Carrie A. Redlich

Diagnosis and Management of Work-Related Asthma: American College of Chest Physicians Consensus Statement

BACKGROUND A previous American College of Chest Physicians Consensus Statement on asthma in the workplace was published in 1995. The current Consensus Statement updates the previous one based on additional research that has been published since then, including findings relevant to preventive measures and work-exacerbated asthma (WEA). METHODS A panel of experts, including allergists, pulmonologists, and occupational medicine physicians, was convened to develop this Consensus Document on the diagnosis and management of work-related asthma (WRA), based in part on a systematic review, that was performed by the University of Alberta/Capital Health Evidence-Based Practice and was supplemented by additional published studies to 2007. RESULTS The Consensus Document defined WRA to include occupational asthma (ie, asthma induced by sensitizer or irritant work exposures) and WEA (ie, preexisting or concurrent asthma worsened by work factors). The Consensus Document focuses on the diagnosis and management of WRA (including diagnostic tests, and work and compensation issues), as well as preventive measures. WRA should be considered in all individuals with new-onset or worsening asthma, and a careful occupational history should be obtained. Diagnostic tests such as serial peak flow recordings, methacholine challenge tests, immunologic tests, and specific inhalation challenge tests (if available), can increase diagnostic certainty. Since the prognosis is better with early diagnosis and appropriate intervention, effective preventive measures for other workers with exposure should be addressed. CONCLUSIONS The substantial prevalence of WRA supports consideration of the diagnosis in all who present with new-onset or worsening asthma, followed by appropriate investigations and intervention including consideration of other exposed workers.

Skin Exposure to Isocyanates: Reasons for Concern

Objective Isocyanates (di- and poly-), important chemicals used worldwide to produce polyurethane products, are a leading cause of occupational asthma. Respiratory exposures have been reduced through improved hygiene controls and the use of less-volatile isocyanates. Yet isocyanate asthma continues to occur, not uncommonly in settings with minimal inhalation exposure but opportunity for skin exposure. In this review we evaluate the potential role of skin exposure in the development of isocyanate asthma. Data sources We reviewed the published animal and human literature on isocyanate skin-exposure methods, workplace skin exposure, skin absorption, and the role of skin exposure in isocyanate sensitization and asthma. Data extraction We selected relevant articles from computerized searches on Medline, U.S. Environmental Protection Agency, Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, and Google databases using the keywords “isocyanate,” “asthma,” “skin,” “sensitization,” and other synonymous terms, and our own extensive collection of isocyanate publications. Data synthesis Isocyanate production and use continues to increase as the polyurethane industry expands. There is substantial opportunity for isocyanate skin exposure in many work settings, but such exposure is challenging to quantify and continues to be underappreciated. Isocyanate skin exposure can occur at work, even with the use of personal protective equipment, and may also occur with consumer use of certain isocyanate products. In animals, isocyanate skin exposure is an efficient route to induce sensitization, with subsequent inhalation challenge resulting in asthma-like responses. Several lines of evidence support a similar role for human isocyanate skin exposure, namely, that such exposure occurs and can contribute to the development of isocyanate asthma in certain settings, presumably by inducing systemic sensitization. Conclusions Integrated animal and human research is needed to better understand the role of skin exposure in human isocyanate asthma and to improve diagnosis and prevention. In spite of substantial research needs, sufficient evidence already exists to justify greater emphasis on the potential risks of isocyanate skin exposure and the importance of preventing such exposures at work and during consumer use of certain isocyanate products.

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.

Diisocyanate asthma: clinical aspects and immunopathogenesis.

Diisocyanates, highly reactive chemicals used in the production of polyurethanes, are currently the most frequently reported cause of chemically induced occupational asthma and their use continues to rise. The prevalence of diisocyanate asthma among exposed workers is estimated to range from 5% to 15%. Routes of exposure include the respiratory tract and skin. Workplace exposures are difficult to quantify and control, and there is no simple diagnostic test for the disease. This review considers recent concepts in exposure. clinical aspects and pathogenesis of the disease. The pathogenesis of diisocyanate asthma remains unclear, with evidence supporting both immunological and nonimmunological mechanisms. Knowledge of the chemical reactivity of diisocyanates, the target biomolecules, and the cellular sites of reaction are fundamental to understanding diisocyanate toxicity and disease. Recent findings of chemical interactions with biological nucleophiles will be described. The importance of diisocyanate-adducted biomolecules will be emphasized and their potential contributions to pathogenesis discussed. It is anticipated that greater understanding of the immunopathogenesis of diisocyanate asthma, including the initial cell/diisocyanate reactions, should lead to clinically useful markers of exposure and early disease.

Liver Disease Associated with Occupational Exposure to the Solvent Dimethylformamide

STUDY OBJECTIVE to characterize an outbreak of liver disease among workers in a fabric coating factory; and to determine the outbreaks cause and natural history and strategies for clinical recognition, treatment, and prevention. DESIGN clinical-epidemiological investigation. SETTING academic medical center, Occupational Medicine Clinic, and worksite. PATIENTS fifty-eight of sixty-six workers participated in the study. All had standard liver function tests at least once. Forty-six workers completed a questionnaire; 27 had more extensive clinical evaluation for recognized liver abnormalities. RESULTS a plant-wide outbreak of liver disease was recognized after a new employee presented with signs and symptoms of hepatitis. Evaluation of the worksite showed that dimethylformamide, a widely used industrial solvent and known hepatotoxin, was being used to coat fabric in poorly ventilated areas without appropriate skin protection. No other major hepatotoxic exposure was identified. Overall, 36 of 58 (62%) workers tested had elevations of either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels. Enzyme abnormalities occurred almost exclusively in production workers (35 of 46 were abnormal), whereas only 1 of 12 nonproduction workers showed any elevations in enzyme levels (P less than 0.0001). Serologic tests excluded known infectious causes of hepatitis in all but 2 workers and changes characteristic of toxic liver injury were confirmed by histologic examinations of biopsy specimens from 4 workers. The ratio of AST to ALT levels was one or less in all but 1 worker. After modification of work practices and removal of workers most severely affected from exposure, improvement in liver enzyme abnormalities and symptoms in most patients were seen, although some patients showed persistent elevations of enzyme levels. CONCLUSIONS an outbreak of toxic liver disease has been associated with exposure to dimethylformamide in the workplace. The diagnosis of toxic liver disease was established by the clinical histories, negative viral serologies, an enzyme pattern of ALT levels being greater than AST levels, epidemiologic data on coworkers, and liver biopsy specimens. The high prevalence of unsuspected liver enzyme abnormalities in these workers suggests that occupational liver disease may occur more frequently than is generally recognized.

Recent developments in diisocyanate asthma.

Despite recent advances in our understanding of diisocyanate-induced asthma, this disease remains a perplexing phenomenon. Studies reported in the past year have focused on: (i) diisocyanate antigens; (ii) the role of airway and skin epithelium; (iii) human immune responses to exposure; (iv) neurogenic pathways; and (v) genetic factors that may confer susceptibility. These studies support the hypothesis that diisocyanate asthma results from the host immune response to these chemicals, and may represent a mixed T helper type 1/2 response. A better understanding of the pathogenesis of diisocyanate asthma should facilitate the development of better diagnostic tests and strategies for disease surveillance and intervention.

Lung/skin connections in occupational lung disease.

Purpose of reviewExposure to occupational and environmental agents can cause a spectrum of lung diseases that are predominantly immune-mediated. Research and prevention have focused primarily on the respiratory tract. Recent studies, however, suggest that the skin may also be an important route of exposure and site of sensitization. This article highlights key findings, focusing on isocyanate asthma and chronic beryllium disease. Recent findingsOccupational lung diseases such as isocyanate asthma and chronic beryllium disease continue to occur despite reduced airborne exposures. Although challenging to quantify, recent studies have documented isocyanate and beryllium skin exposure, even with the use of personal protective clothing. Factors that impair skin barrier function, such as trauma, may promote sensitization to such agents. Animal studies demonstrate that skin exposure to isocyanates and protein allergens is highly effective at inducing sensitization, with subsequent inhalation challenge eliciting asthmatic responses. Limited clinical studies suggest a similar role for human skin exposure to certain sensitizing agents. SummaryRecent findings support a greater focus on the role of skin exposure in the development of certain occupational and environmental lung diseases. Although further research is needed, it is prudent to reduce both skin and inhalation exposures.

Skin exposure and asthma: is there a connection?

Numerous occupational and environmental exposures that increase asthma risk have been identified. Research and prevention have focused primarily on the respiratory tract. However, recent studies suggest that the skin may also be an important route of exposure and site of sensitization that contributes to asthma development. Factors that impair skin barrier function, such as filaggrin gene mutations or skin trauma, may facilitate allergen entry and promote Th2-like sensitization and subsequent asthma. Animal studies demonstrate that skin exposure to chemical and protein allergens is highly effective at inducing sensitization, with subsequent inhalation challenge eliciting asthmatic responses. A similar role for human skin exposure to certain sensitizing agents, such as isocyanates, is likely. Skin exposure methodologies are being developed to incorporate skin exposure assessment into epidemiology studies investigating asthma risk factors.

Isocyanate-conjugated human lung epithelial cell proteins: A link between exposure and asthma?

BACKGROUND Isocyanates are a group of highly reactive cross-linking chemicals that cause airway inflammation and asthma in exposed individuals. Isocyanates have been detected along the airway epithelia of exposed workers and animals, prompting the hypothesis that isocyanates can directly bind to epithelial cell proteins. OBJECTIVE We tested the hypothesis that hexamethylene diisocyanate (HDI) binds directly to lung epithelial cell proteins and initiated studies to evaluate the immunostimulatory potential of HDI-conjugated lung epithelial cell proteins. METHODS Human lung epithelial cell lines were exposed to vapor- and liquid-phase HDI, and the cellular proteins were analyzed for HDI conjugation by Western blotting and tested for the ability to induce lymphocyte proliferation in vitro. RESULTS A number of epithelial cell polypeptides, ranging from 25 to 110 kd in apparent molecular weight, were conjugated with HDI after exposure of the human lung epithelial cell lines (A549 and NCI-H292) to HDI concentrations greater than 0.005% (vol/vol) in the liquid phase. Vapor-phase HDI exposure resulted in a more restricted HDI conjugation pattern, with major HDI-conjugated polypeptides migrating at 47, 71, and 91 kd. HDI-conjugated epithelial cell proteins specifically stimulated proliferation of PBMCs from subjects with isocyanate-induced asthma but not HDI-exposed nonasthmatic individuals or atopic subjects with nonisocyanate-related asthma. CONCLUSIONS The data demonstrate that epithelial cell proteins readily react with HDI and that HDI-conjugated epithelial cell proteins can stimulate lymphocyte proliferation. Further characterization and evaluation of HDI-conjugated epithelial cell proteins will elucidate their potential role in the pathogenesis of isocyanate-induced asthma.

Primary prevention: exposure reduction, skin exposure and respiratory protection

Interventions for the primary prevention of occupational asthma have been reported in the medical literature, understanding the effectiveness of these efforts could help future interventions. The aim of our study was to evaluate the existing knowledge regarding the impact of controlling work exposure on the prevention of occupational asthma. We conducted systematic literature searches through April 2010 to examine if control of workplace exposures is effective for primary prevention of sensitisation and occupational asthma. The literature search for primary prevention of occupational asthma yielded 29 studies. Assessment of the available information led to the following conclusions and recommendations concerning primary prevention of occupational asthma. Exposure elimination is the strongest and preferred primary preventive approach to reduce the burden of occupational asthma. If elimination is not possible, exposure reduction is the second best option for primary prevention of occupational asthma. The evidence for the effectiveness of respirators in preventing occupational asthma is limited, and other options higher in the list of controls for occupational exposures, notably eliminating or minimising exposures at the source or in the environment, should be used preferentially. There is strong evidence to recommend not using powdered allergen-rich natural rubber latex gloves. There is weak evidence that suggests workers should minimise skin exposure to asthma-inducing agents.