Anna Bodzenta-Lukaszyk

Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: Importance of baseline serum tryptase—a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity

BACKGROUND Severe anaphylaxis to honeybee or vespid stings is associated with a variety of risk factors, which are poorly defined. OBJECTIVE Our aim was to evaluate the association of baseline serum tryptase concentrations and other variables routinely recorded during patient evaluation with the frequency of past severe anaphylaxis after a field sting. METHODS In this observational multicenter study, we enrolled 962 patients with established bee or vespid venom allergy who had a systemic reaction after a field sting. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, and the number of preceding minor systemic reactions before the index field sting. A severe reaction was defined as anaphylactic shock, loss of consciousness, or cardiopulmonary arrest. The index sting was defined as the hitherto first, most severe systemic field-sting reaction. Relative rates were calculated with generalized additive models. RESULTS Two hundred six (21.4%) patients had a severe anaphylactic reaction after a field sting. The frequency of this event increased significantly with higher tryptase concentrations (nonlinear association). Other factors significantly associated with severe reactions after a field sting were vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor medication, and 1 or more preceding field stings with a less severe systemic reaction. CONCLUSION In patients with honeybee or vespid venom allergy, baseline serum tryptase concentrations are associated with the risk for severe anaphylactic reactions. Preventive measures should include substitution of angiotensin-converting enzyme inhibitors.

Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase.

BACKGROUND Severe side effects during venom immunotherapy (VIT) are associated with a variety of risk factors. OBJECTIVE Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters, which are routinely recorded during patient evaluation, with the frequency of severe reactions requiring an emergency intervention during the buildup phase of VIT. METHODS In this observational prospective multicenter study, we enrolled 680 patients with established honeybee or vespid venom allergy who underwent VIT. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, degree of preceding sting reaction, preventive antiallergic medication before therapy, time between last preceding sting reaction and VIT, venom specific IgE concentration, and type of buildup procedure. Relative rates were calculated with generalized additive models. RESULTS Fifty-seven patients (8.4%) required an emergency intervention during buildup because of a severe systemic reaction. The frequency of interventions increased significantly with higher BTC (log-linear association; adjusted odds ratio, 1.56; 95% CI, 1.15-2.11; P < .005). The predictive power of BTC was markedly greater when VIT was performed for vespid venom allergy than for bee venom (for bee VIT, no significant association; for vespid VIT, log-linear association; adjusted odds ratio, 2.33; 95% CI, 1.28-4.26; P = .005). The most important other factor significantly associated with severe reactions during the buildup phase of VIT was bee venom allergy. CONCLUSION Before vespid VIT, measurement of baseline serum tryptase concentration should be used to identify patients with a high risk for side effects. Patients with bee venom allergy require a particularly high degree of surveillance during VIT.

Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, peripheral blood monocytes in severe asthmatic patients

CD16+ monocytes are expanded in various inflammatory conditions. Recently it was reported that CD16+ monocytes can be divided into two subsets with contrasting potential of modulating inflammatory responses, namely CD14++CD16+ and CD14+CD16+ monocytes. Here, we characterized and quantified CD14++CD16+ and CD14+CD16+ monocyte subsets in asthmatic patients in the context of severity of disease and different treatment options. Subjects included seventeen severe asthmatics and eighteen moderate asthmatics treated with moderate-to-high doses of inhaled glucocorticosteroids (GCS), twenty nine steroid-naive mild asthmatics and fifteen healthy controls. First, we demonstrated that CD14++CD16+ monocytes, in contrast to CD14+CD16+ monocytes, present significantly higher expression of anti-inflammatory molecule CD163. The frequency of CD14++CD16+, but not CD14+CD16+ monocytes, was significantly higher in patients with severe asthma as compared to mild and moderate asthmatics. However, the frequency of both CD16+ monocyte subsets did not correlate directly with exhaled nitric oxide levels. Short-term administration of oral GCS in patients with exacerbations resulted in a preferential decrease of CD14+CD16+ monocytes. Our study indicates that CD14++CD16+ and CD14+CD16+ monocyte subsets in asthmatics are differentially modulated by both the inflammatory process and GCS treatment.

Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study.

BackgroundThe inhaled corticosteroid (ICS) fluticasone propionate (fluticasone) and the long-acting β2-agonist (LABA) formoterol fumarate (formoterol) are being made available as a combination product (fluticasone/formoterol, flutiform®) in a single aerosol inhaler. This 12-week, open-label, randomized, active-controlled, parallel-group, multicentre, phase 3 study compared the efficacy and safety of fluticasone/formoterol with the commercially available combination product fluticasone/salmeterol.MethodsPatients aged ≥ 18 years (N = 202) with mild-to-moderate–severe, persistent asthma for ≥ 6 months prior to screening were included in the study. After a screening phase (4–10 days), eligible patients were randomized 1:1 to receive fluticasone/formoterol or fluticasone/salmeterol during the 12-week treatment period. The primary objective was to demonstrate non-inferiority of fluticasone/formoterol versus fluticasone/salmeterol, measured by pre-dose forced expiratory volume in the first second (FEV1), at week 12.ResultsFluticasone/formoterol was comparable to fluticasone/salmeterol for the primary efficacy endpoint, mean pre-dose FEV1 at week 12. The new combination was also comparable to fluticasone/salmeterol for change from baseline to week 12 in pre-dose FEV1, change from pre-dose FEV1 at baseline to 2-hour post-dose FEV1 at week 12 and discontinuations due to lack of efficacy. Importantly, fluticasone/formoterol was superior to fluticasone/salmeterol in time to onset of action throughout the duration of the study. The two treatments demonstrated similar results for various other secondary efficacy parameters, including other lung function tests, patient-reported outcomes, rescue medication use, asthma exacerbations and Asthma Quality of Life Questionnaire scores. Fluticasone/formoterol was well tolerated and had a good safety profile that was similar to fluticasone/salmeterol.ConclusionsThe results of this study indicate that fluticasone/formoterol is as effective as fluticasone/salmeterol, and has a more rapid onset of action, reflecting the faster bronchodilatory effects of formoterol compared with those of salmeterol. If patients perceive the benefits of therapy with fluticasone/formoterol more rapidly than with fluticasone/salmeterol, this could have a positive impact on preference and adherence.Trial RegistrationClinicalTrials.gov: NCT00476073

Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler

BACKGROUND Fluticasone and formoterol are well established medications for the treatment of asthma. This study (Clinicaltrials.gov identifier: NCT00734318) compares the efficacy and safety of a combination of these drugs in a single inhaler (fluticasone/formoterol) versus the individual components (fluticasone + formoterol). METHODS Patients aged ≥ 18 years (n=620) with a history of severe, persistent reversible asthma for ≥ 6 months prior to screening were included in this randomized, double-blind study, which consisted of a screening phase of up to 5 days, a 2-week run-in phase and an 8-week treatment period. RESULTS Fluticasone/formoterol (500/20 μg, b.i.d.) was at least as effective as fluticasone + formoterol (500 μg + 24 μg, b.i.d.) with respect to the primary outcome measure: there were similar increases in mean pre-morning dose forced expiratory volume in the first second (FEV(1)) in these two groups. Fluticasone/formoterol (500/20 μg, b.i.d.) also demonstrated similar efficacy to fluticasone + formoterol in terms of change in mean FEV(1) from baseline pre-morning dose to 2 h post-morning dose at week 8, as well as for several secondary parameters. Fluticasone/formoterol (500/20 μg, b.i.d.) demonstrated superiority to fluticasone monotherapy (500 μg, b.i.d.) and fluticasone/formoterol (100/10 μg, b.i.d.) for several secondary efficacy parameters. Fluticasone/formoterol had a similar safety and tolerability profile to fluticasone + formoterol. CONCLUSION This study demonstrated that the fluticasone/formoterol combination is at least as effective as its components administered concurrently from separate inhalers. Fluticasone/formoterol (500/20 μg, b.i.d.) showed superior efficacy to its inhaled corticosteroid component alone and the efficacy of fluticasone/formoterol was dose-dependent for several clinically important parameters.

Endothelin-1 in exhaled breath condensate of allergic asthma patients with exercise-induced bronchoconstriction

BackgroundExercise-induced bronchoconstriction (EIB) is a highly prevalent condition, whose pathophysiology is not well understood. Endothelins are proinflammatory, profibrotic, broncho- and vasoconstrictive peptides which play an important role in the development of airway inflammation and remodeling in asthma. The aim of the study was to evaluate the changes in endothelin-1 levels in exhaled breath condensate following intensive exercise in asthmatic patients.MethodsThe study was conducted in a group of 19 asthmatic patients (11 with EIB, 8 without EIB) and 7 healthy volunteers. Changes induced by intensive exercise in the concentrations of endothelin-1 (ET-1) in exhaled breath condensate (EBC) during 24 hours after an exercise challenge test were determined. Moreover, the possible correlations of these measurements with the results of other tests commonly associated with asthma and with the changes of airway inflammation after exercise were observed.ResultsIn asthmatic patients with EIB a statistically significant increase in the concentration of ET-1 in EBC collected between 10 minutes and 6 hours after an exercise test was observed. The concentration of ET-1 had returned to its initial level 24 hours after exercise. No effects of the exercise test on changes in the concentrations of ET-1 in EBC in either asthmatic patients without EIB or healthy volunteers were observed. A statistically significant correlation between the maximum increase in ET-1 concentrations in EBC after exercise and either baseline FENO and the increase in FENO or BHR to histamine 24 hours after exercise in the groups of asthmatics with EIB was revealed.ConclusionThe release of ET-1 from bronchial epithelium through the influence of many inflammatory cells essential in asthma and interactions with other cytokines, may play an important role in increase of airway inflammation which was observed after postexercise bronchoconstriction in asthmatic patients.

Anti-IgE Therapy with Omalizumab Decreases Endothelin-1 in Exhaled Breath Condensate of Patients with Severe Persistent Allergic Asthma

Background: Omalizumab is a humanized monoclonal anti-IgE antibody, especially useful for the treatment of severe persistent allergic asthma, inadequately controlled despite regular therapy. Objectives: The aim of the study was to determine the effect of omalizumab treatment on changes in endothelin-1 (ET-1), which plays an important role in the development of airway inflammation and remodeling in exhaled breath condensate (EBC) in patients with severe asthma. Methods: The study was conducted in a group of 19 patients with severe persistent allergic asthma treated with conventional therapy (according to the Global Initiative for Asthma, 2006) and with or without omalizumab (9 vs. 10 patients). Changes in ET-1 in EBC compared with other inflammatory parameters [exhaled nitric oxide – (FENO), blood eosinophil count, and serum eosinophil cationic protein (ECP)] were measured after 16 and 52 weeks of therapy. Results: Omalizumab-treated patients demonstrated a statistically significant decrease in the concentrations of ET-1 in EBC, FENO, serum ECP, and blood eosinophil count and an increase in spirometry parameters compared to patients with conventional therapy. In the group of omalizumab-treated patients, statistically significant correlations between the decrease in ET-1 in EBC and a decrease in FENO, ECP, and blood eosinophil count as well as the increase in forced expiratory volume in 1 s after omalizumab therapy were revealed. Conclusions: Our results confirmed that anti-IgE therapy with omalizumab in patients with severe persistent allergic asthma results in decreased expression of ET-1 in the airways. This could be very important in limiting airway inflammation and bronchial structural changes caused by such treatment in asthmatic patients.

Fluticasone/Formoterol Combination Therapy versus Budesonide/Formoterol for the Treatment of Asthma: A Randomized, Controlled, Non-Inferiority Trial of Efficacy and Safety

Objectives. The inhaled corticosteroid fluticasone propionate (fluticasone) and the long-acting β2 agonist formoterol fumarate (formoterol) have been combined in a single aerosol inhaler fluticasone/formoterol (flutiform®). This study compared the efficacy and safety of fluticasone/formoterol with the combination product budesonide/formoterol (Symbicort® Turbohaler®). Methods. A randomized, double-blind, double-dummy, multicenter, Phase 3 study comprising a 7- (±3) day screening, 2–4-week run-in, and 12-week treatment periods. Patients aged ≥12 years with moderate to severe persistent asthma for ≥6 months before screening and forced expiratory volume in one second (FEV1) 50–80% predicted and ≥15% reversibility following salbutamol inhalation were randomized to fluticasone/formoterol 250/10 μg twice daily (n = 140) or budesonide/formoterol 400/12 μg twice daily (n = 139). Results. Fluticasone/formoterol was comparable to budesonide/formoterol with respect to the primary endpoint, change in pre-dose FEV1 from baseline to Week 12. The LS mean treatment difference was −0.044 L, with a lower 95% confidence interval (CI) greater than the pre-defined non-inferiority limit of −0.2 L (95% CI: −0.130, 0.043 L; p < 0.001). Non-inferiority was also demonstrated for the secondary endpoints mean change in FEV1 from baseline (pre-dose) to 2 hours post-dose at Week 12, and discontinuations due to lack of efficacy. Similar results were obtained for both treatment groups for all other secondary endpoints. Fluticasone/formoterol had a good safety profile that was comparable with budesonide/formoterol. Conclusions. This study demonstrated comparable efficacy of fluticasone/formoterol to budesonide/formoterol in terms of the primary endpoint, change in pre-dose FEV1 from baseline to Week 12. This was supported by comparable results for both treatments for all secondary endpoints.

ß Thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis

Objective: To evaluate concentrations of the platelet activation markers β thromboglobulin (BTG) and platelet factor 4 (PF4) in bronchoalveolar lavage fluid (BALF) from patients with systemic sclerosis with and without scleroderma interstitial lung disease (SLD). Methods: BTG and PF-4 were measured by enzyme immunoassay in BALF from 37 patients with systemic sclerosis. Controls were 10 healthy subjects. BALF was collected during routine bronchoscopy from the right middle lobe. SLD was diagnosed by high resolution computed tomography of the lungs. Results: BTG was detected in 11 of the patients with systemic sclerosis (29.7%) and PF4 was found in eight (21.6%). Mean (SD) concentrations of BTG and PF4 in BALF from patients with detectable levels of these platelet activation markers were 106.9 (69.8) and 35.2 (17.4) IU/ml, respectively. The BTG:PF4 ratio was more than 2:1, indicating in vivo release. Both markers were found exclusively in patients with SLD. SLD patients with detectable platelet activation markers had a significantly shorter disease duration than those with undetectable BTG/PF4. Conclusions: The study provides evidence that activation of blood platelets takes place within the lungs of patients with SLD and may contribute to the development of lung fibrosis.

Eotaxin-1 in exhaled breath condensate of stable and unstable asthma patients.

BackgroundAirway eosinophilia is considered a central event in the pathogenesis of asthma. Eotaxin plays a key role in selective eosinophil accumulation in the airways and, subsequently, their activation and degranulation. The study was undertaken to evaluate eotaxin-1 levels in the exhaled breath condensate (EBC) of asthmatics with different degrees of asthma severity and to establish the possible correlation of these measurements with other recognized parameters of airway inflammation.MethodsEBC was collected from 46 patients with allergic asthma (14 with steroid-naïve asthma, 16 with ICS-treated, stable asthma, 16 with ICS-treated unstable asthma) and 12 healthy volunteers. Concentrations of eotaxin-1 were measured by ELISA.ResultsIn the three groups of asthmatics, eotaxin-1 concentrations in EBC were significantly higher compared with healthy volunteers (steroid-naïve asthma: 9.70 pg/ml ± 1.70, stable ICS-treated asthma: 10.45 ± 2.00, unstable ICS-treated asthma: 17.97 ± 3.60, healthy volunteers: 6.24 ± 0.70). Eotaxin-1 levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. We observed statistically significant correlations between the concentrations of eotaxin-1 in EBC and exhaled nitric oxide (FENO) or serum eosinophil cationic protein (ECP) in the three studied groups of asthmatics. We also discovered a significantly positive correlation between eotaxin-1 in EBC and blood eosinophil count in the groups of patients with unstable asthma and steroid-naïve asthma.ConclusionsMeasurements of eotaxin-1 in the EBC of asthma patients may provide another useful diagnostic tool for detecting and monitoring airway inflammation and disease severity.