Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti-IgE treatment.

BACKGROUND: Anti-IgE, omalizumab, inhibits the allergen response in patients with asthma. This has not been directly related to changes in inflammatory conditions. We hypothesized that anti-IgE exerts its effects by reducing airway inflammation. To that end, the effect of anti-IgE on allergen-induced inflammation in bronchial biopsies in 25 patients with asthma was investigated in a randomized, double-blind, placebo-controlled study. METHODS: Allergen challenge followed by a bronchoscopy at 24 h was performed at baseline and after 12 weeks of treatment with anti-IgE or placebo. Provocative concentration that causes a 20% fall in forced expiratory volume in 1 s (PC(20)) methacholine and induced sputum was performed at baseline, 8 and 12 weeks of treatment. Changes in the early and late responses to allergen, PC(20), inflammatory cells in biopsies and sputum were assessed. RESULTS: Both the early and late asthmatic responses were suppressed to 15.3% and 4.7% following anti-IgE treatment as compared with placebo (P < 0.002). This was paralleled by a decrease in eosinophil counts in sputum (4-0.5%) and postallergen biopsies (15-2 cells/0.1 mm(2)) (P < 0.03). Furthermore, biopsy IgE+ cells were significantly reduced between both the groups, whereas high-affinity IgE receptor and CD4+ cells were decreased within the anti-IgE group. There were no significant differences for PC(20) methacholine. CONCLUSION: The response to inhaled allergen in asthma is diminished by anti-IgE, which in bronchial mucosa is paralleled by a reduction in eosinophils and a decline in IgE-bearing cells postallergen without changing PC(20) methacholine. This suggests that the benefits of anti-IgE in asthma may be explained by a decrease in eosinophilic inflammation and IgE-bearing cells.

Validated safety predictions of airway responses to house dust mite in asthma.

BACKGROUND: House dust mite (HDM) is the most common aeroallergen causing sensitization in many Western countries and is often used in allergen inhalation challenges. The concentration of inhaled allergen causing an early asthmatic reaction [provocative concentration of inhaled allergen causing a 20% fall of forced expiratory volume in 1 s (FEV(1))(PC(20) allergen)] needs to be predicted for safety reasons to estimate accurately the severity of allergen-induced airway responsiveness. This can be accomplished by using the degree of non-specific airway responsiveness and skin sensitivity to allergen. OBJECTIVE: We derived prediction equations for HDM challenges using PC(20) histamine or PC(20) methacholine and skin sensitivity data obtained from patients with mild to moderate persistent asthma and validated these equations in an independent asthma population. METHODS: PC(20) histamine or PC(20) methacholine, skin sensitivity, and PC(20) allergen were collected retrospectively from 159 asthmatic patients participating in allergen challenge trials. Both the histamine and methacholine groups (n=75 and n=84, respectively), were divided randomly into a reference group to derive new equations to predict PC(20) allergen, and a validation group to test the new equations. RESULTS: Multiple linear regression analysis revealed that PC(20) allergen could be predicted either from PC(20) methacholine only ((10)log PC(20) allergen=-0.902+0.741.(10)log PC(20) methacholine) or from PC(20) histamine and skin sensitivity (SS) ((10)log PC(20) allergen=-0.494+0.231.(10)log SS+0.546.(10)log PC(20) histamine). In the validation study, these new equations accurately predicted PC(20) allergen following inhalation of HDM allergen allowing a safe starting concentration of allergen of three doubling concentrations below predicted PC(20) allergen in all cases. CONCLUSION: The early asthmatic response to inhaled HDM extract is predominantly determined by non-specific airway responsiveness to methacholine or histamine, whereas the influence of the cutaneous sensitivity to HDM appears to be rather limited. Our new equations accurately predict PC(20) allergen and hence are suitable for implementation in HDM inhalation studies.

Inhaled hyaluronic acid against exercise-induced bronchoconstriction in asthma.

Hyaluronic acid (HA) is a polysaccharide that is present in human tissues and body fluids. HA has various functions, including a barrier effect, water homeostasis, stabilizing the extracellular matrix, increased mucociliary clearance and elastin injury prevention. It may therefore exert prophylactic activity in the treatment of asthma. We tested the hypothesis that HA inhalation will prevent exercise-induced bronchoconstriction (EIB) in a randomised double-blinded placebo-controlled crossover study. Sixteen asthmatic patients with EIB were included in the study (mean (SD)) (age 24.5 (7.3) yr, FEV1 88.6 (11.3) %predicted, PC20 methacholine (g-mean (SD in DD)) 0.4 (1.5) mg/ml). On two separate visits an exercise challenge was performed 15 min post-inhalation of either HA (3 ml 0.1% in PBS) or placebo (3 ml PBS). The maximum fall in FEV1 and the AUC 30 min post-exercise were used as outcomes. After inhalation of both HA and placebo, baseline FEV1 decreased significantly (HA 4.1 (3.1)%, placebo 2.9 (4.1)%, P<0.017). The maximum fall in FEV1 following exercise challenge was not significantly different between HA versus placebo (median HA 22.50%, placebo 27.20%, P=0.379), as was the AUC (median HA 379.3 min*%fall, placebo 498.9 min*%fall, P=0.501). We conclude that at the current dose, inhaled HA does not significantly protect against EIB. This suggests that HA is not effective as a prophylaxis for EIB in patients with asthma.

Exhaled breath condensate: methodological recommendations and unresolved questions.

Collection of exhaled breath condensate (EBC) is a noninvasive method for obtaining samples from the lungs. EBC contains large number of mediators including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, nitrogen oxides, peptides and cytokines. Concentrations of these mediators are influenced by lung diseases and modulated by therapeutic interventions. Similarly EBC pH also changes in respiratory diseases. The aim of the American Thoracic Society/European Respiratory Society Task Force on EBC was to identify the important methodological issues surrounding EBC collection and assay, to provide recommendations for the measurements and to highlight areas where further research is required. Based on the currently available evidence and the consensus of the expert panel for EBC collection, the following general recommendations were put together for oral sample collection: collect during tidal breathing using a noseclip and a saliva trap; define cooling temperature and collection time (10 min is generally sufficient to obtain 1-2 mL of sample and well tolerated by patients); use inert material for condenser; do not use resistor and do not use filter between the subject and the condenser. These are only general recommendations and certain circumstances may dictate variation from them. Important areas for future research involve: ascertaining mechanisms and site of exhaled breath condensate particle formation; determination of dilution markers; improving reproducibility; employment of EBC in longitudinal studies; and determining the utility of exhaled breath condensate measures for the management of individual patients. These studies are required before recommending this technique for use in clinical practice.