Interpretation of Spirometry, Peak Flow, and Provocation Testing for Asthma.

Spirometry plays a crucial role in the diagnosis of asthma. The hallmark spirometry finding of expiratory airflow variability can be demonstrated in several ways including peak airflow and bronchodilator and bronchoprovocation testing. Challenges of overdiagnosis and underdiagnosis underscore the need to consider clinical context while interpreting these tests. A meticulous and multifaceted approach prioritizing objective testing is imperative while diagnosing asthma.

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.

Unsupervised field-based exercise challenge tests to support the detection of exercise-induced lower airway dysfunction in athletes.

Background: Athletes are at risk for developing exercise-induced lower airway narrowing. The diagnostic assessment of such lower airway dysfunction (LAD) requires an objective bronchial provocation test (BPT). Objectives: Our primary aim was to assess if unsupervised field-based exercise challenge tests (ECTs) could confirm LAD by using app-based spirometry. We also aimed to evaluate the diagnostic test performance of field-based and sport-specific ECTs, compared with established eucapnic voluntary hyperpnoea (EVH) and methacholine BPT. Methods: In athletes with LAD symptoms, sensitivity and specificity analyses were performed to compare outcomes of (1) standardised field-based 8 min ECT at 85% maximal heart rate with forced expiratory volume in 1 s (FEV1) measured prechallenge and 1 min, 3 min, 5 min, 10 min, 15 min and 30 min postchallenge, (2) unstandardised field-based sport-specific ECT with FEV1 measured prechallenge and within 10 min postchallenge, (3) EVH and (4) methacholine BPT. Results: Of 60 athletes (median age 17.5; range 16-28 years.; 40% females), 67% performed winter-sports, 43% reported asthma diagnosis. At least one positive BPT was observed in 68% (n=41/60), with rates of 51% (n=21/41) for standardised ECT, 49% (n=20/41) for unstandardised ECT, 32% (n=13/41) for EVH and methacholine BPT, while both standardised and unstandardised ECTs were simultaneously positive in only 20% (n=7/35). Standardised and unstandardised ECTs confirmed LAD with 54% sensitivity and 70% specificity, and 46% sensitivity and 68% specificity, respectively, using EVH as a reference, while EVH and methacholine BPT were both 33% sensitive and 85% specific, using standardised ECTs as reference. Conclusion: App-based spirometry for unsupervised field-based ECTs may support the diagnostic process in athletes with LAD symptoms. Trial registration number: NCT04275648.

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.).

Clinical effects and pharmacokinetics of nebulized lidocaine in healthy horses.

Background: Nebulized lidocaine appears promising as a novel corticosteroid-sparing therapeutic for equine asthma, but its safety and pharmacokinetic behavior have yet to be confirmed. Objective: To describe the effect of nebulized lidocaine on upper airway sensitivity, lung mechanics, and lower respiratory cellular response of healthy horses, as well as delivery of lidocaine to lower airways, and its subsequent absorption, clearance, and duration of detectability. Animals: Six healthy university- and client-owned horses with normal physical examination and serum amyloid A, and no history of respiratory disease within 6 months. Methods: Prospective, descriptive study evaluating the immediate effects of 1 mg/kg 4% preservative-free lidocaine following nebulization with the Flexineb®. Prior to and following nebulization, horses were assessed using upper airway endoscopy, bronchoalveolar lavage, and pulmonary function testing with esophageal balloon/pneumotachography and histamine bronchoprovocation. Additionally, blood and urine were collected at predetermined times following single-dose intravenous and nebulized lidocaine administration for pharmacokinetic analysis. Results: Upper airway sensitivity was unchanged following lidocaine nebulization, and no laryngospasm or excessive salivation was noted. Lidocaine nebulization (1 mg/kg) resulted in a mean epithelial lining fluid concentration of 9.63 ± 5.05 µg/mL, and a bioavailability of 29.7 ± 7.76%. Lidocaine concentrations were higher in epithelial lining fluid than in systemic circulation (Cmax 149.23 ± 78.74 µg/L, CELF:Cmaxplasma 64.4, range 26.5-136.8). Serum and urine lidocaine levels remained detectable for 24 and 48 h, respectively, following nebulization of a single dose. Baseline spirometry, lung resistance and dynamic compliance, remained normal following lidocaine nebulization, with resistance decreasing post-nebulization. Compared to the pre-nebulization group, two additional horses were hyperresponsive following lidocaine nebulization. There was a significant increase in mean airway responsiveness post-lidocaine nebulization, based on lung resistance, but not dynamic compliance. One horse had BAL cytology consistent with airway inflammation both before and after lidocaine treatment. Conclusions: Nebulized lidocaine was not associated with adverse effects on upper airway sensitivity or BAL cytology. While baseline lung resistance was unchanged, increased airway reactivity to histamine bronchoprovocation in the absence of clinical signs was seen in some horses following nebulization. Further research is necessary to evaluate drug delivery, adverse events, and efficacy in asthmatic horses.

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.

The use of the mannitol test as an outcome measure in asthma intervention studies: a review and practical recommendations.

BACKGROUND: The mannitol test is an indirect bronchial challenge test widely used in diagnosing asthma. Response to the mannitol test correlates with the level of eosinophilic and mast cell airway inflammation, and a positive mannitol test is highly predictive of a response to anti-inflammatory treatment with inhaled corticosteroids. The response to mannitol is a physiological biomarker that may, therefore, be used to assess the response to other anti-inflammatory treatments and may be of particular interest in early phase studies that require surrogate markers to predict a clinical response. The main objectives of this review were to assess the practical aspects of using mannitol as an endpoint in clinical trials and provide the clinical researcher and respiratory physician with recommendations when designing early clinical trials. METHODS: The aim of this review was to summarise previous uses of the mannitol test as an outcome measure in clinical intervention studies. The PubMed database was searched using a combination of MeSH and keywords. Eligible studies included intervention or repeatability studies using the standard mannitol test, at multiple timepoints, reporting the use of PD15 as a measure, and published in English. RESULTS: Of the 193 papers identified, 12 studies met the inclusion criteria and data from these are discussed in detail. Data on the mode of action, correlation with airway inflammation, its diagnostic properties, and repeatability have been summarised, and suggestions for the reporting of test results provided. Worked examples of power calculations for dimensioning study populations are presented for different types of study designs. Finally, interpretation and reporting of the change in the response to the mannitol test are discussed. CONCLUSIONS: The mechanistic and practical features of the mannitol test make it a useful marker of disease, not only in clinical diagnoses, but also as an outcome measure in intervention trials. Measuring airway hyperresponsiveness to mannitol provides a novel and reproducible test for assessing efficacy in intervention trials, and importantly, utilises a test that links directly to underlying drivers of disease.

Reproducibility of eucapnic voluntary hyperpnoea for exercise-induced bronchoconstriction diagnosis in asthmatic children and adolescents.

BACKGROUND: Respiratory symptoms after exercise are frequently reported by asthmatic patients, and exercise-induced bronchoconstriction (EIB) is a frequent cause, which requires objective testing for diagnosis. Eucapnic voluntary hyperpnea (EVH) is recommended as a surrogate stimulus for this purpose. Its short-term reproducibility is not yet established in children and young adolescents with asthma. OBJECTIVE: To evaluate the short-term test-retest agreement and reproducibility of FEV1 changes after EVH in this population. METHODS: Asthmatic patients aged between 10 and 20 years underwent EVH for EIB diagnosis on two occasions 2-4 days apart at a specialized university clinic. FEV1 was measured at 5, 15, and 30 min after EVH with a target ventilation rate 21 times the baseline FEV1 . EIB was diagnosed as a decrease ≥10% in FEV1 from baseline. RESULTS: A total of 26 of 62 recruited individuals tested positive for EIB on both visits (positive group) and 17 on one visit only (divergent group), while 19 tested negative on both visits (negative group). The overall agreement was 72.5% (95%CI 61.6%, 83.6%), and Cohen's kappa coefficient was 0.452. Low bias (0.87%) and high intra-class correlation coefficient (0.854, 95%CI 0.758,0.912; p < .001) for FEV1 response between test days were found, but with wide limits of agreement (±20.72%). There were no differences in pre-challenge FEV1 or achieved ventilation rate between visits either between groups (p = .097 and p = .461) or within groups (p = .828 and p = .780). There were no safety issues. CONCLUSIONS: More than one EVH test should be performed in children and young adolescents with asthma to exclude EIB and minimize misdiagnosis and mistreatment.

Spirometric Response to Bronchodilator and Eucapnic Voluntary Hyperpnea in Adults With Asthma.

BACKGROUND: The spirometric response to fast-acting bronchodilator is used clinically to diagnose asthma and in clinical research to verify its presence. However, bronchodilator responsiveness does not correlate with airway hyper-responsiveness measured with the direct-acting stimulus of methacholine, demonstrating that bronchodilator responsiveness is a problematic method for diagnosing asthma. The relationship between bronchodilator responsiveness and airway hyper-responsiveness assessed with indirect-acting stimuli is not known. METHODS: Retrospectively, the spirometric responses to inhaled bronchodilator and a eucapnic voluntary hyperpnea challenge (EVH) were compared in 39 non-smoking adult subjects with asthma (26 male, 13 female; mean ± SD age 26.9 ± 7.8 y; mean ± SD body mass index 26.3 ± 4.7 kg/m2). All subjects met one or both of 2 criteria: ≥ 12% and 200 mL increase in FEV1 after inhaled bronchodilator, and ≥ 10% decrease in FEV1 after an EVH challenge. RESULTS: Overall, FEV1 increased by 9.9 ± 7.9% after bronchodilator (3.93 ± 0.97 to 4.28 ± 0.91 L, P < .001) and decreased by 23.9 ± 15.0% after the EVH challenge (3.89 ± 0.89 to 2.96 ± 0.88 L, P < .001). However, the change in FEV1 after bronchodilator did not correlate with the change after EVH challenge (r = 0.062, P = .71). Significant bronchodilator responsiveness predicted a positive response to EVH challenge in 9 of 33 subjects (sensitivity 27%). Following EVH, the change in FEV1 strongly correlated with the change in FVC (FEV1 percent change vs FVC percent change, r = 0.831, P < .001; FEV1 ΔL vs FVC ΔL, r = 0.799, P < .001). CONCLUSIONS: These results extend previous findings that demonstrate a lack of association between bronchodilator responsiveness and methacholine responsiveness. Given the poor concordance between the spirometric response to fast-acting bronchodilator and the EVH challenge, these findings suggest that the airway response to inhaled ß2-agonist must be interpreted with caution and in the context of its determinants and limitations.

Diagnostic value of bronchoprovocation challenge with adenosine monophosphate versus exercise testing in early diagnosis of asthma.

BACKGROUND: Airway hyperresponsiveness (AHR) is a characteristic feature of bronchial asthma and is diagnosed using direct and indirect bronchoprovocation tests. The diagnosis of AHR is a challenge in symptomatic patients with a normal baseline prebronchodilator spirometry and postbronchodilator spirometry. Exercise-induced asthma or exercise-induced bronchoconstriction (EIB) is a distinct form of AHR. There is no single test that is sufficient to exclude AHR in symptomatic military personnel with normal spirometry. This study was conducted to compare the diagnostic value of indirect bronchoprovocation test using inhaled adenosine monophosphate (AMP) and exercise challenge test (ECT) in the diagnosis of EIB. METHODS: A crossover study was conducted with consecutive sampling of patients presenting with symptoms suggestive of asthma and with normal spirometry results who were subjected to both ECT and bronchoprovocation test using inhaled AMP on separate days. RESULTS: Forty participants were recruited (the mean age: 25 yrs, 100% male). The commonest presentation was breathlessness on exercise (55%). With exercise alone, 40% tested positive for AHR, while with AMP alone, the positivity increased to 53%, and the difference was statistically significant (p= 0.03). Exercise alone failed to detect 8 cases that tested positive for AHR by inhaled AMP challenge. CONCLUSION: Indirect bronchoprovocation test using inhaled AMP may be used to diagnose AHR in conditions in which exercise challenge testing is not available or the patient is unable to complete ECT.

Utility and efficiency of methacholine challenge testing in evaluating pediatric asthma: unraveling the diagnostic conundrum.

OBJECTIVE: Interpretation of methacholine challenge testing (MCT) results depends on the patient's pretest probability of asthma as well as the provocative concentration (PC20); however, ordering providers rarely understand the complexity associated with its interpretation. This study investigated the clinical utility and efficiency of MCT at a tertiary center in evaluating pediatric asthma. METHODS: Retrospective chart review was done for all MCT done at a tertiary center over a six year period (2011-2017). Demographics, referring provider, referral diagnosis, current symptoms with and without exercise, and baseline spirometry were collected. Pretest probability of asthma was assigned by author (RB) who was blinded to MCT results and PC20. Post-test probability of asthma was assigned based on pretest probability, MCT result (+/-), and PC20. Three assigned asthma probability categories were "unlikely" "likely", and "very likely". RESULTS: Of 172 subjects (91 Females, age range 5-21 years), 64.9% of MCT results (n = 111)) were negative and 35.1% (n = 60)) were positive. One was inconclusive. Those who tested positive were shorter, lighter, younger and had lower forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio than those who tested negative (p < 0.05). Subjects with exercise symptoms only were less likely to test positive (OR 0.2, CI 0.1-0.5). In a majority of subjects (91.8%; 157/171), MCT increased the certainty of presence or absence of asthma. CONCLUSIONS: In our subject population, MCT could be useful in evaluating pediatric asthma if subject's pretest probability of asthma and PC20 was taken into account. It was not as useful for subjects with exercise symptoms only.

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.

Direct and indirect bronchoprovocation tests in dose-response studies of inhaled corticosteroids: Past, present, and future directions.

Inhaled corticosteroids (ICS) are a mainstay of treatment in eosinophilic asthma. Many studies have explored the dose-response effect of different formulations of ICS through direct or indirect bronchoprovocation testing. Such studies are important for investigating efficacy and identifying the relative potency between formulations. However, lack of consistency in methods and designs has hindered the comparability of study findings. This review discusses current knowledge of the dose-response, or lack thereof, of different formulations of ICS through direct and indirect bronchoprovocation testing. The strengths and weaknesses of past studies inform recommendations for future methodological considerations in this field, such as utilizing a randomized double-blind crossover design, enrolling participants likely to respond to ICS therapy, and carefully selecting treatment durations and washout periods to assess incremental improvement in airway hyperresponsiveness while reducing the likelihood of a carryover effect.

Obesity alters the topographical distribution of ventilation and the regional response to bronchoconstriction.

Obesity is associated with reduced operating lung volumes that may contribute to increased airway closure during tidal breathing and abnormalities in ventilation distribution. We investigated the effect of obesity on the topographical distribution of ventilation before and after methacholine-induced bronchoconstriction using single-photon emission computed tomography (SPECT)-computed tomography (CT) in healthy subjects. Subjects with obesity (n = 9) and subjects without obesity (n = 10) underwent baseline and postbronchoprovocation SPECT-CT imaging, in which Technegas was inhaled upright and followed by supine scanning. Lung regions that were nonventilated (Ventnon), low ventilated (Ventlow), or well ventilated (Ventwell) were calculated using an adaptive threshold method and were expressed as a percentage of total lung volume. To determine regional ventilation, lungs were divided into upper, middle, and lower thirds of axial length, derived from CT. At baseline, Ventnon and Ventlow for the entire lung were similar in subjects with and without obesity. However, in the upper lung zone, Ventnon (17.5 ± 10.6% vs. 34.7 ± 7.8%, P < 0.001) and Ventlow (25.7 ± 6.3% vs. 33.6 ± 5.1%, P < 0.05) were decreased in subjects with obesity, with a consequent increase in Ventwell (56.8 ± 9.2% vs. 31.7 ± 10.1%, P < 0.001). The greater diversion of ventilation to the upper zone was correlated with body mass index (rs = 0.74, P < 0.001), respiratory system resistance (rs = 0.72, P < 0.001), and respiratory system reactance (rs = -0.64, P = 0.003) but not with lung volumes or basal airway closure. Following bronchoprovocation, overall Ventnon increased similarly in both groups; however, in subjects without obesity, Ventnon only increased in the lower zone, whereas in subjects with obesity, Ventnon increased more evenly across all lung zones. In conclusion, obesity is associated with altered ventilation distribution during baseline and following bronchoprovocation, independent of reduced lung volumes.NEW & NOTEWORTHY Using ventilation SPECT-computed tomography imaging in healthy subjects, we demonstrate that ventilation in obesity is diverted to the upper lung zone and that this is strongly correlated with body mass index but is independent of operating lung volumes and of airway closure. Furthermore, methacholine-induced bronchoconstriction only occurred in the lower lung zone in individuals who were not obese, whereas in subjects who were obese, it occurred more evenly across all lung zones. These findings show that obesity-associated factors alter the topographical distribution of ventilation.

Evaluation of histamine-provoked changes in airflow using electrical impedance tomography in horses.

BACKGROUND: Electrical impedance tomography (EIT) generates thoracic impedance images of the lungs and has been used to assess ventilation in horses. This technique may have application in the detection of changes in airflow associated with equine asthma. OBJECTIVES: The objective was to determine if histamine-induced airflow changes observed with flowmetric plethysmography (Δflow) could also be explained using global and regional respiratory gas flow signals calculated from EIT signals. STUDY DESIGN: Experimental in vivo study. METHODS: Six horses, sedated using detomidine were fitted with a thoracic EIT belt and flowmetric plethysmography hardware. Saline (baseline = BL) and increasing concentrations of histamine (C1-4) were nebulised into the face mask until a change in breathing pattern was clinically confirmed and Δflow increased greater or equal to 50%. After nebulisation Δflow and EIT images were recorded over 3 minutes and peak global inspiratory (InFglobal ) and expiratory (ExFglobal ) flow as well as peak regional expiratory and inspiratory flow for the dorsal and the ventral area of the right and left lungs were evaluated. Delta flow, InFglobal and ExFglobal at subsequent concentrations were indexed to baseline (yi  = Ci /BL-1). Indexed and nonindexed variables were evaluated for a difference from baseline at sequential histamine doses (time). Multiple linear regression assessment of variance in delta flow was also investigated. RESULTS: Consistent with histamine-provoked increases in Δflow, the global flow indices increased significantly. A significant increase in regional inspiratory flow was seen in the right and left ventral lung and dorsal right lung. Multiple regression revealed that the variance in ExFglobal , and right and left ventral expiratory flow best explained the variance in Δflow (r2  = .82). MAIN LIMITATIONS: Low number of horses and horses were healthy. CONCLUSIONS: Standardised changes in airflow during histamine challenge could be detected using EIT gas flow variables.

Predictive factors for a shortened methacholine challenge protocol in children.

RATIONALE: Although the methacholine challenge test is useful in the diagnosis of asthma, it is time-consuming in children. While protocols that quadruple methacholine concentrations are widely used in adults to shorten testing time, this has not been evaluated in children. Studies have not identified predictors associated with the safe use of a quadrupled concentration protocol. OBJECTIVES: To identify clinical predictors associated with the preclusion of a quadrupled concentration protocol in children. METHODS: We included subjects <18 years who performed a methacholine challenge tests between April 2016 to February 2017 (derivation cohort) and March 2017 to September 2017 (validation cohort). We determined the eligibility of a subject to omit the 0.5 mg/ml and 2.0 mg/ml concentrations based on their PC20 and identified baseline characteristics that are associated with the preclusion of the quadrupled protocol using bivariate analysis. The derived algorithm was applied to the validation cohort. RESULTS: We included 399 and 195 patients in the derivation and validation cohorts, respectively. A baseline FEV1 ≤90% predicted, FEV1/FVC ≤0.8, FEF25-75 ≤70% predicted, and a decrease in FEV1 ≥10% with the previous concentration significantly precluded the omission of the 0.5 mg/ml concentration. A baseline FEF25-75 ≤70% predicted and a drop in FEV1 ≥10% with the previous concentration significantly precluded the omission of the 2.0 mg/ml concentration. Applying these 4 criteria to the validation cohort resulted in an overall sensitivity and specificity of 74.0% and 84.6%, respectively. CONCLUSIONS: We identified objective pulmonary function measures that may personalize and shorten the methacholine challenge protocol in children by quadrupling concentrations.

The relationship between bronchoalveolar lavage fluid cytology and airway hyper-reactivity in a population of Australian horses presented for poor performance.

OBJECTIVE: To investigate the relationship between bronchoalveolar lavage fluid cytology, particularly mast cells, and airway hyper-reactivity in athletic horses presented for poor performance that included a respiratory tract evaluation in two disparate locations in Australia. DESIGN: Multi-centre, retrospective and prospective cross-sectional study METHODS: Eighty four adult horses underwent both pulmonary function testing and histamine bronchoprovocation with a commercial flowmetric plethysmography system. A bronchoalveolar lavage was performed four to twelve hours later. Bronchoalveolar lavage fluid cytology was categorised using two differing classification systems to define mild equine asthma. Statistical analysis was used to assess associations between bronchoalveolar lavage fluid relative inflammatory cell percentages, and airway hyper-reactivity and their associated categorisations. RESULTS: Sixty four percent (54/84) of horses displayed airway hyper-reactivity, as defined by PC35 < 6 mg/ml of histamine. A relative mastocytosis was the most common bronchoalveolar lavage fluid cytological abnormality. Horses with a sole mast cell response of ≥ 5% within their bronchoalveolar lavage fluid displayed airway hyper-reactivity at a lower dose of nebulized histamine than horses with normal bronchoalveolar lavage fluid cytology. Horses with mixed cell responses (relative mast cell percentage > 2% and/or relative neutrophil percentage > 5% and/or eosinophil relative cell percentage ≥ 1%) displayed airway hyper-reactivity at a lower dose of nebulized histamine than horses with normal bronchoalveolar lavage fluid cytology. CONCLUSION: In the Australian context, recently revised increased bronchoalveolar lavage fluid cytology relative cell percentage cut offs appear appropriate for sole mast cell responses. The historical lower cut offs appear to be appropriate for mixed inflammatory cell responses.

Bronchial Asthma and Bronchial Hyperresponsiveness and Their Characteristics in Patients with Common Variable Immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is one of the most frequent primary immunodeficiencies and is characterized by disturbed immunoglobulin production and dysregulation of the immune system. Results of previous studies suggest a higher prevalence of bronchial asthma (BA) in CVID patients than in the general population. We initiated this study to evaluate lung functions and identify risk factors for BA and bronchial hyperresponsiveness (BHR) in patients with CVID. METHODS: Twenty-three patients with CVID were included in this study. In all of them, spirometry and a metacholine bronchoprovocation test were performed. We also investigated the role of atopy, eosinophilic inflammation, and potential risk factors such as gender, age, or immunoglobulin levels at the time of diagnosis. RESULTS: BHR was confirmed in 12 patients (52%), all of whom had normal FEV1 and FEV1/FVC. However, BHR-positive patients had significantly decreased MEF25. BHR-positive patients had also more symptoms related to bronchial obstruction, with 8 of them (35%) being suspected of having BA at the end of the study. A higher prevalence of BHR was found in females, with a relative risk of 2.89. CONCLUSIONS: An increased prevalence of BHR and BA was detected in CVID patients compared to the general population. BA may develop despite the disturbed immunoglobulin production, and the majority of patients display nonatopic and noneosinophilic properties. These results suggest a limited role of atopy and eosinophilic inflammation in the pathogenesis of BA in CVID patients.

Bronchoprovocation Testing in Asthma: An Update.

Bronchial hyperresponsiveness (BHR) is defined as a heightened bronchoconstrictive response to airway stimuli. It complements the cardinal features in asthma, such as variable or reversible airflow limitation and airway inflammation. Although BHR is considered a pathophysiologic hallmark of asthma, it should be acknowledged that this property of the airway is dynamic, because its severity and even presence can vary over time with disease activity, triggers or specific exposure, and with treatment. In addition, it is important to recognize that there is a component that is not reflective of a specific disease entity.