Are high- and low-molecular-weight sensitizing agents associated with different clinical phenotypes of occupational asthma?

BACKGROUND: High-molecular-weight (HMW) proteins and low-molecular-weight (LMW) chemicals can cause occupational asthma (OA) although few studies have thoroughly compared the clinical, physiological, and inflammatory patterns associated with these different types of agents. The aim of this study was to determine whether OA induced by HMW and LMW agents shows distinct phenotypic profiles. METHODS: Clinical and functional characteristics, and markers of airway inflammation were analyzed in an international, multicenter, retrospective cohort of subjects with OA ascertained by a positive inhalation challenge response to HMW (n = 544) and LMW (n = 635) agents. RESULTS: Multivariate logistic regression analysis showed significant associations between OA caused by HMW agents and work-related rhinitis (OR [95% CI]: 4.79 [3.28-7.12]), conjunctivitis (2.13 [1.52-2.98]), atopy (1.49 [1.09-2.05]), and early asthmatic reactions (2.86 [1.98-4.16]). By contrast, OA due to LMW agents was associated with chest tightness at work (2.22 [1.59-3.03]), daily sputum (1.69 [1.19-2.38]), and late asthmatic reactions (1.52 [1.09-2.08]). Furthermore, OA caused by HMW agents showed a higher risk of airflow limitation (1.76 [1.07-2.91]), whereas OA due to LMW agents exhibited a higher risk of severe exacerbations (1.32 [1.01-1.69]). There were no differences between the two types of agents in the baseline sputum inflammatory profiles, but OA caused by HMW agents showed higher baseline blood eosinophilia and a greater postchallenge increase in fractional nitric oxide. CONCLUSION: This large cohort study describes distinct phenotypic profiles in OA caused by HMW and LMW agents. There is a need to further explore differences in underlying pathophysiological pathways and outcome after environmental interventions.

Addressing Molecular Diagnosis of Occupational Allergies.

PURPOSE OF REVIEW: Numerous clinically relevant allergenic molecules enhance the performance of specific (s) IgE tests and improve the specificity of allergy diagnosis. This review aimed to summarize our current knowledge of the high-molecular-weight allergens involved in the development of occupational asthma and rhinitis and to critically analyze the contribution of component-resolved diagnosis in the management of these conditions. RECENT FINDINGS: There is a lack of standardization and validation for most available extracts of occupational agents, and assessment of sIgE reactivity to occupational allergen components has been poorly investigated, with the notable exception of natural rubber latex (NRL) and wheat flour. In the case of NRL, the application of recombinant single allergens and amplification of natural extracts with stable recombinant allergens improved the test sensitivity. IgE-sensitization profile in patients with baker's asthma showed great interindividual variation, and extract-based diagnostic is still recommended. For other occupational allergens, it remains necessary to evaluate the relevance of single allergen molecules for the sensitization induced by occupational exposure. Progress has been made to characterize occupational allergens especially NRL and wheat, although there is still an unmet need to increase the knowledge of occupational allergens, to include standardized tools into routine diagnostic, and to evaluate their usefulness in clinical practice.

Occupational Latex Allergy: the Current State of Affairs.

PURPOSE OF REVIEW: Allergy to natural rubber latex (NRL) reached epidemic proportions during the nineties and led to intense preventive efforts. The aim of this review was to provide a comprehensive compilation of the current status of occupational NRL allergy. RECENT FINDINGS: Recent advances led to the characterization of 15 NRL allergens and the development of assays for measuring the allergen content of NRL materials and specific IgE antibodies against NRL allergen components. Preventive measures aimed at reducing workplace exposure to NRL allergens were associated with decreasing incidence rates of NRL allergy. However, a pooled analysis of epidemiological surveys published during the last 10 years provided prevalence estimates of NRL sensitization and allergy similar to those derived from studies conducted before 2003. Substantial progress has been made in the understanding and prevention of NRL allergy, although the disease may still remain a worldwide cause of concern.

Persistence of asthma following allergen avoidance is associated with proTh2 myeloid dendritic cell activation.

BACKGROUND: The natural history of asthma includes in some patients periods of disease remission, but the underlying mechanisms are unknown. OBJECTIVES: We explored whether type 1 myeloid dendritic cell (mDC) dysfunction could be involved in the persistence of asthma, studying the controlled setting of occupational asthma after allergen avoidance. METHODS: We recruited 32 patients with occupational asthma to flour or latex ascertained by specific inhalation challenge and who were no longer exposed to the causal allergen. Leukapheresis was performed in each patient to isolate and characterise blood type 1 mDCs, and their functionality was studied in coculture with allogeneic CD4(+) T cells from controls. RESULTS: At follow-up, 11/32 patients (34%) were characterised by the absence of symptoms and non-specific bronchial hyper-responsiveness to histamine and were considered to be cured. When compared with cured patients, mDCs from patients with persistent disease increased the production of interleukin (IL) 5 and IL-13 by CD4(+) T cells, and upregulated programmed death ligand 2 (PD-L2) upon allergen pulsing. In addition, IL-5 and IL-13 responses could be reversed by exogenous IL-12, as well as by PD-L2 blockade. CONCLUSIONS: This study indicates that pro-Th2 features of mDCs correlate with disease activity in asthma after cessation of exposure to the causal allergen. The findings also highlight that the Th2 programming by dendritic cells is flexible and partly mediated by PD-L2.

Occupational asthma phenotypes identified by increased fractional exhaled nitric oxide after exposure to causal agents.

BACKGROUND: The added value of fractional exhaled nitric oxide (Feno) remains controversial in the investigation of occupational asthma (OA). OBJECTIVE: We sought to assess whether or not the increase of Feno levels following positive specific inhalation challenge (SIC) was restricted to phenotypes of subjects sharing common clinical characteristics by using a statistical cluster analysis. METHODS: Subjects were investigated for possible OA in a tertiary center using SICs from 2006 to 2012. Feno levels and sputum eosinophil counts were assessed at baseline and 24 hours after SIC. We performed a 2-step cluster analysis of the subgroup of subjects with OA. A multivariate logistic regression was performed in order to identify the variables associated with an increase in Feno in subjects with OA. RESULTS: One hundred and seventy-eight subjects underwent SIC; 98 had a positive test. The cluster analysis performed in the OA subgroup identified 3 clusters. Despite a positive SIC, there was no increase in the Feno levels after exposure to occupational agents in Cluster 3, in which subjects were only exposed to low-molecular-weight (LMW) agents. The molecular weight of the agent (high molecular weight vs LMW) was the only factor associated with an increase in Feno (OR: 4.2 [1.1-16.8]) in subjects with a positive SIC. CONCLUSION: An increase in Feno after exposure to agents causing OA seems to occur more consistently in subjects with OA caused by high molecular weight than in those with OA due to LMW.

Specific inhalation challenge in the diagnosis of occupational asthma: consensus statement.

This consensus statement provides practical recommendations for specific inhalation challenge (SIC) in the diagnosis of occupational asthma. They are derived from a systematic literature search, a census of active European centres, a Delphi conference and expert consensus. This article details each step of a SIC, including safety requirements, techniques for delivering agents, and methods for assessing and interpreting bronchial responses. The limitations of the procedure are also discussed. Testing should only be carried out in hospitals where physicians and healthcare professionals have appropriate expertise. Tests should always include a control challenge, a gradual increase of exposure to the suspected agent, and close monitoring of the patient during the challenge and for at least 6 h afterwards. In expert centres, excessive reactions provoked by SIC are rare. A positive response is defined by a fall in forced expiratory volume in 1 s ≥ 15% from baseline. Equivocal reactions can sometimes be clarified by finding changes in nonspecific bronchial responsiveness, sputum eosinophils or exhaled nitric oxide. The sensitivity and specificity of SIC are high but not easily quantified, as the method is usually used as the reference standard for the diagnosis of occupational asthma.

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.

Work-Related Asthma and Its Impact on Quality of Life and Work Productivity.

BACKGROUND: The impact of work-related asthma (WRA) on quality of life (QoL) and work productivity remains largely neglected/uncertain despite its high prevalence. OBJECTIVE: To investigate the association of WRA with QoL and work productivity as compared with subjects with non-WRA and those without asthma and rhinitis. METHODS: A cross-sectional survey was carried out among workers during their periodic occupational health visit in Belgium. The Mini Asthma Quality of Life Questionnaire, the 8-item Medical Outcome Study Short Form instrument, and the Work Productivity and Activity Impairment-General Health questionnaire were administered. Survey participants were divided into 3 groups: (1) WRA (current asthma with ≥2 respiratory symptoms at work; n = 89); (2) non-WRA (current asthma without work-related respiratory symptoms; n = 119); and (3) the reference group (no asthma and no lower respiratory, nasal, or eye symptoms; n = 815). Associations of QoL and work productivity with WRA were evaluated by multivariable regression analyses. RESULTS: WRA and having poor asthma control were significantly associated with lower global Mini Asthma Quality of Life Questionnaire scores compared with non-WRA. Asthmatic subjects had significantly lower physical and mental health component scores of the 8-item Medical Outcome Study Short Form instrument and overall work productivity compared with the reference group, with greater impairment in workers with WRA than in those without WRA. Moreover, workers with WRA had higher percentages of doctor visits and income reduction because of respiratory symptoms than those with non-WRA. Work-related rhinitis and depression were associated with reduced QoL, independent of the effect of WRA. CONCLUSIONS: WRA should be managed comprehensively to reduce the worsening of QoL and work productivity of those affected.

Diagnostic Accuracy of Specific IgE Against Wheat and Rye in Flour-Induced Occupational Asthma.

BACKGROUND: Assessment of IgE-mediated sensitization to flour allergens is widely used to investigate flour-induced occupational asthma. The diagnostic efficiency of detecting specific IgE antibodies (sIgEs) against wheat and rye flour, however, has not been thoroughly compared with other diagnostic procedures. OBJECTIVE: We sought to evaluate the diagnostic accuracy of sIgE against wheat and rye compared with specific inhalation challenge (SIC) with flour as the reference standard. METHODS: This retrospective multicenter study included 264 subjects who completed an SIC with flour in eight tertiary centers, of whom 205 subjects showed a positive SIC result. RESULTS: Compared with SIC, sIgE levels of 0.35 kUA/L or greater against wheat and rye provided similar sensitivities (84% to 85%, respectively), specificities (71% to 78%), positive predictive values (91% to 93%), and negative predictive values (56% to 61%). Increasing the threshold sIgE value to 5.10 kUA/L for wheat and to 6.20 kUA/L for rye provided a specificity of 95% or greater and further enhanced the positive predictive value to 98%. Among subjects with a positive SIC, those who failed to demonstrate sIgE against wheat and rye (n = 26) had significantly lower total serum IgE level and blood and sputum eosinophil counts and a lesser increase in postchallenge FeNO compared with subjects with a detectable sIgE. CONCLUSION: High levels of sIgE against wheat and/or rye flour strongly support a diagnosis of flour-induced occupational asthma without the need to perform an SIC. The absence of detectable sIgE against wheat and rye in subjects with a positive SIC seems to be associated with lower levels of TH2 biomarkers.

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.

An official american thoracic society statement: work-exacerbated asthma.

RATIONALE: Occupational exposures can contribute to the exacerbation as well as the onset of asthma. However, work-exacerbated asthma (WEA) has received less attention than occupational asthma (OA) that is caused by work. OBJECTIVES: The purpose of this Statement is to summarize current knowledge about the descriptive epidemiology, clinical characteristics, and management and treatment of WEA; propose a case definition for WEA; and discuss needs for prevention and research. METHODS: Information about WEA was identified primarily by systematic searches of the medical literature. Statements about prevention and research needs were reached by consensus. MEASUREMENTS AND MAIN RESULTS: WEA is defined as the worsening of asthma due to conditions at work. WEA is common, with a median prevalence of 21.5% among adults with asthma. Different types of agents or conditions at work may exacerbate asthma. WEA cases with persistent work-related symptoms can have clinical characteristics (level of severity, medication needs) and adverse socioeconomic outcomes (unemployment, reduction in income) similar to those of OA cases. Compared with adults with asthma unrelated to work, WEA cases report more days with symptoms, seek more medical care, and have a lower quality of life. WEA should be considered in any patient with asthma that is getting worse or who has work-related symptoms. Management of WEA should focus on reducing work exposures and optimizing standard medical management, with a change in jobs only if these measures are not successful. CONCLUSIONS: WEA is a common and underrecognized adverse outcome resulting from conditions at work. Additional research is needed to improve the understanding of the risk factors for, and mechanisms and outcomes of, WEA, and to inform and evaluate preventive interventions.

Irritant-Induced Asthma.

Irritant-induced asthma (IIA) is a phenotype of asthma caused by the inhalation of irritant agents. Definite, probable, or possible IIA have been described, depending on the concentration of the inhaled irritants and the onset of respiratory symptoms respective to the time of exposure. Definite IIA represents approximately 4% to 14% of all cases of new-onset work-related asthma. Agents responsible for IIA can be encountered as fumes, gases, aerosols, or dusts. The most frequent are chlorine, nitrogen oxides, sulfur dioxide, ammonia, acetic acid, solvents, and cleaning materials. Although the diagnosis of definite IIA is based on a suggestive clinical history along with evidence of reversible airflow limitation and/or nonspecific bronchial hyperresponsiveness, possible IIA cannot be diagnosed with certainty because the relationship between exposure and the onset of symptoms is difficult to establish. This article reviews the epidemiology, pathophysiology, diagnostic approach, and management of IIA.

Occupational Asthma Caused by Quaternary Ammonium Compounds: A Multicenter Cohort Study.

BACKGROUND: Quaternary ammonium compounds (QACs) are used extensively for cleaning and disinfection and have been documented in scattered reports as a cause of occupational asthma (OA) through bronchoprovocation tests (BPTs). OBJECTIVE: To examine the clinical, functional, and inflammatory profile of QAC-induced OA compared with OA caused by other low-molecular weight (LMW) agents. METHODS: The study was conducted in a retrospective multicenter cohort of 871 subjects with OA ascertained by a positive BPT. Subjects with QAC-induced OA (n = 22) were identified based on a positive BPT to QACs after exclusion of those challenged with cleaning products or disinfectants that contained other potential respiratory sensitizers. They were compared with 289 subjects with OA caused by other LMW agents. RESULTS: Most subjects with QAC-induced OA were working in the health care sector (n = 14). A twofold or greater increase in the postchallenge level of nonspecific bronchial hyperresponsiveness was recorded in eight of 11 subjects with QAC-induced OA (72.7%) and in 49.7% of those with OA caused by other LMW agents. Although sputum assessment was available in only eight subjects with QAC-induced OA, they showed a significantly greater median (interquartile) increase in sputum eosinophils (18.1% [range, 12.1% to 21.1%]) compared with those with OA caused by other LMW agents (2.0% [range, 0% to 5.2%]; P < .001). CONCLUSIONS: This study indicates that QAC-induced OA is associated with a highly eosinophilic pattern of airway response and provides further evidence supporting the sensitizing potential of QACs. The findings highlight the heterogeneous nature of the pathobiologic pathways involved in OA caused by LMW agents.

Characterization of Occupational Eosinophilic Bronchitis in a Multicenter Cohort of Subjects with Work-Related Asthma Symptoms.

BACKGROUND: Occupational eosinophilic bronchitis (OEB) has been described only as anecdotal case reports. OBJECTIVE: We investigated the clinical and inflammatory characteristics of subjects with OEB identified in a cohort of subjects who completed a specific inhalation challenge (SIC) with occupational agents. METHODS: In this retrospective multicenter study, OEB was defined by (1) a fall in FEV1 less than 15% during the SIC and the absence of nonspecific bronchial hyperresponsiveness both before and after the SIC and (2) a postchallenge increase of 3% or more in sputum eosinophils. The subjects who fulfilled these criteria were compared with 226 subjects with a negative SIC and 30 subjects with a positive SIC who failed to show baseline nonspecific bronchial hyperresponsiveness. RESULTS: An isolated increase in postchallenge sputum eosinophils was documented in 33 of 259 subjects (13%) with a negative SIC. These subjects reported significantly more often an isolated cough at work compared with the negative and positive SIC controls. When compared with positive SIC controls, the subjects with OEB experienced less frequently work-related wheezing and reported a shorter duration of symptoms at work. The sensitivity of the post-SIC increase in fractional exhaled nitric oxide in identifying OEB among subjects with a negative SIC was low, ranging from 43% to 24% using cutoff values of 8 ppb to 17.5 ppb, whereas the specificity was high (90%-97%). CONCLUSIONS: This study highlights the relevance of induced sputum analysis in the investigation of work-related asthma symptoms to identify isolated increases in sputum eosinophils that are consistent with a diagnosis of OEB.

The impact of concomitant rhinitis on asthma-related quality of life and asthma control.

BACKGROUND: Characterizing the interactions between the upper and lower airways is important for the management of asthma. This study aimed at assessing the specific impact of concomitant rhinitis on asthma-related quality of life (QOL) and asthma control. METHODS: A cross-sectional, observational survey was conducted among 1173 patients with asthma (aged 12-45) recruited by general practitioners and chest physicians. AR was defined by self-reported rhinitis symptoms and previously documented sensitization to inhalant allergens. The primary outcomes were (1) asthma control assessed by the Asthma Control Questionnaire (ACQ) and (2) asthma-specific QOL evaluated through the Mini Asthma Quality of Life Questionnaire (mAQLQ). RESULTS: AR was present in 73.9% of the population with asthma and nonallergic rhinitis (NAR) in 13.6%. AR and NAR were associated with an increased risk of uncontrolled asthma (i.e. ACQ score > 1.5) with adjusted odds ratios (OR) of 2.00 (95% confidence interval [CI]: 1.35-2.97) and 1.77 (95%CI: 1.09-2.89), respectively. Multivariate linear regression analysis showed that AR and NAR had a modest, although significant, negative impact on the global mAQLQ score (beta coefficient: -0.293, standard error [SE]: 0.063 and beta coefficient: -0.221, SE: 0.080, P < 0.001, respectively), even after adjustment for the level of asthma control and demographic characteristics. CONCLUSION: This survey provides direct evidence that AR and NAR are associated with an incremental adverse impact on the disease-specific QOL of patients with asthma and the level of asthma control. Further investigations are required to determine whether appropriate treatment of rhinitis would efficiently reduce asthma morbidity.

Asthma and rhinitis in the workplace.

Accumulating evidence indicates that the workplace environment substantially contributes to the global burden of asthma and rhinitis. Work-related asthma and rhinitis represent a public health concern due to their health and socioeconomic impacts. This article summarizes the scientific evidence on sensitizer-induced occupational asthma and rhinitis that has been published during the past 5 years. The review addresses the strategies for diagnosing and managing these highly prevalent occupational diseases.

Occupational Rhinitis.

There is convincing evidence that tight relationships between the upper and lower airways also apply to the workplace context. Most patients with occupational asthma (OA) also suffer from occupational rhinitis (OR), although OR is 2 to 3 times more common than OA. OR most often precedes the development of OA, especially when high-molecular-weight protein agents are involved, and longitudinal cohort studies have confirmed that OR is associated with an increased risk for the development of OA. The level of exposure to sensitizing agents at the workplace is the most important determinant for the development of IgE-mediated sensitization and OR. Atopy is a risk factor for the development of IgE-mediated sensitization only to high-molecular-weight agents. In workers with work-related rhinitis symptoms, documentation of IgE-mediated sensitization to a workplace agent via skin prick testing or serum specific IgE confirms a diagnosis of probable OR, whereas specific nasal provocation testing in the laboratory remains the reference method to establish a definite diagnosis of OR. Complete avoidance of exposure to the causal agent is the most effective therapeutic option for controlling work-related nasal symptoms and preventing the development of OA. If complete elimination of exposure is expected to induce meaningful adverse socioeconomic consequences, reduction of exposure can be considered as an alternative approach, but it is important to consider the individual risk factors for the development of OA to implement a more personalized management of OR.