First-in-human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy.

BACKGROUND: Polymerized allergens conjugated to non-oxidized mannan (PM-allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM-allergoids are readily taken up by DCs and induce Treg cells. This first-in-human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM-allergoid (PM-HDM) administered subcutaneously (SC) or sublingually (SL). METHODS: In a randomized, double-blind, double-dummy, placebo-controlled trial, 196 subjects received placebo or PM-HDM at 500, 1000, 3000, or 5000 mannan-conjugated therapeutic units (mTU)/mL in 9-arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers. RESULTS: No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups. CONCLUSIONS: PM-HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.

Effects of cigarette smoke on methacholine- and AMP-induced air trapping in asthmatics.

UNLABELLED: Abstract Objective: No information is available on the effect of cigarette smoke on bronchoconstrictor-induced air trapping in asthma. The aim of this study was to evaluate the additional influence of smoking on methacholine- and adenosine 5'-monophosphate (AMP)-induced air trapping in subjects with asthma. METHODS: Airway responsiveness to methacholine and AMP, bronchial (J'awNO) and alveolar (CANO) nitric oxide (NO) and exhaled breath condensate pH were measured in 68 adults (23 current smokers with asthma, 23 non-smokers with asthma and 22 current or former smokers with chronic obstructive pulmonary disease; COPD). The degree of air trapping induced by each bronchoconstrictor agent was expressed by the percent fall in forced vital capacity (FVC) at a 20% fall in forced expiratory volume in 1 s relative to FVC after saline inhalation (ΔFVC%). RESULTS: The ΔFVC% for AMP was higher in both smokers with asthma and patients with COPD than in non-smokers with asthma (p<0.001). By contrast, ΔFVC% for methacholine was similar in the three groups of subjects (p=0.69). In smokers with asthma, but not in the other two groups, there was a correlation between the residual volume/total lung capacity at baseline and the ΔFVC% induced by each bronchoconstrictor agent. Mean values for J'awNO were higher in non-smokers with asthma than in the other two groups (p<0.05). CONCLUSIONS: The results of this study suggest that factors underlying bronchoconstriction induced by indirect agonists are different in smokers and non-smokers with asthma. These observations might be clinically relevant, because triggers that frequently induce bronchial obstruction in the real world act by an indirect mechanism.

[Prevalence of rhinitis and asthma respiratory symptoms in Spanish working population]. / Síntomas respiratorios de rinitis y asma en población laboral española.

OBJECTIVE: The aims were to examine the prevalence of respiratory symptoms associated with rhinitis and asthma in Spanish workers and its variations by age, sex, work sector, location in the workplace, smoking habits and the relationship between symptoms in the upper and lower respiratory tract. METHODS: The sample was of 2603 workers in different sectors and regions throughout the country. They agreed and answered the questions regarding respiratory symptoms, with the supervision of the company's physician. RESULTS: Chronic nasal symptoms were present in 438 workers (16.9 %); 193 (7.5 %) had pulmonary symptoms. With nasal and pulmonary symptoms were 124 patients (28.3 %). Likewise, of the 190 workers with pulmonary symptoms, 124 (64.2 %) had also nasal manifestations. We observed variations in nasal symptoms by sex, professional sector, work area and smoking habits, and variations in pulmonary symptoms by work sector. A higher prevalence was noted in the healthcare, postal, and transport sector as opposed to the construction, furniture or metal sector. CONCLUSIONS: The prevalence of nasal symptoms was higher than that of pulmonary symptoms in the working population. The workers affected by these pathologies were not treated adequately, despite they were presenting symptoms. We observed a relationship between pulmonary and nasal symptoms.

INTRODUCCIÓN: en salud laboral interesa conocer la prevalencia de los síntomas respiratorios relacionados con la rinitis y el asma en trabajadores españoles y sus variaciones por factores demográficos y laborales. El objetivo de esta investigación fue interrelacionar los síntomas respiratorios de vías altas y bajas. MÉTODOS: se solicitó a 2603 trabajadores de distintos sectores y provincias españolas contestar una encuesta que fue supervisada por un médico del trabajo. RESULTADOS: 438 trabajadores presentaron síntomas nasales crónicos (16.9 %) y 193 (7.5 %), síntomas pulmonares. De los 438 con síntomas nasales, 124 (28.3 %) presentaron síntomas pulmonares. Se observaron variaciones en los síntomas nasales por sexo, sector profesional, área de trabajo, tabaquismo y variaciones en los síntomas pulmonares por sector laboral, con mayor prevalencia en el sanitario, postal y transporte, en comparación con los sectores de la construcción, mueble o el metal. CONCLUSIONES: la prevalencia de los síntomas nasales en la población trabajadora fue más elevada que la de los síntomas pulmonares. Los trabajadores afectados estaban infratratados, a pesar de padecer síntomas. Se observó interrelación entre los síntomas pulmonares y nasales de los trabajadores afectados.

Maximal degree of airway narrowing induced by methacholine and adenosine monophosphate: relationship with the decrease in forced vital capacity.

BACKGROUND: Changes in forced vital capacity (FVC) may represent an indirect method for the detection of plateau in response to inhaled bronchoconstrictor agents. OBJECTIVE: To determine the relationship between the level of plateau obtained with either methacholine or adenosine monophosphate (AMP) and the decrease in FVC induced by each bronchoconstrictor agent. METHODS: Airway responsiveness to high concentrations of methacholine and AMP was determined in patients with intermittent asthma (n = 41) or allergic rhinitis (n = 26). Furthermore, allergen-induced changes in the response to each bronchoconstrictor agent were investigated in 18 pollen-sensitive patients. Concentration-response curves were characterized by the slope of the FVC values recorded at each step of the challenge against the corresponding forced expiratory volume in 1 second (FEV1) values and, if possible, by the level of plateau. RESULTS: The slope FVC vs FEV1 was similar in patients with plateau and in those without plateau. In patients with pollen allergy, the mean (95% confidence interval) for the level of plateau detected with methacholine increased from 16.8% (11.8%-22.0%) before the pollen season to 21.7% (14.8%-28.6%, P = .008) during the pollen season, whereas pollen-induced changes in the slope FVC vs FEV1 were not significant. Similar results were obtained with AMP. CONCLUSIONS: In patients with allergic rhinitis or intermittent asthma, methacholine or AMP-induced changes in FVC are not significantly related to the presence or level of plateau. Furthermore, these 2 constituents of the concentration-response curve can be modified independently by a proinflammatory stimulus. These results suggest that the bronchoconstrictor-induced change in FVC cannot be used as a surrogate estimation of the level of plateau.

Effect of allergen-specific immunotherapy with purified Alt a1 on AMP responsiveness, exhaled nitric oxide and exhaled breath condensate pH: a randomized double blind study.

BACKGROUND: Little information is available on the effect of allergen-specific immunotherapy on airway responsiveness and markers in exhaled air. The aims of this study were to assess the safety of immunotherapy with purified natural Alt a1 and its effect on airway responsiveness to direct and indirect bronchoconstrictor agents and markers in exhaled air. METHODS: This was a randomized double-blind trial. Subjects with allergic rhinitis with or without mild/moderate asthma sensitized to A alternata and who also had a positive skin prick test to Alt a1 were randomized to treatment with placebo (n = 18) or purified natural Alt a1 (n = 22) subcutaneously for 12 months. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine, exhaled nitric oxide (ENO), exhaled breath condensate (EBC) pH, and serum Alt a1-specific IgG4 antibodies were measured at baseline and after 6 and 12 months of treatment. Local and systemic adverse events were also registered. RESULTS: The mean (95% CI) allergen-specific IgG4 value for the active treatment group increased from 0.07 µg/mL (0.03-0.11) at baseline to 1.21 µg/mL (0.69-1.73, P < 0.001) at 6 months and to 1.62 µg/mL (1.02-2.22, P < 0.001) at 12 months of treatment. In the placebo group, IgG4 value increased nonsignificantly from 0.09 µg/mL (0.06-0.12) at baseline to 0.13 µg/mL (0.07-0.18) at 6 months and to 0.11 µg/mL (0.07-0.15) at 12 months of treatment. Changes in the active treatment group were significantly higher than in the placebo group both at 6 months (P < 0.001) and at 12 months of treatment (P < 0.0001). However, changes in AMP and methacholine responsiveness, ENO and EBC pH levels were not significantly different between treatment groups. The overall incidence of adverse events was comparable between the treatment groups. CONCLUSION: Although allergen-specific immunotherapy with purified natural Alt a1 is well tolerated and induces an allergen-specific IgG4 response, treatment is not associated with changes in AMP or methacholine responsiveness or with significant improvements in markers of inflammation in exhaled air. These findings suggest dissociation between the immunotherapy-induced increase in IgG4 levels and its effect on airway responsiveness and inflammation.

Effect of challenge method on sensitivity, reactivity, and maximal response to methacholine.

BACKGROUND: Recent data suggest that the tidal breathing method may produce methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20) values significantly lower than the dosimeter method; however, the effect of the challenge method on the shape of the concentration-response curve has not been investigated. OBJECTIVE: To determine the effect of the challenge method on sensitivity, reactivity, and maximal response to methacholine. METHODS: We measured airway responsiveness to methacholine using dosimeter and tidal breathing methods in 30 individuals with suspected asthma. Concentration-response curves were characterized by their PC20 (sensitivity), slope (reactivity), and, if possible, level of plateau. RESULTS: Dosimeter PC20 values were significantly higher than tidal breathing values (geometric mean, 8.9 and 5.2 mg/mL, respectively); the mean difference in PC20 values obtained using each method was 0.78 doubling concentrations (P = .01). The mean slopes were 22.7%/log mg/mL using the tidal breathing method and 24.9%/log mg/mL using the dosimeter method; the mean difference in the slopes obtained using each method was -2.17%/log mg/mL (P = .18). In 10 individuals who showed a plateau with the 2 methacholine challenge tests, the mean level of plateau was 19.8% using the tidal breathing method and 19.5% using the dosimeter method; the mean difference in the plateau values obtained with each method was 0.3% (P = .87). CONCLUSIONS: Although the tidal breathing method produces methacholine PC20 values significantly lower than the dosimeter method, both methods provide similar values for slope and level of plateau. These results suggest that the technical factors that affect methacholine sensitivity and the shape of the curve are different.

Effect of fluticasone propionate-salmeterol therapy on seasonal changes in airway responsiveness and exhaled nitric oxide levels in patients with pollen-induced asthma.

BACKGROUND: There has been concern that in allergic asthmatic patients there might be an interactive effect on inflammation between regular salmeterol use and exposure to allergens, resulting in increased airway responsiveness. OBJECTIVE: To determine the effects of salmeterol on allergen-induced changes in airway responsiveness and exhaled nitric oxide (ENO) levels in allergic asthmatic patients concomitantly taking inhaled corticosteroids. METHODS: Forty-two asthmatic patients sensitized to pollen allergens were randomly allocated to treatment with fluticasone propionate-salmeterol (n=21) or fluticasone propionate alone (n=21). Spirometry, the methacholine provocation concentration causing a 20% decline in forced expiratory volume in 1 second (PC20), the adenosine 5'-monophosphate (AMP) PC20, and ENO levels were measured before and at the height of the pollen season after 6 weeks of treatment. RESULTS: Changes in the methacholine PC20, the AMP PC20, and ENO levels were not significantly different between treatment groups. No significant changes in the AMP PC20 were observed among the fluticasone propionate-salmeterol and fluticasone propionate groups during natural pollen exposure. However, a significant increase in the methacholine PC20 was observed in the fluticasone propionate-salmeterol group (P = .03) and in the fluticasone propionate group (P = .04); ENO concentrations decreased significantly in both groups during natural allergen exposure (P = .009 and .005). CONCLUSIONS: In patients with pollen-induced asthma, treatment with either fluticasone propionate or fluticasone propionate-salmeterol is associated with significant reductions in methacholine responsiveness and ENO concentrations, even during natural pollen exposure. Furthermore, at least in patients with mild asthma, natural allergen exposure and the regular use of fluticasone propionate-salmeterol are not associated with a greater increase in ENO levels and airway responsiveness than natural allergen exposure and fluticasone propionate use alone.

Phenol-containing saline solution as a diluent for adenosine 5'-monophosphate in bronchial challenge testing.

OBJECTIVES: To investigate the effect of dissolving adenosine 5'-monophosphate (AMP) with phenol-containing saline solution on the stability and the bronchoconstrictive properties of this indirect agonist. METHODS: Eleven subjects with asthma well controlled with short-acting inhaled beta2-agonists as required or with inhaled corticosteroids were studied. Bronchial challenge tests with AMP dissolved with either normal saline solution or saline solution containing 0.4% phenol were performed on separate days. Furthermore, to assess the potential influence of the phenol-containing saline solution on the stability of the bronchoconstrictor agent, AMP solutions in concentrations of 40 microg/mL and 400 microg/mL were prepared in saline solution and phenol-containing saline solution and, after 30 min, the AMP levels were determined by high-performance liquid chromatography (HPLC) assay. RESULTS: The geometric mean AMP provocative concentration causing a 20% fall in FEV1 (PC20) was 13.49 mg/mL (95% confidence interval [CI], 6.76 to 26.91) for the saline solution method, and AMP PC20 for the saline solution with phenol method was 8.91 mg/mL (95% CI, 3.39 to 23.44) [p = 0.18]. No significant differences were found between the concentrations of AMP made in saline solution compared to those made in phenol-containing saline solution measured by HPLC. CONCLUSION: These observations indicate that normal saline solution with or without phenol can be used as the diluent for AMP. However, since a potential risk with AMP of industrial sources is the bacterial contamination, adding a preservative such as phenol to a saline solution diluent might be recommended.

Airway responsiveness to adenosine 5'-monophosphate and exhaled nitric oxide measurements: predictive value as markers for reducing the dose of inhaled corticosteroids in asthmatic subjects.

OBJECTIVES: To investigate the utility of the determination of airway responsiveness to inhaled adenosine 5'-monophosphate (AMP) and exhaled nitric oxide (ENO) levels as markers for safely reducing the dose of inhaled corticosteroids (ICS) in patients with asthma well controlled with a moderately high ICS dose. METHODS: A total of 37 patients with asthma well controlled for at least 3 months by treatment with a moderately high ICS dose (beclomethasone dipropionate, 500 to 1,000 microg or equivalent daily) were included in the study. Patients were treated for a 2-week run-in (baseline) period with their usual dose of ICS. For the next 12 weeks, patients were treated with ICS at half the previous dose, maintaining the same inhalation device. At the end of the baseline period and after 2 weeks, 8 weeks, and 12 weeks of treatment with a reduced dose of ICS, measurements were made in the following order: ENO, spirometry, and AMP challenge. Furthermore, patients completed a diary twice daily recording peak expiratory flow, daytime and nighttime symptoms, and use of rescue albuterol. RESULTS: Ten patients had an asthma exacerbation. Using a Kaplan-Meier survival analysis, the significant predictors of a failure of ICS reduction were having both bronchoconstriction in response to AMP and ENO levels > or = 15 parts per billion (ppb) at baseline (p = 0.006), as well as having both bronchoconstriction in response to AMP and ENO levels > or = 20 ppb at baseline (p = 0.033). Having a decrease in the provocative concentration of AMP causing a 20% fall in FEV(1) of at least one doubling concentration 2 weeks after the dose of ICS was halved was a borderline significant predictor for failure of ICS reduction (p = 0.062). CONCLUSION: These observations suggest that in asthmatic patients well controlled with ICS, the determination of AMP responsiveness and ENO levels may be useful to identifying those subjects whose condition will or will not deteriorate when the dose of ICS is reduced.

Idiopathic anaphylaxis: a descriptive study of 81 patients in Spain.

BACKGROUND: Few European groups have published data on series of patients with idiopathic anaphylaxis. OBJECTIVE: Our aim was to report on our experience with this entity in Spain. METHODS: We conducted a two-part investigation. The first part was a descriptive cross-sectional study of 81 patients with idiopathic anaphylaxis, diagnosed between January 1990 and December 1995 in the allergy unit of the General Hospital of Albacete in Albacete, Spain. The second prong was a prospective, longitudinal study that evaluated the activity of the condition. RESULTS: Female patients constituted 68% of the study group with idiopathic anaphylaxis; the mean age of the 81 patients was 30.0 +/- 17.3 years. The number of episodes of idiopathic anaphylaxis during the year of greatest frequency varied widely (median, 2; range, 1 to 130). The duration also varied considerably, with a range of 0.03 to 300 months (median, 2 years). Most patients entered the study in remission, and 93% of these patients remained in remission throughout the followup period. Only 9% of the patients had vascular involvement. Our series of patients with idiopathic anaphylaxis had a notable prevalence of atopic diseases (48%), food allergy (20%), and episodes of anaphylaxis with an identifiable cause (15%). In addition, a high frequency (58%) of idiopathic urticaria was noted; the urticaria was acute in 62% of the affected patients. CONCLUSIONS: Our series of patients with idiopathic anaphylaxis is similar to previously published series.