Occupational asthma: Current concepts in pathogenesis, diagnosis, and management
2009; Elsevier BV; Volume: 123; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2009.01.061
ISSN1097-6825
Autores Tópico(s)Air Quality and Health Impacts
ResumoOccupational asthma (OA) may account for 25% or more of de novo adult asthma. The nomenclature has now better defined categories of OA caused by sensitizing agents and irritants, the latter best typified by the reactive airways dysfunction syndrome. Selecting the most appropriate diagnostic testing and management is driven by assessing whether a sensitizer is involved, and if so, identifying whether the sensitizing agent is a high-molecular-weight agent such as a protein or a low-molecular-weight reactive chemical such as an isocyanate. Increased understanding of the pathogenesis of OA from reactive chemical sensitizers is leading to development of better diagnostic testing and also an understanding of why testing for sensitization to such agents can be problematic. Risk factors for OA including possible genetic factors are being delineated better. Recently published guidelines for the diagnosis and management of occupational asthma are summarized; these reflect an increasingly robust evidence basis for recommendations. The utility of diagnostic tests for OA is being better defined by evidence, including sputum analysis performed in relation to work exposure with suspected sensitizers. Preventive and management approaches are reviewed. Longitudinal studies of patients with OA continue to show that timely removal from exposure leads to the best prognosis. Occupational asthma (OA) may account for 25% or more of de novo adult asthma. The nomenclature has now better defined categories of OA caused by sensitizing agents and irritants, the latter best typified by the reactive airways dysfunction syndrome. Selecting the most appropriate diagnostic testing and management is driven by assessing whether a sensitizer is involved, and if so, identifying whether the sensitizing agent is a high-molecular-weight agent such as a protein or a low-molecular-weight reactive chemical such as an isocyanate. Increased understanding of the pathogenesis of OA from reactive chemical sensitizers is leading to development of better diagnostic testing and also an understanding of why testing for sensitization to such agents can be problematic. Risk factors for OA including possible genetic factors are being delineated better. Recently published guidelines for the diagnosis and management of occupational asthma are summarized; these reflect an increasingly robust evidence basis for recommendations. The utility of diagnostic tests for OA is being better defined by evidence, including sputum analysis performed in relation to work exposure with suspected sensitizers. Preventive and management approaches are reviewed. Longitudinal studies of patients with OA continue to show that timely removal from exposure leads to the best prognosis. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: March 2009. Credit may be obtained for these courses until February 28, 2011.Copyright Statement: Copyright © 2009-2011. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members:Authors: Mark S. Dykewicz, MDActivity Objectives1. To become familiar with the revised classification and nomenclature for occupational asthma (OA) outlined in recent consensus guidelines.2. To review the various subtypes of respiratory illnesses categorized under the board heading of work-related asthma (WRA).3. To review current theories of the pathogenesis and risk factors of WRA.4. To provide evidence-based recommendations for diagnosis and management of OA.5. To review prognostic indicators of OA.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: Mark S. Dykewicz is an advisor and is on the speakers' bureau for Alcon, AstraZeneca, and GlaxoSmithKline; is an advisor for Dyax, Sepracor, and ViroPharm; is on the speakers'bureau for Merck; and has received research support from Allergy Therapeutics, Genentech/Novartis, GlaxoSmithKline, Lev Pharmaceuticals, Lincoln Diagnostics, and Schering-Plough.Several terms are now used to define subsets of patients with work-related asthma (WRA), a broad term that refers to asthma that is exacerbated or induced by inhalation exposures in the workplace. The nomenclature of work related asthma has been evolving, so medical literature and studies must be considered in that context. Occupational asthma (OA), a subset of WRA, has been the subject of a number of recently published reviews and guidelines.1Balmes J. Becklake M. Blanc P. Henneberger P. Kreiss K. Mapp C. et al.Environmental and Occupational Health Assembly, American Thoracic Society. American Thoracic Society Statement: occupational contribution to the burden of airway disease.Am J Respir Crit Care Med. 2003; 167: 787-797Crossref PubMed Scopus (667) Google Scholar, 2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google Scholar, 3Malo J.L. Lemière C. Gautrin D. Labrecque M. Occupational asthma.Curr Opin Pulm Med. 2004; 10: 57-61Crossref PubMed Scopus (30) Google Scholar, 4Boulet L.P. Lemière C. Gautrin D. Cartier A. New insights into occupational asthma.Curr Opin Allergy Clin Immunol. 2007; 7: 96-101PubMed Google Scholar, 5Mapp C.E. Boschetto P. Maestrelli P. Fabbri L.M. Occupational asthma.Am J Respir Crit Care Med. 2005; 172: 280-305Crossref PubMed Scopus (272) Google Scholar, 6Bardana Jr., E.J. Occupational asthma.J Allergy Clin Immunol. 2008; 121: S408-S411Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 7Nicholson P.J. Cullinan P. Taylor A.J. Burge P.S. Boyle C. Evidence based guidelines for the prevention, identification, and management of occupational asthma.Occup Environ Med. 2005; 62: 290-299Crossref PubMed Scopus (254) Google Scholar As defined by the 2008 Guidelines of the American College of Chest Physicians (ACCP), WRA includes OA that refers to de novo asthma or the recurrence of previously quiescent asthma induced either (1) by sensitization to a workplace substance, termed sensitizer-induced OA, or (2) by exposure to an inhaled irritant at work, termed irritant-induced OA. Previously, OA was defined to refer only to sensitizer-induced OA. A distinct subset of WRA is work-exacerbated asthma (WEA), defined to be present in workers with pre-existing or concurrent asthma that is triggered by work-related factors (eg, aeroallergens, irritants, or exercise), but not considered to be OA. Estimates of the incidence and prevalence of OA vary. It has generally been accepted that at least 9% to 15% of adult asthma can be attributed to workplace exposures, although recent data indicate that 25% or more of de novo asthma may have an occupational basis.1Balmes J. Becklake M. Blanc P. Henneberger P. Kreiss K. Mapp C. et al.Environmental and Occupational Health Assembly, American Thoracic Society. American Thoracic Society Statement: occupational contribution to the burden of airway disease.Am J Respir Crit Care Med. 2003; 167: 787-797Crossref PubMed Scopus (667) Google Scholar, 2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google Scholar WRA results in considerable morbidity to affected individuals, but also results in tremendous costs to society.2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google Scholar Failure to recognize OA in a timely fashion can lead to permanent respiratory impairment, underscoring the need for early diagnosis and intervention.Types of OASensitizer-induced OAOccupational asthma from sensitizers typically presents with a latent period of exposure, followed by the onset of clinical disease. After sensitization, airway reactions develop from levels of exposure to the sensitizing agent that were tolerated before sensitization. Although the mechanism causing OA from some sensitizers has been demonstrated to have an immunologic basis (IgE antibody–mediated or otherwise), no immunologic mechanism has been demonstrated for some suspected sensitizers (eg, colophony). OA sensitizers (Table I) may be categorized on the basis of their molecular weight. By convention, high-molecular-weight (HMW) sensitizers are >10 kd, with common examples being inhaled protein agents. HMW agents typically cause occupational asthma by IgE antibody–mediated mechanisms. Low-molecular-weight (LMW) sensitizers are often reactive chemicals that act as haptens in that they can only induce an adaptive immune response and be recognized as antigens after combining with self-proteins to form immunogenic conjugates after inhalation. Some LMW agents have been demonstrated to cause sensitization via IgE-mediated mechanisms, whereas have not. There are more than 250 reported workplace sensitizers.Table IExamples of sensitizers reported to cause OAAgentIndustry, process, or occupationHigh molecular weight Animal and insect–derived Bird proteins (feathers, serum)Bird breeders Crustaceans: snow crab, prawnSeafood processors Eggs (chicken)Food processors InsectsBeekeepers, farmers, granary workers, silk processing, dockworkers Mammalian proteins in hair, dander, urineResearch labs, veterinarians, breeders, pet shop workers Pharmaceutical enzymes, eg, pancreasePharmaceutical industry, health care workers Sea squirt (oyster parasite)Oyster processing workers Bacterial and fungal–derived Bacillus subtilis–derived enzymesDetergent formulators Penicillium caseiiCheese workers Thermophilic moldsMushroom workers Plant-derived Henna dyeBeauticians Latex, natural rubberHealth care workers Plant enzymes (papain, bromelain)Food, pharmaceutical industries PsylliumLaxative manufacture, nursing Vegetable gums (arabic, guar, tragacanth)Printing/bookbinders, food, carpet manufacture Wheat flourBakersLow molecular weight Persulfates (in hair bleaching solutions)Hairdressers Metals and metal salts ChromiumMiners and cement, electroplating and tanning workers CobaltMetal workers and diamond polishers Nickel sulfateMetal plating PlatinumAlloy makers Organic chemicals Acid anhydrides (prototype: trimellitic anhydride)Plastics industry, dye, insecticide makers, organic chemical manufacture (used in epoxy resins) Acrylates, methacrylate (artificial nail glue)Printing industry, beauticians EthylenediamineShellac/lacquer industry workers Paraphenyldiamine in hair dyeHairdressers Polyisocyanates (prototype: toluene diisocyanate)Polyurethane, foam coatings, adhesives production, and end-use settings (eg, spray painters, foam workers) Pharmaceuticals (antibiotics, cimetidine)Hospital and pharmaceutical workersRelevant components uncertain Wood dusts (red cedar, oak, mahogany, redwood, iroko)Foresters, woodworkers and furniture makers Open table in a new tab Irritant-induced OANot previously considered a form of occupational asthma, de novo asthma caused by exposure to inhaled irritants at work now is commonly termed irritant-induced OA.2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google ScholarThe existence of the reactive airways dysfunction syndrome (RADS) resulting from a single episode of a high level exposure to an irritant agent (usually from an occupational accident) has long been recognized.2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google Scholar, 8Brooks S.M. Weiss M.A. Bernstein I.L. Reactive airways dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures.Chest. 1985; 88: 376-384Crossref PubMed Scopus (617) Google Scholar Examples of agents reported to cause RADS include chlorine gas, hydrochloric acid, anhydrous ammonia, hydrogen sulfide, fumigating fog, heated acids, and smoke by inhalation. In 1984, a toxic cloud of methyl isocyanate gas released from a chemical plant in Bhopal, India, killed thousands of people, and caused thousands more to develop persistent respiratory disease, some with reversible airway obstruction. After the collapse of the World Trade Center towers in New York City during the 2001 terrorist attacks, a complex mixture of airborne dusts and pollutants was elaborated that has been associated with RADS (and other respiratory disorders) in exposed rescue and recovery workers and residents of the surrounding area.9Banauch G.I. Dhala A. Prezant D.J. Pulmonary disease in rescue workers at the World Trade Center site.Curr Opin Pulm Med. 2005; 11: 160-168Crossref PubMed Scopus (72) Google ScholarThe 2008 ACCP consensus guidelines retain use of the RADS term, but consider it to be a form of irritant-induced asthma.2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google Scholar By definition, the diagnosis of RADS can be made only when defined criteria are satisfied and should not be made in patients with pre-existing asthma (Table II). This leaves open another debate about how to define worsening of pre-existing asthma caused by inhalation of high levels of irritants or worsening of pre-existing smoking-related chronic obstructive pulmonary disease.Table IIDiagnostic criteria for RADS1. There is an absence of pre-existing respiratory disorder, asthma symptomatology, or a history of asthma in remission and an exclusion of conditions that can simulate asthma.2. The onset of asthma occurs after a single exposure or accident.3. The exposure is to an irritant vapor, gas, fumes, or smoke in very high concentrations.4. The onset of asthma symptoms develops within minutes to hours and <24 h after the exposure.5. There is a positive methacholine challenge test finding or equivalent test, which signifies hyperreactive airways, after the exposure.6. There may or may not be airflow obstruction confirmed with pulmonary function testing.7. There is exclusion of another pulmonary disorder that explains the symptoms and findings.Reprinted with permission from Tarlo SM, Balmes J, Balkissoon R, Beach J, Beckett W, Bernstein D, et al. Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement. Chest 2008;134(3 Suppl):1S-41S.2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google Scholar Adapted with permission from Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures. Chest 1985;88:376-84.8Brooks S.M. Weiss M.A. Bernstein I.L. Reactive airways dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures.Chest. 1985; 88: 376-384Crossref PubMed Scopus (617) Google Scholar Open table in a new tab There is still controversy about whether chronic lower-level exposure to irritants can cause OA.2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google Scholar, 5Mapp C.E. Boschetto P. Maestrelli P. Fabbri L.M. Occupational asthma.Am J Respir Crit Care Med. 2005; 172: 280-305Crossref PubMed Scopus (272) Google Scholar Repeated peak exposure to irritant gases in the pulp industry has been shown to increase the risk for both adult-onset asthma and wheezing.10Andersson E. Olin A.C. Hagberg S. Nilsson R. Nilsson T. Toren K. Adult-onset asthma and wheeze among irritant-exposed bleachery workers.Am J Ind Med. 2003; 43: 532-538Crossref PubMed Scopus (19) Google Scholar There is also a report that asthma symptoms developed in 3 patients after repetitive exposure to irritants that occurred over several days to months.11Quirce S. Gala G. Perez-Camo I. Sanchez-Fernandez C. Pacheco A. Losada E. Irritant-induced asthma: clinical and functional aspects.J Asthma. 2000; 37: 267-274Crossref PubMed Scopus (20) Google Scholar According to the 2008 ACCP guidelines, cases that do not meet the stringent criteria for RADS (eg, when there is several-day lag before the onset of symptoms, or when there is no single massive exposure but rather repeated exposures over days or weeks, less massive exposures, or a shorter duration of symptoms) are all classified under the general category of irritant-induced asthma. Specific examples include meat wrapper's asthma, pot room asthma, asthma from professional cleaning materials, and asthma from exposure to ozone, endotoxin, formaldehyde, and quaternary ammonium compounds.PathophysiologyPathophysiology of sensitizer-induced OAOA from HMW sensitizersHigh-molecular-weight agents such as proteins and glycoproteins (Table I) characteristically act as complete antigens that cause sensitizer OA through a classic IgE antibody–mediated mechanism. The allergens responsible for OA from some HMW agents have been well characterized—for example, in detergent workers who develop asthma from exposure to Bacillus subtilis enzymes, or in egg processing workers. However, identifying the actual protein sensitizers in complex plant or animal materials can be problematic, confounding studies about the pathogenesis of OA and development of appropriate agents for diagnostic testing. For example, baker's asthma caused by wheat inhalation typically does not occur because of sensitization to wheat ω-5 gliadin [Tri a 19], an allergen commonly important for wheat allergy from oral ingestion such as food allergy in children or wheat-dependent exercise-induced anaphylaxis. Instead, baker's asthma may be caused by an increasingly recognized number of other allergens present in wheat flour (eg, α-amylase inhibitors, thioredoxins cross-reactive with grass allergens, a wheat lipid transfer protein, Tri a 14, a wheat serine proteinase inhibitor, and baking additives such as fungal α-amylase [Asp o 21]).12Weichel M. Glaser A.G. Ballmer-Weber B.K. Schmid-Grendelmeier P. Crameri R. Wheat and maize thioredoxins: a novel cross-reactive cereal allergen family related to baker's asthma.J Allergy Clin Immunol. 2006; 117: 676-681Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 13Palacin A. Quirce S. Armentia A. Fernandez-Nieto M. Pacios L.F. Asensio T. et al.Wheat lipid transfer protein is a major allergen associated with baker's asthma.J Allergy Clin Immunol. 2007; 120: 1132-1138Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 14Constantin C. Quirce S. Grote M. Touraev A. Swoboda I. Stoecklinger A. et al.Molecular and immunological characterization of a wheat serine proteinase inhibitor as a novel allergen in baker's asthma.J Immunol. 2008; 180: 7451-7460PubMed Google Scholar It is unclear why some allergens are more important for developing IgE-mediated sensitivity to wheat from inhalational exposure, whereas others are important for oral ingestion.Baker's asthma also provides an example of OA from HMW sensitizers that may have a more complex cascade of events related to IgE-mediated sensitivity than would be expected from what is known about nonoccupational allergic asthma to common aeroallergens. Using serum from patients with baker's asthma, IgE binding inhibition studies have demonstrated that thioredoxin wheat allergens can have partial cross-reactivity with endogenous human thioredoxins in lungs. It has been hypothesized that the sharing of B-cell epitopes by cereal and human thioredoxins could provide the potential for molecular mimicry/cross reactivity, with consequent cross-linking of thioredoxin-specific IgE by human thioredoxin. It is speculated that this might induce mediator release and inflammatory processes without external exposure and be a mechanism by which there might be maintenance and deterioration of allergic lung inflammation once baker's asthma has developed.12Weichel M. Glaser A.G. Ballmer-Weber B.K. Schmid-Grendelmeier P. Crameri R. Wheat and maize thioredoxins: a novel cross-reactive cereal allergen family related to baker's asthma.J Allergy Clin Immunol. 2006; 117: 676-681Abstract Full Text Full Text PDF PubMed Scopus (95) Google ScholarEosinophils typically characterize airway inflammation observed in most OA from HMW sensitizers, in contrast with inflammation seen in OA from some LMW sensitizers that may be more likely characterized by neutrophils.15Lemiere C. Chaboillez S. Malo J.L. Cartier A. Changes in sputum cell counts after exposure to occupational agents: what do they mean?.J Allergy Clin Immunol. 2001; 107: 1063-1068Abstract Full Text Full Text PDF PubMed Scopus (89) Google ScholarOA from LMW sensitizersIn contrast with the typically IgE-mediated mechanism of OA caused by HMW agents, IgE antibody appears to be of key relevance to the pathogenesis of OA from only some LMW agents. LMW agents that cause OA through IgE-mediated mechanisms include phthalic anhydride; trimellitic anhydride (TMA); complex salts of metals such as platinum (including hexachloroplatinate salts that are immunogenic without need for protein conjugation), chromium, and nickel; epoxy amines; and penicillin.2Tarlo S.M. Balmes J. Balkissoon R. Beach J. Beckett W. Bernstein D. et al.Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement.Chest. 2008; 134: 1S-41SCrossref PubMed Scopus (337) Google Scholar, 3Malo J.L. Lemière C. Gautrin D. Labrecque M. Occupational asthma.Curr Opin Pulm Med. 2004; 10: 57-61Crossref PubMed Scopus (30) Google Scholar, 4Boulet L.P. Lemière C. Gautrin D. Cartier A. New insights into occupational asthma.Curr Opin Allergy Clin Immunol. 2007; 7: 96-101PubMed Google Scholar, 5Mapp C.E. Boschetto P. Maestrelli P. Fabbri L.M. Occupational asthma.Am J Respir Crit Care Med. 2005; 172: 280-305Crossref PubMed Scopus (272) Google Scholar, 6Bardana Jr., E.J. Occupational asthma.J Allergy Clin Immunol. 2008; 121: S408-S411Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 16Cristaudo A. Sera F. Severino V. DeRocco M. DiLella E. Picardo M. Occupational hypersensitivity to metal salts, including platinum, in the secondary industry.Allergy. 2005; 60: 159-164Crossref PubMed Scopus (109) Google Scholar Other LMW agents may lead to airway sensitization through non–IgE-mediated immunologic mechanisms that are not completely understood.Acid anhydridesTrimellitic anhydride (encountered in plastics, epoxy resins, and drug manufacture) is the best described model of a LMW agent that causes OA through an IgE antibody–mediated mechanism. Positive immediate skin tests to trimellityl–human serum albumin (HSA) and in vitro tests for IgE to trimellityl-HSA correlate well with OA, as do immediate skin tests and in vitro tests to other acid anhydrides that cause OA. It has been demonstrated that after sensitization, there is antigen recognition not only of epitopes of the trimellityl hapten but also of new antigenic determinants formed during the conjugation of TMA to protein.17Patterson R. Zeiss C.R. Pruzansky J.J. Immunology and immunopathology of trimellitic anhydride pulmonary reactions.J Allergy Clin Immunol. 1982; 70: 19-23Abstract Full Text PDF PubMed Scopus (47) Google Scholar Novel mechanisms can promote immediate-type hypersensitivity reactions from TMA. As 1 example, inhaled TMA reacting with any IgE antibody bound to mast cells in the airways could produce trimellityl-modified IgE conjugates that would be recognized as antigenic targets by antitrimellityl IgG antibodies, resulting in IgE cross-linking and mast cell activation.PolyisocyanatesLow-vapor polyisocyanates and their prepolymers are sensitizers widely encountered in paints and varnishes, elastomers, and the manufacture of flexible and rigid foams and fibers. For brevity, these agents are referred to as isocyanates, although methyl isocyanate, a lethal toxic gas (discussed under Irritant-induced OA section), is not a known sensitizer. Although there is incomplete understanding of the pathophysiology of OA from many LMW sensitizers, studies of OA from isocyanates—chemicals that are some of the most common causes of OA—have provided important insights about putative non–IgE-mediated mechanisms in OA. Specific IgE antibodies to isocyanates are present in only a minority of affected patients with OA from toluene diisocyanate (TDI), although they are more commonly present in OA from hexamethylene diisocyanate, indicating that non—IgE antibody–mediated immunologic mechanisms may be of relevance in many patients.18Mapp C.E. Boschetto P. Miotto D. De R.E. Asthma induced by isocyanates: a model of IgE-independent asthma.Acta Biomed Ateneo Parmense. 2005; 76: 15-19Google Scholar Nonetheless, the presence of IgE to isocyanates is a relatively specific marker for isocyanate-induced asthma demonstrated by specific bronchial challenge.19Wisnewski A.V. Developments in laboratory diagnostics for isocyanate asthma.Curr Opin Allergy Clin Immunol. 2007; 7: 138-145Crossref PubMed Scopus (48) Google ScholarIn contrast with specific IgE, IgG to isocyanates is a more sensitive but less specific marker for OA from isocyanates. IgG to isocyanates is not thought to cause OA from isocyanates but is best viewed as a marker of exposure. Temporally, serum levels of IgE specific for TDI decline over time after TDI exposure ends, whereas IgG to TDI does not.20Malo J.L. L'Archevêque J. Lummus Z. Bernstein D. Changes in specific IgE and IgG and monocyte chemoattractant protein-1 in workers with occupational asthma caused by diisocyanates and removed from exposure.J Allergy Clin Immunol. 2006; 118: 530-533Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Recently, it has been shown that assays for specific IgE to TDI-albumin conjugates are improved by preparing conjugates in an optimal substitution ratio to avoid oversubstitution of the hapten, which can lead to many false-positive results.21Ye Y.M. Kim C.W. Kim H.R. Kim H.M. Suh C.H. Nahm D.H. et al.Biophysical determinants of toluene diisocyanate antigenicity associated with exposure and asthma.J Allergy Clin Immunol. 2006; 118: 885-891Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 22Campo P. Wisnewski A.V. Lummus Z. Cartier A. Malo J.L. Boulet L.P. et al.Diisocyanate conjugate and immunoassay characteristics influence detection of specific antibodies in HDI-exposed workers.Clin Exp Allergy. 2007; 37: 1095-1102Crossref PubMed Scopus (37) Google ScholarSeveral non–IgE-mediated immunologic mechanisms have been implicated. In patients with OA to isocyanates, coincubation of PBMCs with diisocyanate-HSA increases secretion of monocyte chemoattractant protein 1.23Bernstein D.I. Cartier A. Cote J. Malo J.L. Boulet L.P. Wanner M. et al.Diisocyanate antigen-stimulated monocyte chemoattractant protein-1 synthesis has greater test efficiency than specific antibodies for identification of diisocyanate asthma.Am J Respir Crit Care Med. 2002; 166: 445-450Crossref PubMed Scopus (108) Google Scholar Diisocyanate-HSA–stimulated production of monocyte chemoattractant protein 1 by peripheral blood monocytes has a reported sensitivity of 79% and specificity of 91% in patients with isocyanate OA, far superior to the sensitivity and test efficiency of serum assays for isocyanate-specific antibodies.In patients with OA from isocyanates who did not have serum IgE to isocyanates, bronchial challenge with isocyanates can generate CD4-positive, IL-5–positive, and CD25-positive lymphocytes in bronchial mucosa, but in the absence of expression of ε heavy-chain and IL-4 mRNA that would typically occur during the generation of IgE antibody.24Jones M.G. Floyd A. Nouri-Aria K.T. Jacobson M.R. Durham S.R. Taylor A.N. et al.Is occupational asthma to diisocyanates a non-IgE-mediated disease?.J Allergy Clin Immunol. 2006; 117: 663-669Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar In mous
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