Clinical analysis of the "small plateau" sign on the flow-volume curve followed by deep learning automated recognition.

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 FEV1% 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.

Evaluation of bronchial challenge test results for use in assessment of paediatric eczema: a retrospective series.

BACKGROUND: Atopic dermatitis (AD), asthma, and allergic rhinitis are associated diseases involved in the atopic march. The bronchial challenge test (BCT) is a tool that evaluates airway hyperresponsiveness in patients with asthma. This study aimed to evaluate whether a positive BCT result is useful in assessment of paediatric AD. METHODS: This retrospective case series included 284 patients with AD who had BCT results. Clinical information and laboratory parameters were reviewed, including AD severity (using the SCORing Atopic Dermatitis [SCORAD]), skin hydration, and transepidermal water loss. RESULTS: Of the 284 patients who had BCT, 106 had positive BCT results and 178 had negative BCT results. A positive BCT result was associated with a history of asthma (P<0.0005), sibling with asthma (P=0.048), serum immunoglobulin E (P=0.045), eosinophil count (P=0.017), and sensitisation to food allergens in the skin prick test (P=0.027). There was no association between a positive BCT result and personal allergic rhinitis, parental atopy, sibling allergic rhinitis or AD, skin prick response to dust mites, objective SCORAD score, skin hydration, transepidermal water loss, exposure to smoking, incense burning, cat or dog ownership, or AD treatment aspects (eg, food avoidance and traditional Chinese medicine). Logistic regression showed significant associations of a positive BCT result with a history of asthma (adjusted odds ratio=4.05; 95% confidence interval=1.92-8.55; P<0.0005) and sibling atopy (adjusted odds ratio=2.25; 95% confidence interval=1.03-4.92; P=0.042). CONCLUSIONS: In patients with paediatric AD, a positive BCT result was independently and positively associated with personal history of asthma and sibling history of atopy, but not with any other clinical parameters.

Identification of late asthmatic reactions following specific inhalation challenge.

Specific inhalation challenge (SIC) is the reference standard for the diagnosis of occupational asthma. Current guidelines for identifying late asthmatic reactions are not evidence based. OBJECTIVES: To identify the fall in forced expiratory volume in 1 s (FEV1) required following SIC to exceed the 95% CI for control days, factors which influence this and to show how this can be applied in routine practice using a statistical method based on the pooled SD for FEV1 from three control days. METHODS: Fifty consecutive workers being investigated for occupational asthma were asked to self-record FEV1 hourly for 2 days before admission for SIC. These 2 days were added to the in-hospital control day to calculate the pooled SD and 95% CI. RESULTS: 45/50 kept adequate measurements. The pooled 95% CI was 385 mL (SD 126), or 14.2% (SD 6.2) of the baseline FEV1, but was unrelated to the baseline FEV1 (r=0.06, p=0.68), or gender, atopy, smoking, non-specific reactivity or treatment before or during SIC. Thirteen workers had a late asthmatic reaction with ≥2 consecutive FEV1 measurements below the 95% CI for pooled control days, 4/13 had <15% and 9/13 >15% late fall from baseline. The four workers with ≥2 values below the 95% CI all had independent evidence of occupational asthma. CONCLUSION: The pooled SD method for defining late asthmatic reactions has scientific validity, accounts for interpatient spirometric variability and diurnal variation and can identify clinically relevant late asthmatic reactions from smaller exposures. For baseline FEV1 <2.5 L, a 15% fall is within the 95% CI.

Hyperpolarized Helium 3 MRI in Mild-to-Moderate Asthma: Prediction of Postbronchodilator Reversibility.

Background Longitudinal progression to irreversible airflow limitation occurs in approximately 10% of patients with asthma, but it is difficult to identify patients who are at risk for this transition. Purpose To investigate 6-year longitudinal changes in hyperpolarized helium 3 (3He) MRI ventilation defects in study participants with mild-to-moderate asthma and identify predictors of longitudinal changes in postbronchodilator forced expiratory volume in 1 second (FEV1) reversibility Materials and Methods Spirometry and hyperpolarized 3He MRI were evaluated in participants with mild-to-moderate asthma in two prospectively planned visits approximately 6 years apart. Participants underwent methacholine challenge at baseline (January 2010 to April 2011) and pre- and postbronchodilator evaluations at follow-up (November 2016 to June 2017). FEV1 and MRI ventilation defects, quantified as ventilation defect volume (VDV), were compared between visits by using paired t tests. Participants were dichotomized by postbronchodilator change in FEV1 at follow-up, and differences between reversible and not-reversible groups were determined by using unpaired t tests. Multivariable models were generated to explain postbronchodilator FEV1 reversibility at follow-up. Results Eleven participants with asthma (mean age, 42 years ± 9 [standard deviation]; seven men) were evaluated at baseline and after mean 78 months ± 7. Medications, exacerbations, FEV1 (76% predicted vs 76% predicted; P = .91), and VDV (240 mL vs 250 mL; P = .92) were not different between visits. In eight of 11 participants (73%), MRI ventilation defects at baseline were at the same location in the lung at follow-up MRI. In the remaining three participants (27%), MRI ventilation defects worsened at the same lung locations as depicted at baseline methacholine-induced ventilation. At follow-up, postbronchodilator FEV1 was not reversible in six of 11 participants; the concentration of methacholine to decrease FEV1 by 20% (PC20) was greater in FEV1-irreversible participants at follow-up (P = .01). In a multivariable model, baseline MRI VDV helped to predict postbronchodilator reversibility at follow-up (R 2 = 0.80; P < .01), but PC20, age, and FEV1 did not (R 2 = 0.63; P = .15). Conclusion MRI-derived, spatially persistent ventilation defects predict postbronchodilator reversibility 78 months ± 7 later for participants with mild-to-moderate asthma in whom there were no changes in lung function, medication, or exacerbations. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Stojanovska in this issue.

Detection of smoothly distributed spatial outliers, with applications to identifying the distribution of parenchymal hyperinflation following an airway challenge in asthmatics.

Methacholine challenge tests are used to measure changes in pulmonary function that indicate symptoms of asthma. In addition to pulmonary function tests, which measure global changes in pulmonary function, computed tomography images taken at full inspiration before and after administration of methacholine provide local air volume changes (hyper-inflation post methacholine) at individual acinar units, indicating local airway hyperresponsiveness. Some of the acini may have extreme air volume changes relative to the global average, indicating hyperresponsiveness, and those extreme values may occur in clusters. We propose a Gaussian mixture model with a spatial smoothness penalty to improve prediction of hyperresponsive locations that occur in spatial clusters. A simulation study provides evidence that the spatial smoothness penalty improves prediction under different data-generating mechanisms. We apply this method to computed tomography data from Seoul National University Hospital on five healthy and ten asthmatic subjects. Copyright © 2017 John Wiley & Sons, Ltd.

Variability of methacholine bronchoprovocation and the effect of inhaled corticosteroids in mild asthma.

BACKGROUND: The methacholine challenge test quantifies airway hyper-responsiveness, which is measured by the provocative concentration of methacholine causing a 20% decrease in forced expiration volume in 1 second (PC20). The dose-response effect of inhaled corticosteroids (ICS) on PC20 has been inconsistent and within-patient variability of PC20 is not well established. OBJECTIVE: To determine the effect of high- vs low-dose ICS on PC20 and within-patient variability in those with repeated measurements of PC20. METHODS: A randomized, double-masked, crossover trial was conducted in patients with asthma on controller medications with PC20 of 8 mg/mL or lower (n = 64) to evaluate the effect of high-dose (1,000 µg/d) vs low-dose (250 µg/d) fluticasone for 4 weeks on PC20. In addition, the variability of PC20 was assessed in participants who underwent 2 or 3 PC20 measurements on the same dose of ICS (n = 27) over a 4-week interval. RESULTS: Because there was a significant period effect, dose comparison of the change in PC20 was assessed in the first treatment period. There was no significant difference in the change in PC20 for high- vs low-dose ICS (39% vs 30% increase, respectively; P = .87). The within- and between-participant variances for log PC20 were 0.84 and 0.96, respectively, with an intra-class correlation of 0.53, and 37% of participants had more than 2 doubling dose changes in PC20 in those with repeated measurements. CONCLUSION: The effect of ICS on PC20 is not dose dependent at fluticasone levels of 250 and 1,000 µg/d. Interpersonal variability for PC20 is large. A lack of precise measurements should be taken into account when interpreting any change in PC20.

Bronchodilation test in patients with allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) may be considered a risk factor for the onset of asthma. Recently, it has been reported that forced expiratory flow between 25% and 75% of vital capacity (FEF25₋75) may predict a positive response to bronchodilation test in asthmatic children. The aim of this study was to evaluate a large group of adult AR patients to investigate the frequency of response to bronchodilation test and FEF25₋75 values. METHODS: One thousand four hundred and sixty-nine consecutive patients suffering from persistent AR were evaluated. Clinical examination, spirometry, and bronchodilation test were performed in all patients. RESULTS: In this study, 62.9% of patients had reversibility to bronchodilation test and 17.8% had impaired FEF25₋75 values (≤ 65% of predicted). Impaired FEF25₋75 values associated with longer rhinitis duration may predict reversibility to bronchodilation test (OR = 11.3; P < 0.001). In addition, a FEF25₋75 cutoff value ≤ 71% of predicted may already discriminate patients with reversibility. CONCLUSIONS: This study highlights that about two-thirds of patients with persistent AR may be considered at risk of becoming asthmatic. This finding should be adequately considered as a precocious spirometry may allow the early detection of patients prone to develop asthma and consequently to treat them.

[Occurrence of delayed symptoms after a challenge test with methacholine]. / Survenue de symptômes tardifs après un test de provocation par la méthacholine.

There are few prospective studies available on the development of delayed symptoms following challenge tests with methacholine (MCT) at the currently recommended doses. The objective of this study was to describe the nature and frequency of respiratory symptoms suggestive of bronchospasm developing within 24hours after a MCT. The study was offered to adult patients who underwent MCT seen consecutively between June and October 2015. Following the test, a questionnaire adapted from the GINA asthma control questionnaire bearing on diurnal and nocturnal symptoms (cough, dyspnoea, wheeze and tightness), was delivered to the patient and the replies collected by telephone 24hours later. Of the 101 patients included (initial FEV1 2.82±0.79L), 46 (46 %) were MCT+ and 55 (54 %) MCT-. Among the MCT-, 4 (7 %) presented with immediate symptoms (S+) and 4 (7 %) with delayed symptoms. Among the MCT+ patients, 36 (78 %) presented with immediate symptoms (P<0.001 compared with the MCT- patients), and 39 (85 %) with delayed symptoms (P<0.001 compared with the MCT- patients). Delayed symptoms developed with a mean of 5h30 after the provocation test. Immediate and delayed symptoms were more frequent in subjects having significant non-specific bronchial hyper-reactivity. Informing patients of the risk of developing delayed symptoms seems useful and allows optimization of their management after a MCT.

Patterns of sensitization to inhalant and food allergens among pediatric patients from the Moscow region (Russian Federation).

The immunological profiles of human specific IgE (sIgE) and specific IgG4 (sIgG4) vary by genetic predisposition, living conditions in different geographical locations and patient's age. The aim of our study was to analyze sIgE and sIgG4 patterns and their age-dependent changes in patients from the Moscow region. For identifying sIgE and sIgG4 profiles the blood samples from 513 patients aged 6 months to 17 years who were showing symptoms of allergic diseases were analyzed using microarrays containing 31 allergens. The highest sIgE prevalence was observed for birch pollen (32%) among pollen allergens, cat dander (24%) among indoor allergens, and egg whites (21%) among food allergens. The most common sIgG4 response was developed toward egg whites (80% of patients). Age-related elevation was identified for patients with increased sIgE to pollen allergens and indoor allergens (cat or dog dander and house dust mites). For each allergen, the proportion of cases with significant levels of sIgG4 appeared to increase with patients' age. The data on allergen-specific sIgE and sIgG4 prevalence show both general trends and some local special aspects that are indicative for the Moscow region. This information should be useful in terms of epidemiology of allergic diseases.

Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma.

BACKGROUND: In diagnosing cough due to asthma, methacholine chloride inhalation challenge (MIC) interpreted in a traditional fashion has been shown to have positive predictive values from 60% to 82%. OBJECTIVE: To determine whether any features of positive results of an MIC or the results of a 1-week trial of inhaled beta-agonist therapy were helpful in predicting when the cough was due to asthma. METHODS: The study design was a prospective, randomized, double-blind, placebo-controlled, crossover format performed in adult, nonsmoking subjects, who were referred for diagnosis and treatment of chronic cough. The subjects had no other respiratory complaints or medical conditions for which they were taking medications, the results of baseline spirometry and chest roentgenograms were normal, and the results of MIC were positive. After obtaining baseline data, including MICs on 2 separate days, objective cough counting, and self-assessment of cough severity using a visual analog scale, subjects were randomized to receive 2 inhalations (1.3 mg) of metaproterenol sulfate or placebo by metered dose inhaler attached to a spacer device every 4 hours while awake. At 1 week, data identical to baseline were collected, and subjects received the other metered dose inhaler for 7 days. At 1 week, data identical to baseline were collected. After completion of the protocol, subjects were followed up in the clinic to observe the final response of the cough to specific therapy. RESULTS: Based on the disappearance of the cough with specific therapy, the cough was due to asthma in 9 of 15 subjects and nonasthma in 6 of 15 subjects. Baseline data were similar between groups. With respect to MICs, there were no significant differences between groups in the cumulative dose of methacholine that provoked a 20% decrease in forced expiratory volume in 1 second from the postsaline baseline value (PD20 values), slopes of dose-response curves, and maximal-response plateaus. Cough severity significantly improved after 1 week of metaproterenol use compared with the severity of the cough at baseline (P = .03) and with placebo (P = .02) only in subjects with asthma. CONCLUSIONS: No matter how the results are analyzed, positive MIC results, without observing response to therapy, are only consistent with asthma as the cause of the cough. The results are only diagnostic of asthma when they are followed by a favorable response to asthma therapy. After 1 week of inhaled beta-agonist, only the cough due to cough-variant asthma is significantly better.

Challenge studies of a leukotriene receptor antagonist.

The leukotriene receptor antagonist pranlukast (SB 205312, ONO-1078) has demonstrated clinical activity as an antiasthma drug in traditional challenge models, including exercise-induced asthma and inhaled bronchoprovocations with sulpyrine (an aspirin analogue), antigen, methacholine, leukotriene C4, and leukotriene D4. This article reviews the results of a published sulpyrine-challenge study and two unpublished house dust mite antigen challenge studies. Statistically significant attenuation of the decrease in FEV1 induced by bronchoprovocation was observed with pranlukast compared with placebo or baseline control in all challenge studies. These challenge studies demonstrate that pranlukast significantly protects against aspirin-induced bronchoconstriction and significantly attenuates both the immediate (early) and late airway responses to inhaled allergen.

Post-test probability of asthma following methacholine challenge.

Using recently published data, a nomogram was constructed to estimate the likelihood of asthma following methacholine challenge. Based on Bayes' theorem, the nomogram makes use of the sensitivity and specificity of methacholine challenge to calculate the post-test probability of asthma once the physician makes a determination of the pretest probability, that is, the likelihood of asthma before the test results are considered. A family of curves is presented to cover several levels of cumulative breath units at which the test could become positive, and a single curve is presented for a negative test after 224 cumulative breath units. Separate curves are presented for smokers and nonsmokers. The estimate of pretest probability is most crucial in negative tests where likelihood of asthma is considered high, and in positive tests in patients in whom asthma is considered unlikely. Although these curves will not apply precisely to a different data base, the concept of the relationship between pretest and post-test probability helps in the interpretation of the test results and stresses the importance of using all available information in making a diagnosis.

The lack of a role for saline solution inhalation in bronchoprovocation challenge.

The purpose of this study was to look prospectively at the practice of prefacing methacholine bronchoprovocation challenge (BPC) with diluent challenge using physiologic saline solution (NaCl) as the diluent. We wished to determine whether NaCl challenge added to the safety or diagnostic accuracy of BPC. We studied 108 consecutive patients undergoing methacholine BPC. We determined (1) the FEV1 response of all patients to the inhalation of NaCl (the difference between the FEV1 before NaCl and the FEV1 after NaCl), and (2) the correlation between the response to saline solution and bronchial hyperresponsiveness (BHR) measured using methacholine. Paired Student's t testing demonstrated a small but significant difference between the values for FEV1 before and after NaCl for the group as a whole (n = 108; mean change, -0.9 +/- 4 percent [+/- SD]; p = 0.023). When the mean changes in the FEV1 after NaCl for the group with increased BHR (BHR+) (n = 62; mean, -1.1 +/- 4.9 percent) and the group with no increase in BHR (BHR-) (n = 46; mean, -0.6 +/- 2.4 percent) were contrasted, there was no significant difference between the two groups (p = 0.46). Only 4 of 108 patients had a drop in FEV1 of 10 percent or more after NaCl, with the greatest drop being 16 percent. All four patients were BHR+, but none had marked BHR. For the BHR+ group, there was no correlation between response to saline solution and subsequent response to methacholine (r = 0.02). We conclude that saline solution challenge adds time and expense to BPC without increasing the safety or yield of BPC. We suggest that NaCl challenge can be omitted from the standard performance of BPC.

Normal range of methacholine responsiveness in relation to prechallenge pulmonary function. The Normative Aging Study.

Methacholine airway responsiveness has been observed to be related to prechallenge level of pulmonary function; however, normal ranges of responsiveness for specific levels of lung function have not been reported. We examined methacholine airway responsiveness in relation to level of prechallenge pulmonary function in a sample of 547 middle-aged and elderly men who denied any history of respiratory illness or symptoms and who had normal levels of prechallenge FEV1 and FEV1/FVC ratio. The cumulative dose of methacholine provoking a 20 percent decline in FEV1 (PD20FEV1) was positively correlated with prechallenge FEV1 percent predicted (Spearman correlation r = 0.35, p < 0.0001). The fifth percentile of PD20FEV1, chosen as an estimate of the lower limit of the normal range, varied with the level of prechallenge FEV1. When applied to a larger sample of 838 men with normal pulmonary function, the use of FEV1-specific cut-off values to separate "normal" from "abnormal" PD20FEV1 did not improve the sensitivity or specificity of methacholine challenge as a test for questionnaire-reported asthma or wheezing. These data provide lower limits of normal PD20FEV1 which are specific for a subject's prechallenge FEV1; however, these FEV1-specific lower limits of normal PD20FEV1 provided no greater sensitivity and specificity for detecting asthma and wheezing than did a single lower limit of normal PD20FEV1 for all subjects.

Diagnostic value of the bronchial provocation test with methacholine in asthma. A Bayesian analysis approach.

The Bayesian analysis was used in this study to investigate the diagnostic value of the bronchial provocation test with methacholine in patients with asthma. The best cutoff value of accumulated concentration of methacholine administered that caused a 20 percent fall in FEV1 post-saline (PC20) in our sample, determined with a receiver operator characteristic curve, was 15 mg/ml. The interval security of the test was established by a pretest probability between 0.16 and 0.87 and the best test results were obtained when pretest probability was 0.48. The positive final diagnostic gain of the test was maximal at this pretest probability. We conclude that the application of Bayes' theorem, considering the pretest probability of asthma and the sensitivity and specificity of the individual PC20 obtained, increases the accuracy of the bronchial provocation test with methacholine in the diagnosis of asthma.

Effect of posture on bronchial reactivity to inhaled methacholine in patients with mitral valve stenosis.

To compare the effects of posture on bronchial reactivity in 12 patients with mitral valve stenosis (MS) and 10 with bronchial asthma (BA), a methacholine inhalation test was performed 2 h after being in either a supine or sitting position. All patients showed bronchial hyperreactivity to inhaled methacholine before the study. In MS patients, logarithmic values of the cumulative dose producing a 35 percent decrease in respiratory conductance (log PD35Grs) were significantly lower 2 h after being in a supine position than in those after being in a sitting position (0.71 +/- 0.78, 1.02 +/- 0.53 log units, respectively, p < 0.05). In BA patients, however, log PD35Grs did not show significant changes (0.42 +/- 0.51, 0.58 +/- 0.48 log units, respectively). Variables of pulmonary function tests showed no significant differences between the two positions in both patients with MS and BA. We conclude that the bronchial hyperreactivity in MS is enhanced after the supine position for 2 h and that the supine posture may play an important role in the pathogenesis of cardiac asthma.

Use of specific inhalation challenge in the evaluation of workers at risk for occupational asthma: a survey of pulmonary, allergy, and occupational medicine residency training programs in the United States and Canada.

STUDY OBJECTIVES: To document the current practice of occupational asthma (OA) diagnosis and use of specific inhalation challenge (SIC). DESIGN, SETTING, AND PARTICIPANTS: A survey evaluating the current practice of SIC was mailed to 259 residency training programs in adult pulmonary diseases, allergy and immunology, and occupational medicine accredited in the United States and Canada during the year 2000. RESULTS: Forty-six percent (123 of 259 programs) participated. Ninety-two programs reported that patients with OA were seen during the previous year, 15 programs reported that SIC had been performed, and 10 programs reported that patients had been referred to other sites for SIC. A total of 259 patients underwent SIC. No unexpected adverse reactions were reported. Forty-one programs reported that they had been willing to undertake SIC but were unable to do so. The most common barriers cited were lack of availability of SIC within the evaluating institution, inability to locate a site for referral, concerns about reimbursement, and lack of an appropriate diagnostic reagent for use in SIC. Seventy-four programs indicated that SIC was useful, and 34 programs included training in the use of SIC was part of the residency curriculum. CONCLUSION: Although SIC is considered the "gold standard" for objective documentation of OA, the test is performed in only a few institutions in the United States and Canada. Many institutions indicate that SIC is not available, even when desired for patient management. Only a minority of participating residency training programs include SIC as a formal part of the training curriculum.

Bronchial reactivity to methacholine in HIV-infected individuals without AIDS.

To evaluate bronchial reactivity to methacholine in human immunodeficiency virus (HIV) infection, we submitted 25 HIV-seropositive subjects without full-blown AIDS and 25 HIV-seronegative subjects, all inmates in a drug rehabilitation center for previous intravenous drug abuse, to interview and to bronchial challenge with methacholine. Four (16 percent) HIV-seropositve and three (12 percent) HIV-seronegative subjects noted bronchospastic symptoms. Baseline FEV1 and MEF50 percent were within the normal range in every patient. Bronchial hyperreactivity to methacholine (PD20FEV1 < 1,400 micrograms) was found in two (8 percent) HIV-seropositive and in four (16 percent) HIV-seronegative subjects, with no significant difference in the frequency between the two groups. We conclude that HIV infection without AIDS in intravenous drug users does not appear to be associated with an increased frequency of bronchospastic disorders and to bronchial hyperreactivity to methacholine.