Development of a graphical tool to measure medication adherence in asthma patients: A mixed-methods pilot study.

OBJECTIVES: ( 1 ) To develop Med-Resp, a graphical tool based on prescription refills to measure adherence and use of asthma medications; ( 2 ) To test the feasibility of implementing Med-Resp in a hospital outpatient asthma clinic; ( 3 ) To explore the effectiveness of Med-Resp to improve medication adherence to asthma controller medications. METHODS: A sequential exploratory design was used: ( 1 ) Prototype design in collaboration with respiratory physicians and patients via focus groups; ( 2 ) Med-Resp creation based on algorithms developed and applied to prescription refills data recorded in the drug claims database reMed; ( 3 ) Feasibility assessment of the implementation of Med-Resp in the outpatient asthma clinic; and ( 4 ) Exploration of the effectiveness of Med-Resp through a pre-post design. RESULTS: A total of 29 patients and six respiratory physicians participated in this pilot study. The tool was highly appreciated by the participants, while the majority believed that Med-Resp has the potential to enhance physician-patient communication and aid in treatment decisions. The feasibility of implementing Med-Resp in clinical practice was demonstrated. However, we did not observe an increase in medication adherence in the six months following its implementation. CONCLUSION: In the clinical setting, the use of prescription refills data may constitute a non-invasive and objective measure of medication adherence. This study highlights the importance of providing clinicians with objective and easily interpretable measures of medication adherence and use in routine clinical practice. Med-Resp has the potential to become implemented on a larger scale if integrated in electronic medical records.

Novel clinical scores for occupational asthma due to exposure to high-molecular-weight agents.

OBJECTIVE: Specific inhalation challenge (SIC) as the reference diagnostic test for occupational asthma (OA) is not widely available worldwide. We aimed to develop non-SIC-based models for OA. METHODS: Of 427 workers who were exposed to high-molecular-weight agents and referred to OA clinic at Montréal Sacré-Cœur Hospital between 1983 and 2016, we analysed 160 workers who completed non-specific bronchial hyper-responsiveness (NSBHR) tests and still worked 1 month before SIC. OA was defined as positive SIC. Logistic regression models were developed. The accuracy of the models was quantified using calibration and discrimination measures. Their internal validity was evaluated with bootstrapping procedures. The final models were translated into clinical scores and stratified into probability groups. RESULTS: The final model, which included age ≤40 years, rhinoconjunctivitis, inhaled corticosteroid use, agent type, NSBHR, and work-specific sensitisation had a reasonable internal validity. The area under the receiver operating characteristics curve (AUC) was 0.91 (95% CI 0.86 to 0.95), statistically significantly higher than the combination of positive NSBHR and work-specific sensitisation (AUC=0.84). The top 70% of the clinical scores (ie, the high probability group) showed a significantly higher sensitivity (96.4%vs86.9%) and negative predictive value (93.6%vs84.1%) than the combination of positive NSBHR and work-specific sensitisation (p value <0.001). CONCLUSIONS: We developed novel scores for OA induced by high-molecular-weight agents with excellent discrimination. It could be helpful for secondary-care physicians who have access to pulmonary function test and allergy testing in identifying subjects at a high risk of having OA and in deciding on appropriate referral to a tertiary centre.

Genetic variants with gene regulatory effects are associated with diisocyanate-induced asthma.

BACKGROUND: Isocyanates are major causes of occupational asthma, but susceptibility and mechanisms of diisocyanate-induced asthma (DA) remain uncertain. OBJECTIVE: The aim of this study was to identify DA-associated functional genetic variants through next-generation sequencing (NGS), bioinformatics, and functional assays. METHODS: NGS was performed in 91 workers with DA. Fourteen loci with known DA-associated single nucleotide polymorphisms (SNPs) were sequenced and compared with data from 238 unexposed subjects. Ranking of DA-associated SNPs based on their likelihood to affect gene regulatory mechanisms in the lung yielded 21 prioritized SNPs. Risk and nonrisk oligonucleotides were tested for binding of nuclear extracts from A549, BEAS-2B, and IMR-90 lung cell lines by using electrophoretic mobility shift assays. DNA constructs were cloned into a pGL3 promoter vector for luciferase gene reporter assays. RESULTS: NGS detected 130 risk variants associated with DA (3.1 × 10-6 to 6.21 × 10-4), 129 of which were located in noncoding regions. The 21 SNPs prioritized by using functional genomic data sets were in or proximal to 5 genes: cadherin 17 (CDH17; n = 10), activating transcription factor 3 (ATF3; n = 7), family with sequence similarity, member A (FAM71A; n = 2), tachykinin receptor 1 (TACR1; n = 1), and zinc finger and BTB domain-containing protein 16 (ZBTB16; n = 1). Electrophoretic mobility shift assays detected allele-dependent nuclear protein binding in A549 cells for 8 of 21 variants. In the luciferase assay 4 of the 21 SNPs exhibited allele-dependent changes in gene expression. DNA affinity precipitation and mass spectroscopy of rs147978008 revealed allele-dependent binding of H1 histones, which was confirmed by using Western blotting. CONCLUSIONS: We identified 5 DA-associated potential regulatory SNPs. Four variants exhibited effects on gene regulation (ATF rs11571537, CDH17 rs2446824 and rs2513789, and TACR1 rs2287231). A fifth variant (FAM71A rs147978008) showed nonrisk allele preferential binding to H1 histones. These results demonstrate that many DA-associated genetic variants likely act by modulating gene regulation.

Impact of Panic Attacks on Bronchoconstriction and Subjective Distress in Asthma Patients With and Without Panic Disorder.

OBJECTIVE: Panic disorder (PD) is common among asthma patients and is associated with worse asthma outcomes. This may occur because of psychophysiological factors or cognitive/affective factors. This study evaluated the impact of panic attacks (PAs) on bronchoconstriction and subjective distress in people who have asthma with and without PD. METHODS: A total of 25 asthma patients (15 with PD who had a PA [PD/PA], 10 without PD who did not have a PA [no PD/no PA]) were recruited from an outpatient clinic. They underwent a panic challenge (one vital capacity inhalation of 35% carbon dioxide [CO2]) and completed the Panic Symptom Scale, the Subjective Distress Visual Analogue Scale, and the Borg Scale before and after CO2. Forced expiratory volume in 1 second was assessed pre- and post-CO2; respiratory (i.e., CO2 production, minute ventilation, tidal volume) was continuously recorded, and physiological measures (i.e., systolic and diastolic blood pressure [SBP/DBP]) were recorded every 2 minutes. RESULTS: Analyses adjusting for age, sex, and provocative concentration of methacholine revealed no significant differences between groups in forced expiratory volume in 1 second change after CO2 inhalation (F(1, 23) < 0.01, p = .961). However, patients with PD/PA reported more panic (F(1, 22) = 18.10, p < .001), anxiety (F(1, 22) = 21.93, p < .001), worry (F(1, 22) = 26.31, p < .001), and dyspnea (F(1,22) = 4.68, p = .042) and exhibited higher levels of CO2 production (F(1, 2843) = 5.89, p = .015), minute ventilation (F(1, 2844) = 4.48, p = .034), and tidal volume (F(1, 2844) = 4.62, p = .032) after the CO2 challenge, compared with patients with no PD/no PA. CONCLUSIONS: Results, presented as hypothesis generating, suggest that asthma patients with PD/PA exhibit increased panic-like anxiety, breathlessness, and a respiratory pattern consistent with hyperventilation that was not linked to statistically significant drops in bronchoconstriction.

Review of Diagnostic Challenges in Occupational Asthma.

PURPOSE OF REVIEW: Occupational asthma (OA) is one of the most frequent occupational diseases and its diagnosis is often difficult. This review summarizes its current diagnostic challenges. RECENT FINDINGS: OA is associated with significant health and socio-economic burden. It is underdiagnosed and physicians need to adopt a stepwise approach to confirm the diagnosis. Although early removal from exposure to the offending agent is associated with a better prognosis, physicians should try to confirm the diagnosis of work-related asthma before taking a worker off work. A proper occupational and medical history is very important but is not enough to make the diagnosis of OA. Objective evidence of work-related asthma is required and this represents a serious challenge to most physicians. Measurement of non-specific bronchial responsiveness (NSBR) and spirometry may confirm the diagnosis of asthma but do not confirm the diagnosis of OA. Serial monitoring of peak expiratory flows (PEF), NSBR, and airway inflammation at and off work may confirm the diagnosis of OA but are often difficult to perform. Confirming sensitization by skin prick tests or specific IgE may help to support the diagnosis of OA. Specific inhalation challenges (SIC) in the lab or at work are considered the reference standard but are of limited access. Medical surveillance programs along with primary prevention (reducing exposure) may help to reduce the burden of OA, but the ideal program has yet to be defined. The diagnostic workup of OA remains a challenge and needs a rigorous stepwise evaluation.

Predictive value of nonspecific bronchial responsiveness in occupational asthma.

BACKGROUND: The diagnosis of occupational asthma (OA) can be challenging and needs a stepwise approach. However, the predictive value of the methacholine challenge has never been addressed specifically in this context. OBJECTIVE: We sought to evaluate the sensitivity, specificity, and positive and negative predictive values of the methacholine challenge in OA. METHODS: A Canadian database was used to review 1012 cases of workers referred for a suspicion of OA between 1983 and 2011 and having had a specific inhalation challenge. We calculated the sensitivity, specificity, and positive and negative predictive values of methacholine challenges at baseline of the specific inhalation challenge, at the workplace, and outside work. RESULTS: At baseline, the methacholine challenge showed an overall sensitivity of 80.2% and a specificity of 47.1%, with positive and negative predictive values of 36.5% and 86.3%, respectively. Among the 430 subjects who were still working, the baseline measures displayed a sensitivity of 95.4%, a specificity of 40.1%, and positive and negative predictive values of 41.1% and 95.2%, respectively. Among the 582 subjects tested outside work, the baseline measures demonstrated a sensitivity and specificity of 66.7% and 52%, respectively, and positive and negative predictive values of 31.9% and 82.2%, respectively. When considering all subjects tested by a methacholine challenge at least once while at work (479), the sensitivity, specificity, and positive and negative predictive values were 98.1%, 39.1%, and 44.0% and 97.7%, respectively. CONCLUSION: A negative methacholine challenge in a patient still exposed to the causative agent at work makes the diagnosis of OA very unlikely.

Prevalence of psychiatric disorders among patients investigated for occupational asthma: an overlooked differential diagnosis?

RATIONALE: Up to one-third of patients assessed for occupational asthma (OA) do not receive a diagnosis of OA or any other medical disorder. Although several differential diagnoses are considered (e.g., rhinitis, chronic obstructive pulmonary disease), psychiatric disorders (many with somatic complaints that mimic asthma) are rarely considered or assessed. OBJECTIVES: To assess the prevalence of psychiatric disorders (mood and anxiety disorders and hypochondriasis) in patients suspected of having OA, and whether psychiatric morbidity increases the risk of not receiving any medical diagnosis. METHODS: A total of 219 consecutive patients (57% male; mean age, 41.8 ± 11.1 yr) underwent sociodemographic and medical history interviews on the control or specific inhalation testing day of their OA evaluation. The Primary Care Evaluation of Mental Disorders was used to assess mood and anxiety disorders, and the Whiteley Hypochondriasis Index was used to assess hypochondriasis. MEASUREMENTS AND MAIN RESULTS: A total of 26% (n = 50) of patients had OA; 25% (n = 48) had asthma or work-exacerbated asthma; 14% (n = 28) had another inflammatory disorder; 13% (n = 26) had a noninflammatory disorder; and 22% (n = 44) did not receive any medical diagnosis. A total of 34% (n = 67) of patients had a psychiatric disorder: mood and anxiety disorders affected 29% (n = 57) and 24% (n = 46) of the sample, respectively, and 7% (n = 12) had scores on the Whiteley Hypochondriasis Index indicating hypochondriasis. Hypochondriasis, but not mood or anxiety disorders, was associated with an increased risk of not receiving any medical diagnosis (adjusted odds ratio, 3.92; 95% confidence interval, 1.18-13.05; P = 0.026). CONCLUSIONS: Psychiatric morbidity is common in this population, and hypochondriasis may account for a significant proportion of the "undiagnosable" cases of patients who present for evaluation of OA.

New causes of immunologic occupational asthma 2014-2020.

PURPOSE OF REVIEW: The purpose of this review was to list all new confirmed cases of immunological occupational asthma (IOA) described between mid-2014 and April 2020. RECENT FINDINGS: Several new agents, both of high and low molecular weight, have been identified in the last 6 years as potential respiratory sensitizers being able to induce immunological occupational asthma. This review confirms that new causes of IOA are still identified regularly, particularly in subjects exposed to high molecular agents, in the food industry (farming, pest control, food processing), pharmaceutical industry (antibiotics, various drugs) and cosmetic environment (dyes, powders). SUMMARY: It stressed the need for clinicians to stay alert and suspect occupational asthma in any adult with new onset asthma or newly uncontrolled asthma.

The role of inhalant food allergens in occupational asthma.

Workers handling food products and derivatives are at increased risk of developing occupational asthma. Exposure to food allergens occurs primarily through inhalation of dust, steam, vapors, and aerosolized proteins generated during cutting, scrubbing or cleaning, cooking or boiling, and drying activities. Suspicion of the diagnosis of occupational asthma should lead to proper investigation to confirm the diagnosis objectively. Most inhaled food allergy is IgE mediated, and skin prick tests or specific IgE tests are useful tools to support the diagnosis, but objective evidence of asthma by monitoring of peak expiratory flows at and off work or specific inhalation challenges offers a better diagnostic value. This article provides a list of the various foods, food additives, and contaminants that have been associated with occupational asthma.

Identification of crab proteins that elicit IgE reactivity in snow crab-processing workers.

BACKGROUND: The expanding snow crab-processing industry has resulted in increased numbers of workers at risk of occupational allergy. OBJECTIVE: Our study is to identify relevant allergenic proteins in cooked snow crab meat (CM) and crab water (CW) used for cooking for improved remediation, diagnosis, and treatment. METHODS: Extracts were prepared from CM extracts, CW extracts, and an air-filter collection near the crab cooker. Of the 207 workers, 24 with the highest IgE antibody reactivity to CM and CW extracts, as determined by using RASTs, were tested for reactivity to nitrocellulose membranes containing CM and CW proteins separated with SDS-PAGE. A 3-serum pool was similarly incubated against nitrocellulose-bound proteins from air samples collected near the crab cooker. RESULTS: Of the 207 sera tested, 27 and 39 sera exhibited positive IgE antibody reactivity (>or=2%) to CM and CW extracts, respectively. Twenty-two of 24 sera with the highest RAST activity (>or=3.5% binding) demonstrated IgE binding to multiple proteins (13.6-50 kd). A majority of the sera reacted to 4 proteins: 79% and 71% to a 34.0-kd protein, 79% and 42% to a 25-kd protein, 67% and 71% to an 18.5-kd protein, and 75% to a 14.4-kd protein in both CM and CW extracts, respectively. The pool of IgE-positive sera blotted against the air-filter extract reacted to 14.4-, 18.5-, 34.0-, 43.2-, and 50-kd proteins present in both crab extracts. CONCLUSION: Four major IgE-reactive proteins were identified in CM extracts, CW extracts, and air-filter eluate. Analysis of any potential association of protein reactivity with disease suggested crab proteins at 34.0 and 14.4 kd might be more relevant.

Chronic obstructive pulmonary disease patients with psychiatric disorders are at greater risk of exacerbations.

OBJECTIVE: To assess prospectively the impact of psychiatric disorders on risk for exacerbations. The course of chronic obstructive pulmonary disease (COPD) is punctuated by acute exacerbations. Although anxiety and mood disorders are common in patients with COPD, no studies have assessed prospectively the association between these disorders and exacerbations. METHODS: Psychiatric disorders were evaluated by a structured psychiatric interview in 110 patients (51% women, age (mean +/- standard deviation) = 66 +/- 8 years) with stable COPD and previous admission for exacerbations recruited from two outpatient clinics. Patients were followed for a mean of 2 years and both inpatient-treated (i.e., treated in the emergency department or hospital) and outpatient-treated (i.e., treated with medication in the patient's own environment) exacerbations were recorded. RESULTS: Independent of covariates, patients with psychiatric disorders exhibited a significantly higher weighted annual rate of exacerbations treated in an outpatient setting after adjustment for covariates (3 versus 2, p = .003) than patients without psychiatric disorders, but no difference in exacerbations treated in the inpatient setting. They were also at a higher risk for any (relative risk (RR) = 1.56, 95% Confidence Interval (CI) = 1.02-2.37) and outpatient (RR = 1.68, 95% CI = 1.08-2.59) exacerbations, but not inpatient exacerbations (RR = 1.36, 95% CI = 0.82-2.25). CONCLUSIONS: Patients with psychiatric disorders are at greater risk of exacerbations treated in an outpatient setting but not those treated in an inpatient setting. These outpatient-managed exacerbations account for a significant proportion of the healthcare burden for COPD, so interventions should target patients with psychiatric disorders to improve management of COPD.

Association Between Depression, Lung Function, and Inflammatory Markers in Patients with Asthma and Occupational Asthma.

OBJECTIVE: Depression is associated with autonomic and immune dysregulation, yet this remains poorly explored in asthma. We assessed associations between depressive disorder, lung function, and inflammatory markers in patients under investigation for occupational asthma (OA). METHODS: One hundred twelve patients under investigation for OA (60% men) underwent a psychiatric interview to assess depressive disorder, and spirometry, a methacholine test, sputum induction, and specific inhalation challenge (SIC) to assess OA. Blood and sputum inflammatory markers were assessed. RESULTS: There was a statistically significant association between depressive disorder (P = 0.0195) and forced expiratory volume in 1 second (FEV1) responses, with the drop in FEV1 post-SIC smaller in patients with OA and depression, versus OA with no depression (P < 0.001). CONCLUSION: The presence of depressive disorder may influence FEV1 in patients with OA, which may be via autonomic pathways. However, further studies are warranted in order to determine the mechanisms that underlie these effects.

New insights into occupational asthma.

PURPOSE OF REVIEW: To examine recent publications on the types of agents involved in occupational asthma, the mechanisms by which they induce asthma, and how best to evaluate and treat workers suspected of this respiratory condition. RECENT FINDINGS: High rates of occupational asthma and inhalation accidents were found in workers in crafts and related occupations in the manufacturing industries, and in plant and machine operatives; cleaners and construction workers may also be at risk. Further data support a role for CD4 T cells in low-molecular-weight agent-induced asthma, such as with isocyanates, and neurogenic mechanisms may also be involved. The use of noninvasive measures of airway inflammation in the diagnosis and management of occupational asthma such as sputum eosinophils monitoring is promising, although this is less obvious for exhaled nitric oxide. Finally, the persistence of troublesome asthma even after withdrawal from relevant exposure has been re-emphasized and surveillance programs have been proposed. SUMMARY: Further data have been gathered on the prevalence of occupational asthma in various working populations, its mechanisms of development, the contribution of noninvasive measures of airway inflammation in the diagnosis and management of this condition, and its management and prevention.

Comparison of peak expiratory flow variability between workers with work-exacerbated asthma and occupational asthma.

BACKGROUND: Peak expiratory flow (PEF) monitoring is frequently used to diagnose occupational asthma (OA). The variability of PEF between periods at work and away from work has not been described in workers with work-exacerbated asthma (WEA). We sought to assess and compare the diurnal variability of PEF during periods at and away from work between subjects with OA and WEA. METHODS: Workers referred for work-related asthma underwent PEF monitoring for 2 weeks at and away from work. The diagnostic of OA or WEA was subsequently made according to the respective positivity or negativity of the specific inhalation challenges. PEF mean diurnal variability was calculated during periods at and away from work. PEF graphs were also interpreted using direct visual analysis by five observers and using a computer program (Oasys-2, Expert System ) [available at: http://www.occupationalasthma.com]. RESULTS: Thirty-four subjects were investigated (WEA, n = 15; OA, n = 19). There was a greater variability of PEF at work than away from work in both OA (19.8 +/- 8.7% vs 10.7 +/- 6.3%, p < 0.001) and WEA (14.2 +/- 4.8% vs 10.6 +/- 5.6%, p = 0.02). However, the magnitude of the variability was higher in OA than in WEA (p = 0.02). The visual interpretation of PEF or the Oasys-2 program failed to distinguish WEA from OA. CONCLUSION: Although workers with OA showed a higher PEF variability than workers with WEA when at work, clinicians were unable to reliably differentiate OA from WEA using the visual interpretation of PEF graphs or the computerized analysis.

Sex differences in the prevalence of psychiatric disorders and psychological distress in patients with COPD.

BACKGROUND: Psychiatric disorders are highly prevalent in patients with COPD. In general, psychiatric disorders are more common in women than in men. The extent to which women with COPD suffer from greater psychiatric and psychological morbidity is not known. The present cross-sectional study evaluated the prevalence of mood and anxiety disorders, levels of psychological distress, and quality of life in 62 women and 54 men with documented, stable COPD. METHODS: All patients (n = 116) underwent a sociodemographic and medical history interview, followed by a structured psychiatric interview and standard spirometry. Patients also completed a battery of questionnaires measuring psychological distress and quality of life. RESULTS: The overall prevalence of psychiatric disorders was 49%. Significantly more women than men met the diagnostic criteria for anxiety disorders (56% vs 35%), and a trend for greater levels of major depression in women was found (18% vs 7%). Women had significantly higher anxiety sensitivity and depressive symptoms compared to men but did not report more limitations in psychological functioning. Women also reported being less confident in their ability to control respiratory symptoms, and more daily physical limitations compared to men, despite having comparable COPD severity, dyspnea scores, and exacerbation rates. CONCLUSIONS: Results indicate that psychiatric disorders are at least three times higher in COPD patients compared to the general population, and nearly two times higher in women than in men. Women also have greater psychological distress, worse perceived control of symptoms, and greater functional impairment. Greater efforts should be made to identify and treat psychiatric disorders in COPD patients, particularly in women.

Cost-effectiveness of various diagnostic approaches for occupational asthma.

BACKGROUND: Diagnosis of occupational asthma (OA) by specific inhalation challenge (SIC) can be costly and is not always available. The use of sputum testing to avoid this in some patients may be a more cost-effective alternative. OBJECTIVES: To compare the cost-effectiveness of SIC with serial measurements of sputum cell counts (sputum testing) and peak expiratory flow (PEF) monitoring. METHODS: Clinical data and testing costs for OA in 49 patients were collected during a previously published trial, modelled and compared using TreeAge Pro. Clinical outcome was the percentage of accurately diagnosed patients, using SIC as the gold standard. The PEF approach used the most accurate assessment of five experts who were blinded to SIC results. Differences in the proportion of eosinophils during periods on and off work were used for the sputum testing approach and in PEF/sputum for the combined approach. Unit costs were estimated from charges in Canadian hospitals. Data were analyzed by one-way and two-way analyses, and by probabilistic sensitivity analysis using a Monte Carlo simulation technique. RESULTS: The PEF approach had an estimated accuracy of 52% and cost $365 per patient tested. Compared with PEF monitoring, sputum testing was more accurate and cost an estimated $255 for each additional OA patient correctly diagnosed. SIC costs per additional correct diagnosis were $11,032 compared with sputum testing and $6,458 compared with PEF monitoring. The combined PEF/sputum testing approach was not cost-effective in the base case analysis, but cannot be excluded according to probabilistic sensitivity analyses. CONCLUSIONS: Although SIC remains the reference test to diagnose OA, when this test is not available, sputum testing is a cost-effective alternative to PEF for diagnosis of OA.