Luis Prieto

Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial

IMPORTANCEnThe house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy-related asthma.nnnOBJECTIVESnTo evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticosteroid (ICS) reduction period.nnnDESIGN, SETTINGS, AND PARTICIPANTSnDouble-blind, randomized, placebo-controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products, and with HDM allergy-related rhinitis. Key exclusion criteria were FEV1 less than 70% of predicted value or hospitalization due to asthma within 3 months before randomization. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and then completely withdrawn for 3 months.nnnINTERVENTIONSn1:1:1 randomization to once-daily treatment with placebo (nu2009=u2009277) or HDM SLIT tablet (dosage groups: 6 SQ-HDM [nu2009=u2009275] or 12 SQ-HDM [nu2009=u2009282]) in addition to ICS and the short-acting β2-agonist salbutamol.nnnMAIN OUTCOMES AND MEASURESnPrimary outcome was time to first moderate or severe asthma exacerbation during the ICS reduction period. Secondary outcomes were deterioration in asthma symptoms, change in allergen-specific immunoglobulin G4 (IgG4), change in asthma control or asthma quality-of-life questionnaires, and adverse events.nnnRESULTSnAmong 834 randomized patients (mean age, 33 years [range, 17-83]; women, 48%), 693 completed the study. The 6 SQ-HDM and 12 SQ-HDM doses both significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo (hazard ratio [HR]: 0.72 [95% CI, 0.52-0.99] for the 6 SQ-HDM group, Pu2009=u2009.045, and 0.69 [95% CI, 0.50-0.96] for the 12 SQ-HDM group, Pu2009=u2009.03). The absolute risk differences based on the observed data (full analysis set) in the active groups vs the placebo group were 0.09 (95% CI, 0.01-0.15) for the 6 SQ-HDM group and 0.10 (95% CI, 0.02-0.16) for the 12 SQ-HDM group. There was no significant difference between the 2 active groups. Compared with placebo, there was a reduced risk of an exacerbation with deterioration in asthma symptoms (HR, 0.72 [95% CI, 0.49-1.02] for the 6 SQ-HDM group, Pu2009=u2009.11, and 0.64 [95% CI, 0.42-0.96] for the 12 SQ-HDM group, Pu2009=u2009.03) and a significant increase in allergen-specific IgG4. However, there was no significant difference for change in asthma control questionnaire or asthma quality-of-life questionnaire for either dose. There were no reports of severe systemic allergic reactions. The most frequent adverse events were mild to moderate oral pruritus (13% for the 6 SQ-HDM group, 20% for the 12 SQ-HDM group, and 3% for the placebo group), mouth edema, and throat irritation.nnnCONCLUSIONS AND RELEVANCEnAmong adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate or severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6 months of 9 to 10 percentage points; the reduction was primarily due to an effect on moderate exacerbations. Treatment-related adverse events were common at both active doses. Further studies are needed to assess long-term efficacy and safety.nnnTRIAL REGISTRATIONnclinicaltrialsregister.eu Identifier: 2010-018621-19.

Peak Flow Variability and Sputum Eosinophilia in Allergic Rhinits

BACKGROUNDnAlthough some non-asthmatic subjects with allergic rhinitis exhibit airway hyperresponsiveness and increased diurnal peak expiratory flow (PEF) variation, little is known about the critical features that determine these physiologic alterations.nnnOBJECTIVEnIn subjects with allergic rhinitis and methacholine hyperresponsiveness but no asthma symptoms, we examined whether there were features of asthmatic airway inflammation.nnnMETHODSnForty non-asthmatic adults (11 with allergic rhinitis and methacholine hyperresponsiveness, 20 with allergic rhinitis and normal methacholine responsiveness, and 9 healthy control subjects) were studied. Sputum was induced with inhaled hypertonic saline for 5-minute periods for up to 20 minutes. Plugs from the lower respiratory tract were selected for differential counting in cytocentrifuged preparations. For the next 14 days, subjects measured their PEF two times daily. Peak expiratory flow variation was expressed as amplitude % mean.nnnRESULTSnPeak expiratory flow variation was significantly higher in subjects with allergic rhinitis and methacholine hyperresponsiveness than in allergic rhinitis patients with normal methacholine responsiveness and healthy controls. Eosinophil counts in the induced sputum were significantly higher in the subjects with allergic rhinitis and methacholine hyperresponsiveness [median (interquartile range), 7.3 (9.0)%] compared with allergic rhinitis patients with normal methacholine responsiveness [2.5 (3.8)%, P = .03] and healthy controls [1.0 (1.0)%, P = .02].nnnCONCLUSIONnWe conclude that eosinophilic inflammation may be present in subjects with allergic rhinitis and airway hyperresponsiveness even when there are no symptoms of asthma. This could indicate that bronchial eosinophilia is insufficient to cause asthmatic symptoms.

SQ HDM SLIT-tablet (ALK) in treatment of asthma – Post hoc results from a randomised trial

INTRODUCTIONnIn a double-blind, placebo-controlled trial (EudraCT identifier: 2006-001795-20), the standardised quality (SQ) house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) was investigated.nnnMETHODnThe trial included 604 subjects, ≥14 years, with mild-moderate HDM allergic asthma. Subjects were randomised 1:1:1:1 to 1, 3 or 6 SQ-HDM or placebo once daily. The primary endpoint was reduction in inhaled corticosteroid (ICS) after one year. ICS reduction, asthma quality of life questionnaire (AQLQ) and asthma control questionnaire (ACQ) score was analysed post hoc in a subgroup with daily ICS use of 400-800xa0μg and ACQ score of 1-1.5, corresponding to partly controlled asthma (Nxa0=xa0108).nnnRESULTSnThe trial met its primary endpoint. In the subgroup, the difference between placebo and 6 SQ-HDM in change from baseline in daily ICS use was 327xa0μg (pxa0<xa00.0001), while it was 0.52 (pxa0=xa00.010) for AQLQ. The treatment effect on ICS reduction and AQLQ was increased for the subgroup versus the residual population (ICS reduction: pxa0<xa00.001); AQLQ: pxa0=xa00.044).nnnCONCLUSIONnIn this subgroup, including only patients with partly controlled asthma, the benefit of 1 year of treatment with SQ HDM SLIT-tablet was significantly higher than for the less severe full population, both in terms of increased asthma control and improved quality of life.

Differences in sensitivity, maximal response and position of the concentration-response curve to methacholine between asthmatics, patients with allergic rhinitis and healthy subjects

The aim of this study was to detect differences in maximal response and position of the concentration-response curves to methacholine between asthmatics and subjects with allergic rhinitis. A total of 228 adults (107 mild asthmatics, 96 allergic rhinitics and 25 healthy control subjects) were challenged with methacholine. The test was interrupted when FEV1 dropped by more than 40% or when the highest concentration of methacholine (200 mg ml-1) had been administered. Concentration-response curves were characterized by their PC20 (concentration of methacholine that produced 20% fall in FEV1 = airway sensitivity), and if possible, by their EC50 (concentration of methacholine that produced 50% of the maximal response = position) and level of plateau. The proportion of subjects with plateau was significantly lower in asthmatics (18.7%) than in either allergic rhinitics (57.3%) or healthy subjects (92%). It was also significantly lower in allergic rhinitics than in healthy subjects. The level of plateau for asthmatics was (means +/- SD) 31.5 +/- 5.5%, compared with 20.8 +/- 8.1% in allergic rhinitics and 13.7 +/- 6.7% in healthy subjects (P < 0.01). It was also higher in allergic rhinitics than in healthy subjects (P < 0.01). The EC50 values were decreased in asthmatics when they were compared with either allergic rhinitics or healthy subjects (geometric mean EC50: asthmatics = 2.7 mg ml-1, allergic rhinitics = 6.2 mg ml-1, healthy subjects = 8.7 mg ml-1; P < 0.01), but no significant differences were detected between allergic rhinitics and healthy subjects. These results demonstrate that in subjects with allergic rhinitis, the prevalence and level of the plateau on the methacholine concentration-response curve is intermediate between that of asthmatics and normals. Furthermore, while the asthmatic curves differ from normal in having both an increased maximal response and a leftward shift, the rhinitic curves differ only in terms of plateau level. These results suggest that airway responsiveness in asthma and allergic rhinitis may be a consequence of mechanisms that are at least partially different.

Variability of Peak Expiratory Flow Rate in Allergic Rhinitis and Mild Asthma: Relationship to Maximal Airway Narrowing

BACKGROUNDnPrevious studies have demonstrated a significant correlation between airway sensitivity to pharmacologic agents and daily peak expiratory flow rate (PEF) variation in asthmatic and nonasthmatic subjects.nnnOBJECTIVEnThe aim of this study was to investigate, both in patients with asthma and in subjects with allergic rhinitis, differences in daily PEF variation between subjects with plateau on the concentration-response curves to methacholine and those without plateau.nnnMETHODSnA total of 120 adults (50 with mild asthma, 52 with allergic rhinitis, and 18 healthy control subjects) were challenged with methacholine (up to 200 mg/mL) and, for the next 14 days, measured their PEF three times daily. The response to methacholine was measured by the percent decrease in FEV1. A maximal response plateau was considered if three or more of the highest concentrations fell within a 5% response range. Diurnal PEF variation was expressed as the amplitude percent mean.nnnRESULTSnA plateau response was detected in 11 (22%) asthmatic patients, in 33 (63%) subjects with allergic rhinitis, and in 17 (94%) healthy subjects. Diurnal PEF variation was significantly greater (P < .01) in the asthmatic group without a plateau (8.8 +/- 3.7%) compared with the three groups with a plateau (asthma = 5.5 +/- 2.9%; allergic rhinitis = 4.6 +/- 2.1%; healthy = 4.7 +/- 2.3%). Those three groups with a plateau were not significantly different from each other with respect to PEF variability. Diurnal PEF variation was significantly higher in allergic rhinitis patients without plateau (7.6 +/- 3.5%) than in allergic rhinitis patients with plateau (P < .01) and healthy subjects (P < .05). The rhinitic group without a plateau, however, was not significantly different from either the asthmatic group without plateau or the asthmatic group with plateau.nnnCONCLUSIONSnWe conclude that in both asthmatic patients and subjects with allergic rhinitis, the shape of the concentration-response curve to methacholine provides new information on the relationship between airway responsiveness and PEF variability. Further, allergic rhinitis subjects without evidence of plateau have a degree of diurnal PEF variation similar to that found in patients with mild asthma. This could indicate that those subjects may have subclinical inflammatory changes in the airways.

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

BackgroundLittle 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.MethodsThis 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.ResultsThe 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.ConclusionAlthough 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.

Relationship between induced sputum cell counts and fluid-phase eosinophil cationic protein and clinical or physiologic profiles in mild asthma

BACKGROUNDnSputum analysis is the only non-invasive method to examine airway inflammatory processes in subjects with asthma. The aim of this study was to investigate the relationship between cell counts and fluid phase levels in induced sputum in subjects with mild asthma, and the severity of asthma as assessed by clinical, physiologic and blood measurements.nnnMETHODSnForty patients with mild asthma, aged 17 to 49 years were studied (good sputum sample only from 31). On the first day, spirometry and methacholine challenges were performed. After 2 to 4 days, venous blood for absolute eosinophil count and eosinophil cationic protein (ECP) measurement was obtained and sputum was induced by inhalation of hypertonic saline. For the next 15 days subjects recorded their peak expiratory flow (PEF), symptom scores, and beta2-agonist requirements twice daily. Differential counts of leukocytes were done on cytospin preparations of homogenized sputum and the supernatant was examined for eosinophil cationic protein (ECP).nnnRESULTSnSputum eosinophil counts and not neutrophil, epithelial cells, macrophages, or lymphocytes, were inversely correlated to FEV1/FVC % (r = -.57, P = .0008) and to PC20-methacholine (r = -.40, P = .024). No statistical relationship was obtained between eosinophil counts and either symptom scores, bronchodilator requirements, or daily PEF variability. Sputum ECP values were correlated to FEV1/FVC% (r = -.41, P = .026) but not to PC20 (r = -.32, P = .08) or clinical scores or PEF variation. A trend to significance was appreciated between peripheral blood and sputum eosinophil counts (r = .34, P = .067) and no relationship was found between sputum and serum ECP values (r = .10, P = .38).nnnCONCLUSIONSnAlthough sputum markers give some information about disordered lung function and physiologic changes in the airways, they are not the only factors concerned in the clinical expression of mild asthma.

The Effect of Spirometry on Bronchial and Alveolar Nitric Oxide in Subjects with Asthma

Objective. The effect of spirometric maneuvers on exhaled nitric oxide (NO) at the constant flow rate of 50 ml/s (FENO) has been studied with equivocal results. Furthermore, the effects of spirometry on bronchial NO flux (J’awNO) and alveolar NO (CANO), two measurements increasingly being used in clinical and research protocols, are unknown. The aim of this study was to evaluate the effect of spirometry on FENO, J’awNO, and CANO in adults with asthma. Methods. Forty-four adults with asthma were studied. To assess the impact of exhaled NO measurement itself on exhaled NO values, FENO, J’awNO, and CANO were obtained twice, at baseline and after a resting period of 10 min. Then spirometry (with or without bronchodilator) was performed followed by exhaled NO measurements at 10 min. Results. In the group with pre-bronchodilator study only (n = 26), mean (95% CI) values before spirometry were 37.3 ppb (22.2–52.4) for FENO, 2375 pl/s (1613–3137) for J’awNO, and 1.65 ppb (0.95–2.35) for CANO, compared with 35.5 ppb (21.1–49.0, p = .10), 2402 pl/s (1663–3141, p = .85), and 1.60 ppb (0.64–2.56, p = .87) after spirometry, respectively. Spirometry-induced changes in exhaled NO values were also not significant in the group with both pre- and post-bronchodilators (n = 18). Furthermore, changes in FENO, J’awNO, and CANO values were similar in the two groups. Conclusions. Our findings demonstrate that spirometry (with or without bronchodilator) does not induce significant changes in bronchial NO flux or alveolar NO values. Therefore, exhaled NO values may be obtained after spirometric maneuvers.

The Effect of Different Periods of Argon Deaeration on Exhaled Breath Condensate pH

Background. Exhaled breath condensate (EBC) pH has been considered as a biomarker of airway inflammation in asthma. However, little information is available on the duration of argon deaeration required to achieve a stable pH in EBC samples. Objective. To identify differences in EBC pH after argon deaeration for 2, 4, and 8 min. Methods. EBC pH was determined in EBC samples from 48 subjects with allergic rhinitis (11 asthmatics) and 14 healthy volunteers without deaeration and after argon deaeration for 2, 4, and 8 min. Results. The mean (95% CI) pH values obtained from samples analyzed after 4 min [7.66 (7.52–7.80)] and 8 min [7.70 (7.55–7.85)] of argon deaeration were significantly less acidic (p < .001) than those identified after 2 min of deaeration [7.53 (7.40–7.66)]; differences between pH values at 4 and 8 min were not significant. Furthermore, changes in EBC pH of nondeaerated samples after 4 and 8 min of deaeration were significantly greater than those after 2 min, the mean difference being 0.11 (95% CI, 0.02–0.20, p < .05) and 0.13 (95% CI, 0.04–0.22, p < .01), respectively; differences between changes at 4 and 8 min were not significant. Conclusions. Stabilization of EBC pH is achieved after argon deaeration for 4 min. Therefore, this deaeration period may be recommended instead of the 7–8 min used in several studies.

Natural pollen exposure increases the response plateau to adenosine 5'-monophosphate and bronchial but not alveolar nitric oxide in sensitized subjects.

Background: The effect of allergen exposure on airway responsiveness and exhaled nitric oxide (NO) has been well documented, but no information is available on allergen-induced changes in the response plateau to adenosine 5′-monophosphate (AMP) and in bronchial NO flux (JawNO) and alveolar NO (CANO). Objectives: To determine the effect of natural allergen exposure, a proinflammatory stimulus, on the shape of the concentration-response curve to AMP and NO production in airway and alveolar sites. Methods: Airway responsiveness to high concentrations of methacholine and AMP, JawNO and CANO values were obtained in 31 subjects with pollen allergy and in 11 healthy controls. Subjects with pollen allergy were studied before and at the height of the pollen season whereas healthy controls were tested on one occasion only. Results: In the group with pollen allergy, natural pollen exposure increased JawNO (p = 0.03), but had no effect on CANO (p = 0.12). In the 18 subjects with pollen allergy who showed a response plateau to AMP in at least one period, the response plateau to AMP increased from a mean of 13.4% (95% CI: 8.2-18.5) out of season to 22.5% (95% CI: 15.5-29.4, p = 0.004) during the pollen season. Similar results were obtained with methacholine. Compared with healthy controls, subjects with pollen allergy had a higher response plateau and higher JawNO values. Conclusions: These findings suggest that inflammatory changes induced by natural allergen exposure in sensitized subjects are predominantly located in the airways and associated with modifications in the shape of the concentration-response curve to direct and indirect agonists.