S. T. Holgate

The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma

Since severe asthma is a poorly understood, major health problem, 12 clinical specialist centres in nine European countries formed a European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA). In a cross-sectional observational study, a total of 163 subjects with severe asthma were compared with 158 subjects whose asthma was controlled by low doses of inhaled corticosteroids (median dose of beclomethasone equivalents 666 µg). Despite being treated with higher doses of inhaled corticosteroids (median dose 1773 µg) and for a third of the severe asthmatics also being treated with regular, oral-steroid therapy (median daily dose 19 mg), the subjects with severe asthma met the inclusion criteria. The criteria required subjects to have undergone at least one asthma exacerbation in the past year requiring oral steroid treatment. Females dominated the severe asthma group (female/male ratio 4.4:1 versus 1.6:1 in the controlled asthmatics), and compared with controlled asthmatics, they had a predominantly neutrophilic inflammation (sputum neutrophils, 36 versus 28%) and evidence of ongoing mediator release but less atopy. From these findings and other physiological and clinical data reported in this paper, it is suggested that severe asthma might be a different form of asthma rather than an increase in asthma symptoms. The findings prompt for longitudinal studies and interventions to define the mechanisms in severe asthma.

Protection against allergen-induced asthma by salmeterol

The effects of the long-acting beta 2-agonist salmeterol on early and late phase airways events provoked by inhaled allergen were assessed in a group of atopic asthmatic patients. In a placebo-controlled study, salmeterol 50 micrograms inhaled before allergen challenge ablated both the early and late phase of allergen-induced bronchoconstriction over a 34 h time period. Salmeterol also completely inhibited the allergen-induced rise in non-specific bronchial responsiveness over the same time period. These effects were shown to be unrelated to prolonged bronchodilatation or functional antagonism. These data suggest novel actions for topically active long-acting beta 2-agonists in asthma that extend beyond their protective action on airways smooth muscle.

The bronchial epithelium as a target for inflammatory attack in asthma

The authors acknowledge grant support from the Medical Research Council, British Lung Foundation and Eli Lilly. They would also like to thank Dr D. Garrod for kindly donating some of the monoclonal antibodies used and Ms J. Baker and the staff at the Southampton General Hospital electronmicroscopy unit for their technical assistance.

Amplified rhinovirus colds in atopic subjects

Abstract. Evidence suggests that atopic individuals may be predisposed to more severe rhinoviral colds coupled to a worsening of existing airway disease than those with asthma. The role of atopy and IgE levels, as well as their relationship to clinical disease expression have not been defined. We hypothesized that an allergic diathesis modulates rhinoviral colds and have initiated studies of normal, atopic and asthmatic subjects employing experimental rhinoviral infection, with measurements of symptom scores, viral shedding and cultures, albumin in nasal washes and serological responses. Twenty‐two subjects (11 normal, 5 atopic, 6 atopic and asthmatic) participated and were inoculated with human rhinovirus serotype 16 (HRV 16). Measurements of neutralizing antibody and viral culture were performed at screening, pre‐inoculation, during the cold and at 8–10 weeks convalescence. Daily symptoms were noted, nasal washes done, IgE measured and atopy was diagnosed by skin tests. Seventeen volunteers developed clinical colds as assessed by symptom scores, virus shedding was demonstrated (with positive culture) in all subjects and a fourfold or higher seroconversion occurred in 11/22. Neutralizing HRV antibody developed unexpectedly in 10 subjects between screening and inoculation and the presence or absence of this pre‐inoculation antibody determined subsequent severity of colds in normal but not in atopic subjects. Atopic antibody positive individuals developed severe clinical colds that were independent of preinoculation antibody in contrast to normal subjects who developed mild colds in the presence of a neutralizing antibody (.P= 0.01). Both atopic and normal antibody negative subjects developed severe colds. This differential response was matched by nasal wash albumin levels which were significantly increased (P= 0–01) during the cold in atopic (but not in normal) volunteers with pre‐inoculation antibody. Levels of IgE were not correlated with severity of clinical disease or viral shedding. Our studies of HRV disease in atopic subjects suggest heightened susceptibility to the detrimental effects of colds; additional studies are needed to clarify the relevant mechanisms.

The comparative actions and adverse effect profile of single doses of H1-receptor antihistamines in the airways and skin of subjects with asthma

BACKGROUND The development of potent H1-receptor antagonists that are free of adverse effects has renewed interest in their use in the treatment of asthma. METHODS We performed a study of the action of chlorpheniramine, terfenadine, brompheniramine, cetirizine, cyproheptadine, clemastine, and astemizole compared with placebo on histamine-induced skin wheals and bronchoconstriction in a single group of patients with asthma. Another group underwent methacholine bronchoprovocation. RESULTS Antihistamine pretreatment increased mean baseline measurements of forced expiratory volume in 1 second (FEV1) between 2.58% and 9.28% compared with placebo, which was significant for all drugs except brompheniramine and clemastine. Compared with placebo, all antihistamines provided significant protection against histamine-induced bronchoconstriction when measured as the provocation concentration required to cause a 20% fall in FEV1; terfenadine and cetirizine provided significantly greater protection than other antihistamines. Protection against histamine-induced skin wheals, measured as the slope of the log concentration-response curve, was only significant for the new drugs, terfenadine and cetirizine. There was a good correlation between the protective effect of the drugs in the skin and airways (r = 0.85; p < 0.01). No significant difference in methacholine provocation concentration required to cause a 20% fall in FEV1 values between treatments was found. CONCLUSIONS The new H1-receptor antagonists terfenadine and cetirizine provided significantly better protection than the older antihistamines against the action of histamine in the skin and airways. None of the antihistamines showed evidence of anticholinergic activity in the asthmatic airways at the doses studied.

The inhibitory effect of terfenadine and flurbiprofen on early and late‐phase bronchoconstriction following allergen challenge in atopic asthma

We have studied the effect of cyclo‐oxygenase inhibition and H1‐receptor antagonism on the early and late bronchoconstrictor responses to inhaled allergen in mild atopic asthmatics. In the first phase of the study histamine inhalation challenge tests were performed in seven mild, atopic asthmatics 2 h after treatment with placebo or flurbiprofen (50, 100 or 150 mg). Flurbiprofen in these single doses had no effect on histamine reactivity. Ten atopic asthmatics participated in the second phase of the study in which the time course of the bronchoconstrictor response to inhalation of allergen was observed on four separate occasions after treatment with (a) placebo, (b) flurbiprofen, 150 mg, (c) terfenadine 180 mg, and (d) the combination of flurbiprofen and terfenadine. On each occasion subjects inhaled a concentration of allergen (Dermatagaphoide & pteronyssinus, grass pollen) that had previously been shown to produce a 30% fall in FEV1 (PC30 allergen). The mean maximum fall in FEV1 during the early reaction was 33·2 ± 3·3% from the post‐saline baseline value following placebo and this was reduced to 27·5 ± 5·3% after flurbiprofen (n.s.), 20·3 ± 3·2% after terfenadine (P < 0·05), and 23·1 ±2·3 after the treatment combination (P < 0·05). Seven subjects developed late asthmatic reactions (LAR) after placebo and in these subjects the mean maximum fall in PEFR during the LAR was reduced from 22·6 ± 3·1 % after placebo to 16·7 ± 3·2% after flurbiprofen (P < 0·05), 15·2 ± 2·3% after terfenadine (P < 0·05) and 11·5 ± 3·1% after the treatment combination (P < 0·01). Both terfenadine and flurbiprofen exhibited inhibitory effects on the early and late bronchoconstrictor responses to inhaled allergen implying roles for histamine and cyclo‐oxygenase products in both phases of the response. As the inhibitory effect of the drugs was not purely additive when administered in combination, this implies that the bronchoconstrictor actions of histamine and the prostaglandins are not independent following allergen challenge.

Davos declaration: allergy as a global problem.

Allergy and allergic diseases represent a major health problem not only in industrialized ‘modern’ societies, but worldwide. There has been an epidemic increase in prevalence of allergic diseases in the last few decades with 10–30% of the population affected. Apart from individual suffering, because of their life-threatening or chronic course, these diseases present a high socioeconomic burden. In many countries, patient care of affected individuals is insufficient and/or inadequate. In spite of great progress in research into the causes and treatment of allergy in the last decades, there are still many problems to be solved in moving to reach our goals of more effective therapies and eventual prevention (1–3). Therefore, a group of 40 scientists and clinicians from four continents and all fields of allergy and related disciplines gathered under the sponsorship of the Christine-Kühne Center of Allergy Research and Education (CK-CARE) in Davos, Switzerland from 17 to 20 July 2011 for the first ‘Global Allergy Forum’. Under the topic ‘Allergy and Allergic Diseases: Barriers to Cure’, the participants formed five working groups to discuss and define the most urgent problems in the field and seek solutions and recommend an action plan. There are numerous unmet clinical needs and millions of patients are undertreated or not treated with the most appropriate methods. Accessibility to and affordability of effective therapeutic regimens are not provided in many countries. The development of innovative therapies is slow compared to most other fields of medicine. Allergic diseases encompass broad fields of medicine and show a wide heterogeneity involving different organs such as eyes, respiratory tract, gut, and skin. Diseases include rhinoconjunctivitis, asthma, anaphylaxis, eczema, urticaria, and angioedema as well as drug and food allergies. Allergic diseases show variability in severity and clinical course which at the moment are only poorly defined. Much better definition of the subtypes of allergic patients (phenotyping) appears crucial and very much needed to address the right therapy to the right patient. A new integrative approach is needed to understand how a complex network of immunological, genetic, and environmental factors leads to a complex allergic phenotype (1). There is a tremendous lack of knowledge regarding many unsolved issues such as: • The causes of the epidemic increase in allergic diseases are unknown. Environmental exposures that appear to be critical factors include factors as diverse as air quality, diet and nutrition, climate, UV radiation, and direct skin contact as well as psycho-social interactions. Moreover, when genetic predisposition is taken into account, environment can provide either risk or protection. • The effects of changes in climate, urbanization, etc. have to be anticipated. Better ways to assess spatial and temporal environmental exposure at population and individual levels are much needed and should be related to the assessment of individual genetic susceptibility. • The interactions between microbes, pollutants, and the immune system are marginally understood. • There is inadequate understanding of the natural mechanisms that limit acute vs. chronic disease or spontaneous resolution. • There is a need for better subclassification of allergic disorders based on pathobiology. • There is a need for new agents acting on specific pathways in pathogenesis with regard to new therapeutic approaches. • There is a need for better preclinical models for translational research. • There is a need to develop better tools for complex data analysis. • There is a need for efficient strategies for primary and secondary allergy prevention. • There is a need for better approaches in diagnosis and prediction of treatment responses and the monitoring of therapeutic effectiveness. Apart from true lack of information, there is a tremendous gap between actual existing knowledge and its effective application for the millions of people in need. • There is a shortage of well-trained allergy specialists in most countries. • Education and training efforts should also be directed toward medical students at the curricular level and extended to primary care physicians who have to be involved in a strategy for diagnosing and managing allergic diseases with such high prevalence rates of 20% of the population. • Awareness campaigns for targeted public groups should be performed. Allied health professionals, such as nurses, school teachers, etc., should be included. Better and more effective tools to spread the available information should be developed. • Close cooperation with patient organizations is highly recommended. • Decision makers involved in developing and approving health policies and administration must be made more aware of the problem of allergic diseases. Action should be taken at various levels and through existing doctors, scientists, and lay organizations to solve these problems. The global expertise from clinical allergists, immunologists, microbiologists, biologists, nutritionists,

Experimental rhinovirus infection in volunteers

Experimental viral disease studies in volunteers have clarified many aspects of the pathogenesis of human viral disease. Recently, interest has focused on rhinovirus-associated asthma exacerbations, and new volunteer studies have suggested that airway responsiveness (AR) is enhanced during a cold. For scientific, ethical and safety reasons, it is important to use validated methods for the preparation of a virus inoculum and that the particular virological characteristics and host responses should not be altered. We have prepared a new human rhinovirus (HRV) inoculum using recent guidelines and assessed whether disease characteristics (for example, severity of colds or changes in AR) were retained. Studies were conducted in 25 clinically healthy volunteers using a validated HRV inoculum in the first 17 and a new inoculum in the subsequent eight subjects. Severity of cold symptoms, nasal wash albumin levels and airway responsiveness were measured, and the new inoculum was prepared from nasal washes obtained during the cold. The new inoculum was tested using standard virological and serological techniques, as well as a polymerase chain reaction for Mycoplasma pneumoniae. No contaminating viruses or organisms were detected and the methods suggested were workable. Good clinical colds developed in 20 of the 25 subjects and median symptom scores were similar in the validated and new inoculum groups (18 and 17.5, respectively; p=0.19). All subjects shed virus, and there were no differences noted in viral culture scores, nasal wash albumin and rates of seroconversion in the two groups. Although airway responsiveness increased in both groups (p=0.02 and p=0.05), the degree of change was similar. We have performed experimental rhinovirus infection studies and demonstrated similar clinical disease in two inoculum groups. Amplified airway responsiveness was induced; continuing studies will define the mechanisms and suggest modes of treatment.

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma.

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV, by 20% of baseline (PC20) from 0.7 to > 22.9 mg/ml for histamine (P < 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P < 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin. geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P < 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin‐induced bronchoconstriction, they are unlikely to account for the majority of the response.

Histamine and its antagonists in asthma

Histamine has been recognized as a potent effector agent in allergic responses for many years. Windaus and Vogt’ first synthesized histamine in 1907, but it was Dale and Laidlaw who originally suggested that this substance could be liberated during an anaphylactic reaction when they observed that the features of anaphylaxis could be reproduced by the intravenous injection of histamine. Best et a1.3 later demonstrated that high concentrations of histamine were present in lung tissue. The association of histamine with asthma came when Weis et a1.4 found that intravenous injection of the amine in subjects with asthma induced wheezing. Further circumstantial evidence linking histamine and asthma came when blood from subjects with asthma was demonstrated to release histamine when blood was challenged with specific antigen in vitro,‘. 6 Subsequently, several authors7. * found increased plasma histamine concentrations in subjects with asthma during exacerbation of asthma. In 1951 Schild et a1.9 described the release of histamine from lung tissue after allergen challenge and commented that this coincided with the bronchoconstriction that was induced. Histamine is found in human mast cells and basophils” and is stored in secretory granules in association with heparin proteoglycan” and a variety of other preformed mediators. In Ishizaka’~‘~ classical description of mast cell activation, histamine and the remaining granule constituents are released when antigen interacts with specific IgE FcRl receptors on the surface of the mast cell. This results in the stimulation of membrane phospholipid metabolism, followed by influx of extracellular and mobilization of intracellular calcium. This intracellular signal results in the secretion of granule constituents and the mobilization of arachidonic acid from membrane phospholipid stores. Although several authors found elevations of