million (ppm) O3 and filtered air for 2 h, using a standard intermittent exercise and rest protocol. Lung function was assessed pre- and immediately post-exposure. Bronchoscopy was performed with endobronchial mucosal biopsies, bronchial wash (BW) and bronchoalveolar lavage (BAL) 1.5 h after the end of the exposure period. Respiratory tract lining fluid (RTLF) redox status was assessed by measuring a range of antioxidants and oxidative damage markers in BW and BAL fluid samples. There was a significant upregulation after O3 exposure in the expression of vascular endothelial P-selectin (p

Effector mechanisms in anaphylaxis were reviewed. Current approaches to confirmation of the clinical diagnosis were discussed. Improved methods for distinguishing between allergen sensitization (which is common in the general population) and clinical risk of anaphylaxis (which is uncommon) were deliberated. Innovative techniques that will improve risk assessment in anaphylaxis in the future were described.

SUMMARYT cells are thought to play an important regulatory role in asthma, but little is known about the T cell repertoire of the human lung or whether asthma is associated with any specific repertoire changes. Flow cytometry and MoAbs to TCR VB (TCRBV) families were used to quantify bronchoalveolar lavage (BAL) and blood T cells from normal and atopic individuals. Clonality was then assessed by polymerase chain reaction (PCR) amplification of cDNA and gene scanning using consensus and family-specific TCRBV primers and confirmed by sequence analysis. In addition, blood and BAL T cell populations were studied pre- and post-allergen challenge in four patients with allergic asthma. The majority of TCRBV families detected in blood by MoAb staining were also represented in BAL. While differences between BAL and blood populations were evident in each individual studied, these differences were not consistent between individuals or between CD4+ and CD8+ T cell subpopulations. These results are in broad agreement with other published studies, but in contrast to previous work we found a consistent difference between TCRBV7 family usage in blood and BAL in all individuals studied, and a consistently increased proportion of CD4+ BAL T cells bearing BV5S2/3 in asthmatics only. After allergen challenge, the pattern of TCRBV gene usage was largely unchanged as judged by flow cytometry. Gene scanning of PCR products generated from consensus VB primers revealed polyclonal lymphocyte populations in blood and BAL from all seven atopic individuals: in one normal tested polyclonal populations were found in blood and oligoclonal populations in BAL. Selected families amplified with family-specific primers BV5S2/3, BV6 and BV7 (chosen because of their predominance in BAL compared with blood) were more variable and revealed predominant polyclonal populations in blood and polyclonal or oligoclonal populations in BAL. In one asthmatic patient a clonal BV5S2 family was found in BAL. Following allergen challenge there were no significant changes in polyclonality/oligoclonality/clonality in three cases, but in one case a clonal BV5S2 population was found after challenge, that had not been evident beforehand. The lung T cell repertoire is thus broadly representative of blood T cells, but shows population differences that may result from response to persistent exposure to airborne antigens common to normal and atopic individuals. Oligoclonal TCRBV family expansion appears to be primarily lung-specific but independent of atopic asthma, although our challenge data in one case support the concept that clonal populations may follow local allergen challenge. These data are consistent with selection and amplification of specific T cell families in the lung in response to local antigenic exposure.

Short-term exposure to ozone at peak ambient levels induces neutrophil influx and impairs lung function in healthy humans. In order to investigate the mechanisms contributing to neutrophil recruitment and to examine the role of T-cells in the acute inflammatory response, we exposed 12 healthy humans to 0.2 parts per million (ppm) of ozone and filtered air on two separate occasions for 2 h with intermittent periods of rest and exercise (minute ventilation = 30 L x min(-1)). Fibreoptic bronchoscopy was performed 6 h after the end of exposures. Total protein, tryptase, histamine, myeloperoxidase, interleukin (IL)-8 and growth-related oncogene-alpha (Gro-alpha) were measured and total and differential cell counts were performed in bronchoalveolar lavage (BAL) fluid. Flow cytometry was performed on BAL cells to study total T-cells, T-cell receptors (alphabeta and gammadelta), T-cell subsets (CD4+ and CD8+ cells) and activated T-cell subsets (CD25+). Using immunohistochemistry, neutrophils, mast cells, total T-cell numbers, T-cell subsets, CD25+ T-cells and leukocyte endothelial adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 were quantified in the bronchial biopsies. Paired samples were available from nine subjects. Following ozone exposure there was a threefold increase in the proportion of polymorphonuclear neutrophils (PMNs) (p=0.07) and epithelial cells (p=0.05) in BAL fluid. This was accompanied by increased concentrations of IL-8 (p=0.01), Gro-alpha (p=0.05) and total protein (p=0.058). A significant positive correlation was demonstrated between the two chemokines and proportion of PMNs in BAL fluid. After ozone exposure there was a significant decrease in the CD4/CD8 ratio (p=0.05) and the proportion of activated CD4+ (p=0.01) and CD8+ T-cells (p=0.04). However, no significant changes were demonstrable in any of the inflammatory markers studied in the biopsies. Short-term exposure of healthy humans to 0.2 ppm ozone induced a neutrophil influx in peripheral airways at 6 h post exposure, but no apparent inflammatory response in proximal airways. This response seems to be mediated at least in part by interleukin-8 and growth-related oncogene-alpha.

Airway wall remodeling is an established pathological feature in asthma. Its causes are not well understood, but one mediator of potential relevance is transforming growth factor-beta 1 (TGF-beta 1). We have measured levels of immunoreactive TGF-beta 1 in bronchoalveolar lavage (BAL) fluid from clinically stable atopic asthmatics and healthy control subjects. We have also examined the influence of allergen exposure on TGF-beta 1 release in the airways using a segmental bronchoprovocation model, with BAL performed at two time points following endobronchial allergen and sham saline challenges. Basal concentrations of TGF-beta 1 were significantly higher in asthmatics than control subjects (median 8.0 versus 5.5 pg/ml, p = 0.027). Following segmental bronchoprovocation, concentrations of TGF-beta 1 at the allergen- and saline-challenged sites were not significantly different after 10 min, (31.3 versus 25.0 pg/ml, p = 0.78), but after 24 h there were significantly higher TGF-beta 1 concentrations at the allergen-challenged sites (46.0 versus 21.5 pg/ml, p = 0.017). We conclude that basal TGF-beta 1 levels in the airways are elevated in atopic asthma and that these levels increase further in response to allergen exposure. These findings are consistent with the hypothesis that TGF-beta 1 is implicated in airway wall remodeling in asthma.

Endothelins (ETs) are 21 amino acid peptides which, in addition to their other properties, are potent bronchoconstrictors. Whilst there is evidence of the involvement of ET in the pathophysiology of chronic asthma, its contribution to the acute allergic response is undefined. To examine this, we have undertaken segmental bronchoprovocation with allergen and saline at separate sites in six atopic asthmatics receiving treatment with bronchodilators only and six atopic asthmatics additionally receiving treatment with inhaled corticosteroids. Each challenged segment was lavaged 10 min after bronchoprovocation and concentrations of immunoreactive ET were measured in bronchoalveolar lavage fluid. In the non-steroid-treated subjects, there were significantly lower ET levels at the allergen-challenged sites compared to the saline-challenged sites (p

OBJECTIVES: To assess the distribution of personal exposures to nitrogen dioxide (NO2) in school children, and to investigate factors that might influence personal exposure. METHODS: NO2 exposures were assessed by use of passive diffusion tubes for 46 children aged 9-11 years, selected from two Southampton schools. The tubes were worn for seven days, and parallel measurements were made with static samplers in the child's kitchen, living room, classroom, and playground. Information about potential exposures was collected by questionnaire. RESULTS: Personal exposures to NO2, averaged over seven days, ranged from 11 to 257 micrograms/m3 (6 to 137 ppb) with a geometric mean of 36 micrograms/m3 (19 ppb). Exposures correlated with concentrations of NO2 recorded in the home, but the relation was far from exact. Factors associated with increased personal exposure included the use of gas appliances in the home, living with one or more smokers, and travel to school by means other than a car. However, together these variables only explained a small part of the variation in personal exposures. CONCLUSIONS: These findings reinforce the need for personal monitoring of exposure in studies investigating potential health effects of NO2 in children.

A hypothesis was postulated that the characteristic clinical course of fatal soybean asthma may be reflected by specific immunopathological findings. Seven cases of fatal soybean dust-induced asthma from Barcelona, Spain were compared with 25 fatal asthma cases from New Zealand. Sections of lung tissue were stained by monoclonal antibodies using standard streptavidin-biotin peroxidase technique. The following cell types were identified: mast cells, "activated" eosinophils, neutrophils, monocytes/macrophages, CD3+ T-cells and CD8+ T-cells. The positively staining cells were counted in the epithelium and the submucosa and their numbers expressed per mm and mm2, respectively. The airways were divided into larger (internal perimeter (Pi) > 2 mm) and smaller (Pi < 2 mm). Firstly, all airways were studied together; and subsequently, larger and smaller airways were studied separately. Differences in the numbers of mast cells, eosinophils, neutrophils and monocytes/macrophages between the two groups were not significant. The numbers of CD3+ and CD8+ T-cells were significantly reduced in fatal soybean asthma when all airways were taken together. In larger airways, the difference was not significant in the epithelium, but was significant in the submucosa for CD3+ cells. CD8+ cells were significantly reduced in fatal soybean asthma both in the epithelium and the submucosa. The cell counts in smaller airways were not significantly different either in the epithelium or in the submucosa for CD3+ cells. The numbers of CD8+ cells were not different in the epithelium, but were significantly reduced in the submucosa of fatal soybean asthma cases. We conclude that the numbers of CD3+ and CD8+ T-cells are substantially reduced in fatal soybean asthma. These data together with the clinical features of the fatal attack suggest a different mechanism(s) from that described for most asthma deaths, probably involving anaphylaxis.

Background: Although effective medication for hayfever (seasonal allergic rhinitis) is available, treatment outcomes are often be poor. Patient beliefs influence outcomes in many other diseases. Assessing patients’ beliefs about their illness and medication may identify targets for intervention to optimize self management and lessen disease impact.\ud \ud Objective: The application of validated health-related analytical models (Leventhal’s illness representations and Horne’s beliefs about medications) to explore patients’ understanding and experience of hayfever and its treatment.\ud \ud Methods: Cross-sectional postal questionnaire sent to 20% sample of adults attending four General Practices in South England and prescribed medication for hayfever symptoms in the previous two years. Measures included the Revised Illness Perception Questionnaire and the Beliefs about Medicines Questionnaire.\ud \ud Results: 316/586 questionnaires were returned (54%). Cluster analysis identified two patient groups; those with negative beliefs (n=132) and those with more positive beliefs about hayfever and its treatment (n=182). Those with negative beliefs were more likely to believe that their hayfever would last for a long time, that they have little personal control over their illness and that their treatment is not effective. Conversely, they reported greater consequences, greater emotional impact, less understanding of hayfever and more medication concerns than those with more positive beliefs.\ud \ud Conclusions and clinical relevance: Patients with hayfever fall into two distinct groups: nearly half (41% of those sampled) have negative beliefs about their condition. Eliciting patient beliefs during the consultation may reveal assumptions that differ from those of healthcare professionals. Such beliefs should be considered when negotiating treatment plans.

Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy. Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies. Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases. Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits. We call upon Europe’s policy-makers to coordinate actions and improve individual and public health in allergy by: Promoting awareness of the effectiveness of allergen specific immunotherapy Updating national healthcare policies to support allergen specific immunotherapy Prioritising funding for allergen specific immunotherapy research Monitoring the macroeconomic and health economic parameters of allergy Reinforcing allergy teaching in medical disciplines and specialties The effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.

We have studied the influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. In a double-blind, placebo-controlled trial of immunotherapy in 40 adult hay fever sufferers, clinical improvement was accompanied by a decrease in the size of the late-phase skin response. When the immunotherapy-treated group was compared with the placebo group, analysis of skin biopsies obtained 24 h after intradermal allergen revealed a significant reduction in the number of infiltrating CD3+ (P = 0.04) and CD4+ (P = 0.009) cells and a trend for a decrease in EG2+ eosinophils (P = 0.08). Treatment did not influence allergen-induced recruitment of CD8+ cells, neutrophils, or macrophages. Unexpected increases in expression of CD25 (P = 0.006) and HLA-DR (P = 0.007) were observed in the actively treated group. In situ hybridization using a panel of riboprobes demonstrated "TH2-type" (IL-4, IL-5) cytokine mRNA responses in both groups of patients. In contrast, significant hybridization for IL-2 (8/16 patients, P = 0.02) and for interferon-gamma (6/16 patients, P = 0.04) was observed only in the actively treated group. These findings indicate that immunotherapy is associated with suppression of allergen-induced CD4+ T lymphocyte infiltration, but among the cells that are recruited, there is upregulation of CD25 and HLA-DR. At least in this model, immunotherapy does not appear to affect expression of TH2-pattern cytokines in response to allergen exposure, but expression of mRNA for Th1-type cytokines was enhanced in half of the patients. The results support the view that immunotherapy may possibly be working through induction of T cell tolerance.

This is the protocol for a review and there is no abstract. The objectives are as follows: The review aims to determine the effectiveness of written emotional disclosure for people with asthma. 1. To assess the overall efficacy of emotional disclosure compared to emotionally neutral writing in people with asthma on self reported quality of life. 2. To assess the overall efficacy of emotional disclosure compared to emotionally neutral writing in people with asthma on objective measures of health outcome. 3. To assess the comparative efficacy of different types of emotional disclosure for people with asthma.

OBJECTIVE--To evaluate the efficacy and safety of immunotherapy (hyposensitisation) in patients with severe summer hay fever. DESIGN--A randomised, double blind, placebo controlled study of a biologically standardised depot grass pollen extract. SETTING--Allergy clinic, Royal Brompton and National Heart Hospital, London. PATIENTS--40 adults (mean age 35 years) with a history of severe grass pollen allergy uncontrolled by standard antiallergic drugs. Patients with perennial asthma were specifically excluded. INTERVENTION--Patients were randomised to receive either an active preparation (Alutard SQ, a grass pollen (Phleum pratense) extract) or placebo at a rate of two subcutaneous injections a week in increasing doses until a maintenance dose was reached. This maintenance dose was given once a month. MAIN OUTCOME MEASURES--Clinical efficacy was evaluated by symptom and drug diary cards, visual analogue scores during the grass pollen season, and a postseasonal assessment by the patients and a doctor. Conjunctival and skin sensitivity to local allergen provocation was measured before and after eight months of treatment. RESULTS--There was a highly significant decrease (median Alutard SQ v median placebo (95% confidence interval for difference between medians] in total symptom scores (p=0.001) in the Alutard SQ treated group (360 v 928 (238 to 825]. Significant differences were also found in total drug use (p=0.002, 129 v 627 (178 to 574]. Visual analogue symptom scores were also reduced in the active group (p=0.02, 2.2 v 5.5 (-4.8 to -0.5]. The postseasonal assessment, by either the doctor or the patients, showed a large improvement (p less than 0.001) in favour of Alutard SQ. Provocation tests showed a greater than 10-fold reduction for the active group in immediate conjunctival allergen sensitivity (p=0.001), a 40% decrease in early phase response (p=0.02), and a 57% decrease in the late phase (p=0.001) cutaneous response after intradermal allergen. A total of 523 active injections were given. There was one systemic reaction at 10 minutes after injection, which was rapidly reversed with intramuscular adrenaline. There was one mild delayed urticarial reaction at 2 1/2 hours. CONCLUSION--Immunotherapy is effective in patients with severe summer hay fever, but immediate anaphylactic reactions limit its use to specialised centres. Patient selection is extremely important, and chronic perennial asthma should be specifically excluded. As serious reactions occur within minutes a two hour wait for all patients after each injection seems unnecessary.

Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of

Allergology and Clinical Immunology (ACI) is an area of clinical medicine with a precise identity, relevant recent scientific achievements and well-defined educational and professional needs. In spite of the high individual and socio-economic impact of allergic diseases in Europe, the organization of ACI services is imperfect and varies among countries according to their health policies and priorities. In the firm belief of the role of ACI specialists in addressing clinical issues related to the involvement of the immune system in health and diseases—such as vaccination, immunodeficiencies, susceptibility and response to microbial agents, autoimmune and allergic diseases, immune aspects of transplantation and malignancies, in vivo and in vitro immunological tests, vaccinations, immuno-modifiers—the European Academy of Allergology and Clinical Immunology appointed an ad hoc Task Force to produce standards for ACI Services in Europe. The resulting position paper should be used as a consulting reference for National Health Services as a necessary pre-requisite for the free circulation to patients and health care professionals.

Epidemiological studies have demonstrated adverse health effects of environmental pollution. Diesel exhaust (DE) is an important contributor to ambient particulate matter pollution. DE exposure has been shown to induce a pronounced inflammatory response in the airways, with an enhanced epithelial expression of IL-8, and Gro-alpha in healthy subjects. The present investigation was aimed to further characterise the epithelial response to DE in vivo, with particular reference to possible TH2 response, in non-atopic healthy subjects. To determine this response, 15 healthy, non-atopic non-smoking subjects with normal lung function were exposed to DE (PM10 300 microg/m3) and filtered air during 1 h on two separate randomised occasions. Bronchoscopy sampling of bronchial mucosal biopsies was performed 6 h after exposure. Immunohistochemical staining were performed using mAb for IL-10, IL-13 and IL-18 expression. DE exposure induced a significant increase in the expression of IL-13 in the bronchial epithelium cells, 2.1 (1.35-4.88) Md (Q1-Q3) vs. air 0.94 (0.53-1.23); P = 0.009. No significant changes were seen in IL-10 and IL-18 expression. This finding suggests an TH2-inflammatory response in the airways of non-atopic healthy individuals.

The purpose of this study was to assess the impact of short-term exposure to concentrated ambient particles (CAPs*) on lung function and on inflammatory parameters in blood and airways of healthy human subjects. Particles were concentrated from the ambient air in Chapel Hill, North Carolina, using a Harvard/EPA (US Environmental Protection Agency) ambient fine particle concentrator (HAPC). Each of 38 subjects was exposed either to filtered air (n = 8) or to CAPs (n = 30) for two hours, during which all subjects intermittently exercised. Blood was obtained immediately before and 18 hours after exposure. Also at 18 hours after exposure, viable bronchial biopsy tissues and lavage samples were obtained from 10 CAPs-exposed and 7 control subjects by fiberoptic bronchoscopy. To balance these two groups, additional biopsy tissues were obtained from 4 control subjects participating in an identical protocol for another study. For the CAPs-exposed group, the concentration of particulate matter measuring 2.5 microm or less in aerodynamic diameter (PM2.5) in the exposure aerosols varied from 23.1 to 311.1 microg/m3; for the filtered air group, mean particle concentration was 2.9 microg/m3. For comparative analyses, the CAPs-exposed subjects were separated into three tertiles on the basis of the final concentration of particles to which they were exposed. Lung function, assessed by spirometry and plethysmography before and immediately after exposure, was unaffected by CAPs. Of the inflammatory parameters studied in blood, subjects exposed to CAPs showed mean increases in fibrinogen of 40 to 48 mg/dL with no obvious differentiation by dose, whereas subjects exposed to filtered air showed no change; red and white blood cell counts were unaffected by CAPs exposure. In bronchoalveolar lavage fluid from CAPs-exposed subjects, neutrophils showed a dose-dependent increase both when analyzed as an absolute cell count and as a percentage of total lavaged cells. Bronchial biopsy tissues from 10 CAPs-exposed subjects and 11 control subjects did not show any consistent effect of CAPs exposure on cell counts or adhesion molecule expression. We conclude that CAPs induced a modest degree of airway inflammation as judged by lavage, but this effect was not reflected in biopsy tissues from proximal airways. This discrepant finding may mean that the inflammatory effect of CAPs occurs in more distal airways or that the health effects of PM are driven by processes other than those investigated in this study.

Particulate matter (PM) pollution adversely affects the airways, with asthmatic subjects thought to be especially sensitive. The authors hypothesised that exposure to diesel exhaust (DE), a major source of PM, would induce airway neutrophilia in healthy subjects, and that either these responses would be exaggerated in subjects with mild allergic asthma, or DE would exacerbate pre-existent allergic airways. Healthy and mild asthmatic subjects were exposed for 2 h to ambient levels of DE (particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10) 108 microg x m(-3)) and lung function and airway inflammation were assessed. Both groups showed an increase in airway resistance of similar magnitude after DE exposure. Healthy subjects developed airway inflammation 6 h after DE exposure, with airways neutrophilia and lymphocytosis together with an increase in interleukin-8 (IL-8) protein in lavage fluid, increased IL-8 messenger ribonucleic acid expression in the bronchial mucosa and upregulation of the endothelial adhesion molecules. In asthmatic subjects, DE exposure did not induce a neutrophilic response or exacerbate their pre-existing eosinophilic airway inflammation. Epithelial staining for the cytokine IL-10 was increased after DE in the asthmatic group. Differential effects on the airways of healthy subjects and asthmatics of particles with a 50% cut-off aerodynamic diameter of 10 microm at concentrations below current World Health Organisation air quality standards have been observed in this study. Further work is required to elucidate the significance of these differential responses.

Background: Repeated daily exposure of healthy human subjects to NO2 induces an acute airway inflammatory response characterised by neutrophil influx in the bronchial mucosa Aims: To assess the expression of NF-κB, cytokines, and ICAM-1 in the bronchial epithelium. Methods: Twelve healthy, young non-smoking volunteers were exposed to 2 ppm of NO2/filtered air (four hours/day) for four successive days on separate occasions. Fibreoptic bronchoscopy was performed one hour after air and final NO2 exposures. Bronchial biopsy specimens were immunostained for NF-κB, TNF-α, eotaxin, Gro-α, GM-CSF, IL-5, -6, -8, -10, -13, and ICAM-1 and their expression was quantified using computerised image analysis. Results: Expression of IL-5, IL-10, IL-13, and ICAM-1 increased following NO2 exposure. Conclusion: Upregulation of the Th2 cytokines suggests that repeated exposure to NO2 has the potential to exert a "pro-allergic" effect on the bronchial epithelium. Upregulation of ICAM-1 highlights an underlying mechanism for leucocyte influx, and could also explain the predisposition to respiratory tract viral infections following NO2 exposure since ICAM-1 is a major receptor for rhino and respiratory syncytial viruses.

Specific immunotherapy involves the administration of allergen extracts to achieve clinical tolerance of the allergens which cause symptoms in patients with allergic conditions. Immunotherapy has been shown to be effective in patients with mild forms of allergic disease, and also in those who do not respond well to standard drug therapy. Recent studies suggest that specific immunotherapy may also modify the course of allergic disease, by reducing the risk of developing new allergic sensitizations, and also inhibiting the development of clinical asthma in children treated for allergic rhinitis. Specific immunotherapy remains the treatment of choice for patients with systemic allergic reactions to wasp and bee stings. The precise mechanisms responsible for the beneficial effects of SIT remain a matter of research and debate. An effect on regulatory T cells seems most probable, associated with switching of allergen-specific B cells towards IgG4 production. Few direct comparisons of specific immunotherapy and drug therapy have been made. Existing data suggest that the effects of specific immunotherapy take longer to come on, but once established, specific immunotherapy will give long-lasting relief of allergic symptoms, whereas the benefits of drugs only last as long as they are continued. (J Allergy Clin Immunol 2003;111:S712-9.)

This study investigated the effect of low dose of budesonide 100 μg b.d from a new multi-dose dry powder inhaler (AirmaxTM) and from a conventional inhaler (Turbuhaler®) on bronchial hyper-responsiveness, lung function and asthma symptoms in mild stable asthmatics. Twenty-five patients were enrolled into a double-blind double-dummy crossover study with two 4-week treatment periods separated by a 4-week washout. Patients had a mean forced expiratory volume in 1 s (FEV1) of 91±13% predicted, had previously received inhaled short-acting β2-agonists only and had a PC20 to adenosine 5′ monophosphate (AMP)

SUMMARY In this study we examined the cytokine production by T cells and TCRVβ subsets in peripheral blood (PB) and synovial fluid (SF) from six RA patients and PB from 10 normal subjects, using three-colour flow cytometry. In two RA subjects we assessed T cell clonality by RT PCR using TCRBV family-specific primers and analysed the CDR3 (complementarity determining region 3) length by GeneScan analysis. A high percentage of IFN-γ- and IL-2- producing cells was observed among the PB T cells in both the RA patients and normal controls and among the SF T cells in RA patients. In contrast, the percentage of T cells producing IL-4 and IL-5 was small among PB T cells in both RA patients and normal controls and among SF T cells in RA patients. There was no significant difference in the production of IFN-γ, IL-2 and IL-5 between the two compartments (PB and SF); however, there were significantly more IL-4-producing cells in SF. Molecular analysis revealed clonal expansions of four TCRBV families in SF of two of the RA patients studied: TCRBV6·7, TCRBV13·1 and TCRBV22 in one and TCRBV6·7, TCRBV21·3 and TCRBV22 in the second. These expansions demonstrated cytokine expression profiles that differed from total CD3+ cells, implying that T cell subsets bearing various TCR-Vβ families may have the potential to modulate the immune response in RA patients.

Epidemiological studies suggest that asthmatics are more affected by ozone than healthy people. This study tested three hypotheses (1) that short-term exposure to ozone induces inflammatory cell increases and up-regulation of vascular adhesion molecules in airway lavages and bronchial tissue 6 h after ozone exposure in healthy subjects; (2) these responses are exaggerated in subjects with mild allergic asthma; (3) ozone exacerbates pre-existent allergic airways inflammation.We exposed 15 mild asthmatic and 15 healthy subjects to 0·2 ppm of ozone or filtered air for 2 h on two separate occasions. Airway lavages and bronchial biopsies were obtained 6 h post-challenge.We found that ozone induced similar increases in bronchial wash neutrophils in both groups, although the neutrophil increase in the asthmatic group was on top of an elevated baseline. In healthy subjects, ozone exposure increased the expression of the vascular endothelial adhesion molecules P-selectin and ICAM-1, as well as increasing tissue neutrophil and mast cell numbers. The asthmatics showed allergic airways inflammation at baseline but ozone did not aggravate this at the investigated time point.At 6 h post-ozone-exposure, we found no evidence that mild asthmatics were more responsive than healthy to ozone in terms of exaggerated neutrophil recruitment or exacerbation of pre-existing allergic inflammation. Further work is needed to assess the possibility of a difference in time kinetics between healthy and asthmatic subjects in their response to ozone.

The RCGP’s week-by-week guide to pregnancy ( Emma’s Diary ) advises that ‘a family with a history of nut allergy should avoid giving foods containing nuts until their baby is at least 3 years old’, but current thinking is exactly the opposite. Instead of restricting exposure to peanut protein during weaning, there …

OBJECTIVES: To determine the prevalence and risk factors for symptoms related to gloves, and the relation between symptoms and immunological evidence of type 1 hypersensitivity to latex in a United Kingdom health care setting. METHODS: A cross sectional survey was carried out among 773 employees at a British hospital. A self administered questionnaire was used to collect information about symptoms related to gloves and associated risk factors in a sample of hospital staff who were likely to use gloves at work. All of those who reported symptoms suggestive of type 1 hypersensitivity were invited for skin prick testing and measurement of specific IgE to latex (RAST). RESULTS: Among the 372 responders, symptoms related to gloves were common, 49% reported redness or itching of the hands, 14% reported urticaria, and 6% reported chest tightness. However, the frequency of positive skin prick tests and RASTs was surprisingly low (only two subjects tested positive). CONCLUSIONS: These findings indicate the need for caution in the interpretation of symptoms related to gloves even when they seem to suggest type 1 hypersensitivity.

OBJECTIVES: Ozone (O3) imposes an oxidative burden on the lung in two ways. Firstly, directly as a consequence of its oxidising character during exposure, and secondly, indirectly by engendering inflammation. In this study the second pathway was considered by ascertaining the impact of O3 on the redox state of the fluid lining the respiratory tract 6 hours after challenge. METHODS: Nine subjects were exposed in a double blind crossover control trial to air and 200 ppb O3 for 2 hours with an intermittent exercise and rest protocol. Blood samples were obtained and lung function (forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1)) assessed before, immediately after, and 6 hours after exposure. Bronchoalveolar lavage (BAL) was performed 6 hours after challenge. Inflammation was assessed in BAL fluid (total and differential cell counts, plus myeloperoxidase concentrations), and plasma and BAL fluid redox state were determined by measuring concentrations of antioxidants and markers of oxidative damage. RESULTS: Neutrophil numbers in BAL fluid increased 2.2-fold (p = 0.07) 6 hours after exposure and this was accompanied by increased myeloperoxidase concentrations in BAL fluid (p = 0.08). On the other hand, BAL fluid macrophage and lymphocyte numbers decreased 2.5-fold (p = 0.08) and 3.1-fold (p = 0.08), respectively at this time. Of the antioxidants examined, only ascorbate in BAL fluid was affected by O3, falling in all subjects relative to air values (0.1 (0.0-0.3) v 0.3 (0.2-1.2) mumol/l (p = 0.008)). A marginal decrease in plasma ascorbate was also detected at this time (p < 0.05). Although the decrease in macrophage numbers seemed to be causally related to the increase in neutrophils (R = -0.79), myeloperoxidase concentrations (R = -0.93) and ascorbate concentrations (R = 0.6), no clear associations were apparent between ascorbate changes and neutrophils or myeloperoxidase concentration after O3. CONCLUSIONS: Ascorbate in the fluid lining the respiratory tract is depleted as a consequence of O3 exposure at 6 hours after exposure. This was contemporaneous with, although not quantitatively related to the increase in neutrophil numbers and myeloperoxidase concentrations. Decreased macrophage numbers 6 hours after O3 related to the degree of neutrophilic inflammation with populations conserved where ascorbate concentration in the fluid lining the respiratory tract were high after exposure. These results imply that ascorbate has a critical protective role against inflammatory oxidative stress induced by O3.

OBJECTIVE--To determine the prevalence of work related symptoms among radiographers compared with a control group of physiotherapists. METHOD--A postal questionnaire was used to collect information from radiographers and physiotherapists who registered in the United Kingdom during 1985-9. RESULTS--Satisfactory questionnaires were returned by 2354 (65%) of the radiographers and 3048 (69%) of the physiotherapists. There was a clear excess of work related symptoms among the radiographers. In particular, they were more likely to complain of symptoms that were worse at work, mouth soreness, sore, itchy, or runny eyes, persistent blocked nose, persistent itchy nose or sneezing, sore throat, headache, and of lower respiratory tract symptoms, which were also worse on workdays. These symptoms were associated particularly with the use of automatic processing machines. 235 radiographers gave a history of wheeze or chest tightness that had been worse at work or on days when at work. CONCLUSIONS--Work related symptoms suggesting irritation of the eyes and upper airways were more common in radiographers than controls, and may be related to exposure to x ray film processing chemicals. Men and women who reported work related wheeze or chest tightness will be followed up in more detail to assess the prevalence of occupational asthma in the cohort.

To obtain information on the real-time events occurring within human respiratory tract lining fluids (RTLFs) during ozone exposure, sequential nasal lavage was performed on 13 human volunteers exposed on separate occasions to 0.2 parts per million O3 and filtered air (2-h exposures, with intermittent exercise). Nasal lavage was performed and blood samples obtained at four time points throughout each exposure: pre-exposure (Pre-E), 1 h into exposure (1h-E), immediately post-exposure (0h-PE) and 1 h post-exposure (1h-PE). Endobronchial mucosal biopsies were obtained at 1.5 h-post exposure (1.5h-PE). Nasal RTLF neutrophilia was not apparent during, or 1.5 h after, 03 exposure. Furthermore, activation of the pre-existing neutrophil population did not occur. Airway permeability was not altered by this 03 exposure regimen. Sequential lavage resulted in significant washout of RTLF ascorbic acid, reduced glutathione, extracellular superoxide dismutase and myeloperoxidase at 1h-E, 0h-PE and 1.5h-PE relative to baseline Pre-E values. In contrast, RTLF uric acid (UA), total protein and albumin concentrations did not display washout kinetics. Of the antioxidants examined, only UA was clearly depleted by 03, concentrations, falling by 6.22 micromol x L(-1) at 1h-E, compared with 1.61 micromol x L(-1) (p