Laryngeal hypersensitivity and abnormal cough response during mannitol bronchoprovocation challenge.

BACKGROUND AND OBJECTIVE: Inhalational challenge with dry mannitol powder may potentially induce cough by two mechanisms: airway bronchoconstriction or laryngeal irritation. This prospective observational study investigated laryngeal and bronchial components of cough induced by mannitol challenge. METHODS: We recruited consecutive patients referred for clinical mannitol challenge. The Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ) was administered. Throughout testing, coughs were audio-recorded to derive a cough frequency index per time and dose of mannitol. Relationships between cough indices, laryngeal hypersensitivity and bronchial hyperresponsiveness (BHR) were examined. Participants were classified by cough characteristics with k-means cluster analysis. RESULTS: Of 90 patients who underwent challenge, 83 completed both the questionnaire and challenge. Cough frequency was greater in patients with abnormal laryngeal hypersensitivity (p = 0.042), but not in those with BHR. There was a moderate negative correlation between coughs per minute and laryngeal hypersensitivity score (r = -0.315, p = 0.004), with lower LHQ scores being abnormal. Cluster analysis identified an older, female-predominant cluster with higher cough frequency and laryngeal hypersensitivity, and a younger, gender-balanced cluster with lower cough frequency and normal laryngeal sensitivity. CONCLUSION: Cough frequency during mannitol challenge in our cohort reflected laryngeal hypersensitivity rather than BHR. Laryngeal hypersensitivity was more often present among older female patients. With the incorporation of cough indices, mannitol challenge may be useful to test for laryngeal hypersensitivity as well as BHR.

Effects of low- versus high-dose fluticasone propionate/formoterol fumarate combination therapy on AMP challenge in asthmatic patients: A double-blind, randomised clinical trial.

BACKGROUND: The dose-response relationship between two dose levels of fluticasone/formoterol (flutiform(®), 100/10 µg and 500/20 µg) was evaluated in asthmatic patients. Non-invasive inflammatory markers were used including adenosine monophosphate (AMP) challenge (primary endpoint), and sputum eosinophils and fractional exhaled nitric oxide (FeNO) (secondary endpoints). METHODS: Patients aged ≥18 years with forced expiratory volume in 1 s (FEV1) ≥60% predicted and who required a dose of <60 mg AMP to elicit a 20% drop in FEV1 (AMP PD20) were randomised in this incomplete block, crossover study to receive 2 of 3 treatments b.i.d.: fluticasone/formoterol 500/20 µg (high dose), 100/10 µg (low dose) or placebo, during 2 periods of 28 ± 3 days each, separated by 2-3 weeks. AMP challenges were performed pre-dose and 12 h after last dose at the end of each treatment period. A series of post hoc analyses were performed only in patients allocated to both fluticasone/formoterol doses, who completed the study and had evaluable AMP PD20 data for both treatments ("fluticasone/formoterol subgroup"). Changes in AMP PD20 FEV1, percentage sputum eosinophils and FeNO levels (Day 1 vs Day 28) between treatments were compared by an analysis of covariance (ANCOVA). RESULTS: Sixty-two patients were randomised and 46 completed the study. Fifteen patients received both high- and low-dose fluticasone/formoterol (post hoc subgroup). The difference in AMP PD20 for the overall population was not statistically significant between high- and low-dose fluticasone/formoterol (LS mean fold difference: 1.3; p = 0.489), although both dose levels were superior to placebo: high-dose vs placebo LS mean fold difference: 4.4, p < 0.001; low-dose vs placebo LS mean fold difference: 3.5, p < 0.001. In the post hoc subgroup, the difference in AMP PD20 between the doses was statistically significant in favour of the high-dose (LS mean fold difference: 2.4, p = 0.012). Other inflammatory parameters (sputum eosinophil counts and FeNO) showed small differences and statistically non-significant changes between high- and low-dose fluticasone/formoterol. CONCLUSIONS: A significant dose-response was found between low- and high-dose fluticasone/formoterol in the post hoc subgroup (patients who received both doses), but not in the overall population, with the higher dose demonstrating a greater reduction in airway responsiveness to AMP.

Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics.

BACKGROUND: CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses. OBJECTIVE: To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses. METHODS: In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's t-test. RESULTS: Fifteen subjects completed the study per-protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter-subject variability. Compared with placebo, setipiprant significantly reduced the allergen-induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve (AUC(3-10 h) ) by on average 25.6% (P = 0.006) and significantly protected against the allergen-induced airway hyperresponsiveness (AHR) to methacholine (P = 0.0029). There was no difference in the early asthmatic response (EAR) or in allergen-induced changes in eNO between treatments. CONCLUSION AND CLINICAL RELEVANCE: Setipiprant at multiple oral doses was well tolerated and reduced both the allergen-induced LAR and the associated AHR in allergic asthmatics. Our findings confirm that CRTH2 may be a promising target for the treatment of allergic disorders.

Allergen bronchoprovocation: correlation between FEV1 maximal percent fall and area under the FEV1 curve and impact of allergen on recovery.

BACKGROUND: House dust mite (HDM) induces greater responses than other allergens during allergen bronchoprovocation (ABP) testing. The two standardized methods for reporting results of ABP tests are the maximal percent fall in forced expiratory volume in one second (FEV1, max; %) and the area under the FEV1 vs time curve (AUC; %FEV1 x min). The relationship between these methods has not been previously investigated. AIMS: We aimed to measure the correlation between FEV1, max and AUC during the early asthmatic response (EAR) and the late asthmatic response (LAR), and to determine if the EAR recovery period for HDM would be longer than other allergens (cat, grass, horse, and ragweed). METHODS: We retrospectively calculated the AUC and correlation between FEV1, max and AUC during the EAR(0-2 h) and LAR(3-7 h) for each allergen. We compared EAR(0-3 h) and LAR(3-7 h) FEV1, max, AUC and absolute difference in FEV1, max to the most recovered FEV1 (FEV1, min). We performed pairwise comparisons of correlation and slope values using Fischer's r to z transformation and t-tests, respectively. AUC and absolute differences in FEV1, max and FEV1, min were compared using a one-way ANOVA test, followed by a post-hoc Scheffe test. RESULTS: Correlation between the FEV1, max and AUC during the EAR(0-2 h) (n = 221) was 0.807, and was 0.798 during the LAR(3-7 h) (n = 157 of 221), (difference p = 0.408). The EAR(0-3 h) AUC and FEV1, max did differ between allergens (both p < 0.0001) but the LAR(3-7 h) AUC and FEV1, max did not (p = 0.548 and 0.824, respectively). HDM did not have a larger AUC or FEV1, max, than all other allergens during the EAR(0-3 h) or the LAR(3-7 h). The absolute difference between the FEV1, max and FEV1, min during the EAR(0-3 h) did not differ between allergens (p = 0.180). CONCLUSION: The FEV1, max and AUC for both the EAR(0-2 h) and LAR(3-7 h) had excellent correlation, with no significant difference. Thus, significant bronchoconstriction will likely result in a longer recovery period. There was no evidence of delayed EAR(0-3 h) recovery following HDM challenges, so HDM did not induce a larger response compared to all the other allergens examined. REGISTRATION: Not registered. This is not a clinical trial. (This study is a retrospective analysis of data collected during several registered trials.).

Airway Hyperresponsiveness, but Not Bronchoalveolar Inflammatory Cytokines Profiles, Is Modified at the Subclinical Onset of Severe Equine Asthma.

Airway hyperresponsiveness (AHR) and inflammation are both observed in human and equine asthma. The aim of this study was to assess the timeline and relationship of both features at the subclinical onset of severe equine asthma (SEA). First, the repeatability of the pulmonary function test (PFT) using impulse oscillometry system, and the methacholine bronchoprovocation test (BPT) were assessed at a 1-day interval on six SEA horses in clinical remission and six control horses. Then, clinical and ancillary tests were performed before and after a 1-week low-dust environmental challenge, including weighted clinical score, respiratory endoscopy, bronchoalveolar fluid cytology, PFT, and BPT. Both PFT and BPT showed acceptable repeatability. No test allowed SEA horses in clinical remission to be distinguished from control, unlike in human patients. Because of the low-dust environment, no significant difference was observed in the results of clinical and conventional ancillary examinations after the challenge. However, SEA horses showed increased AHR after the environmental challenge. At that stage, no signs of inflammation or changes in pro-inflammatory cytokines profiles (quantification and gene expression) were observed, suggesting AHR is present at an earlier stage of equine asthma than airway inflammation. This feature indicates SEA could present in a different disease pathway than neutrophilic human asthma.

Manifestation of Bronchial Hyperreactivity from Exposure to Heavy and Precious Metal Vapors among the Ore Smeltery Workers of Zveçan, Kosovo.

CONTEXT: Kosovo is a region in the Western Balkans that is rich in minerals and coal, so pollution is a serious public health problem there. Workers in the heavy and precious metal smeltery in Zveqan, Kosovo, were studied with regard to the roles that vapor from the smelting of metals (Pb, Zn, Au, Ag, P, and Cu) and particulate matter play in causing bronchial hyperreactivity. OBJECTIVES: The purpose of the article was to measure the parameters of lung function as determined by body plethysmography, diagnosis of respiratory diseases, and assessment of respiratory function using a histamine bronchoprovocation test. SETTINGS AND DESIGN: The present study was conducted in two groups of participants: A control group, which included 25 healthy persons, and a smeltery worker group, which included 45 mine workers (15 smokers and 30 nonsmokers) holding permanent jobs in the mineral foundry of Zvecan, Kosovo. SUBJECTS AND METHODS: Pulmonary function parameters (specific airway resistance [Raw] and intrathoracic gas volume) were measured and used to calculate the specific resistance (SRaw)and specific conductance (SGaw) of the airways, and a histamine bronchoprovocation test was conducted. STATISTICAL ANALYSIS USED: The data were entered and analyzed using the Microsoft Excel and INSTAT 3 software. RESULTS: Airway specific resistance (SRaw) was significantly higher in the smeltery worker group (P < 0.01) as compared to the control group (P > 0.1). CONCLUSION: These results suggest that occupational exposure to vapors during the metal refining process poses a risk to the workers' health and can cause bronchial hyperreactivity, bronchial asthma, or chronic obstructive pulmonary disease.

Targeting the small airways with dry powder adenosine: a challenging concept.

Background: Small-particle inhaled corticosteroids (ICS) provide a higher small airway deposition than large-particle ICS. However, we are still not able to identify asthma patients who will profit most from small-particle treatment. Objective: We aimed to identify these patients by selectively challenging the small and large airways. We hypothesized that the airways could be challenged selectively using small- and large-particle adenosine, both inhaled at a high and a low flow rate. Design: In this cross-over study 11 asthma subjects performed four dry powder adenosine tests, with either small (MMAD 2.7 µm) or large (MMAD 6.0 µm) particles, inhaled once with a low flow rate (30 l min-1) and once with a high flow rate (60 l min-1). Spirometry and impulse oscillometry were performed after every bronchoprovocation step. We assumed that FEV1 reflects the large airways, and FEF25-75%, R5-R20 and X5 reflect the small airways. Results: The four adenosine tests were not significantly different with respect to the threshold values of FEV1 (p = 0.12), FEF25-75% (p = 0.37), R5-R20 (p = 0.60) or X5 (p = 0.46). Both small- and large-particle adenosine induced a response in the small airways in the majority of the tests. Conclusions: In contrast to our hypothesis, all four adenosine tests provoked a response in the small airways and we could not identify different large- or small-airway responders. Interestingly, even the test with large particles and a high flow rate induced a small-airway response, suggesting that selective challenging of the small airways is not necessary. Future studies should investigate the relation between particle deposition and the site of an airway response.

Teste de provocação brônquica: comparação de um protocolo encurtado recomendado pela european respiratory society com um protocolo padronizado / Bronchoprovocation test: comparison of a shortened protocol recommended for european respiratory society with one standard protocol

Introdução: o objetivo deste estudo foi testar o protocolo encurtado de provocação brônquica, modificado, recomendado pela European Respiratory Society, comparando-o com outro considerado padrão. Métodos: foram estudados 20 pacientes com sintomas respiratórios de tosse e/ou dispnéia nos quais o teste doi indicado. A técnica de provocação brônquica foi a de inalação de solução de metacolina, em etapas com concentrações crescentes, durante respiração espontânea. As concentrações de metacolina, no protocolo padrão, iniciam com 0,3mg/ml, dobrando-se, segudamente, até 16mg/ml. No protocolo encurtado, a diferença foi na dose inicial, de 0,25 à 1,0 mg/ml, na dependência das drogas usadas para controle dos sintomas. Resultados: a incidência e a intensidade dos efeitos colaterais, assim como os resultados de PC20, foram iguais em ambos os protocolos. Valores médios de PC20 foram de 3,24 e 3,47 mg/ml respectivamente nos protocolos padrão e encurtado. O tempo total gasto para a realização do teste foi significamente inferior no encurtado, reduzindo o número de etapas. Conclusão: concluímos que os protocolos, encurtado e padrão, mostraram resultados equivalentes, sendo o protocolo encurtado mais rápido.