bluuebunny/crossref_metadata_2025 huggingface dataset:
Environmental risk factors in childhood asthma
Authors: Weiss
Published: March 2003

Eighty per cent of all childhood asthma has its onset by 3 years of age. A similar percentage of childhood asthma is associated with atopy (presence of allergic rhinitis or eczema and/or positive skin prick tests). Defined risk factors for childhood asthma include allergen exposure, environmental tobacco smoke, viral respiratory illness, the presence of other atopic disease, and gender. Although a large percentage of children will have remission of asthma as they grow, they will retain the intermediate phenotypes of increased airway responsiveness and allergen and, therefore, be at risk of recrudescence of disease in adult life.
The current cardiac safety situation with antihistamines
Authors: Yap Y.G. , Camm A.J.
Published: March 2003

Antihistamines (H1‐receptor antagonists) are amongst the most frequently prescribed drugs worldwide for the treatment of allergic conditions. The clinical interest of classical ‘first generation’ antihistamines is currently rather limited by their anticholinergic and sedative properties. The second generation of antihistamines, so‐called non‐sedating antihistamines, are free of these side‐effects. However, since the 1990s, there have been reports that certain non‐sedating antihistamines, mainly terfenadine and astemizole, might be associated with the risk of rare but severe dysrhythmias. These drugs prolong the monophasic action potential and surface electrocardiographic QT interval and may lead to the development of early after‐depolarization and possibly torsades de pointes through an inhibition of potassium channel repolarization. Concomitant administration with drugs that inhibit the hepatic cytochrome P‐450 (imidazole antifungals, macrolide antibiotics) or those that prolong the QT interval by the same or other mechanism (e.g. antiarrhythmics, antipsychotics, tricyclic antidepressants) increases their effect on the cardiac repolarization.

 The cardiac safety profile of newer non‐sedating antihistamines requires confirmation. Drugs with low or no potential to block the K+ rectification channel (e.g. IKr channels) are likely to possess cardiac safety advantages. Other drug‐related factors such as the physico‐chemical properties of the antihistamines and its metabolic profile may also contribute to the cardiac response.

 Mizolastine is a new non‐sedating antihistamine with antiallergic properties. It has a good bioavailability and a metabolism via the cytochrome P‐450 oxidation accounting for only 35% of its hepatic clearance. In addition, mizolastine displays low lipophilicity and consequently low cardiac tissue fixation. In clinical studies, mizolastine has not shown any dose‐related increase in QT intervals. Its clinical use has not been associated with ventricular dysrhythmias. Thus, although the post‐marketing experience with mizolastine is still limited, mizolastine offers a safe alternative for the therapeutic management of allergic rhinitis and urticaria. However, more data are still needed on the cardiac safety of this and other non‐sedating antihistamines.
Beyond the histamine receptor: effect of antihistamines on mast cells
Authors: Cuss
Published: March 2003

Many antihistamines exhibit inhibition of mediator release from mast cells and basophils, in in vitro studies in addition to H1 antagonism. The underlying mechanism is unclear but is unrelated to H1‐receptor antagonism. Clinical studies of antihistamins in antigen challenge and seasonal allergy demonstrate reduction of mast cell mediators in nasal lavage. It is not known what mechanism(s) underly these observations, although the concentrations required in in vitro studies suggests that a direct effect on mast cells is unlikely. Furthermore, the therapeutic contribution of this effect is difficult to assess because of concomitant clinically significant H1 antagonism. This and other potential anti‐allergic effects may enhance the therapeutic benefit of antihistamines and long‐term studies are underway to explore this possibility.
Airway endothelin levels in asthma: influence of endobronchial hypertonic saline challenge
Authors: Makker  , Springall  , Redington  , Ghatei  , Bloom  , Polak  , Howarth  , Holgate
Published: March 2003

Background

The pathophysiology of exercise‐induced asthma is not well understood. Hypertonicity of the airway lining fluid resulting from loss of water due to hyperventilation is considered to play a role, but the precise mechanism by which hypertonicity can induce bronchoconstriction is unknown. Peptides of the endothelin (ET) family have potent smooth muscle contractile properties, and have been linked to airway narrowing in stable asthma. We postulated that ET release may contribute to the acute bronchoconstrictor response induced by a hypertonic stimulus.

Methods

Seven male asthmatic subjects underwent local endobronchial challenge with hypertonic (3.6%) saline and, as a control, isotonic (0.9%) saline aerosols in separate bronchopulmonary segments. Bronchoalveolar lavage (BAL) was performed at both sites during the phase of immediate bronchoconstriction. Concentrations of immunoreactive ET and of the mast cell products, histamine, tryptase and prostaglandin D2, in BAL fluid were measured.

Results

Concentrations of ET in BAL fluid from the hypertonic saline‐challenged sites were significantly lower than those in BAL fluid from sites exposed to isotonic saline (0.19 [0.11–1.24] fmol/mL vs 0.40 [0.20–2.36] fmol/mL, P < 0.05). Concentrations of histamine, tryptase, and prostaglandin D2 did not differ significantly between the two sites.

Conclusions

These findings do not support the hypothesis that ET release within the airway lumen is involved in the bronchoconstrictor response induced by hypertonic saline.
Between‐observer repeatability of sputum differential cell counts. Influence of cell viability and squamous cell contamination
Authors: Ward  , Woltmann  , Wardlaw  , Pavord
Published: March 2003

Background

Induced sputum differential cell counts have been advocated as a method of noninvasively assessing airway inflammation in asthma and other airway diseases. Relatively little is known about the between‐observer repeatability of sputum differential cell counts and the factors that influence it.

Objective

To assess the between‐observer variability of induced sputum cell counts.

Methods

Sputum was induced and processed using standard techniques. Forty‐two slides from 38 patients (31 with asthma, seven normal subjects) were randomly selected. Slides were classified as good (< 20% squamous cells and > 50% viability; n = 24); low viability (< 50% viability; n = 10) and high squamous cell contamination (> 20% squamous cells; n = 8). Two blinded observers counted between 200 and 400 nonsquamous cells and agreement was assessed by the intraclass correlation coefficient (ICC) and the standard deviation of between‐observer differences (
sd).

Results

The overall ICC were 0.9, 0.89, 0.9 for eosinophils, neutrophils and macrophages and 0.29 and 0.69 for lymphocytes and epithelial cells. Repeatability was greater in slides classified as good compared with slides with low cell viability and particularly excess squamous cell contamination.

Conclusions

We have shown that the overall between‐observer repeatability of the differential eosinophil, neutrophil and macrophage cell counts is good. Low cell viability and particularly excess squamous cell contamination reduce between‐observer repeatability suggesting that techniques that ensure high cell viability and reduce squamous contamination would be an advantage.
Inflammatory mediators in bronchoalveolar lavage samples from children with and without asthma
Authors: Ennis  , Turner  , Schock  , Stevenson  , Brown  , Fitch  , Heaney  , Taylor  , Shields
Published: March 2003

Background

We investigated whether eosinophils and mast cells, found in the airways of children with wheeze, were activated during relatively asymptomatic periods.

Methods

A nonbronchoscopic bronchoalveolar lavage (BAL) procedure was performed on children presenting for an elective surgical procedure. Eosinophil‐derived (eosinophil cationic protein, ECP) and mast cell‐derived (histamine/tryptase) mediator concentrations were measured in the BAL fluid. A detailed history and serum immunoglobulin E were used to classify the children into four groups: atopic with and without asthma, viral‐associated wheeze and normal controls.

Results

The ECP concentrations in BAL from atopic asthmatic subjects were significantly higher than those measured in BAL from normal controls (P < 0.01), no other groups differed significantly. Histamine concentrations were elevated in both the atopic asthmatic and viral‐associated wheeze groups compared with controls (P < 0.02) and additionally higher concentrations were obtained in atopics with asthma compared with atopics without asthma (P < 0.03). Tryptase concentrations did not differ between groups, although the tryptase and histamine concentrations correlated significantly (r = 0.78, P < 0.0001).

Conclusions

Elevated histamine concentrations were found in children with wheeze regardless of the aetiology, whereas ECP was only elevated in those asthmatics with atopy. This suggests that even in relatively quiescent periods, there is some on going activation of airway eosinophils in children with atopic asthma.
Mast cell tryptase in dermal neurogenic inflammation
Authors: SCHMELZ  , ZECK  , RAITHEL  , RUKWIED
Published: March 2003

Background    Mast cell activation has been assumed to play a role in dermal neurogenic inflammation: C fibre‐derived neuropeptides activating mast cells and releasing histamine, which in turn would activate C fibres. Objective    To test this hypothesis mast cell tryptase (MCT) was measured inside the axon reflex flare area. Axon reflexes were elicited by histamine or compound 48/80, a polyanionic mast cell‐degranulating substance. The time course of plasma extravasation and release of histamine and MCT from dermal mast cells in neurogenic inflammation was measured in vivo by intradermal microdialysis in humans. Methods    Single hollow plasmapheresis fibres (pore cutoff size: 3000 kDa) were inserted intracutaneously at the volar forearm and perfused with Ringer’s solution (4 μL/min) with one microdialysis fibre located at the planned stimulation site and a second inside the axon reflex area. Neurogenic inflammation was induced by intraprobe delivery of either histamine or the mast cell‐degranulating agent compound 48/80. Mediator release was measured at the stimulation sites and inside the arising axon reflex flare area. Results    Mast cell degranulation induced marked plasma protein extravasation (PPE 0.25 ± 0.04–1.31 ± 0.6 mg/mL; pre‐ and post‐stimulation, mean ± sem, n = 7) and release of histamine (2.0 ± 0.9–38.7 ± 1.4 ng/mL) and MCT (9.84 ± 2.4–92.2 ± 21.6 ng/mL). Interestingly, in addition to increasing PPE (0.33 ± 0.11–1.85 ± 0.9 mg/mL), histamine also induced a slight but significant increase in MCT (11.3 ± 3.0–12.4 ± 2.3 ng/mL). No evidence for mast cell activation was observed inside the axon reflex areas, where PPE (0.34 ± 0.03–0.25 ± 0.02 mg/mL), histamine (1.64 ± 0.5–1.46 ± 0.4 ng/mL) and MCT concentration (11.6 ± 3.1–7.6 ± 1.7 ng/mL) gradually decreased. Conclusion    It is concluded that dermal neurogenic inflammation does not degranulate mast cells.
Molecular characterization of Dau c 1, the Bet v 1 homologous protein from carrot and its cross‐reactivity with Bet v 1 and Api g 1
Authors: HOFFMANN‐SOMMERGRUBER  , O'RIORDAIN  , AHORN  , EBNER  , DA CAMARA MACHADO  , PÜHRINGER  , SCHEINER  , BREITENEDER
Published: March 2003

Background

Up to 70% of patients with birch pollen allergy exhibit the so‐called oral allergy syndrome, an IgE‐mediated food allergy. The most frequent and therefore best characterized pollen–fruit syndrome is apple allergy in patients suffering from tree pollen‐induced pollinosis. The occurrence of adverse reactions to proteins present in vegetables such as celery and carrots in patients suffering from pollen allergy has also been reported. cDNAs for Bet v 1 homologous proteins have been cloned from celery, apple and cherry. Objective    The aim of the study was to identify Bet v 1 homologues from carrot (Daucus carota), to isolate the respective cDNA, to compare the IgE‐binding capacity of the natural protein to the recombinant allergen and determine the cross‐reactivity to Api g 1 and Bet v 1.

Methods

Molecular characterization of the carrot allergen was performed using IgE‐immunoblotting, cross‐inhibition assays, N‐terminal sequencing, PCR‐based cDNA cloning and expression of the recombinant protein in Escherichia coli.

Results

A 16‐kDa protein from carrot was identified as a major IgE‐binding component and designated Dau c 1. Sequencing corresponding cDNAs revealed three extremely similar sequences (Dau c 1.1, 1.2 and 1.3) with an open reading frame of 462 bp coding for 154 amino acid residues.

Conclusions

Purified recombinant Dau c 1.2 was tested in immunoblots displaying IgE‐binding capacity comparable to its natural counterpart. Cross‐inhibition assays verified the existence of common B‐cell epitopes present on Dau c 1, Api g 1 as well as on Bet v 1.
Serological characterization of allergens in poppy seeds
Authors: Jensen‐Jarolim  , Gerstmayer  , Kraft  , Scheiner  , Ebner  , Ebner
Published: March 2003

Background and objective

Poppy seeds in food can induce immediate‐type allergic reactions ranging from mild local symptoms to severe anaphylactic reactions. Previous publications showed that poppy seeds cross‐react with other plant‐derived allergens. The IgE‐binding components have not been defined so far.

Methods

We analysed sera from 11 patients with adverse reactions after ingestion of poppy seed‐containing food by IgE‐immunoblotting. Nine of 11 patients showed concomitant IgE binding to allergens of birch, mugwort or grass pollen in RAST‐CAP, and suffered from characteristic seasonal symptoms.

Results

Ten of 11 patients showed IgE binding to a 45‐kDa protein, 4/11 to a 34‐kDa, 5/11 to a 17‐kDa, 5/11 to a 14‐kDa, and 3/11 to a 5‐kDa component. Furthermore, individual IgE binding to proteins of 20, 25, 30 and 40 kDa proteins could be observed. Periodate treatment of blots markedly reduced the IgE binding capacity of the 40‐ and 45‐kDa compounds, indicating the existence of IgE epitopes of the carbohydrate type. Inhibition studies indicated the presence of homologues of pollen allergens in extracts from poppy seeds, i.e. Bet v 1 and Bet v 2.

Conclusion

The serological analysis showed IgE binding to protein and sugar components of poppy seeds. The 40‐ and 45‐kDa allergens are glycoproteins and contain IgE binding carbohydrate moieties. Moreover, cross‐reacting homologues of pollen allergens including Bet v 1 and profilin were detected in poppy seed extract.
Effect of topical corticosteroids on seasonal increases in epithelial eosinophils and mast cells in allergic rhinitis: a comparison of nasal brush and biopsy methods
Authors: Jacobson  , Juliusson  , Löwhagen  , Balder  , Kay  , Durham
Published: March 2003

Background

Nasal brushing and nasal biopsy are well‐tolerated sampling techniques. Seasonal grass pollen‐induced rhinitis is characterized by epithelial mast cell infiltration and seasonal increases in both epithelial and sub‐mucosal eosinophils.

Objective

To compare the ability of the nasal brush and nasal biopsy techniques to detect natural seasonal increases in eosinophils and mast cells, and to assess the influence of topical corticosteroid.

Methods

Nasal brush samples and nasal biopsies were collected from 46 grass pollen‐sensitive seasonal rhinitis patients before the grass pollen season and at the peak of the pollen season following 6 weeks' treatment with either fluticasone propionate aqueous nasal spray (200 μg, twice daily) or placebo nasal spray.

Results

Placebo patients showed seasonal increases in epithelial eosinophils both with nasal brushing (P < 0.0001) and biopsy (P < 0.001). Epithelial mast cell numbers also increased during the pollen season as detectable by brushing (P < 0.0001) and biopsy (P < 0.03). Changes in cell numbers measured by nasal brushing correlated with those observed with nasal biopsy, both for eosinophils and mast cells (P < 0.05). Sub‐mucosal eosinophils but not mast cells also increased during the pollen season (P < 0.002). Nasal brushing and biopsy revealed that fluticasone treatment inhibited seasonal increases in epithelial eosinophils (P < 0.00001) and epithelial infiltration by mast cells (nasal brushing P < 0.00001 and nasal biopsy P < 0.01). Fluticasone also inhibited seasonal increases in sub‐mucosal eosinophils (P < 0.001) and significantly reduced nasal symptoms (P < 0.001).

Conclusion

Nasal brushing harvests sufficient inflammatory cells from the surface of the nasal mucosa to be used in lieu of nasal biopsies in observation of the effect of drugs on the nasal epithelium.
Detection of inhaled Der p 1
Authors: Poulos  , O'Meara  , Sporik  , Tovey
Published: March 2003

Background

Measurement of personal exposure to Der p 1 aeroallergen has previously been limited by the low quantity of material collected by sampling systems and the assay sensitivity. This has meant that exposure could only be detected if long sampling periods were used or reservoir dust was artificially disturbed. We have developed a sampling method to sample true personal exposure and combined it with a novel method which is sensitive enough to measure allergen exposure over shorter time frames.

Objective

To describe normal domestic exposure to dust mite allergen during a range of activities in houses in Sydney, Australia.

Methods

Inhaled particles containing mite allergen Der p 1 were collected using a nasal air sampler which impacts particles (> ≈5 μm) onto a protein‐binding membrane coated with a thin, porous, adhesive film. The allergen is bound to the membrane in the immediate vicinity of the particle and detected by immunostaining with monoclonal antibodies specific for Der p 1. In addition, samples were collected using a standard Institute of Occupational Medicine (IOM) personal air sampler and the amount of eluted Der p 1 was assayed by ELISA.

Results

The median number (range) of inhaled particles containing Der p 1 collected in each 10‐min sampling period was: dust raising 5 (2–10); lying in bed, 0 (0–2); sitting on the bed, 1 (0–2); walking around the bedroom, 0 (0–2). This represented 0–5.1% of all particles captured. The Der p 1 concentration of floor and bed dust was 19.4 and 55.1 μg/g, respectively. The standard IOM personal sampler and ELISA were unable to detect Der p 1 for any of the activities performed.

Conclusions

We were able to count individual allergen‐carrying particles inhaled over short time periods, during different domestic exposure situations. This will offer new insight into several aspects of personal allergen exposure.
Effects of house dust mite avoidance measures on Der p 1 concentrations and clinical condition of mild adult house dust mite‐allergic asthmatic patients, using no inhaled steroids
Authors: Cloosterman  , Schermer  , Bijl‐Hofland  , Van Der Heide  , Brunekreef  , Van Den Elshout  , Van Herwaarden  , Van Schayck
Published: March 2003

Background

Exposure to house dust mite (HDM) allergens often results in worsening of asthma. Therefore, avoidance of exposure to HDM allergens is often proposed. Unfortunately, the most effective and feasible avoidance strategy is still not completely assessed. Consequently, we investigated the effects of a combined HDM avoidance strategy on HDM allergen concentrations and clinical condition of allergic, mild asthmatic, patients using no inhaled steroids.

Methods

Asthmatic patients, allergic to HDM, using no inhaled corticosteroids, were randomly allocated to an active (n = 76) or a placebo allergen‐avoidance group (n = 81). Avoidance measures consisted of applying Acarosan® (placebo: water) to the living room and bedroom floors, and the use of HDM‐impermeable covers for mattresses and bedding (placebo: cotton covers for mattresses only). Effects on allergen concentrations (Der p 1), FEV1, bronchial hyperresponsiveness, peak flow parameters and asthma symptom scores were studied during 20 weeks and controlled for the allergic status of the patients.

Results

The active covers reduced Der p 1 concentrations to 9.4% (P = 0.0001), and were always significant lower than in the placebo group (P = 0.0002). Acarosan® resulted in slight but significant decreases (twofold, P = 0.0001), both on living room and bedroom floors, but concentrations were never significantly lower than the placebo group. Although the combined avoidance strategy resulted in a considerable reduction in allergen load in the active group, no differences were seen between the two groups in any of the clinical parameters during the follow‐up period in this group of allergic asthmatics, using no inhaled corticosteroids. Corrections for the allergic status did not alter these results.

Conclusions

The combined avoidance strategy was effective in reducing HDM allergen concentration. This was especially achieved by the allergen‐impermeable covers, while the effects of Acarosan® were only marginal. However, this allergen reduction was not reflected in a convincing improvement in clinical condition in this group of mild allergic asthmatics, using no inhaled steroids. Perhaps, a longer follow‐up period would have resulted in more pronounced effects.
Association between − 308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma
Authors: Li Kam Wa  , Mansur  , Britton  , Williams  , Pavord  , Richards  , Campbell  , Morton  , Holgate  , Morrison
Published: March 2003

Background

Tumour necrosis factor (TNF) is a pivotal cytokine in the inflammation underlying asthma. The TNF gene is located in the polymorphic HLA class 3 region on chromosome 6p. Several polymorphisms in this region have been described and associated with alteration of TNF secretion in vitro.

Objective

In this study we tested the hypothesis that two such polymorphisms, lymphotoxin α NcoI B*1 and − 308 TNF2 may be components of the genetic predisposition to asthma.

Methods

Five hundred and fifty‐six random individuals were studied, comprising approximately equal numbers of asthmatic subjects, with or without atopy, and a nonatopic nonasthmatic control group. In addition, 355 subjects (172 asthmatics) from 60 multiplex families were typed at the LTα NcoI locus.

Results

There was an association between allele two of the − 308 TNF polymorphism and bronchial hyperreactivity (OR 2.12, 95% CI 1.04–4.32, P = 0.036). However, there was no association with LTα NcoI alleles. To determine whether this was influenced by linkage disequilibrium within the MHC, 91 subjects with bronchial hyperreactivity and 85 control subjects were typed for class 2 and 3 alleles. Following identification of the extended TNF2 haplotype, we found no independent association of these alleles with BHR.

Conclusions

We conclude that the − 308 TNF2 promoter polymorphism may form a component of the genetic predisposition to BHR in asthma.
Means of increasing sensitivity of an in vitro diagnostic test for aspirin intolerance
Authors: May  , Weber  , Gall  , Kaufmann  , Zollner
Published: March 2003

Background

Pseudo‐allergic reactions caused by aspirin (acetyl salicylic acid; ASA) often resemble immediate‐type hypersensitivity reactions consisting of urticaria and angioedema or rhinoconjunctivitis, asthma and nasal polyps. In the last few years, a new in vitro assay based on determination of sulfidoleucotrienes from isolated leucocytes (cellular allergen stimulation test — CAST) has been introduced for type I allergies and pseudoallergic reactions. In ASA intolerance, there is only limited experience using this assay with — in some studies — only moderate sensitivity. Furthermore, the necessity to use freshly isolated leucocytes from untreated patients is inconvenient for routine settings.

Objective

The purpose of our study was to search for possibilities of increasing the sensitivity of the test and to use stored blood samples which would permit shipping, two requirements for the clinical suitability of this test.

Patients and methods

Leucotriene release in response to ASA and other non‐steroidal anti‐inflammatory drugs (NSAIDs) was analysed in 38 ASA‐intolerant patients (predominantly airway‐related symptoms n = 22; predominantly cutaneous symptoms n = 16) and 50 controls. The diagnosis of ASA intolerance was established by history and placebo‐controlled oral challenge tests.

Results

Using 24 h‐stored leucocytes obtained from 10 ASA‐intolerant patients and 10 healthy controls there were no significant differences of leucotriene release by resting, ionomycin‐, and anti FcεRIα‐stimulated leucocytes compared with freshly isolated leucocytes. Analysis of ASA + C5a‐mediated leucotriene release by stored blood samples in combination with indomethacin‐ and diclofenac‐mediated leucotriene release in ASA‐intolerant patients (n = 38) resulted in an increased sensitivity (from 50 to 72.7% in ASA‐intolerant patients with predominantly airway‐related symptoms and from 81 to 100% in ASA‐intolerant patients with predominantly skin symptoms) compared with assays in which only ASA + C5a‐mediated leucotriene release has been determined. Moreover, the specificity of the assay remained high (96.7% when analysing different NSAIDs compared with > 99% when analysing only ASA + C5a‐mediated leucotriene release).

Conclusion

In vitro stimulation with ASA + C5a leucocyte stimulation with other NSAIDs should be performed to achieve a higher sensitivity. This finding can be explained by the clinical observation of a high ratio of cross‐reactivities between the mentioned NSAIDs.
A retrospective study of the relationship between childhood asthma and respiratory infection during gestation
Authors: Hughes  , Jones  , Wright  , Dobbs
Published: March 2003

Background

Wheeze in children has been found to be associated with prior antepartum haemorrhage and raised levels of IgE in cord blood, and acute wheezing episodes are intimately linked with respiratory viral infections.

Objective

To assess the relationship between maternal presentation with respiratory tract infections in pregnancy and childhood asthma, taking into account factors which could affect presentation.

Methods

This was a case‐control study of 200 asthmatic children, 5–16‐year‐old, age‐matched with one control, having no recorded history of wheeze. Data on respiratory tract infections, maternal wheeze, atopy and smoking was collected from primary care records. Deprivation score was assessed according to small residential areas andsubjects were equally distributed between four general practices in Plymouth, UK.

Results

Presentation with respiratory tract infections during pregnancy was significantly associated with childhood asthma (OR 1.69, 95% confidence interval 1.05–2.77, P = 0.03). The association was marginally stronger for infections in the first trimester (OR 2.30, 95% CI 1.05–5.41, P = 0.04) and for those with cough during pregnancy (OR 2.24, 95% CI 1.23–4.22, P = 0.007). The associations remained significant after allowing for the effect of the independent variables (gender, maternal smoking, maternal wheeze, allergic rhinitis, eczema, asthma treatment in pregnancy and deprivation [Townsend] score), using multiple logistic regression analysis (ORs and 95% CIs 1.91, 1.14–3.22; 2.32, 1.01–5.34 and 2.29, 1.17–4.48, respectively). There was also an association between numbers of presentations with respiratory infections and childhood asthma (test for trend, P = 0.02).

Conclusions

This study has shown an association between presentation with respiratory infection during gestation and childhood asthma. The results were not affected by the other independent variable factors studied and therefore provide some evidence to support the theory that respiratory viruses may be implicated in the aetiology of asthma.
Non‐cardiac adverse effects of antihistamines (H1‐receptor antagonists)
Authors: Simons F. E. R.
Published: March 2003

Antihistamines, available without prescription in many countries, are generally considered to be safe medications; however, the old first‐generation H1 antagonists commonly cause adverse central nervous system (CNS) effects, even when administered in usual doses. Patients may not be aware of these effects and do not necessarily develop tolerance to them. In contrast, the new, second‐generation H1 antagonists are relatively free from adverse effects in the CNS, primarily because they do not cross the blood–brain barrier and block the important neurotransmitter function of histamine. Most o fthe H1 antagonists in current use are unlikely to cause cardiac toxicity. There is no evidence that H1 antagonists, which have been approved by regulatory agencies, have carcinogenic, tumour‐promoting, or teratogenic effects in humans.
The non‐cardiac systemic side‐effects of antihistamines: ebastine
Authors: Roberts D. J. , Gispert J.
Published: March 2003

Ebastine and its active metabolite carebastine show potent antagonism of histamine H1‐mediated phenomena in a wide variety of in vitro and in vivo non‐clinical experimental models. By contrast, activity is not seen against histamine H2‐ or H3‐mediated, nor acetylcholine‐ or serotonin‐mediated phenomena, and both compounds are virtually without effect in models measuring pharmacological effects on the central nervous system (CNS). Explanation of these observations is found in their high selectivity for the histamine H1 receptor and in their low in vivo potency in displacing [3H]‐mepyramine from central histamine H1 receptors, indicating that they do not readily pass the blood–brain barrier. These findings have been mirrored in clinical experimental models where oral doses of ebastine (1–30 mg) showed clear dose‐related inhibition of intradermal histamine‐induced weal and flare responses, whereas doses of 90 mg were without anticholinergic effects on salivary flow, cardiovascular reflexes or pilocarpine‐induced miosis. Furthermore, in an extensive series of controlled studies in specific clinical models for measuring objective effects on the CNS, ebastine in single doses of 10–90 mg and repeated doses of 10–30 mg once daily, had no clinically relevant effects on cognitive performance and visual co‐ordination tests, nor on simulated car‐tracking tests and real car‐driving tests. Nor was their any interaction with ethanol or diazepam. On subjective test parameters (questionnaires and visual analogue scales) there were only a few isolated and random incidences of minor increases in some indices of sedation at the highest doses. Not suprisingly, therefore, the clear therapeutic benefit seen during the extensive and international use of ebastine (5–20 mg once daily) in the treatment of seasonal and perennial rhinitis and chronic idiopathic urticaria, has not been accompanied by signs of drug‐induced anticholinergic effects (dry mouth, disturbances of visual accommodation) or sedation, making it an effective and well‐tolerated first‐line treatment alternative to other second‐generation antihistamines.
Cardiovascular profile of loratadine
Authors: Hey J. A. , Affrime M. , Cobert B. , Kreutner W. , Cuss F. M.
Published: March 2003

The extremely low reporting rate of cardiovascular adverse events for loratadine, the possible preferential use of loratadine in patients with pre‐existing cardiovascular disorders, and the impressive lack of cardiovascular effects at extremely high concentrations in clinical and preclinical studies demonstrate the very safe cardiovascular profile of loratadine.
Epithelial damage and response
Authors: Holgate
Published: March 2003

Epithelial damage is a characteristic feature of asthma. The epithelium is not merely a passive barrier but can generate a range of mediators that may play a role in the inflammatory and remodelling responses that occur in the lungs in asthma. For example, the cytokine granulocyte macrophage colony‐stimulating factor (GM‐CSF), whose principal source is the epithelium, can prolong eosinophil survival while transforming growth factor is a potent profibrogenic cytokine. Deposition of collagen in the epithelial subbasement membrane is a characteristic feature of the remodelling response in asthma. This may be due to abnormal associations between myofibroblasts and epithelium, both of which are involved in early lung development (epithelial–mesenchymal trophic unit). In asthma, there may be a primary defect in the epithelium such that it responds abnormally to various stimuli and cannot undergo the normal repair response. Epidermal growth factor (EGF) appears to be a key factor in bronchial epithelial repair; it stimulates epithelial cell proliferation and migration. The 3v isoform of the adhesion molecule CD44 is overexpressed in damaged epithelium and seems to regulate the repair response by presenting EGF more efficiently to its receptor. Although EGF receptor expression is increased in asthma, it does not lead to an appropriate proliferative response and restitution of normal epithelium. Other factors such as transforming growth factor (TGF)β which are generated by inflammatory cells and epithelium are also upregulated in asthma. An epithelial/fibroblast co‐culture system has shown that following epithelial damage various growth factors are released from the underlying myofibroblasts and are responsible for the proliferative response. The TGFβ family are most likely responsible for collagen production. In an in vitro study, an EGF receptor inhibitor slowed epithelial repair but enhanced TGFβ production by the slowly repairing epithelial cells. In conclusion, the interaction between epithelial cells and myofibroblasts, i.e. reactivation of the epithelial–mesenchymal trophic unit appears to be central to the airway wall remodelling response.
Allergen‐specific production of interferon‐γ by peripheral blood mononuclear cells and CD8 T cells in allergic disease and following immunotherapy
Authors: O'brien  , Xu  , Rolland  , Byron  , Thomas
Published: March 2003

Background

CD8 T cells are important immunoregulatory cells in animal models of allergic disease, but their role in human allergic immune responses has not been defined. With the development of novel immunotherapeutic reagents, it is clearly important to ascertain whether CD8 T‐cell responses are altered following conventional allergen‐specific immunotherapy (SIT) and hence targets for future developments/strategies.

Objective

To study the allergen‐specific cytokine release of freshly isolated CD8 T cells from the blood of separate groups of house dust mite‐ (HDM) allergic patients, patients post‐SIT and control nonatopic donors.

Methods

CD8 T cells were isolated by positive selection with immunomagnetic beads and cultured with the affinity purified major mite allergen Der p 1 or with different mitogens, using irradiated autologous peripheral blood mononuclear cells as antigen‐presenting cells (APCs). Supernatants were collected at a number of time points and assayed by ELISA for the cytokines interleukin (IL) ‐4, IL‐5 and interferon‐gamma (IFNγ).

Results

CD8 T cells stimulated with Der p 1 produced significant quantities of IFNγ with cells from HDM‐allergic subjects releasing considerably more IFNγ than cells from nonatopic subjects, an average of 804 ± 283 pg/mL of supernatant compared with 30.2 ± 18.8 pg/mL (P = 0.006). The cytokine was detected in cultures of 16/17 of the allergic subjects and 4/7 of the nonatopic. CD8 T cells from 6/10 patients who had received HDM‐SIT released IFNγ at an average of 363 ± 202 pg/mL, which was less than the allergic group but still higher than the nonatopic (P = 0.05). Equivalent levels of IFNγ were detected when the cells were stimulated with the mitogen PHA and this was the same in all groups. Reliable allergen‐specific release of significant quantities of IL‐4 or IL‐5 was not detected from CD8 T cells.

Conclusion

Allergen‐specific IFNγ is produced at far greater levels from CD8 T cells of HDM‐sensitive allergic patients than from nonatopic control individuals and this level is reduced following SIT.
Evaluation of treatment response in patients with seasonal allergic rhinitis using domiciliary nasal peak inspiratory flow
Authors: Wilson  , Dempsey  , Sims  , Coutie  , Paterson  , Lipworth
Published: March 2003

Background

Measurement of domiciliary nasal peak inspiratory flow rate (PIFR) may have a role in the objective assessment of treatment response in seasonal allergic rhinitis (SAR).

Objective

We wished to evaluate the relationship between domiciliary measurement of nasal PIFR and a variety of symptoms associated with rhinitis.

Methods

Thirty‐eight nonasthmatic patients, mean age (SEM) 30 years (1.4), with symptomatic SAR were evaluated in a placebo‐controlled, single‐blind, double‐dummy, three way parallel group study. Patients received oral cetirizine 10 mg once daily and were randomized to receive, in addition, either: (i) intranasal mometasone furoate 200 μg (n = 14); (ii) oral montelukast 10 mg (n = 11); or (iii) placebo (n = 13). All treatments were given once daily for 4 weeks and were preceded by a 1 week placebo period. Domiciliary diary cards were used to record morning (am) and evening (pm) domiciliary nasal PIFR and symptom (nasal, eye, throat) scores and impact on daily activity. A total daily symptom score was then calculated from the sum of these separate symptom scores.

Results

Baseline values for symptom scores and PIFR after placebo run‐in were not significantly different when comparing the three groups. After 4 weeks of active treatment, there were significant (P < 0.05) improvements in nasal symptoms, total daily symptoms and PIFR with all treatments, with there being no significant confounding effect of pollen count, when analysed as a covariate. There were significant (P < 0.01) correlations for nasal symptom scores vs PIFRam (r = − 0.51) and PIFRpm (r = − 0.56), and similarly for daily activity vs PIFRam (r = − 0.42) and PIFRpm (r = − 0.48).

Conclusions

These results suggest that domiciliary measurements of nasal peak flow correlate significantly with symptoms of seasonal allergic rhinitis and may therefore be a potentially useful objective short‐term marker of treatment response.
Skin and laboratory tests in amoxicillin‐ and penicillin‐induced morbilliform skin eruption
Authors: Schnyder  , Pichler
Published: March 2003

Background

Cutaneous amoxicillin‐ and penicillin‐mediated reactions can be classified as immediate and delayed‐type reactions. Immediate reactions are thought to involve IgE antibodies and have been studied extensively. In contrast only few data exist about delayed reactions such as morbilliform or maculopapular rash.

Objective

To assess the predictive value of immediate skin tests, skin‐patch tests, specific IgE and lymphocyte transformation tests with regard to the diagnosis of delayed skin eruptions.

Methods

Skin and in vitro tests were performed in 18 subjects. Twelve subjects had penicillin‐ or amoxicillin‐induced morbilliform exanthema and six were controls without hypersensitivity reaction, tested before and after exposure.

Results

Specific IgE to penicillin and immediate penicillin skin tests were negative in amoxicillin‐ or penicillin‐induced delayed skin eruptions. In contrast, skin‐patch testing and LTT were positive in 9/12 or 10/12, respectively, but negative in all six controls.

Conclusion

These findings substantiate a T‐cell‐mediated immune pathomechanism in the majority of penicillin‐induced delayed skin reaction. Moreover, they underline the necessity to adapt the test procedures to underlying pathomechanisms and support the diagnostic value of skin‐patch testing and LTT in delayed cutaneous reactions to penicillins.
Putative virulence factors of Aspergillus fumigatus
Authors: Tomee  , Kauffman
Published: March 2003

Various putative virulence factors of Aspergillus fumigatus have been studied over the past decades. A. fumigatus gliotoxin is a potent inhibitor of the mucociliary system. Several fungal metabolites interfere with phagocytosis and opsonization including toxins, ‘conidial inhibitory factor’, ‘A. fumigatus diffusible product’ and ‘complement inhibitory factor’. A. fumigatus can bind specifically to different host tissues components, whereas toxins give a general and significant immunosuppressive effect on host defences. Circumstantial evidence links the production of elastinolytic proteases with the ability to cause disease. However, none of the reports demonstrates conclusively a decisive role for any of the virulence factors described thus far. It is conceivable that proteolytic enzyme activities such as those expressed by AFAlp are one of a number of factors, each with a minor effect, that combine to facilitate disease progression.
Identification of peptide motifs recognized by a human IgG autoanti‐IgE antibody using a phage display library
Authors: Shakib  , Hooi  , Smith  , Furmonaviciene  , Sewell
Published: March 2003

Background

The potential of murine monoclonal anti‐IgE antibodies as long‐term therapy for atopic diseases will have to rely, for the time being, on passive antibody administration. There is therefore considerable interest in developing a peptide‐based vaccine for active immunization to elicit long‐term protective anti‐IgE antibodies in the patient. It has been shown that some human IgG autoanti‐IgE antibodies have the ability to partially block the binding of IgE to Fc receptors such as FcεRI. Therefore, the epitopes recognized by such antibodies could have vaccine potential.

Objective

To determine the epitope specificity of one such human IgG anti‐IgE antibody.

Methods

A 15‐mer phage‐peptide library was used to establish the epitope specificity of an IgG anti‐IgE antibody isolated from the serum of an asthma patient.

Results

The SRPSP sequence, or part of it (i.e. RPS, RPSP, SPS or PSP), was present in all 18 phage‐peptides that have been sequenced. This common motif was found to be within the human ε chain sequence Ser341‐Thr355 near the N‐terminus of the Cε3 domain. According to the human Fcε model, the most accessible residues in this sequence are Arg342, Ile350, Arg351, Lys352 and Ser353.

Conclusions

The present data should provide the molecular basis for the rational design of a suitable peptide immunogen (vaccine) for boosting the production of protective autoanti‐IgE antibodies.
Topical glucocorticoids application induced an augmentation in the expression of IL‐1α while inhibiting the expression of IL‐10 in the epidermis in murine contact hypersensitivity
Authors: Igawa K. , Yokozeki H. , Miyazaki Y. , Minatohara K. , Satoh T. , Katayama I. , Nishioka K.
Published: March 2003

The repeated application of glucocorticoids (GC) on the skin augmented the inflammatory response of both allergic and irritant contact dermatitis in our studies.

In order to further clarify the mechanism of such an augmentation of contact hypersensitivity (CHS), we investigated the modulatory effects of cytokines in the epidermis after the administration of GC at challenged sites in CHS.

Diflucortolone valerate was applied to BALB/c mice on alternate days for a total of nine times. On day 12, they were contact sensitized with dinitrofluorobenzene (DNFB). Next, on day 17, one day after the last application of GC, they were challenged with DNFB on the ear. The whole challenged ear lobes were removed after a hapten challenge and then were analysed by the RT‐PCR method or underwent an immunohistochemical analysis. To clarify the modulatory effects of cytokines in vivo, DNFB sensitized mice pre‐treated with GC were injected with rIL‐10, IL‐1 receptor antagonist (ra) and anti‐IL‐1α monoclonal antibody (mAb) and thereafter were challenged with DNFB.

A RT‐PCR analysis has demonstrated IL‐10 mRNA to be detected in the challenged skin of non‐GC‐pretreated mice but not in that of GC‐pre‐treated mice after challenge. On the other hand, the expression of IL‐1α mRNA in the challenged skin of mice pretreated with GC was more strongly detected that that in mice without GC‐pretreatment. Furthermore, an immuno‐histochemical analysis in the challenge showed the expression of IL‐10 in the skin showed the expression of IL‐10 in the challenged epidermis of the non‐GC‐pretreated mice but not in the GC‐pretreated mice and IL‐1α was also strongly expressed in the epidermis of the GC‐pretreated mice. A subcutaneous injection of anti‐IL‐1α mAb or IL‐1 ra inhibited the augmented CHS reaction in the GC‐pretreated mice. A subcutaneous injection of rIL‐10 also inhibited the augmentation of the CHS reaction in the GC‐pretreated mice; however, no such inhibition was observed in the non‐GC‐pretreated mice.

These results indicated that both an up‐regulation of IL‐1α production and the inhibition of the IL‐10 production in the epidermis at the challenged skin sites in the GC‐pretreated mice appear to play a critical role in the GC‐induced augmentation of murine CHS.
Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study
Authors: Purello‐D'Ambrosio F. , Gangemi S. , Merendino R. A. , Isola S. , Puccinelli P. , Parmiani S. , Ricciardi L.
Published: March 2003

Background Specific immunotherapy is the only currently available allergen‐orientated treatment able to modify the natural history of respiratory allergic diseases. Safety and clinical efficacy of this treatment are well documented, but evidence about the ability to reduce new sensitizations is still poor.

Objective We report a retrospective study conducted in order to assess the prevention of new sensitizations in monosensitized subjects treated with specific immunotherapy vs. monosensitized patients treated with anti‐allergic drugs.

Methods 8396 monosensitized patients with respiratory symptoms were selected according to an open, retrospective design. Group A included 7182 patients submitted to specific immunotherapy (and anti‐allergic drugs when needed) for 4 years and then treated with drugs for at least 3 years. Group B included 1214 patients treated only with drugs for at least 7 years. All patients underwent prick test with a standard panel of allergens and total and specific IgE determination before and after 4 years of treatment and again 3 years later.

Results Groups were well balanced. Polysensitized subjects were 23.75% in Group A and 68.03% in Group B after 4 years (P < 0.0001) and 26.95% and 76.77%, respectively, after 7 years (P < 0.0001). Asthmatic subjects were more prone to develop polysensitization in comparison to subjects suffering only from rhinitis (32.14% instead of 27.29% after 4 years, 36.5% instead of 31.33% after 7 years; P < 0.0001). Specific IgE decreased by 24.11% in Group A and increased by 23.87% in Group B (P < 0.0001). Total IgE decreased by 17.53% in Group A and increased by 13.71% in Group B (P < 0.0001).

Conclusions Specific immunotherapy was observed retrospectively to reduce new sensitizations in monosensitized subjects suffering from respiratory allergic diseases.