Late Asthmatic Reaction Research Articles

MicroRNA Profiling of the Inflammatory Response after Early and Late Asthmatic Reaction.

A high proportion of house dust mite (HDM)-allergic asthmatics suffer from both an early asthmatic reaction (EAR) and a late asthmatic reaction (LAR) which follows it. In these patients, allergic inflammation is more relevant. MiRNAs have been shown to play an important role in the regulation of asthma's pathology. The aim of this study was to analyze the miRNA profile in patients with mild asthma and an HDM allergy after bronchial allergen provocation (BAP). Seventeen patients with EAR/no LAR and 17 patients with EAR plus LAR, determined by a significant fall in FEV1 after BAP, were differentially analyzed. As expected, patients with EAR plus LAR showed a more pronounced allergic inflammation and FEV1 delta drop after 24 h. NGS-miRNA analysis identified the down-regulation of miR-15a-5p, miR-15b-5p, and miR-374a-5p after BAP with the highest significance in patients with EAR plus LAR, which were negatively correlated with eNO and the maximum decrease in FEV1. These miRNAs have shared targets like CCND1, VEGFA, and GSK3B, which are known to be involved in airway remodeling, basement membrane thickening, and Extracellular Matrix deposition. NGS-profiling identified miRNAs involved in the inflammatory response after BAP with HDM extract, which might be useful to predict a LAR.

The novel TRPA1 antagonist BI01305834 inhibits ovalbumin-induced bronchoconstriction in guinea pigs

BackgroundAsthma is a chronic respiratory disease in which the nervous system plays a central role. Sensory nerve activation, amongst others via Transient Receptor Potential Ankyrin 1 (TRPA1) channels, contributes to asthma characteristics including cough, bronchoconstriction, mucus secretion, airway hyperresponsiveness (AHR) and inflammation. In the current study, we evaluated the efficacy of the novel TRPA1 antagonist BI01305834 against AHR and inflammation in guinea-pig models of asthma.MethodsFirst, a pilot study was performed in a guinea-pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on (1) AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), (2) magnitude of EAR and LAR and (3) airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating-effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann–Whitney U test or One-way nonparametric Kruskal–Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett’s post-hoc test where appropriate.ResultsA dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study, 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea-pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea-pig trachea strips.ConclusionsTRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.

Identification of late asthmatic reactions following specific inhalation challenge

Specific inhalation challenge (SIC) is the reference standard for the diagnosis of occupational asthma. Current guidelines for identifying late asthmatic reactions are not evidence based.ObjectivesTo identify the fall in forced...

Pharmacological Screening Identifies SHK242 and SHK277 as Novel Arginase Inhibitors with Efficacy against Allergen-Induced Airway Narrowing In Vitro and In Vivo.

Arginase is a potential target for asthma treatment. However, there are currently no arginase inhibitors available for clinical use. Here, a novel class of arginase inhibitors was synthesized, and their efficacy was pharmacologically evaluated. The reference compound 2(S)-amino-6-boronohexanoic acid (ABH) and >200 novel arginase inhibitors were tested for their ability to inhibit recombinant human arginase 1 and 2 in vitro. The most promising compounds were separated as enantiomers. Enantiomer pairs SHK242 and SHK243, and SHK277 and SHK278 were tested for functional efficacy by measuring their effect on allergen-induced airway narrowing in lung slices of ovalbumin-sensitized guinea pigs ex vivo. A guinea pig model of acute allergic asthma was used to examine the effect of the most efficacious enantiopure arginase inhibitors on allergen-induced airway hyper-responsiveness (AHR), early and late asthmatic reactions (EAR and LAR), and airway inflammation in vivo. The novel compounds were efficacious in inhibiting arginase 1 and 2 in vitro. The enantiopure SHK242 and SHK277 fully inhibited arginase activity, with IC50 values of 3.4 and 10.5 μM for arginase 1 and 2.9 and 4.0 µM for arginase 2, respectively. Treatment of slices with ABH or novel compounds resulted in decreased ovalbumin-induced airway narrowing compared with control, explained by increased local nitric oxide production in the airway. In vivo, ABH, SHK242, and SHK277 protected against allergen-induced EAR and LAR but not against AHR or lung inflammation. We have identified promising novel arginase inhibitors for the potential treatment of allergic asthma that were able to protect against allergen-induced early and late asthmatic reactions. SIGNIFICANCE STATEMENT: Arginase is a potential drug target for asthma treatment, but currently there are no arginase inhibitors available for clinical use. We have identified promising novel arginase inhibitors for the potential treatment of allergic asthma that were able to protect against allergen-induced early and late asthmatic reactions. Our new inhibitors show protective effects in reducing airway narrowing in response to allergens and reductions in the early and late asthmatic response.

Validation of Strasbourg environmental exposure chamber (EEC) ALYATEC® in mite allergic subjects with asthma

Objective: Environmental Exposure Chamber (EEC) should have standardized and controlled allergenic and non-allergenic exposures to perform reproducible clinical studies. The aim was to demonstrate that mite exposure in the Alyatec® EEC could induce early (EAR) and/or late asthmatic reactions (LAR) in at least 60% of subjects allergic to mite.Methods: The EEC has a volume of 147-m3 with 20 seats. The nebulized particle number, airborne Der p1, endotoxins, and volatile organic compound (VOC) concentrations were measured. Twenty-four asthmatics allergic to mite were randomly exposed to 15, 25, and 46 ng/m3 Der p1. Specificity was assessed in not mite-sensitized asthmatics.Results: No significant endotoxin or VOC contamination was measured. The mean inter-assay CVs were 12.5% for the airborne particle number and 28.7% for airborne Der p1 concentrations. For the three Der p1 concentrations, at least 88% of the subjects developed EAR and/or LAR, and at least 46% developed a dual response. No reaction occurred with placebo or in the control group. No severe bronchial reaction occurred.Conclusions: The Alyatec® EEC demonstrated a tight control of allergenic and non-allergenic exposures. The EEC was clinically validated, with airborne Der p1 levels close to levels found in natural settings.

Are high- and low-molecular-weight sensitizing agents associated with different clinical phenotypes of occupational asthma?

High-molecular-weight (HMW) proteins and low-molecular-weight (LMW) chemicals can cause occupational asthma (OA) although few studies have thoroughly compared the clinical, physiological, and inflammatory patterns associated with these different types of agents. The aim of this study was to determine whether OA induced by HMW and LMW agents shows distinct phenotypic profiles. Clinical and functional characteristics, and markers of airway inflammation were analyzed in an international, multicenter, retrospective cohort of subjects with OA ascertained by a positive inhalation challenge response to HMW (n=544) and LMW (n=635) agents. Multivariate logistic regression analysis showed significant associations between OA caused by HMW agents and work-related rhinitis (OR [95% CI]: 4.79 [3.28-7.12]), conjunctivitis (2.13 [1.52-2.98]), atopy (1.49 [1.09-2.05]), and early asthmatic reactions (2.86 [1.98-4.16]). By contrast, OA due to LMW agents was associated with chest tightness at work (2.22 [1.59-3.03]), daily sputum (1.69 [1.19-2.38]), and late asthmatic reactions (1.52 [1.09-2.08]). Furthermore, OA caused by HMW agents showed a higher risk of airflow limitation (1.76 [1.07-2.91]), whereas OA due to LMW agents exhibited a higher risk of severe exacerbations (1.32 [1.01-1.69]). There were no differences between the two types of agents in the baseline sputum inflammatory profiles, but OA caused by HMW agents showed higher baseline blood eosinophilia and a greater postchallenge increase in fractional nitric oxide. This large cohort study describes distinct phenotypic profiles in OA caused by HMW and LMW agents. There is a need to further explore differences in underlying pathophysiological pathways and outcome after environmental interventions.

Specific Inhalation Challenge in Persulfate Asthma.

Specific inhalation challenge (SIC) may be considered the 'gold standard' for the diagnosis of occupational asthma due to persulfate salts. The aim of the study was to develop a safe SIC protocol. Between 2003 and 2014, eight patients with suspected occupational asthma due to persulfate salts were examined (7 females, all hair-dressers). SIC was done with a dosimeter and a nebulizer using ammonium persulfate dissolved in phosphate buffer. Until 2009, a four-step-protocol (doses: 0.0004, 0.0045, 0.045, 0.45mg; cumulative: 0.5mg) was used, afterwards a six-step-protocol (doses: 0.0004, 0.0018, 0.007, 0.028, 0.113, 0.45mg; cumulative: 0.6mg). With each SIC protocol, four subjects were tested. Skin prick tests with ammonium persulfate (20mg/mL) were performed in all and patch tests in four subjects. In total, four subjects showed a positive SIC, two with each protocol. All subjects showed an isolated late reaction. The greatest decrease of volume in 1s was 35% about 3.5h after the last inhalation (four-step-protocol). Skin prick test with ammonium persulfate was positive in one SIC positive (2mm wheal) and in two SIC negative patients (3 and 4mm wheal). All four subjects tested with patch tests showed a positive reaction; three of them were SICpos. We recommend to include patch-testing in the diagnosis of suspected occupational asthma due to persulfate salts. Isolated late asthmatic reactions may occur after SIC. The proposed six-step SIC protocol was safe in this limited number of subjects.

T cell‐mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells

Inhaled peptide challenge has been shown to induce T cell-mediated, isolated late asthmatic reaction (LAR), characterized by recruitment of CD4(+) T cells and increased levels of thymus and activation-regulated chemokine (TARC; CCL17). Epithelial-derived thymic stromal lymphopoietin (TSLP) has been shown to modulate dendritic cell function to promote TH 2 responses via CCL17 production. To elucidate the mechanisms involved in allergen-specific T cell-induced LAR and recruitment of CD4(+) T cells by examining the effects of T cell-derived factors on the induction of TSLP in primary bronchial epithelial cells (PBEC). PBEC grown at air-liquid interface from healthy individuals and patients with asthma were stimulated with double-stranded RNA (dsRNA) or supernatants from activated allergen-specific T cells. TSLP was measured in PBEC culture supernatants. Neutralizing antibodies and signalling inhibitors were used to examine the mechanisms responsible for the induction of epithelial-derived TSLP. The functional activity of PBEC-derived TSLP was measured using a bioassay involving the induction of CCL17 production from monocyte-derived dendritic cells (moDC). Both dsRNA and allergen-specific T cells induced enhanced TSLP secretion from asthmatic PBEC compared to healthy PBEC. Activated PBEC culture supernatant induced TSLP-dependent CCL17 production from moDC in a manner related to clinical asthmatic status. IL-1β, IL-6, and CXCL8, rather than TH 2 cytokines (IL-4/5/13), appeared to be the principle mediators of allergen-specific T cell-dependent induction of epithelial-derived TSLP, which was regulated by the MEK, MAPK, and NFκB pathways. Our data reveal a novel effect of allergen-specific T cells as a positive regulator of TSLP production by epithelial cells, suggesting T cell-airway epithelium interactions that may lead to maintenance and amplification of allergic inflammation. TSLP is currently a candidate for therapeutic intervention in asthma, but the factors that drive TSLP expression (T cell-derived factors) may be equally relevant in the treatment of allergic inflammation.

Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

17 tipo T ląstelės pagalbininkės ir jų reikšmė alerginės astmos patogenezėje

Astma yra lėtinė kvėpavimo takų uždegimo liga. Jai formuotis svarbūs genetiniai bei daug gyvensenos ir aplinkos veiksnių. Antrojo tipo T ląstelių pagalbininkių, jų išskiriamų citokinų bei eozinofilų įtaka alerginės astmos vystymuisi įrodyta daugeliu mokslinių tyrimų. Deja, šis mechanizmas ne visada gali paaiškinti kvėpavimo takų uždegimo bei klinikinių simptomų įvairovę sergant šia liga. Daugėja duomenų, rodančių, jog alergenų sukelto kvėpavimo takų uždegimo ypatumus, lėtąją ar vėlyvąją (kartais vadinamą dvifaze) astminę reakciją bei lėtinį kvėpavimo takų uždegimą lemia neutrofilai ir pakitusi jų funkcija. Pastarai-siais metais atlikti tyrimai su gyvūnų modeliais rodo 17 tipo T ląstelių pagalbininkių ir jų išskiriamų citokinų reikšmę neutrofilinio kvėpavimo takų uždegimo vystymuisi. Neutrofilų infiltracija į kvėpavimo takų nustatoma ir sergant alergine astma. Pastebėta, jog kvėpavimo takuose vyraujant neutrofilams dažnesnė sunki astmos eiga, ryškesnis plaučių funkcijos sutrikimas ir nepakankamas atsakas į įprastinį gydymą gliukokortikoidais. Šiame straipsnyje nagrinėjamos kvėpavimo takų ir sisteminio uždegimo ypatybės, atkreipiamas dėmesys į 17 tipo T ląstelių pagalbininkių ir neutrofilų svarbą alerginės astmos patogenezėje.

Occupational asthma and rhinitis caused by cyanoacrylate-based eyelash extension glues

Eyelash extensions are applied on top of customers' lashes using instant glue containing cyano acrylate, known to cause occupational rhinitis (OR) and occupational asthma (OA). The number of beauty professionals applying these extensions is increasing due to their popularity. To report on a case of OA with OR and a case of OR attributable to lash extension glue and to evaluate respiratory exposure in lash extension work. Two beauty professionals with suspected OA and/or OR underwent inhalation challenge, including both control challenge and work-mimicking challenges using the lash extension glue, each with a 24-h follow-up. Volatile organic compounds (VOCs) present were assessed during the lash extension glue challenge. The glues were analysed for their (meth)acrylate content. Both beauty professionals (case 1 and case 2) applied lash extensions regularly for several hours per day as part of their work and had work-related rhinitis. Case 1 had a longer history of lash extension work and also had asthmatic symptoms. The first lash extension glue challenge was negative in both cases, but positive OR reactions were detected in the second test. Case 1 also had a late asthmatic reaction. During the lash extension glue challenge, VOC were present in total concentrations below the irritant threshold and ethylcyanoacrylate (ECA) was detected in a concentration of 0.4mg/m(3). Chemical analysis of the glues revealed ECA was the major component. Application of eyelash extensions using small amounts of cyanoacrylate-based glues can cause OA and OR.

S136 Pre- and Post-Specific Inhalational Challenge Measurements of Fractional Exhaled Nitric Oxide (FENO) in the Diagnosis of Occupational Asthma

Introduction The interpretation of Specific Inhalation Challenge (SIC) can be equivocal, particularly for late asthmatic reactions. It has been suggested that increases in FE NO 24-hours post-challenge might help separate positive from negative challenges. Methods We reviewed all positive and equivocal SIC tests with occupational agents between March 2008 and June 2012 from our tertiary referral centre. FENO was measured pre- and 24-hours post control and active challenges using a Niox Mino handheld machine at 50 ml/sec, compliant with ERS/ATS recommendations. Post-challenge changes >20% for FENO >50 ppb, or >10 ppb for Results 24 patients had complete data related to control and active challenges, which were positive in 15 and equivocal in 9 cases. 13/24 patients had raised pre-control challenge FENO (mean=31.3) after adjusting for smoking and inhaled corticosteroid use. Increases in FENO, more than the minimum clinically relevant difference, were seen after 13/24 control challenges: including 6/7 exposures to cleaning agents or hand gels and 2/6 unused metalworking fluids. 5/24 patients had a clinically significant increase in FENO after positive or equivocal challenges: including 1/4 challenges with isocyanates, 1/6 cleaning agents or hand gels, and 2/3 with used metalworking fluids. There was no statistically significant difference in mean percentage change in FENO between control and active challenges. Conclusions The previously defined minimum clinically relevant difference for FENO was seen as commonly following control as active challenges. Measuring changes in FENO pre- and 24-hours post challenge to the diverse range of low molecular weight agents tested did not provide useful additional information for interpreting SIC responses. Reference Dweik RA et al. An Official ATS Clinical Practise Guideline: Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications. Am J Respir Crit Care Med 2011; 184:602–15.

Increase in vesicular hand eczema after house dust mite inhalation provocation: a double‐blind, placebo‐controlled, cross‐over study

It is unclear whether the respiratory tract is involved in eliciting or aggravating eczematous lesions in patients with vesicular hand eczema. Objectives. To investigate the effect of inhalation of house dust mite (HDM) on vesicular hand eczema. Eighteen patients with vesicular hand eczema and HDM allergy received inhalation challenges with four concentrations of HDM in a randomized, double-blind, placebo-controlled, cross-over study. Early asthmatic reactions and late asthmatic reactions were defined as a placebo-corrected fall of 15% or more from baseline of forced expiratory volume in 1 second. Hand eczema was scored according to the Dyshidrotic Eczema Area and Severity Index (DASI) at baseline, and 1, 6, 24 and 48 hr. The median DASI increased significantly as compared with baseline at 6 and 48 hr after HDM inhalation. This increase was significantly different between the provocations at 6 hr. The median vesicles score increased significantly from baseline at 24 and 48 hr. Patients with a placebo-corrected increase in the number of vesicles at 24 hr and 48 hr had significantly more often late asthmatic reactions than those without an increase in the number of vesicles. Patients with a placebo-corrected increase of the DASI score at 24 hours had as a group a higher mean total IgE level than those without an increase of the DASI score. Hand eczema increased significantly more after HDM provocation than after placebo provocation. An increase in the number of vesicles was preceded by late asthmatic reactions. The group patients with an increase of hand eczema tended to have a higher mean total IgE level.

Distinct temporal patterns of immediate asthmatic reactions due to high‐ and low‐molecular‐weight agents

Exposure to occupational agents can cause immediate asthmatic reactions. It can be hypothesized that the pattern of immediate reactions is different for high (HMW)- and low-molecular-weight (LMW) agents. To test this, we studied the temporal features of reactions in workers who underwent specific inhalation challenges for possible occupational asthma. We examined 467 immediate reactions due to HMW (n = 248, 53%) and LWW (n = 219, 47%) agents in regards to timing of the maximum reaction and recovery. The median duration of exposure to elicit significant immediate reactions was comparable for HMW and LMW agents (15 min). The median maximum fall in FEV (1) occurred after 20 min for LMW by comparison with 10 min for HMW agents (P < 0.001). The median timing of recovery of FEV (1) to 10% baseline was shorter for HMW (60 min) than for LMW (90 min) agents (P < 0.01), and significantly more subjects recovered to 10% baseline (89.5%) for HMW than for LMW agents (72.6%) (P < 0.001). Confounding variables such as age, atopy, baseline airway calibre and the maximum fall in FEV (1) at the time of the immediate reaction did not alter the significant effect of the nature of the agent per se. Immediate reactions were followed by a late asthmatic reaction more often in the case of LMW (37.3%) than HMW (26.2%) agents (P < 0.05). Significant changes in non-specific bronchial responsiveness were significantly (P = 0.02) more frequent after reactions to LMW (31.9%) than to HMW (21.4%) agents. We found similar trends by comparing reactions to flour (n = 113), the principal cause of reactions to HMW agents, and diisocyanates (n = 111), the principal LMW agent. This study shows distinct patterns for immediate reactions due to occupational agents. These results can provide useful guidelines for performing specific inhalation challenges and improve the safety of the procedure.

New Omega-3 Derivatives Reduce Airway Inflammation and Prevent Rho-Kinase Activation in an Allergic Model of Asthma

Asthma is a chronic inflammatory airways disease characterized by early and late asthmatic reactions that are associated with infiltration and activation of inflammatory cells in the airways. Bronchial hyperresponsiveness to a variety of stimuli is part of the symptomology which include neurotransmitters and inflammatory mediators. Omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are known to reduce inflammation in the lung. In the present study, we synthesized new omega-3 polyunsaturated fatty acid (n3-PUFA) derivatives, namely DHA monoglyceride (MAG-DHA) and EPA monoglyceride (MAG-EPA), and investigated their effects on lung inflammation and RhoA activation in an in vivo guinea pig model of allergic asthma. Histological analyses and leukocyte count in bronchoalveolar lavages revealed that oral MAG-DHA and MAG-EPA treatments led to less inflammatory cell recruitment in the lung of ovalbumine (OVA)-sensitized guinea pigs when compared to lung from control animals. Results also revealed a reduction in mucus production in OVA-sensitized animals treated with either MAG-DHA or MAG-EPA. Moreover, per os n-3 PUFA administrations prevented NF k B activation and COX2 over-expression in OVA-sensitized animals. Mechanical tension measurements revealed that oral MAG-DHA and MAG-EPA treatments prevented U-46619-induced bronchial hyperresponsiveness in OVA-sensitized guinea pigs. MAG-DHA and MAG-EPA also prevented U-46619-induced Ca 2+ hypersensitivity of bronchial smooth muscle through a decrease in RhoA activation. Together, these findings provide key evidences regarding the mode of action of MAG-DHA and MAG-EPA in the lung and point to new potential therapeutic strategies for modulating inflammation and airway hyperresponsiveness in asthma.

Salmeterol or doxycycline do not inhibit acute bronchospasm and airway inflammation in cats with experimentally-induced asthma

The objective of this study was to determine if inhaled salmeterol, a long-acting β(2)-adrenergic agonist, and oral doxycycline, a tetracycline antibiotic displaying matrix metalloproteinase (MMP) inhibitory activity, reduce airway inflammation and obstruction in cats with experimentally-induced asthma. Eight Ascaris suum (AS)-sensitised cats were enrolled in a prospective study in which they underwent four AS-challenges at 1 month intervals. The challenged animals were given no treatment or were treated on 4 consecutive days with either: (1) oral prednisolone (1mg/kg twice daily), (2) inhaled salmeterol (50 μg twice daily), or (3) oral doxycycline (5mg/kg twice daily), according to a randomised cross-over design. Inhibition of allergen-induced early (EAR) and late (LAR) asthmatic reactions were assessed by barometric whole-body plethysmography. Cytology and measurement of MMP-2 and -9 activities were carried out on bronchoalveolar lavage fluid (BALF). Although none of the treatments prevented the EAR, prednisolone treatment inhibited the LAR. Relative to untreated cats, the eosinophil percentage and MMP-2 activity in BALF were significantly reduced following prednisolone treatment (P<0.05). Short-term therapy with either salmeterol or doxycycline had no effect on the EAR or LAR or on airway inflammation. Given the chronic nature of this disease in cats, long-term therapy may be required to produce more favourable functional and clinical outcomes.

Occupational Asthma in Antibiotic Manufacturing Workers: Case Reports and Systematic Review

Background. The risks of occupational asthma (OA) from antibiotics are uncertain. We report 4 new cases and a systematic review of the literature. Methods. Cases were identified through a specialist clinic, each underwent specific provocation testing (SPT). We subsequently reviewed the published literature. Results. The patients were employed in the manufacture of antibiotics; penicillins were implicated in three cases, in the fourth erythromycin, not previously reported to cause OA. In two, there was evidence of specific IgE sensitisation. At SPT each developed a late asthmatic reaction and increased bronchial hyperresponsiveness. 36 case reports have been previously published, 26 (citing penicillins or cephalosporins). Seven cross-sectional workplace-based surveys found prevalences of 5–8%. Conclusions. OA in antibiotic manufacturers may be more common than is generally recognised. Its pathogenesis remains unclear; immunological tests are of uncertain value and potential cases require confirmation with SPT. Further study of its frequency, mechanisms, and diagnosis is required.

Occupational asthma caused by heated triglycidyl isocyanurate

Six workers exposed as bystanders to heated triglycidyl isocyanurate (TGIC) developed occupational asthma confirmed by serial peak expiratory flow measurement and Oasys analysis. Specific inhalation challenge testing resulted in late or dual asthmatic reactions to heated TGIC in four of four tested and was negative in three control asthmatics. One worker tested only with unheated TGIC had a negative specific challenge test. Heated TGIC can cause occupational asthma from bystander exposure.

Airway response to chlorine inhalation (bleach) among cleaning workers with and without bronchial hyperresponsiveness

Symptoms of obstructive lung disease in domestic cleaning staff have been related to the use of bleach and other irritant cleaning products. Included in the study were thirteen cleaning employees with work-related asthma-like symptoms, three asthmatic controls and three atopic subjects without bronchial hyperresponsiveness (BHR) who had no exposure to cleaning products. The study protocol consisted of a methacholine test, sputum induction and fraction of exhaled nitric oxide measurement (FENO) both at baseline and 24 hr after a 1-hr inhalation challenge with either placebo or bleach at a concentration of 0.4 ppm of chlorine. The inhalation of the placebo caused no bronchial reactions. Mean maximum fall in FEV(1) during challenge testing with bleach was significantly higher than the values obtained during the placebo challenge. Inhalation challenge with bleach elicited two isolated late asthmatic reactions and one dual asthmatic reaction. Of all the patients who underwent challenge testing with bleach, only one had a ≥2-fold decrease in methacholine PC(20) 24 hr after the challenge. No significant correlation was found between maximum fall in FEV(1) and PC(20) methacholine. Following challenge testing with bleach, no clinically significant changes in sputum cell counts or FENO were detected. These results suggest that bleach inhalation at a concentration of 0.4 ppm-a concentration below 8-hr permissible occupational exposure level-brings about a substantial decrease in FEV1 in subjects with and without BHR. Some subjects have a positive challenge response to bleach inhalation.

SQ-standardized house dust mite immunotherapy as an immunomodulatory treatment in patients with asthma.

BackgroundSpecific immunotherapy is the only treatment with the potential to prevent progression of the allergic disease and the potential to cure patients. The immunomodulatory ability of SQ-standardized house dust mite (HDM) subcutaneous immunotherapy (SCIT) was investigated in patients with allergic asthma.MethodsFifty-four adults with HDM-allergic asthma were randomized 1 : 1 to receive SQ-standardized HDM SCIT (ALK) or placebo for 3 years. At baseline, and after 1, 2 and 3 years of treatment, the lowest possible inhaled corticosteroid dose required to maintain asthma control was determined, followed by determinations of nonspecific and HDM-allergen-specific bronchial hyperresponsiveness, late asthmatic reaction (LAR), immediate and late-phase skin reactions, and immunological response.ResultsSQ-standardized HDM SCIT provided a statistically significantly higher HDM-allergen tolerance (P < 0.05 vs placebo) in terms of a 1.6-fold increase in PD20 (HDM-allergen inhalation challenge), a 60-fold increase in skin test histamine equivalent HDM-allergen concentrations, reduced immediate- and reduced or abolished late-phase skin reactions, as well as fewer patients with LAR. PD20 (methacholine inhalation challenge) increased initially and was similar between groups. House dust mite SCIT induced an initial increase in serum HDM-allergen-specific IgE (P = 0.028 vs placebo), which then declined to baseline value. House dust mite SCIT induced an increase in components blocking IgE binding to allergen [ΔIgE-blocking factor: 0.31; 95% CI of (0.26; 0.37)] after 1 year that remained constant after 2 and 3 years (P < 0.0001 vs placebo).ConclusionSQ-standardized HDM SCIT induced a consistent immunomodulatory effect in adults with HDM-allergic asthma; the humoral immune response was changed and the HDM-allergen tolerance in lung and skin increased.