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.

The research on endothelial function in women and men at risk for cardiovascular disease (REWARD) study: methodology.

BACKGROUND: Endothelial function has been shown to be a highly sensitive marker for the overall cardiovascular risk of an individual. Furthermore, there is evidence of important sex differences in endothelial function that may underlie the differential presentation of cardiovascular disease (CVD) in women relative to men. As such, measuring endothelial function may have sex-specific prognostic value for the prediction of CVD events, thus improving risk stratification for the overall prediction of CVD in both men and women. The primary objective of this study is to assess the clinical utility of the forearm hyperaemic reactivity (FHR) test (a proxy measure of endothelial function) for the prediction of CVD events in men vs. women using a novel, noninvasive nuclear medicine -based approach. It is hypothesised that: 1) endothelial dysfunction will be a significant predictor of 5-year CVD events independent of baseline stress test results, clinical, demographic, and psychological variables in both men and women; and 2) endothelial dysfunction will be a better predictor of 5-year CVD events in women compared to men. METHODS/DESIGN: A total of 1972 patients (812 men and 1160 women) undergoing a dipyridamole stress testing were recruited. Medical history, CVD risk factors, health behaviours, psychological status, and gender identity were assessed via structured interview or self-report questionnaires at baseline. In addition, FHR was assessed, as well as levels of sex hormones via blood draw. Patients will be followed for 5 years to assess major CVD events (cardiac mortality, non-fatal MI, revascularization procedures, and cerebrovascular events). DISCUSSION: This is the first study to determine the extent and nature of any sex differences in the ability of endothelial function to predict CVD events. We believe the results of this study will provide data that will better inform the choice of diagnostic tests in men and women and bring the quality of risk stratification in women on par with that of men.

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.

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.

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.

Occupational rhinitis.

PURPOSE OF REVIEW: This review updates existing knowledge on occupational rhinitis based on epidemiological and clinical research studies published from 2003 to 2005. RECENT FINDINGS: The review covers new developments on the pathophysiology, diagnosis, monitoring and management of occupational rhinitis. This article also provides updated information on the prevalence and incidence of both occupational rhinitis and work-related symptoms of rhinitis, as well as on causal agents and personal risk factors associated with this condition. SUMMARY: Occupational rhinitis is frequently under-diagnosed due to a lack of physician awareness. Diagnosis is suspected when symptoms occur in relation to work. Differentiating between immunological sensitization and irritation may be difficult. Given the high prevalence of rhinitis in the general population from all causes, objective tests confirming the occupational origin are essential. Measures of inflammatory parameters via nasal lavage and objective assessment of nasal congestion both offer practical means of monitoring responses. Growing experience with acoustic rhinometry and peak nasal inspiratory flow suggests that these methods will have an increasingly important role in monitoring and diagnosing in the future. Recent findings indicate that work-related rhinitis is to some extent preventable. Surveillance of sensitized workers may allow early detection of occupational rhinitis.

Genetic variants in TNFα, TGFB1, PTGS1 and PTGS2 genes are associated with diisocyanate-induced asthma.

Diisocyanates are the most common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants in inflammatory response genes (TNFα, IL1α, IL1ß, IL1RN, IL10, TGFB1, ADAM33, ALOX-5, PTGS1, PTGS2 and NAG-1/GDF15) are associated with increased susceptibility to diisocyanate asthma (DA). These genes were selected based on their role in asthmatic inflammatory processes and previously reported associations with asthma phenotypes. The main study population consisted of 237 Caucasian French Canadians from among a larger sample of 280 diisocyanate-exposed workers in two groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95) and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5' nuclease PCR assay. After adjusting for potentially confounding variables of age, smoking status and duration of exposure, the PTGS1 rs5788 and TGFB1 rs1800469 single nucleotide polymorphisms (SNP) showed a protective effect under a dominant model (OR = 0.38; 95% CI = 0.17, 0.89 and OR = 0.38; 95% CI = 0.18, 0.74, respectively) while the TNFα rs1800629 SNP was associated with an increased risk of DA (OR = 2.08; 95% CI = 1.03, 4.17). Additionally, the PTGS2 rs20417 variant showed an association with increased risk of DA in a recessive genetic model (OR = 6.40; 95% CI = 1.06, 38.75). These results suggest that genetic variations in TNFα, TGFB1, PTGS1 and PTGS2 genes contribute to DA susceptibility.

N-Acetyltransferase 2 Genotypes Are Associated With Diisocyanate-Induced Asthma.

OBJECTIVE: To investigate whether genetic variants of N-acetyltransferase (NAT) genes are associated with diisocyanate asthma (DA). METHODS: The study population consisted of 354 diisocyanate-exposed workers. Genotyping was performed using a 5'-nuclease polymerase chain reaction assay. RESULTS: The NAT2 rs2410556 and NAT2 rs4271002 variants were significantly associated with DA in the univariate analysis. In the first logistic regression model comparing DA+ and asymptomatic worker groups, the rs2410556 (P = 0.004) and rs4271002 (P < 0.001) single nucleotide polymorphisms and the genotype combination, NAT2 rs4271002*NAT1 rs11777998, showed associations with DA risk (P = 0.014). In the second model comparing DA+ and DA- groups, NAT2 rs4271002 variant and the combined genotype, NAT1 rs8190845*NAT2 rs13277605, were significantly associated with DA risk (P = 0.022, P = 0.036, respectively). CONCLUSIONS: These findings suggest that variations in the NAT2 gene and their interactions contribute to DA susceptibility.

Persistence of airway responsiveness to occupational agents: what does it matter?

In the majority of workers with occupational asthma, the disease remains active even several years after removal from exposure or diminution of the levels of exposure to the causal agent. Only 25% or so normalize their lung function and their bronchial responsiveness to nonspecific agents. The aim of this review is to present recent findings illustrating the persistence of specific bronchial responsiveness and the associated factors in workers who apparently have recovered from occupational asthma. This subject is also examined from a socioeconomic perspective.

Genetic variants in the major histocompatibility complex class I and class II genes are associated with diisocyanate-induced Asthma.

OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) located across the major histocompatibility complex and susceptibility to diisocyanate-induced asthma (DA). METHODS: The study population consisted of 140 diisocyanate-exposed workers. Genotyping was performed using the Illumina GoldenGate major histocompatibility complex panels. RESULTS: The HLA-E rs1573294 and HLA-DPB1 rs928976 SNPs were associated with an increased risk of DA under dominant (odds ratio [OR], 6.27; 95% confidence interval [CI], 2.37 to 16.6; OR, 2.79, 95% CI, 0.99 to 7.81, respectively) and recessive genetic models (OR, 6.27, 95% CI, 1.63 to 24.13; OR, 10.10, 95% CI, 3.16 to 32.33, respectively). The HLA-B rs1811197, HLA-DOA rs3128935, and HLA-DQA2 rs7773955 SNPs conferred an increased risk of DA in a dominant model (OR, 7.64, 95% CI, 2.25 to 26.00; OR, 19.69, 95% CI, 2.89 to 135.25; OR, 8.43, 95% CI, 3.03 to 23.48, respectively). CONCLUSION: These results suggest that genetic variations within HLA genes play a role in DA risk.

Long-term socioprofessional and psychological status in workers investigated for occupational asthma in quebec.

OBJECTIVE: To compare the long-term status of workers with occupational asthma (OA) with those of subjects with work-exacerbated asthma (WEA) and nonasthmatic (NA) workers. METHODS: We contacted 179 subjects investigated for suspected OA at Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada, from 1997 to 2007. Participants completed questionnaires on psychological and functional status, followed by a telephone interview about socioprofessional outcomes and health care utilization. RESULTS: The OA workers are more likely to have been removed from the workplace than the WEA workers. The health-related quality of life of all workers was still impaired. A high prevalence of psychiatric disorders was found among OA and WEA workers. Compared with WEA and OA workers, the NA group showed a higher rate of physician consultations for all causes. CONCLUSIONS: Regardless of the diagnosis they received, these workers need to benefit from psychosocial support in the period after investigation for suspicion of OA.

Interferon-γ promoter is hypermethylated in blood DNA from workers with confirmed diisocyanate asthma.

Risk factors have not been identified that determine susceptibility for development of diisocyanate-induced occupational asthma (DA). We hypothesized that diisocyanate (DI) exposure could modify gene promoter regions regulating transcription of cytokine mediators and thereby influence expression of DA. A cross-sectional study was designed to investigate the promoter methylation status of candidate genes in DI-exposed workers. Subjects consisted of 131 workers in three groups: 40 cases with DA confirmed by a positive specific inhalation challenge (SIC) (DA+), 41 exposed workers with lower respiratory symptoms and negative SIC (DA-), and 50 asymptomatic exposed workers (AWs). We studied four candidate genes (GSTM1, DUSP22, IFN-γ, and IL-4) for which altered promoter methylation has been previously investigated for relationships with a variety of other environmental exposures. Methylation status was determined using methylation-specific quantitative PCR performed on genomic DNA extracted from whole blood. Results showed that relative methylation of IFN-γ promoter was significantly increased in DA+ in comparison with both comparator groups (DA- and AW), and it exhibited good sensitivity (77.5%) and specificity (80%) for identifying DA workers in a multivariate predictive model after adjusting for type of DI exposure, smoking status, methacholine PC20, and gender. IL-4 promoter was slightly less methylated only in DA+ compared with AW among nonsmoking workers. Both GSTM1 and DUSP22 promoter methylations were found not associated with DA. Our finding suggests that exposure to occupational chemicals could play a heretofore undefined mechanistic role via epigenetic modification of specific genes in the promoter region.

The effects of a multisite aerobic exercise intervention on asthma morbidity in sedentary adults with asthma: the Ex-asthma study randomised controlled trial protocol.

OBJECTIVE: Aerobic exercise can improve cardiovascular fitness and does not seem to be detrimental to patients with asthma, though its role in changing asthma control and inflammatory profiles is unclear. The main hypothesis of the current randomised controlled trial is that aerobic exercise will be superior to usual care in improving asthma control. Key secondary outcomes are asthma quality of life and inflammatory profiles. DESIGN: A total of 104 sedentary adults with physician-diagnosed asthma will be recruited. Eligible participants will undergo a series of baseline assessments including: the asthma control questionnaire; the asthma quality-of-life questionnaire and the inflammatory profile (assessed from both the blood and sputum samples). On completion of the assessments, participants will be randomised (1:1 allocation) to either 12-weeks of usual care or usual care plus aerobic exercise. Aerobic exercise will consist of three supervised training sessions per week. Each session will consist of taking a short-acting bronchodilator, 10 min of warm-up, 40 min of aerobic exercise (50-75% of heart rate reserve for weeks 1-4, then 70-85% for weeks 5-12) and a 10 min cool-down. Within 1 week of completion, participants will be reassessed (same battery as at baseline). Analyses will assess the difference between the two intervention arms on postintervention levels of asthma control, quality of life and inflammation, adjusting for age, baseline inhaled corticosteroid prescription, body weight change and pretreatment dependent variable level. Missing data will be handled using standard multiple imputation techniques. ETHICS AND DISSEMINATION: The study has been approved by all relevant research ethics boards. Written consent will be obtained from all participants who will be able to withdraw at any time. RESULTS: The result will be disseminated to three groups of stakeholder groups: (1) the scientific and professional community; (2) the research participants and (3) the general public. REGISTRATION DETAILS CLINICALTRIALSGOV IDENTIFIER: NCT00953342.

Screening for occupational asthma by using a self-administered questionnaire in a clinical setting.

OBJECTIVE: Because of its high prevalence, early screening for occupational asthma (OA) is crucial. We aimed to evaluate the screening performance of the Occupational Asthma Screening Questionnaire-11 items (OASQ-11) in a clinical setting. METHODS: Between January 2009 and December 2011, 169 workers referred for potential OA to our hospital completed the OASQ-11 and underwent workups to determine the final diagnosis. The discriminative abilities of the OASQ-11 as a whole and in relation to demographic and exposure parameters were determined by the area under the receiving operator characteristic curve (AUC). RESULTS: Model 1, consisting of the OASQ's items, showed fair discrimination (AUC, 0.69; 95% confidence interval, 0.58 to 0.80). Addition of age and exposure duration to model 1 improved discrimination (AUC, 0.80; confidence interval, 0.72 to 0.88). CONCLUSION: A simple model consisting of the OASQ-11's items, age, and exposure duration could well discriminate subjects with OA in a clinical setting.