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.

Identification of clinically significant psychological distress and psychiatric morbidity by examining quality of life in subjects with occupational asthma.

BACKGROUND: The Juniper Asthma Specific Quality of Life Questionnaire (AQLQ(S)) is a questionnaire that allows measurement of disease specific quality of life. We wanted to examine correlations between the (AQLQ(S)) general and different subscale scores and both psychiatric morbidity and levels of psychological distress in individuals with occupational asthma (OA) and to determine if results in the emotional function subscale allow identification of individuals with clinically significant psychological distress or current psychiatric disorders. METHODS: This was a cross-sectional study of individuals with OA who were assessed during a re-evaluation for permanent disability, after they were no longer exposed to the sensitizing agent. Patients underwent a general sociodemographic and medical history evaluation, a brief psychiatric interview (Primary Care Evaluation of Mental Disorders, PRIME-MD) and completed a battery of questionnaires including the AQLQ(S), the St-Georges Respiratory Questionnaire (SGRQ), and the Psychiatric Symptom Index (PSI). RESULTS: There was good internal consistency (Cronbach alpha = 0.936 for the AQLQ(S) total score) and construct validity for the AQLQ(S) (Spearman rho = -0.693 for the SGRQ symptom score and rho = -0.650 for the asthma severity score). There were medium to large correlations between the total score of the AQLQ(S) and the SGRQ symptom score (r = -.693), and PSI total (r = -.619) and subscale scores (including depression, r = -.419; anxiety, r = -.664; anger, r = -.367; cognitive disturbances, r = -.419). A cut-off of 5.1 on the AQLQ(S) emotional function subscale (where 0 = high impairment and 7 = no impairment) had the best discriminative value to distinguish individuals with or without clinically significant psychiatric distress according to the PSI, and a cut-off of 4.7 best distinguished individuals with or without a current psychiatric disorder according to the PRIME-MD. CONCLUSIONS: Impaired quality of life is associated with psychological distress and psychiatric disorders in individuals with OA. Findings suggest that the AQLQ(S) questionnaire may be used to identify patients with potentially clinically significant levels of psychological distress.

Direct costs of occupational asthma due to sensitization in Quebec (1988 to 2002): revisited.

BACKGROUND: In a previous study, the authors assessed direct costs for occupational asthma (OA) in a random sample of eight to 10 accepted claims per year for OA between 1988 and 2002. Compensation for loss of income (CLI) was found to be significantly higher for men and for OA caused by low-molecular-weight agents. OBJECTIVES AND METHODS: To identify sociodemographic factors that modulate CLI, the dossier of each claimant in the previous study was re-examined. RESULTS: Higher CLI costs were directly related to the duration of CLI (over which loss of income was reimbursed) (r=0.65). Costs of CLI were higher in patients 30 years of age or older at diagnosis, married subjects and individuals who were offered early retirement or were enrolled in an active interventional rehabilitation program. Higher CLI costs in men, but not in women, were associated with the following sociodemographic factors: older age, different rehabilitation program (early retirement and active program versus no specific program) and married status. Older age was found to be significant in the multivariate analysis performed for men. The cost of CLI was higher in workers with OA caused by low-molecular-weight agents. Although proportionally fewer men and younger workers were affected with OA caused by low-molecular-weight agents, the longer duration of CLI for this category of agent could explain the higher costs. CONCLUSION: Higher costs for CLI were associated in men (but not women) with older age, married status and type of rehabilitation program (early retirement and active rehabilitation). Higher costs of CLI for OA caused by low-molecular-weight agents were associated with a longer duration of CLI per se, and not with sociodemographic factors.

Quality-of-life, psychological, and cost outcomes 2 years after diagnosis of occupational asthma.

OBJECTIVE: To examine the association between clinical and socioeconomic variables and their influence on psychological and cost outcomes in patients with occupational asthma (OA). METHODS: Longitudinal study of 60 subjects who claimed compensation for OA in Quebec. Besides clinical markers of asthma, quality of life (QOL), psychological distress (PD) measures, and an instrument to diagnose mental disorders were used. RESULTS: The QOL and PD parameters had moderate correlations with clinical markers of OA. Asthma severity, employment, marital status, income, and the length of employment with the employer showed the strongest associations with QOL and PD. More-impaired QOL was associated with higher direct costs for compensation. CONCLUSION: Impaired QOL and PD are frequent among subjects with OA receiving compensation and are associated with clinical markers of OA and socioeconomic factors.

Does the methacholine test reproduce symptoms?

BACKGROUND: The interpretation of methacholine test results do not usually consider the symptoms for which the subject was referred and those that occur during the test. OBJECTIVE: To assess the association between methacholine test results and symptoms, and to examine variables that may affect this association. METHODS A total of 400 prospectively chosen subjects who underwent methacholine testing for possible asthma were investigated. The subjects answered a short questionnaire regarding the symptoms for which they had been referred and those that were encountered during the methacholine test. RESULTS: The positive predictive value for the reproduction of symptoms during the test compared with symptoms for which subjects had been referred were 84% for dyspnea, 87% for cough, 81% for wheezing and 72% for chest tightness. The positive predictive value among the values obtained by measuring the provocative concentration of methacholine causing a 20% fall (PC20) in forced expiratory volume in 1 s on the one hand, and specific symptoms on the other, varied by up to approximately 50%; negative predictive values were higher. Forty-eight per cent of subjects with a PC20 of 16 mg/mL or lower reported that the test had globally reproduced their symptoms. This association was significantly stronger in women, young subjects and those taking inhaled steroids. CONCLUSIONS: The methacholine test generally reproduced the symptoms for which the subjects were referred. The absence of a specific symptom (eg, dyspnea, cough, wheezing or chest tightness), either in daily life or at the time of methacholine testing, was more generally associated with a negative test than the reverse. The global impression that the test had reproduced what the patient had experienced in daily life was significantly associated with a positive test (ie, a PC20 of 16 mg/mL or lower), with the association being stronger in young subjects and women.

Long-term pathologic consequences of acute irritant-induced asthma.

BACKGROUND: Acute irritant-induced asthma (IrIa) or reactive airways dysfunction syndrome is caused by exposure to a high concentration of an agent. The long-term pathologic consequences of IrIa remain thus far unknown. OBJECTIVE: The aim of our study was to investigate the chronic airway inflammation and remodeling that occur in association with IrIa. METHODS: Ten subjects with a history of IrIa (mean interval of 10.9 years, minimum of 4 years, since the inhalational accident) underwent bronchoscopy followed by bronchoalveolar lavage and bronchial biopsies. Immunologic and morphologic data from patients with IrIa were compared with those of patients with mild to moderate asthma as well as healthy controls. RESULTS: Bronchoalveolar lavage fluid analysis showed increased eosinophil and neutrophil counts in 30% and 60% of subjects with IrIa, respectively. In the supernatant of bronchoalveolar lavage, we found a significant increase in the majority of mediators compared with healthy subjects and a significant increase in eosinophilic cationic protein, IL-8, basic fibroblast growth factor, and matrix metalloproteinase 1 compared with control patients with asthma. Evaluation of basement membrane thickness (subepithelial fibrosis) demonstrated a significant increase in patients with IrIa compared with healthy subjects and subjects with asthma. Basement membrane thickness also significantly correlated with the PC(20) value. The epithelial cell detachment showed an elevated although not significant trend compared with subjects with asthma and control subjects. Immunocytochemical analysis demonstrated increases in the number of eosinophil cationic protein and TGF-beta1-positive cells compared with healthy controls. CONCLUSION: This study provides evidence of a significant eosinophilic and neutrophilic inflammation as well as remodeling in IrIa many years after an inhalational accident.

Long-term outcomes of acute irritant-induced asthma.

RATIONALE: The long-term outcomes of acute irritant-induced asthma (IIA) are mostly unknown. OBJECTIVES: To study the long-term outcomes of IIA. METHODS: We reassessed 35 subjects who experienced IIA at a mean interval of 13.6 +/- 5.2 years. MEASUREMENTS AND MAIN RESULTS: The causal agent was chlorine in 20 cases (57%). At diagnosis, the mean +/- SD FEV(1) was 74.5 +/- 19.5% predicted, and all subjects showed bronchial hyperresponsiveness. At reassessment, all subjects reported respiratory symptoms, and 24 (68%) were on inhaled steroids. There were no significant improvements in FEV(1) and FEV(1)/FVC values. Twenty-three subjects had a methacholine test, and only six subjects had normal levels of responsiveness. Of the remaining 12 subjects, six had improvement in FEV(1) after bronchodilator >or=10%. In samples of induced sputum obtained from 27 subjects, six had eosinophils >or=2%. Levels of inflammatory and remodeling mediators were higher than in control subjects but were no different from subjects with occupational asthma due to sensitization. Quality of life score was 4.4 +/- 1.5 on a 0 (worst) to 7 (best) scale. Twelve subjects had an abnormal depression score. CONCLUSIONS: This study provides the first evidence of significant long-term impact of acute IIA on various outcomes.

Direct costs of occupational asthma in Quebec between 1988 and 2002.

BACKGROUND: Forty to 70 cases of occupational asthma due to sensitization to an agent present in the workplace are accepted each year by the Commission de la santé et de la sécurité du travail, the Quebec medicolegal agency. OBJECTIVES AND METHODS: In a random sample of eight to 10 accepted claims per year from 1988 to 2002, the direct costs of compensation for loss of income (CLI) and compensation for functional impairment (CFI), as well as the associations of these costs with selected variables, were assessed. RESULTS: Mean costs (presented as Canadian dollars x10(3)) of CLI, CFI and total were 72.5, 11.7 and 92.8, respectively, while the median costs were 40.7, 7.6 and 61.3 for CLI, CFI and total, respectively. Median CLI costs were significantly higher in men than women (69.9 versus 13.1), workers aged 40 years or older versus those younger than 40 years (90.1 versus 27.4), workers with occupational asthma due to workplace exposure to low versus high molecular weight agents (51.2 versus 38.6), and workers taking inhaled steroids at diagnosis (92 versus 52) and reassessment (81 versus 35). Median CFI costs were also higher in those requiring retraining (10.4) and taking early retirement (61.8) than workers who stayed with the same employer but in a different job (5.4). Median CFI costs were significantly higher for individuals being treated with inhaled steroids at the time of diagnosis (14.0 versus 5.2) and reassessment (13 versus 6), and for those left with bronchial hyperresponsiveness (9.5 versus 0.8) related to forced expiratory volume in 1 s and forced expiratory volume in 1 s/forced vital capacity. CONCLUSION: Age, sex, nature of occupational agent, treatment with inhaled steroids and type of rehabilitation all affect CLI, whereas lung function status at baseline and reassessment is related to CFI.

Long-term outcomes in a prospective cohort of apprentices exposed to high-molecular-weight agents.

RATIONALE: We conducted a long-term (8-yr) follow-up of 408 apprentices entering programs involving exposure to high-molecular-weight allergens. OBJECTIVES: The objectives were to assess the frequency of new and persisting sensitization, symptoms, and bronchial hyperresponsiveness in relation with job history after ending apprenticeship and to examine characteristics significantly associated with the incidence and remission of these occupational outcomes. METHODS: A respiratory symptom questionnaire, skin prick tests with work-related allergens (laboratory animals, flour, and latex), spirometry, and methacholine challenge were administered. The association between incidence or remission of these outcomes and individual characteristics at baseline and end of apprenticeship was examined. MEASUREMENTS AND MAIN RESULTS: In subjects who at any time during follow-up held a job related to their training (78%), the incidence of sensitization, rhinoconjunctival and chest symptoms, and bronchial hyperresponsiveness at follow-up was 1.3, 1.7, 0.7, and 2.0 per 100 person-years, respectively. The remission of these outcomes acquired during apprenticeship was 18.5, 9.6, 9.6, and 12.4 per 100 person-years, respectively, in subjects no longer in a job related to training. Several clinical, immunological, and functional characteristics at baseline and acquired during apprenticeship were found to be significantly associated with the incidence and remission of the outcomes. CONCLUSIONS: The incidence of sensitization, symptoms, and bronchial hyperresponsiveness was lower while at work than during the apprenticeship period. A high proportion of subjects in a job not related to training experienced remission of symptoms acquired during apprenticeship.

Does clinical trial subject selection restrict the ability to generalize use and cost of health services to "real life" subjects?

OBJECTIVES: To explore one aspect of the external validity of the randomized controlled trial (RCT), specifically how being selected for inclusion in a trial and having participated has influenced the use and cost of asthma-related health services. METHODS: Services used by asthmatic users of inhaled corticosteroids (iCSTs) having previously participated in an RCT (TS, n = 46) were compared with individuals who had never participated (NS, n = 51). RESULTS: TS were more likely to use higher (> or = 400 microg) daily doses of iCSTs than NS (OR, 3.3; 95% Cl, 1.1-8.3) but less likely to visit emergency departments (OR, 0.3; 95% Cl, 0.1-0.7). Total asthma-related costs did not differ significantly. CONCLUSIONS: Subject differences may impede generalizing from RCTs to real life.

Diisocyanate antigen-stimulated monocyte chemoattractant protein-1 synthesis has greater test efficiency than specific antibodies for identification of diisocyanate asthma.

We previously reported that diisocyanate-human serum albumin (DIISO-HSA) stimulated production of monocyte chemoattractant protein-1 (MCP-1) by peripheral blood mononuclear cells is significantly associated with a clinical diagnosis of diisocyanate asthma (DA). Others have reported that antibodies for DIISO-HSA are specific but insensitive markers of DA. This study was performed to evaluate test characteristics of the in vitro MCP-1 assay compared with DIISO-HSA-specific immunoglobulin (Ig) G and IgE in identifying workers with DA. MCP-1 was quantitated in peripheral blood mononuclear cell supernatants 48 hours after incubation with DIISO-HSA antigens. Assay results were compared with outcomes of specific inhalation challenge (SIC) testing. Nineteen of 54 (35%) workers assayed for antibodies and MCP-1 stimulation had SIC-confirmed DA. Mean MCP-1 produced by SIC-positive workers was greater than SIC-negative workers (p < or = 0.001). Diagnostic sensitivity, specificity, and test efficiency for specific IgG were 47%, 74%, and 65%, respectively, and for specific IgE were 21%, 89%, and 65%, respectively. Sensitivity, specificity, and test efficiency of the MCP-1 test were 79%, 91%, and 87%, respectively. This study indicates that the MCP-1 stimulation assay has greater sensitivity and specificity than the specific antibody assays in correctly identifying DA.