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.

Comparison of high- and low-molecular-weight sensitizing agents causing occupational asthma: an evidence-based insight.

INTRODUCTION: The many substances used at the workplace that can cause sensitizer-induced occupational asthma are conventionally categorized into high-molecular-weight (HMW) agents and low-molecular-weight (LMW) agents, implying implicitly that these two categories of agents are associated with distinct phenotypic profiles and pathophysiological mechanisms. AREAS COVERED: The authors conducted an evidence-based review of available data in order to identify the similarities and differences between HMW and LMW sensitizing agents. EXPERT OPINION: Compared with LMW agents, HMW agents are associated with a few distinct clinical features (i.e. concomitant work-related rhinitis, incidence of immediate asthmatic reactions and increase in fractional exhaled nitric oxide upon exposure) and risk factors (i.e. atopy and smoking). However, some LMW agents may exhibit 'HMW-like' phenotypic characteristics, indicating that LMW agents are a heterogeneous group of agents and that pooling them into a single group may be misleading. Regardless of the presence of detectable specific IgE antibodies, both HMW and LMW agents are associated with a mixed Th1/Th2 immune response and a predominantly eosinophilic pattern of airway inflammation. Large-scale multicenter studies are needed that use objective diagnostic criteria and assessment of airway inflammatory biomarkers to identify the pathobiological pathways involved in OA caused by the various non-protein agents.

Matrix metalloproteinase-9 increases in the sputum from allergic occupational asthma patients after specific inhalation challenge.

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the pathogenesis of asthma. MMP-9 increases in the sputum of asthmatic patients after bronchial challenge with common allergens. We sought to assess whether a high-molecular-weight occupational allergen was able to induce changes in MMP-9 as well as in other MMPs and TIMPs in subjects with occupational asthma. METHODS: Ten patients underwent specific inhalation challenge (SIC) on 2 consecutive days. We monitored changes in lung function by measuring FEV(1) for 7 h. Induced sputum test was performed at 6 h after sham and flour challenge. The total and differential cell counts were analyzed. Levels of MMPs (specifically MMP-2, MMP-7, MMP-9 and MMP-13) were measured using Fluorokine® MultiAnalyte Profiling kits and a Luminex® Bioanalyzer, while levels of TIMP-1 and TIMP-2 were measured by ELISA. RESULTS: Flour challenge increased the percentage of eosinophils in sputum samples. Asthmatic reactions induced by flour were associated with a significant increase in the sputum level of MMP-9 (p = 0.05), but not in the levels of MMP-2, MMP-7, MMP-13, TIMP-1 and TIMP-2. Sputum levels of MMP-9 measured after flour challenge were nearly significantly correlated (r = 0.67; p = 0.06) with the maximal fall in FEV(1) observed during the asthmatic reaction, but they did not correlate with the number of neutrophils (r = 0.18; p = 0.7) and eosinophils (r = 0.55; p = 0.2). CONCLUSIONS: This study showed that MMP-9 increases in sputum samples from sensitized occupational asthma patients after SIC with flour.

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.

Medical surveillance programme for diisocyanate exposure.

OBJECTIVES: Surveillance programmes for occupational asthma should reduce the severity of asthma both at the time of diagnosis and after removal from exposure as well as costs related to functional impairment. The aim of this study was to compare the severity and cost of diisocyanate-induced occupational asthma in workers participating in a surveillance programme and in twice the number of workers diagnosed after being referred by their physician. METHODS: Answers to a self-administered questionnaire led to possible referral for further assessment that included methacholine testing and specific inhalation challenges as the gold standard for confirming occupational asthma. Results Of the 2897 workers who participated, 182 (6.3%) had a positive questionnaire. 79/182 (43%) were referred for further medical assessment and 20 had confirmed occupational asthma by specific inhalation testing. At the time of diagnosis, the 20 screened subjects had a mean PC(20) of 3.35 mg/ml as compared to 1.50 mg/ml (p = 0.05) in the 66 controls. Two years after diagnosis and removal from exposure, the 20 subjects screened had a mean PC(20) of 4.81 mg/ml compared to 1.67 mg/ml (p = 0.03) in controls. Clinical remission occurred in 34% of the screened group compared to 16% of the control group (p = 0.02). The median costs for functional impairment were $C11,900 in screened subjects and $C19,600 in controls (p = 0.04). CONCLUSIONS: Subjects with occupational asthma screened by a medical surveillance programme have a better outcome both at the time of diagnosis and 2 years after removal from exposure, with lower compensation costs compared to controls.

New methodology for specific inhalation challenges with occupational agents.

BACKGROUND: Inhalation challenges are used for diagnosing occupational asthma (OA). The initial methodology consisted of a "realistic" exposure without monitoring nor controlling exposure. Our aim was to design an equipment, called the GenaSIC, that allows the generation of various agents regardless of the formulation and to assess the feasibility of its use in patients investigated for OA. RESULTS: GenaSIC can generate lactose, flour, malt, isocyanates, formaldehyde and N-butyl acetate with precise and fairly stable concentrations. Using N-butyl-acetate as a control agent and real time measurement, we show that normal breathing has a negligible effect on the concentration. We exposed forty-four different subjects to a control agent and/or to a suspected occupational agent. Nineteen of the subjects were only exposed to N-butyl acetate as a control agent without experiencing any significant irritant effect (no significant changes in spirometry thereafter). Eight subjects who were exposed to both N-butyl acetate and formaldehyde did not show significant reactions. Seven subjects were exposed to dry particles (flour in six instances, malt in the other) and five showed immediate asthmatic reactions which changes in FEV1 from 20% to a maximum of 28%. Finally, ten subjects were exposed to isocyanates, four of whom showed a positive reaction, including one subject with immediate maximum changes in FEV1 of 22%. CONCLUSION: GenaSIC offers the possibility of reliable and safe exposures to dry particles, formaldehyde and isocyanates in the investigation of OA.

Risk factors, predictors, and markers for work-related asthma and rhinitis.

The burden of asthma attributable to occupational exposures is significant. A better evaluation of markers of asthma and rhinitis in occupational settings may help reduce the frequency of occupational asthma (OA) and rhinitis (OR). This publication reviews articles published in 2008 and 2009 to provide an update on aspects related to markers of asthma and rhinitis. Markers derived from occupational exposure assessment, questionnaires, clinical data, and noninvasive tests such as functional tests or measures of serum antibodies are used to develop prediction models for the likelihood of OA and OR development. Findings from prospective studies highlight the course of preclinical signs and markers of airway inflammation in the natural history of OA and OR. Airway inflammation, evaluated by quantification of cells and mediators in induced sputum or nasal lavage and by exhaled nitric oxide, is associated with OA and OR; however, the sensitivity and specificity of these means, especially exhaled nitric oxide, have not been sufficiently assessed.

Occupational rhinitis and asthma: where do we stand, where do we go?

This review provides an overview of current and emerging issues regarding occupational rhinitis (OR) and occupational asthma (OA), focusing on studies discussing concepts and results that are relevant to both diseases. OA and OR are conditions that affect the upper and lower airways, are characterized by reduced airway caliber and hyperresponsiveness and by inflammation, and are caused by agents present in the workplace. To explain disease expression, research is moving from the T-helper type 1/type 2 cells paradigm to consider the contribution of diverse alternative pathways such as neural inflammation, a dysfunctional epithelial barrier, and autoimmune mechanisms, among others. Objective assessment of OR and OA has been improved and tested for research and, currently, clinical application. Further developments in the field of OR are expected to lead to more generalized clinical applications, following the example of what has been achieved for OA.

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.

Agents causing occupational asthma.

The workplace is a significant contributor to the burden of asthma. Although the majority of cases probably represent what is labeled work-exacerbated asthma, in a significant number of subjects, asthma is actually caused by 1 or more agents present in the workplace; this is occupational asthma. Two types of occupational asthma are distinguished, according to whether the asthma appears after a latency period. This article discusses (1) two types of agents causing asthma with a latency period and acting through an apparently immunologic mechanism (high-molecular-weight agents and low-molecular-weight agents) and (2) agents causing asthma without a latency period.

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.

Determinants of the incidence of childhood asthma: a two-stage case-control study.

Extensive literature exists on potential risk factors for childhood asthma. To the authors' knowledge, no investigators have yet attempted to disentangle the effects of those determinants within a single study setting. The authors aimed to evaluate the independent effects of 47 potential determinants (from the prenatal, perinatal, and childhood periods) of asthma development in children within the first 10 years of life. From a Canadian birth cohort of 26,265 children (1990-2002), a 2-stage case-control study was conducted. In the first stage, 20 controls per case were selected from 3 administrative databases. In the second stage, selected mothers were mailed questionnaires for assessment of additional determinants. Increased risks of childhood asthma were found for > or =1 previous diagnosis of bronchopulmonary disease and atopic dermatitis in the child, oxygen administration after birth, prescription of antibiotics within the first 6 months of life, male gender, asthma during pregnancy, use of antibiotics during pregnancy, maternal receipt of social aid, paternal asthma, and asthma in siblings. Protective effects included use of intranasal corticosteroids during pregnancy, having a wood-burning fireplace, having pets in the home prior to the index date, breastfeeding, and day-care attendance. This study allowed the authors to identify, within a single setting, the most influential determinants of childhood asthma among 47 predictors assessed for the prenatal, perinatal, and childhood periods.

Maternal asthma, its control and severity in pregnancy, and the incidence of atopic dermatitis and allergic rhinitis in the offspring.

OBJECTIVE: To evaluate the relationship between maternal asthma, its level of control and severity during pregnancy, and atopic dermatitis (AD) and allergic rhinitis (AR) incidence in children. STUDY DESIGN: A cohort of 26 265 singletons born to mothers with and without asthma (1990-2002) was constituted by use of 3 Quebec databases. Mothers with asthma had to have received >or=1 diagnosis and >or=1 prescription for asthma 2 years before or during pregnancy. Asthma control and severity during pregnancy was based on validated indexes. ICD-9 codes 691 and 477 allowed us to identify cases of AD and AR. RESULTS: Maternal asthma during pregnancy was associated with an increased AD risk (adjusted hazard ratio: 1.11, 95% confidence interval: 1.02-1.21), but not of AR (adjusted hazard ratio: 1.04, 95% confidence interval: 0.91-1.20) in children. Asthma control and severity were not associated with either outcome. Maternal AR and intranasal corticosteroid use during pregnancy increased the risk of childhood AR by 70% and 45%. CONCLUSIONS: Children of mothers with asthma or AR during pregnancy should be closely monitored to diagnose and treat AD and AR as early as possible.

EAACI position paper on occupational rhinitis.

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.

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.

Frequency of work-related respiratory symptoms in workers without asthma.

BACKGROUND: Clinicians are faced with subjects complaining of work-related respiratory symptoms (WRS) without any evidence of asthma. We sought to assess the prevalence of subjects with WRS without asthma in a cohort of workers referred for possible work-related asthma (WRA) as well as compare the characteristics and the work environment of subjects with WRS to subjects with WRA. METHODS: A prospective observational study of workers referred for possible WRA over a 1-year period. Detailed medical and occupational questionnaires were administered. Pulmonary function tests as well as specific-inhalation challenges were performed. RESULTS: One hundred twenty workers were investigated. Fifty-one had WRA while 69 had WRS. The type and the severity of the respiratory symptoms were similar in both groups, except for wheezing which was more frequently reported in subjects with WRA (32 (62.7%)) than in subjects with WRS (16 (23.2%)) (P < 0.01). Both the workers with WRS and WRA were mainly employed in the manufacturing sector (64.7% (WRA) and 71% (WRS)). At the time of the first assessment 64.7% of subjects with WRA and 56.5% with WRS had left their workplace because of their bothersome respiratory symptoms. CONCLUSIONS: Subjects with WRS without asthma represent a large proportion of the subjects assessed in clinics specialized in the field of WRA. Like subjects with WRA, the population with WRS is likely to represent a significant medical burden. The similarity of the symptoms between the WRA and the WRS groups emphasizes the need to perform a thorough and objective investigation to diagnose WRA.

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.

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.