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Increases in T helper (Th) 2 cytokine concentrations have been seen in atopic asthma, with interleukin 4 and interleukin 13 thought to have a role in the physiological response to allergen challenge. Our aim was to assess the therapeutic effect of pitrakinra, an interleukin-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of interleukin 4 and interleukin 13 to interleukin-4Rα receptor complexes. In two independent randomised, double-blind, placebo-controlled, parallel group phase 2a clinical trials, patients with atopic asthma were treated with pitrakinra or placebo via two routes. In study 1, patients were randomly assigned to receive either 25 mg pitrakinra (n=12) or placebo (n=12) by subcutaneous injection once daily. In study 2, patients were randomly assigned to receive either 60 mg pitrakinra (n=16) or placebo (n=16) by nebulisation twice daily. Inhaled allergen challenge was done before and after 4 weeks of treatment. The primary endpoint for study 1 was maximum percentage decrease in forced expiratory volume in 1 s (FEV 1) over 4–10 h after allergen challenge, whereas that in study 2 was average percentage decrease in FEV 1 over 4–10 h after allergen challenge. All patients except those with baseline data only were included in our analyses. These trials are registered with ClinicalTrials.gov, numbers NCT00535028 and NCT00535031. No patients dropped out or were lost to follow-up in study 1; in study 2, two patients in the placebo group and one in the pitrakinra group dropped out or were lost to follow-up. These individuals had baseline data only, and were excluded from the analyses. In study 1, there was a 17·1% maximum percentage decrease in FEV 1 in the pitrakinra group; by contrast, the maximum decrease was 23·1% in the placebo group (difference 6%, 95% CI −4·37 to 16·32; p=0·243). In study 2, there was a 4·4% average percentage decrease in FEV 1 in the pitrakinra group; by contrast, the average percentage decrease was 15·9% in the placebo group (3·7 [95% CI 2·08–6·25] times lower in the pitrakinra group; p=0·0001). There were fewer asthma-related adverse events (p=0·069) and fewer adverse events requiring β-agonist rescue (p=0·031) after subcutaneous administration of pitrakinra than with placebo. There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events. Local treatment, targeted at inhibition of interleukins 4 and 13 in the lung, could substantially diminish the symptoms of asthma.

Background It is widely recognized that deep inspiration (DI), either before methacholine (MCh) challenge (Bronchoprotection, BP) or after MCh challenge (Bronchodilation, BD) protects against this challenge in healthy individuals, but not in asthmatics. Sulforaphane, a dietary antioxidant and antiinflammatory phytochemical derived from broccoli, may affect the pulmonary bronchoconstrictor responses to MCh and the responses to DI in asthmatic patients. Methods Forty-five moderate asthmatics were administered sulforaphane (100 μmol daily for 14 days), BP, BD, lung volumes by body-plethsmography, and airway morphology by computed tomography (CT) were measured pre- and post sulforaphane consumption. Results Sulforaphane ameliorated the bronchoconstrictor effects of MCh on FEV 1 significantly (on average by 21 %; p = 0.01) in 60 % of these asthmatics. Interestingly, in 20 % of the asthmatics, sulforaphane aggravated the bronchoconstrictor effects of MCh and in a similar number was without effect, documenting the great heterogeneity of the responsiveness of these individuals to sulforaphane. Moreover, in individuals in whom the FEV 1 response to MCh challenge decreased after sulforaphane administration, i.e., sulforaphane was protective, the activities of Nrf2-regulated antioxidant and anti-inflammatory genes decreased. In contrast, individuals in whom sulforaphane treatment enhanced the FEV 1 response to MCh, had increased expression of the activities of these genes. High resolution CT scans disclosed that in asthmatics sulforaphane treatment resulted in a significant reduction in specific airway resistance and also increased small airway luminal area and airway trapping modestly but significantly. Conclusion These findings suggest the potential value of blocking the bronchoconstrictor hyperresponsiveness in some types of asthmatics by phytochemicals such as sulforaphane.

Abstract Background: The latest methacholine challenge testing (MCT) guidelines published by the European Respiratory Society recommend the characterization of nebulizers before their use in clinics and research. Such investigations are necessary for accurately determining the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) delivered by a given device. The standard English Wright (Wright) jet nebulizer recommended in the 1999 guidelines by the American Thoracic Society has become difficult to obtain and possesses some characteristics that complicate the calculation of dose delivery from this device (e.g. evaporation). Our objective was to determine if the Aerogen® Solo (Solo) vibrating mesh nebulizer provides similar methacholine challenge test results compared to the currently used Wright jet nebulizer. Methods: Sixty mild-to-moderate asthmatics were studied across three research sites in a randomized crossover study. Both methacholine challenges were completed at least 24 hours apart within a 2-week period. Testing with the Wright device was performed as per the 2-minute tidal breathing protocol. The Solo study arm followed the same procedure except for a shorter inhalation time of 1 minute. The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) and the methacholine PD20 were calculated following each methacholine challenge. Results: The geometric mean methacholine PC20 values for the Solo and the Wright differed statistically (0.65 mg/mL vs. 2.58 mg/mL, respectively, p < 0.00001) and clinically. Between-nebulizer geometric mean methacholine PD20 results are comparable by clinical standards [81.7 μg (Solo) vs. 64.7 μg (Wright)], although the slight difference in dose was statistically significant (p = 0.018). Conclusions: The comparability of PD20 values between the Solo and the Wright validates the importance of reporting airway responsiveness to methacholine in terms of dose and not concentration, as stressed in the latest testing guidelines. This finding along with several benefits associated with the Solo make it a promising nebulizer for performing MCT.

Drug provocation test (DPT) is the controlled administration of a drug to diagnose immune- or non-immune-mediated drug hypersensitivity and the last step for accurate recognition of drug hypersensitivity reactions when the previous diagnostic evaluations are negative or unavailable. A DPT is performed only if other conventional tests fail to yield conclusive results. In each clinical presentation, “to provoke or not to provoke” a patient should be decided after careful assessment of the risk–benefit ratio. Well-defined benefits of DPT include confirmative exclusion of diagnoses of drug hypersensitivity and provision of safe alternatives. However, disadvantages such as safety, difficulty in interpretations of results, lack of objective biomarkers, risks of resensitization, efficiency in daily practice, and lack of standardized protocols, are poorly debated. This review summarizes the current published research concerning DPT, with particular emphasis on the advantages and disadvantages of DPT in an evidence-based manner.

Background Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma. Methods 509 people (6–50 yr) were enrolled, 78% were atopic, median FEV 1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV 1 on at least one of two tests, to methacholine a PC 20 ≤ 16 mg/ml and to mannitol a 15% fall in FEV 1 at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results. Results Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV 1 in subjects positive to exercise was 19%, (SD 9.2), mannitol PD 15 158 (CI:129,193) mg, and methacholine PC 20 2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive. Conclusion In this group with normal FEV 1 , mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations. Trial registration This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).

Baseline variables included in the multiple linear regression analysis for PC20 AMP were age, smoking status, blood eosinophils, FEV1, residual volume (RV), and ventilation heterogeneity of the conductive lung zone. The present work shows that bronchial provocation with dry powder adenosine is a suitable method for measuring AHR in asthmatic subjects. [...]the new testing method allowed us to administer higher doses, resulting in fewer false-negative test results, and the degree of AHR to dry powder adenosine correlated well with the degree of AHR to nebulized AMP. There was, however, no apparent relationship between measures of airway obstruction at baseline and PD20 adenosine (e.g., only two out of nine had an FEV1/FVC ratio ,70%) or with their smoking status (four were current and five were former smokers). [...]we expect that increasing the top dose, which was arbitrarily chosen to be 80 mg in this study, could further reduce the number of false negatives and thus increase the test's sensitivity even more. [...]we have shown that bronchial provocation with dry powder adenosine is a suitable alternative to provocation with nebulized AMP, considering the good agreement between the tests and comparable baseline predictors. [...]dry powder adenosine appears to offer an improvement over nebulized AMP because of its higher sensitivity for less hyperresponsive subjects with asthma. n Author disclosures are available with the text of this letter at www.atsjournals.org.

Background Small plateau (SP) on the flow-volume curve was found in parts of patients with suspected asthma or upper airway abnormalities, but it lacks clear scientific proof. Therefore, we aimed to characterize its clinical features. Methods We involved patients by reviewing the bronchoprovocation test (BPT) and bronchodilator test (BDT) completed between October 2017 and October 2020 to assess the characteristics of the sign. Patients who underwent laryngoscopy were assigned to perform spirometry to analyze the relationship of the sign and upper airway abnormalities. SP-Network was developed to recognition of the sign using flow-volume curves. Results Of 13,661 BPTs and 8,168 BDTs completed, we labeled 2,123 (15.5%) and 219 (2.7%) patients with the sign, respectively. Among them, there were 1,782 (83.9%) with the negative-BPT and 194 (88.6%) with the negative-BDT. Patients with SP sign had higher median FVC and FEV 1 % predicted (both P  < .0001). Of 48 patients (16 with and 32 without the sign) who performed laryngoscopy and spirometry, the rate of laryngoscopy-diagnosis upper airway abnormalities in patients with the sign (63%) was higher than those without the sign (31%) ( P  = 0.038). SP-Network achieved an accuracy of 95.2% in the task of automatic recognition of the sign. Conclusions SP sign is featured on the flow-volume curve and recognized by the SP-Network model. Patients with the sign are less likely to have airway hyperresponsiveness, automatic visualizing of this sign is helpful for primary care centers where BPT cannot available.

Abstract Rationale The American Thoracic Society guidelines for methacholine testing for the diagnosis of asthma recommends the 2-minute tidal breathing protocol with the Wright nebulizer, which produces more aerosol than required, generates a small particle size, and requires cleaning between tests. Objectives To evaluate methacholine testing using a disposable, breath-actuated AeroEclipse II, which produces aerosol during inspiration and was developed for single-patient use. Methods Forty-six adult subjects with asthma (19 men), aged 27.3 (SD, 9.5) years, with FEV1 98.5 (SD, 18.1) % predicted participated in a randomized, crossover, observational study. Subjects were first screened using the Wright nebulizer, then assigned to 2 minutes of tidal breathing from the Wright or 20 seconds of tidal breathing from the AeroEclipse nebulizer on 2 separate days, in random order. Provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) values were calculated by linear interpolation of log dose-versus-response curves, log-transformed, and compared using paired Student t test and Pearson correlation. Measurements and Main Results The 38 subjects demonstrating reproducible PC20 measurements of within 1.5 doubling concentrations were included in the comparison. The geometric mean methacholine PC20 measured with the AeroEclipse nebulizer was approximately 1 doubling concentration lower than the geometric mean methacholine PC20 of the Wright nebulizer (P < 0.05). The Pearson correlation coefficient between the two nebulizers was 0.86 (P < 0.05). Conclusions The PC20 measurements using the two nebulizers were highly correlated; however, the PC20 determined with the AeroEclipse nebulizer was significantly lower than those determined using the Wright nebulizer. Clinical trial registered with www.clinicaltrials.gov (NCT 01919424).

Background Methacholine hyperresponsiveness is prevalent in elite athletes. Comparative studies have hitherto been limited to methacholine, eucapnic voluntary hyperpnoea and exercise. This study investigated airway responsiveness to these stimuli as well as to adenosine 5′-monophosphate (AMP) and mannitol, in 58 cross-country ski athletes. Methods Exhaled nitric oxide concentration (FENO), spirometry and bronchial challenge in random order with methacholine, AMP and mannitol were consecutively performed on three study days in the autumn. Specific IgE to eight aeroallergens and a self-completed questionnaire about respiratory symptoms, allergy and asthmatic medication were also performed on day 1. Eucapnic voluntary hyperventilation (EVH) and field exercise tests were randomly performed in 33 of the skiers on two study days in the following winter. Results Of 25 (43%) skiers with airway hyperresponsiveness (AHR), 23, five and three skiers were hyperresponsive to methacholine, AMP and mannitol, respectively. Methacholine hyperresponsiveness was more prevalent in subjects without asthma-like symptoms. The FENO was not significantly different in skiers with and without methacholine hyperresponsiveness. Four of 14 skiers with and four of 19 skiers without methacholine hyperresponsiveness were hyperresponsive to EVH or exercise challenge. AHR to any stimulus was present in 16 asymptomatic and nine symptomatic skiers. Asthma-like symptoms were not correlated with AHR to any stimulus. Conclusions Methacholine hyperresponsiveness is more common in asymptomatic skiers and is a poor predictor of hyperresponsiveness to mannitol and hyperpnoea. The low prevalence of hyperresponsiveness to indirect stimuli may suggest differences in the pathogenesis of methacholine hyperresponsiveness in elite skiers and non-athletes.

Rationale Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR. Objectives An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect. Methods Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC20 FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis. Measurements and Main Results This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC20 FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose‐doubling increases in PC20 FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7‐day observation period. Furthermore, a significant treatment effect was observed in the change in PC20FEV1 from baseline averaged over the 7‐day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs −0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022. Conclusions In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC20 FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S‐nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted. This is an early stage proof of concept cross‐over trial for an S‐nitrosoglutathione reductase inhibitor, N6022, in 14 patients with mild non‐corticosteroid treated asthma. Although the study did not reach its primary endpoint of a reduction in methacholine PC 20 FEV1 at 24 h, a reduced methacholine PC 20 FEV1 at 7 days compared with baseline was achieved.