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Advances in environmental and occupational disorders
Advances in environmental and occupational disorders Anthony J. Frew, MD, FRCP Southampton, United Kingdom The environment plays a crucial role in determining the development and expression of allergic disorders. Epidemiologic studies allow us to understand risk factors for allergic disease, which may lead to interventional studies to provide the evidence base for our clinical advice. Articles published in The Journal of Allergy and Clinical Immunology last year highlighted the relevance of mold exposure and environmental tobacco smoke as risk factors for the development of asthma and the expression of symptoms. The role of fitted carpets as a reservoir for house dust allergens was also challenged by data arising from this work. Occupational allergy is an important clinical and socioeconomic problem. A large body of work on latex allergy has been reported in the past year, demonstrating the impact of containment strategies on exposure to latex and the incidence of sensitization to latex. Other articles have explored the range of latex allergens to which patients are sensitized and the HLA associations of latex allergy. Two models of isocyanate sensitization were reported, providing some insight into possible mechanisms of isocyanate asthma and some clues for understanding nonallergic asthma. Environmental and occupational disorders are highly relevant to our readership, and the new Editorial Board hopes to encourage submission and publication of relevant articles in this area. (J Allergy Clin Immunol 2003;111:S824-8.) Key words: Environment, occupational asthma, latex, isocyanates, epidemiology
The environment plays a crucial role in determining the expression of allergy and allergic diseases. We know that allergy and asthma have a significant genetic component, but to explain the rapid rise in the prevalence of asthma and allergic diseases during the past 40 years, we must invoke environmental factors and triggers. The rise has been too fast to be due to a change in the gene pool of the population, and it follows that some change or several changes in the environment must have been responsible for allowing a genetically susceptible population to acquire clinical disease, whereas in previous times they would have remained symptom free. Understanding the nature of these environmental triggers is fundamental to our aims of trying to prevent allergic disease in the next generation. Equally, understanding the range and nature of relevant environmental allergens may be helpful in controlling allergic disease that has become established.
From the Department of Medical Specialties, Southampton General Hospital, Southampton SO16 6YD, United Kingdom. Reprint requests: Anthony J. Frew, MD, FRCP, Department of Medical Specialties, Mailpoint 810, Level D Centre Block, Southampton General Hospital, Southampton SO16 6YD, United Kingdom. © 2003 Mosby, Inc. All rights reserved. 0091-6749/2003 $30.00 + 0 doi:10.1067/mai.2003.151
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Abbreviations used ECRHS: European Community Respiratory Health Survey GST: Glutathione S-transferase MMP: Matrix metalloproteinase
Occupational allergy is an important cause of morbidity in the working population. Studying occupational allergy allows one to gain a much better idea about exposure-response relationships for allergy, because the timing, duration and extent of allergen exposure can be more precisely defined than is possible for more general environmental allergens, such as house dust mite, animal dander, and pollens. Moreover, allergists need to maintain a high level of suspicion for possible occupational causes in patients who acquire allergic disease for the first time in adulthood or whose allergic disease deteriorates during adulthood. Environmental and occupational disorders should therefore be a relevant and important topic for discussion within the pages of The Journal of Allergy and Clinical Immunology. It is perhaps surprising that a review of the past year’s issues yields only a selected range of topics that have been submitted and published in the Journal’s pages. In some cases, environmental topics have been addressed as etiologic factors for asthma, rhinitis, and related diseases and may therefore not appear in the environmental section of the Journal. Aerobiology and atmospheric chemistry comprise another area of science relevant to asthma and allergic disease. Technical details of atmospheric chemistry are more likely to be published in other journals, but articles detailing the impact of pollutants on airway biology and asthma would clearly be of interest to our readers. Earlier this year, Solomon1 presented a review of the life history of airborne pollens. Understanding the biologic nature and role of pollen helps us to understand the biologic impact of pollen exposure, although clearly the downstream processes involved in the triggering of allergic disease are internal responses, rather than driven by the pollen itself. New understandings of the role of particulate pollution as a vector for pollen proteins may alter the way that we view allergic asthma, because this process will affect both the deposition of allergenic proteins and their presentation to the immune system. Two articles published this year addressed environmental factors in relation to asthma. Zock et al2 reported on housing characteristics and mold exposure in relation to asthma on the basis of data derived from the European Community Respiratory Health Survey (ECRHS). The ECRHS has been a powerful tool for addressing difficult questions in asthma epidemiology. By harnessing a large
J ALLERGY CLIN IMMUNOL VOLUME 111, NUMBER 3
number of investigators in different countries, it has been possible to tease out questions that would have been difficult to address within a single country. Importantly, the ECRHS allows investigation of subsets that would not really be statistically viable when investigated in a single center. The key findings of this ECRHS-based study were that indoor mold exposure was increased in centers that reported a higher prevalence of asthma. Moreover, within the population there was a significant association between mold exposure and both asthma symptoms and bronchial hyperresponsiveness. Importantly, this association was homogeneous across the various centers, indicating that it was not simply an effect that happened in damp areas of Europe. One additional finding of the study was that fitted carpets and rugs in the bedroom were associated with a lower level of asthma symptoms and bronchial responsiveness. Previously it had been suggested that fitted rugs and carpets might be a risk factor for asthma because they would increase the reservoir available for house dust mite antigens. The fact that this negative association was found in Zock et al’s study2 and that the association was more marked in house dust mite–sensitive individuals does raise the possibility that one may be looking at a result of intervention to reduce the use of fitted carpets by patients who are known to be sensitive to house dust mite. However, this argument is weakened by the fact that the negative association was consistent across all centers. The implication is that, as with synthetic pillows and exposure to pets, our initial assumptions about risk factors for allergy may not be correct. The other epidemiologic study, by Morkjaroenpong et al,3 addressed the role of environmental tobacco smoke (ETS) exposure in causing nocturnal symptoms in children with asthma. This study, conducted among innercity children attending elementary school, found an increased frequency of nocturnal symptoms to be associated with exposure to higher levels of ETS. In this cohort smoking in the home was reported by almost 30% of primary caregivers, suggesting that ETS exposure is probably more common than is often appreciated. After controlling for the child’s age and medication use, Morkjaroenpong et al3 found that exposure to higher levels of ETS was associated with a 2.83-fold increase in nocturnal symptoms in children with asthma. One important point raised by Morkjaroenpong et al3 is that as many as a third of inner-city children spend part of their day in a place where they are exposed to ETS, even when their own parents do not smoke. This would tend to reduce the size of the association found in the research and demonstrates that ETS exposure is a substantial cause of symptoms and morbidity in children with asthma. Morkjaroenpong et al3 rightly concluded that controlling ETS exposure should be a high priority for the care of all children with asthma. The only other environmental article in our pages last year was a brief communication from Mitakakis et al4 that compared vacuuming strategies for assessment of house dust mite allergen levels on carpeted floors. Although the research was primarily conducted to assess the validity of
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sampling strategies for estimating allergen concentrations in carpet, Mitakakis et al4 found quite wide-ranging allergen concentrations within short distances within each of the rooms sampled. As a result, they recommended that four nonadjacent areas should be sampled for any future studies in which carpet sampling is used to estimate the level of allergen in a room. This work is important because it raises questions about the validity of previous studies of environmental house dust mite exposure that may have used less rigorous sampling strategies. The largest single body of environmental and occupational disorders work published within the Journal in the past year was related to latex allergy. Latex allergy is an important issue within the health care professions, and perhaps that is why there is so much current research activity in this area. In addition to the seven articles describing original research, the Journal also published a supplement on latex allergy, which covered the full range of historical and practical issues relating to latex allergy. The scope of the supplement was summarized by McFadden,5 and anyone looking for an up-to-date and comprehensive review of the problems posed by latex allergy is strongly advised to read this summary and the associated articles. Of the seven original articles within the Journal’s pages, two addressed the relationship between specific latex allergens and sensitization.6,7 One article described HLA-DQ associations with latex allergy,8 and the remainder were interventional studies addressing the impact of latex control programs in different settings.9-12 Poulos et al6 reported on Hev b 1 exposure in relation to different types of gloves and different working practices. Powdered latex examination gloves generated significant aerosol concentrations of Hev b 1, which was associated both with corn starch granules and with larger dust particles. The article by Wagner et al7 identified the latex allergens recognized by specific IgE from latexallergic patients with spina bifida. Three latex allergens were recognized by most of the subjects: Hev b 1, Hev b 3, and Hev b 7. The principal implications of the study are that any strategy for immunotherapy will need to cover at least these three latex allergens if it is to address the range of sensitivities in this group of patients who are at high risk for latex allergy. MHC class II antigens are crucial for the recognition of allergenic proteins by T cells and may also be critical in our ability to develop T cell vaccines for allergy. Previous reports have indicated an association between latex allergy and the HLA class II antigens DR3 and DQ8. The study by Rihs et al8 focused on a group of healthcare workers with latex allergy and a group of patients with spina bifida. HLA analysis showed significantly increased phenotype frequencies for HLA-DQ8 or the DQ8-DR4 haplotype. These two findings were associated with hevein-specific IgE antibodies relative to control subjects. Interestingly, there was a difference between the health care workers and the patients with spina bifida, who showed a small but nonsignificant association with DQ8. This difference in specificity may relate to the
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smaller number of patients with spina bifida studied here, but this will require further analysis. As with all types of HLA analysis, the presence of an association with a particular HLA haplotype is interesting and confirms the importance of T cells in the regulation of IgE responses. However, the strength of association is usually such that any strategy for treating patients would still have to cover a wide range of HLA types. Prevention of latex allergy is a key issue for hospitals and health care facilities. Allmers et al9 reported on the effectiveness of a primary prevention strategy. About 2 years after the introduction of powder-free natural latex sterile gloves, the incidence of suspected occupational latex allergy began to decline. This change in clinical practice was also linked to educational programs designed to reduce exposure. We can all be encouraged by the positive impact of this intervention, which is in line with trends within current clinical practice in many parts of the developed world. Two articles reviewed the outcomes of programs to reduce exposure to natural rubber latex. The first of these assessed the effect of intervention on the incidence of latex allergy in an Ontario teaching hospital with approximately 8000 employees. In response to the realization that an increasing number of workers were acquiring latex allergy, low-protein, powder-free latex gloves were introduced for nonsterile use in 1995. New diagnoses of latex allergy were reduced dramatically, and a number of workers who had been unable to work because of latex exposure were enabled to return to work. In 1997, sterile gloves were also replaced with a low-protein, powderfree form, and this led to a further reduction in the incidence of latex allergy. These improvements in latex allergy were made without any additional cost and had a substantial benefit in reducing time off work and workers’ compensation claims. This study was retrospective and was based on the records of the local occupational health clinic and allergy clinic. However, it does seem likely that most cases of latex allergy would have been seen in one or other of these settings. Because sensitized workers were able to carry on working in the hospital, it seems unlikely that there was any underreporting related to fear of losing employment.10 Most people who acquire occupational asthma and allergies lose out financially, as well as having reduced prospects within the workplace. Vandenplas et al11 reported a comparison of the health and socioeconomic outcomes of people with latex allergy according to whether they had reduced or ceased exposure to latex. This study focused on 36 subjects with latex-induced asthma who were followed up through a period of 12 to 92 months (median 56 months). At the time of follow-up, 20 subjects had managed to remain in work with reduced exposure, whereas 16 had ceased exposure to latex. The severity of asthma symptoms had improved in both groups of subjects, with comparable decreases in symptom scores and improvements in histamine reactivity in both groups. Those who had ceased exposure were much more likely to have suffered loss of income as a result of
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development of latex allergy than were those who were able to carry on with reduced exposure. This study is important because most patients with occupational asthma are advised to withdraw completely from the workplace and are threatened that if they fail to do so, they will inevitably have chronic progressive airway obstruction develop. With health care workers, there is a pressing need to retain their skills within the medical sector, and so our advice to such affected workers has been less stringent. It is encouraging to see that many of the latexallergic workers were able to stay in the health care sector and were both financially better off and less likely to have had to change jobs if they were allowed to carry on with reduced exposure to latex, as opposed to aiming for zero exposure. Interestingly, 11 of these subjects reported the onset of fruit allergy during the study period, despite avoiding or reducing their exposure to latex. This was in addition to 14 who had fruit allergy symptoms at the time they first were noted to have latex sensitivity. The importance of fruit allergy in patients with latex sensitivity is highlighted by the observation that more than half of the anaphylactic events in this cohort of workers were triggered by fruit ingestion.11 Charous et al12 provided a review of the latex allergy epidemic, emphasizing the dominant role of occupational exposure in causing latex allergy. Although some serologic surveys have estimated a high rate of latex sensitization in the general population, it is suggested that this may reflect a significant rate of false-positive results in a low-risk population. Clinically significant latex allergy is much more common among those who are occupationally exposed to latex, and, as with other allergic diseases, the development of clinical symptoms is principally dependent on the degree of allergen exposure. As have other reviewers of this area, Charous et al12 concluded that the use of nonpowdered gloves substantially reduces the level of allergen exposure and should be adopted for all routine clinical purposes. Further work is clearly needed to provide more specific and sensitive diagnostic reagents, whereas for those who have already acquired the condition a safe and reliable form of desensitizing vaccine would be most welcome. Bumblebees are typically regarded as harmless insects that are unlikely to sting. Hoffman et al13 reminded us that these insects are increasingly being used to pollinate vegetable crops grown in greenhouses. As a result, accidental stings from bumblebees are becoming more common, and, perhaps not surprisingly, some of these have led to anaphylaxis. Hoffman et al13 analyzed the allergenic proteins within bumblebee venom and showed that the venom of Bombus terrestris is antigenically distinct from that of the native North American species Bombus pennsylvanicus. Whereas there is a significant homology between the two species and the honeybee (Apis mellifera), the phospholipases from the two bumblebees differ at only 15 of 135 amino acids. Despite this sequence homology, however, the serologic absorptions for the two venoms were variable, and in some cases there was no cross-reactivity at all. This serologic analysis implies that
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any treatment strategy for bumblebee anaphylaxis would have to use the precise venom involved and not rely on cross-reactivity from a “standard bumblebee.” Isocyanates are by far the most common cause of occupational asthma. Improved working conditions and personal protective equipment have reduced the level of exposure but have not eliminated the problem. Isocyanate asthma is also interesting as a model of nonallergic asthma and has been proposed as an important topic for research.14 Previously reported associations of isocyanate asthma have focused on HLA class II antigens. Mapp et al15 presented data on a relationship between isocyanate asthma and allelic variants of the glutathione S-transferase (GST) enzyme, which serves to protect cells from oxidative stress products, including lipid peroxides. This article extended previous work by the same group relating GST alleles to allergic asthma. The finding by Mapp et al15 that GST variants were also associated with isocyanate asthma raises the possibility that both forms of asthma are affected by resistance to oxidative stress. There are a few problems with the study, in particular the small size of the control group and issues surrounding the appropriate time to assess asthma severity. Ideally, one would like to have a large control group against which to judge the prevalence of any allelic variant. Equally, asthma severity ought to be assessed at the onset of the disease, rather than several years downstream, when some of the subjects have withdrawn from the workplace. Nevertheless, this article provided a good example of how studying occupational asthma can help us to validate concepts that have been developed in relation to regular asthma. Another message is that because the frequency of the protective phenotype was different in those who acquired asthma after 10 years of exposure, one might argue that the role of the GST enzyme and its allelic variants could lie in determining which subjects will eventually have long-term sequelae from their asthma. This is a whole area of biology that requires detailed investigation. Until now, most immunologic and biomedical investigations of asthma have focused on the regulation of the onset of asthma, rather than factors that might encourage its resolution. Both aspects are important, and anyone who discovers how to switch off the asthmatic process should be richly rewarded. The final two environmental and occupational disorders articles in our pages reported on mouse models of isocyanate asthma. Herrick et al16 developed a mouse model that shows a more typical picture of allergic inflammation in the lung than do many of the previous models that have been assessed. This model used epicutaneous exposure to hexamethylene diisocyanate to induce sensitization, and the sensitized animals exhibited both contact hypersensitivity and isocyanate-specific antibody production. Of course, antibody production is not a particularly regular feature in the human form of isocyanate asthma, and there is some uncertainty about whether the antibodies play any role, even in those who demonstrate them. Nevertheless, this model does have a number of features of human asthma, including appro-
TABLE I. Key advances in environmental and occupational diseases • Indoor mold exposure was shown to be associated with asthma symptoms and bronchial hyperresponsiveness. • Exposure to ETS was found to be more common than is often realized. • Exposure to ETS was associated with an increased frequency of nocturnal symptoms in children with asthma. • HLA associations were defined for latex allergy. • Clinical intervention programs for latex allergy were shown to dramatically reduce incidence of latex allergy. • It was confirmed that enabling latex-allergic workers to remain at work results in a much better financial outcome for these workers. • Allelic variants of GST were shown to be associated with isocyanate asthma. • Inhibition of MMPs was found to attenuate most features of a mouse model of isocyanate asthma, suggesting a possible role for MMP inhibitors in treating occupational asthma.
priate cytokine expression by lung inflammatory cells, airway eosinophilia, and mucus hypersecretion. In contrast, Lee et al17 used toluene diisocyanate to develop a mouse model of occupational asthma, which also demonstrated a mixed inflammatory response, peribronchiolar infiltration of inflammatory cells, and accumulation of mucus. The principal focus of Lee et al17 was the demonstration of matrix metalloproteinase (MMP) activity in the inflammatory cells and lumen and the inhibition of most of the inflammatory changes by administration of an MMP inhibitor. The role of MMPs in asthma has been controversial, with rather mixed results in different models. Importantly, MMPs may play a critical role in autocrine feedback loops that are responsible for epithelial cell activation and induction of a wide range of oxidant-induced cytokines regulated by the epidermal growth factor receptor. It is perhaps stretching a point to suggest that MMP inhibition might block occupational asthma, but it is certainly a strategy that has been contemplated for regular asthma, so this article on the occupational model is welcome and strengthens the case for development of MMP inhibitors for clinical use.
CONCLUSION Environmental and occupational disorders cover a broad range of topics relevant to the practicing allergist and to those concerned with understanding the etiology of allergic disease (Table I). We need to understand more about the environmental factors that are influencing the onset of allergic disease, and we also need to be able to give informed advice on environmental manipulation to treat or control allergies. The recent controversy regarding the possible protective role of domestic pets18 illustrates how easy it is to give incorrect advice to patients and their families if one does not have the full facts. Occupational allergy is important to recognize clinically, but it also has the potential to shed considerable light on
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the mechanisms of other forms of allergic disease. Inevitably, collecting data on patients with occupational disorders presents some difficulty, because cases occur sporadically and one must take immediate action to minimize the affected person’s exposure. Nevertheless, it should be possible to construct prospective frameworks that will allow investigation of the key immunologic questions as and when these patients become available. In most cases it would be appropriate to form clinical networks to address such questions within a reasonable period. It is clear that environmental and occupational disorders deserve our attention and have the potential to give us much useful information about key scientific issues within our specialty. The new Editorial Board hopes to encourage publication of relevant articles in these two areas and encourages anyone with clinical or experimental programs in this area to consider submitting their work to the Journal. REFERENCES 1. Solomon WR. Airborne pollen: a brief life. J Allergy Clin Immunol 2002;109:895-900. 2. Zock JP, Jarvis D, Luczynska C, Sunyer J, Burney P. Housing characteristics, reported mold exposure, and asthma in the European Community Respiratory Health Survey. J Allergy Clin Immunol 2002;110:285-92. 3. Morkjaroenpong V, Rand CS, Butz AM, Huss K, Eggleston P, Malveaux FJ, et al. Environmental tobacco smoke exposure and nocturnal symptoms among inner-city children with asthma. J Allergy Clin Immunol 2002;110:147-53. 4. Mitakakis TZ, Mahmic A, Tovey ER. Comparison of vacuuming procedures for reservoir dust mite allergen on carpeted floors. J Allergy Clin Immunol 2002;109:122-4. 5. McFadden ER. Natural rubber latex sensitivity seminar: conference summary. J Allergy Clin Immunol 2002;110(2 Suppl):S137-40.
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6. Poulos LM, O’Meara TJ, Hamilton RG, Tovey ER. Inhaled latex allergen (Hev b 1). J Allergy Clin Immunol 2002;109:701-6. 7. Wagner B, Buck D, Hafner C, Sowka S, Niggemann B, Scheiner O, et al. Hev b 7 is a Hevea brasiliensis protein associated with latex allergy in children with spina bifida. J Allergy Clin Immunol 2001;108:621-7. 8. Rihs HP, Chen Z, Rueff F, Cremer R, Raulf-Heimsoth M, Baur X, et al. HLA-DQ8 and the HLA-DQ8-DR4 haplotype are positively associated with the hevein-specific IgE immune response in health care workers with latex allergy. J Allergy Clin Immunol 2002;110:507-14. 9. Allmers H, Schmengler J, Skudlik C. Primary prevention of natural rubber latex allergy in the German health care system through education and intervention. J Allergy Clin Immunol 2002;110:318-23. 10. Tarlo SM, Easty A, Eubanks K, Parsons CR, Min F, Juvet S, et al. Outcomes of a natural rubber latex control program in an Ontario teaching hospital. J Allergy Clin Immunol 200;108:628-33. 11. Vandenplas O, Jamart J, Delwiche JP, Evrard G, Larbanois A. Occupational asthma caused by natural rubber latex: outcome according to cessation or reduction of exposure. J Allergy Clin Immunol 2002;109:125-30. 12. Charous BL, Blanco C, Tarlo S, Hamilton RG, Baur X, Beezhold D, et al. Natural rubber latex allergy after 12 years: recommendations and perspectives. J Allergy Clin Immunol 2002;109:31-4. 13. Hoffman DR, El-Choufani SE, Smith MM, de Groot H. Occupational allergy to bumblebees: allergens of Bombus terrestris. J Allergy Clin Immunol 2001;108:855-60. 14. Park HS, Frew AJ. Genetic markers for occupational asthma. J Allergy Clin Immunol 2002;109:774-6. 15. Mapp CE, Fryer AA, De Marzo N, Pozzato V, Padoan M, Boschetto P, et al. Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates. J Allergy Clin Immunol 2002;109:867-72. 16. Herrick CA, Xu L, Wisnewski AV, Das J, Redlich CA, Bottomly K. A novel mouse model of diisocyanate-induced asthma showing allergictype inflammation in the lung after inhaled antigen challenge. J Allergy Clin Immunol 2002;109:873-8. 17. Lee YC, Song CH, Lee HB, Oh JL, Rhee YK, Park HS, et al. A murine model of toluene diisocyanate-induced asthma can be treated with matrix metalloproteinase inhibitor. J Allergy Clin Immunol 2001;108:1021-6. 18. Marks GB. What should we tell allergic families about pets? J Allergy Clin Immunol 2001;108:500-2.
The environment plays a crucial role in determining the expression of allergy and allergic diseases. We know that allergy and asthma have a significant genetic component, but to explain the rapid rise in the prevalence of asthma and allergic diseases during the past 40 years, we must invoke environmental factors and triggers. The rise has been too fast to be due to a change in the gene pool of the population, and it follows that some change or several changes in the environment must have been responsible for allowing a genetically susceptible population to acquire clinical disease, whereas in previous times they would have remained symptom free. Understanding the nature of these environmental triggers is fundamental to our aims of trying to prevent allergic disease in the next generation. Equally, understanding the range and nature of relevant environmental allergens may be helpful in controlling allergic disease that has become established.
From the Department of Medical Specialties, Southampton General Hospital, Southampton SO16 6YD, United Kingdom. Reprint requests: Anthony J. Frew, MD, FRCP, Department of Medical Specialties, Mailpoint 810, Level D Centre Block, Southampton General Hospital, Southampton SO16 6YD, United Kingdom. © 2003 Mosby, Inc. All rights reserved. 0091-6749/2003 $30.00 + 0 doi:10.1067/mai.2003.151
S824
Abbreviations used ECRHS: European Community Respiratory Health Survey GST: Glutathione S-transferase MMP: Matrix metalloproteinase
Occupational allergy is an important cause of morbidity in the working population. Studying occupational allergy allows one to gain a much better idea about exposure-response relationships for allergy, because the timing, duration and extent of allergen exposure can be more precisely defined than is possible for more general environmental allergens, such as house dust mite, animal dander, and pollens. Moreover, allergists need to maintain a high level of suspicion for possible occupational causes in patients who acquire allergic disease for the first time in adulthood or whose allergic disease deteriorates during adulthood. Environmental and occupational disorders should therefore be a relevant and important topic for discussion within the pages of The Journal of Allergy and Clinical Immunology. It is perhaps surprising that a review of the past year’s issues yields only a selected range of topics that have been submitted and published in the Journal’s pages. In some cases, environmental topics have been addressed as etiologic factors for asthma, rhinitis, and related diseases and may therefore not appear in the environmental section of the Journal. Aerobiology and atmospheric chemistry comprise another area of science relevant to asthma and allergic disease. Technical details of atmospheric chemistry are more likely to be published in other journals, but articles detailing the impact of pollutants on airway biology and asthma would clearly be of interest to our readers. Earlier this year, Solomon1 presented a review of the life history of airborne pollens. Understanding the biologic nature and role of pollen helps us to understand the biologic impact of pollen exposure, although clearly the downstream processes involved in the triggering of allergic disease are internal responses, rather than driven by the pollen itself. New understandings of the role of particulate pollution as a vector for pollen proteins may alter the way that we view allergic asthma, because this process will affect both the deposition of allergenic proteins and their presentation to the immune system. Two articles published this year addressed environmental factors in relation to asthma. Zock et al2 reported on housing characteristics and mold exposure in relation to asthma on the basis of data derived from the European Community Respiratory Health Survey (ECRHS). The ECRHS has been a powerful tool for addressing difficult questions in asthma epidemiology. By harnessing a large
J ALLERGY CLIN IMMUNOL VOLUME 111, NUMBER 3
number of investigators in different countries, it has been possible to tease out questions that would have been difficult to address within a single country. Importantly, the ECRHS allows investigation of subsets that would not really be statistically viable when investigated in a single center. The key findings of this ECRHS-based study were that indoor mold exposure was increased in centers that reported a higher prevalence of asthma. Moreover, within the population there was a significant association between mold exposure and both asthma symptoms and bronchial hyperresponsiveness. Importantly, this association was homogeneous across the various centers, indicating that it was not simply an effect that happened in damp areas of Europe. One additional finding of the study was that fitted carpets and rugs in the bedroom were associated with a lower level of asthma symptoms and bronchial responsiveness. Previously it had been suggested that fitted rugs and carpets might be a risk factor for asthma because they would increase the reservoir available for house dust mite antigens. The fact that this negative association was found in Zock et al’s study2 and that the association was more marked in house dust mite–sensitive individuals does raise the possibility that one may be looking at a result of intervention to reduce the use of fitted carpets by patients who are known to be sensitive to house dust mite. However, this argument is weakened by the fact that the negative association was consistent across all centers. The implication is that, as with synthetic pillows and exposure to pets, our initial assumptions about risk factors for allergy may not be correct. The other epidemiologic study, by Morkjaroenpong et al,3 addressed the role of environmental tobacco smoke (ETS) exposure in causing nocturnal symptoms in children with asthma. This study, conducted among innercity children attending elementary school, found an increased frequency of nocturnal symptoms to be associated with exposure to higher levels of ETS. In this cohort smoking in the home was reported by almost 30% of primary caregivers, suggesting that ETS exposure is probably more common than is often appreciated. After controlling for the child’s age and medication use, Morkjaroenpong et al3 found that exposure to higher levels of ETS was associated with a 2.83-fold increase in nocturnal symptoms in children with asthma. One important point raised by Morkjaroenpong et al3 is that as many as a third of inner-city children spend part of their day in a place where they are exposed to ETS, even when their own parents do not smoke. This would tend to reduce the size of the association found in the research and demonstrates that ETS exposure is a substantial cause of symptoms and morbidity in children with asthma. Morkjaroenpong et al3 rightly concluded that controlling ETS exposure should be a high priority for the care of all children with asthma. The only other environmental article in our pages last year was a brief communication from Mitakakis et al4 that compared vacuuming strategies for assessment of house dust mite allergen levels on carpeted floors. Although the research was primarily conducted to assess the validity of
Frew S825
sampling strategies for estimating allergen concentrations in carpet, Mitakakis et al4 found quite wide-ranging allergen concentrations within short distances within each of the rooms sampled. As a result, they recommended that four nonadjacent areas should be sampled for any future studies in which carpet sampling is used to estimate the level of allergen in a room. This work is important because it raises questions about the validity of previous studies of environmental house dust mite exposure that may have used less rigorous sampling strategies. The largest single body of environmental and occupational disorders work published within the Journal in the past year was related to latex allergy. Latex allergy is an important issue within the health care professions, and perhaps that is why there is so much current research activity in this area. In addition to the seven articles describing original research, the Journal also published a supplement on latex allergy, which covered the full range of historical and practical issues relating to latex allergy. The scope of the supplement was summarized by McFadden,5 and anyone looking for an up-to-date and comprehensive review of the problems posed by latex allergy is strongly advised to read this summary and the associated articles. Of the seven original articles within the Journal’s pages, two addressed the relationship between specific latex allergens and sensitization.6,7 One article described HLA-DQ associations with latex allergy,8 and the remainder were interventional studies addressing the impact of latex control programs in different settings.9-12 Poulos et al6 reported on Hev b 1 exposure in relation to different types of gloves and different working practices. Powdered latex examination gloves generated significant aerosol concentrations of Hev b 1, which was associated both with corn starch granules and with larger dust particles. The article by Wagner et al7 identified the latex allergens recognized by specific IgE from latexallergic patients with spina bifida. Three latex allergens were recognized by most of the subjects: Hev b 1, Hev b 3, and Hev b 7. The principal implications of the study are that any strategy for immunotherapy will need to cover at least these three latex allergens if it is to address the range of sensitivities in this group of patients who are at high risk for latex allergy. MHC class II antigens are crucial for the recognition of allergenic proteins by T cells and may also be critical in our ability to develop T cell vaccines for allergy. Previous reports have indicated an association between latex allergy and the HLA class II antigens DR3 and DQ8. The study by Rihs et al8 focused on a group of healthcare workers with latex allergy and a group of patients with spina bifida. HLA analysis showed significantly increased phenotype frequencies for HLA-DQ8 or the DQ8-DR4 haplotype. These two findings were associated with hevein-specific IgE antibodies relative to control subjects. Interestingly, there was a difference between the health care workers and the patients with spina bifida, who showed a small but nonsignificant association with DQ8. This difference in specificity may relate to the
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smaller number of patients with spina bifida studied here, but this will require further analysis. As with all types of HLA analysis, the presence of an association with a particular HLA haplotype is interesting and confirms the importance of T cells in the regulation of IgE responses. However, the strength of association is usually such that any strategy for treating patients would still have to cover a wide range of HLA types. Prevention of latex allergy is a key issue for hospitals and health care facilities. Allmers et al9 reported on the effectiveness of a primary prevention strategy. About 2 years after the introduction of powder-free natural latex sterile gloves, the incidence of suspected occupational latex allergy began to decline. This change in clinical practice was also linked to educational programs designed to reduce exposure. We can all be encouraged by the positive impact of this intervention, which is in line with trends within current clinical practice in many parts of the developed world. Two articles reviewed the outcomes of programs to reduce exposure to natural rubber latex. The first of these assessed the effect of intervention on the incidence of latex allergy in an Ontario teaching hospital with approximately 8000 employees. In response to the realization that an increasing number of workers were acquiring latex allergy, low-protein, powder-free latex gloves were introduced for nonsterile use in 1995. New diagnoses of latex allergy were reduced dramatically, and a number of workers who had been unable to work because of latex exposure were enabled to return to work. In 1997, sterile gloves were also replaced with a low-protein, powderfree form, and this led to a further reduction in the incidence of latex allergy. These improvements in latex allergy were made without any additional cost and had a substantial benefit in reducing time off work and workers’ compensation claims. This study was retrospective and was based on the records of the local occupational health clinic and allergy clinic. However, it does seem likely that most cases of latex allergy would have been seen in one or other of these settings. Because sensitized workers were able to carry on working in the hospital, it seems unlikely that there was any underreporting related to fear of losing employment.10 Most people who acquire occupational asthma and allergies lose out financially, as well as having reduced prospects within the workplace. Vandenplas et al11 reported a comparison of the health and socioeconomic outcomes of people with latex allergy according to whether they had reduced or ceased exposure to latex. This study focused on 36 subjects with latex-induced asthma who were followed up through a period of 12 to 92 months (median 56 months). At the time of follow-up, 20 subjects had managed to remain in work with reduced exposure, whereas 16 had ceased exposure to latex. The severity of asthma symptoms had improved in both groups of subjects, with comparable decreases in symptom scores and improvements in histamine reactivity in both groups. Those who had ceased exposure were much more likely to have suffered loss of income as a result of
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development of latex allergy than were those who were able to carry on with reduced exposure. This study is important because most patients with occupational asthma are advised to withdraw completely from the workplace and are threatened that if they fail to do so, they will inevitably have chronic progressive airway obstruction develop. With health care workers, there is a pressing need to retain their skills within the medical sector, and so our advice to such affected workers has been less stringent. It is encouraging to see that many of the latexallergic workers were able to stay in the health care sector and were both financially better off and less likely to have had to change jobs if they were allowed to carry on with reduced exposure to latex, as opposed to aiming for zero exposure. Interestingly, 11 of these subjects reported the onset of fruit allergy during the study period, despite avoiding or reducing their exposure to latex. This was in addition to 14 who had fruit allergy symptoms at the time they first were noted to have latex sensitivity. The importance of fruit allergy in patients with latex sensitivity is highlighted by the observation that more than half of the anaphylactic events in this cohort of workers were triggered by fruit ingestion.11 Charous et al12 provided a review of the latex allergy epidemic, emphasizing the dominant role of occupational exposure in causing latex allergy. Although some serologic surveys have estimated a high rate of latex sensitization in the general population, it is suggested that this may reflect a significant rate of false-positive results in a low-risk population. Clinically significant latex allergy is much more common among those who are occupationally exposed to latex, and, as with other allergic diseases, the development of clinical symptoms is principally dependent on the degree of allergen exposure. As have other reviewers of this area, Charous et al12 concluded that the use of nonpowdered gloves substantially reduces the level of allergen exposure and should be adopted for all routine clinical purposes. Further work is clearly needed to provide more specific and sensitive diagnostic reagents, whereas for those who have already acquired the condition a safe and reliable form of desensitizing vaccine would be most welcome. Bumblebees are typically regarded as harmless insects that are unlikely to sting. Hoffman et al13 reminded us that these insects are increasingly being used to pollinate vegetable crops grown in greenhouses. As a result, accidental stings from bumblebees are becoming more common, and, perhaps not surprisingly, some of these have led to anaphylaxis. Hoffman et al13 analyzed the allergenic proteins within bumblebee venom and showed that the venom of Bombus terrestris is antigenically distinct from that of the native North American species Bombus pennsylvanicus. Whereas there is a significant homology between the two species and the honeybee (Apis mellifera), the phospholipases from the two bumblebees differ at only 15 of 135 amino acids. Despite this sequence homology, however, the serologic absorptions for the two venoms were variable, and in some cases there was no cross-reactivity at all. This serologic analysis implies that
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any treatment strategy for bumblebee anaphylaxis would have to use the precise venom involved and not rely on cross-reactivity from a “standard bumblebee.” Isocyanates are by far the most common cause of occupational asthma. Improved working conditions and personal protective equipment have reduced the level of exposure but have not eliminated the problem. Isocyanate asthma is also interesting as a model of nonallergic asthma and has been proposed as an important topic for research.14 Previously reported associations of isocyanate asthma have focused on HLA class II antigens. Mapp et al15 presented data on a relationship between isocyanate asthma and allelic variants of the glutathione S-transferase (GST) enzyme, which serves to protect cells from oxidative stress products, including lipid peroxides. This article extended previous work by the same group relating GST alleles to allergic asthma. The finding by Mapp et al15 that GST variants were also associated with isocyanate asthma raises the possibility that both forms of asthma are affected by resistance to oxidative stress. There are a few problems with the study, in particular the small size of the control group and issues surrounding the appropriate time to assess asthma severity. Ideally, one would like to have a large control group against which to judge the prevalence of any allelic variant. Equally, asthma severity ought to be assessed at the onset of the disease, rather than several years downstream, when some of the subjects have withdrawn from the workplace. Nevertheless, this article provided a good example of how studying occupational asthma can help us to validate concepts that have been developed in relation to regular asthma. Another message is that because the frequency of the protective phenotype was different in those who acquired asthma after 10 years of exposure, one might argue that the role of the GST enzyme and its allelic variants could lie in determining which subjects will eventually have long-term sequelae from their asthma. This is a whole area of biology that requires detailed investigation. Until now, most immunologic and biomedical investigations of asthma have focused on the regulation of the onset of asthma, rather than factors that might encourage its resolution. Both aspects are important, and anyone who discovers how to switch off the asthmatic process should be richly rewarded. The final two environmental and occupational disorders articles in our pages reported on mouse models of isocyanate asthma. Herrick et al16 developed a mouse model that shows a more typical picture of allergic inflammation in the lung than do many of the previous models that have been assessed. This model used epicutaneous exposure to hexamethylene diisocyanate to induce sensitization, and the sensitized animals exhibited both contact hypersensitivity and isocyanate-specific antibody production. Of course, antibody production is not a particularly regular feature in the human form of isocyanate asthma, and there is some uncertainty about whether the antibodies play any role, even in those who demonstrate them. Nevertheless, this model does have a number of features of human asthma, including appro-
TABLE I. Key advances in environmental and occupational diseases • Indoor mold exposure was shown to be associated with asthma symptoms and bronchial hyperresponsiveness. • Exposure to ETS was found to be more common than is often realized. • Exposure to ETS was associated with an increased frequency of nocturnal symptoms in children with asthma. • HLA associations were defined for latex allergy. • Clinical intervention programs for latex allergy were shown to dramatically reduce incidence of latex allergy. • It was confirmed that enabling latex-allergic workers to remain at work results in a much better financial outcome for these workers. • Allelic variants of GST were shown to be associated with isocyanate asthma. • Inhibition of MMPs was found to attenuate most features of a mouse model of isocyanate asthma, suggesting a possible role for MMP inhibitors in treating occupational asthma.
priate cytokine expression by lung inflammatory cells, airway eosinophilia, and mucus hypersecretion. In contrast, Lee et al17 used toluene diisocyanate to develop a mouse model of occupational asthma, which also demonstrated a mixed inflammatory response, peribronchiolar infiltration of inflammatory cells, and accumulation of mucus. The principal focus of Lee et al17 was the demonstration of matrix metalloproteinase (MMP) activity in the inflammatory cells and lumen and the inhibition of most of the inflammatory changes by administration of an MMP inhibitor. The role of MMPs in asthma has been controversial, with rather mixed results in different models. Importantly, MMPs may play a critical role in autocrine feedback loops that are responsible for epithelial cell activation and induction of a wide range of oxidant-induced cytokines regulated by the epidermal growth factor receptor. It is perhaps stretching a point to suggest that MMP inhibition might block occupational asthma, but it is certainly a strategy that has been contemplated for regular asthma, so this article on the occupational model is welcome and strengthens the case for development of MMP inhibitors for clinical use.
CONCLUSION Environmental and occupational disorders cover a broad range of topics relevant to the practicing allergist and to those concerned with understanding the etiology of allergic disease (Table I). We need to understand more about the environmental factors that are influencing the onset of allergic disease, and we also need to be able to give informed advice on environmental manipulation to treat or control allergies. The recent controversy regarding the possible protective role of domestic pets18 illustrates how easy it is to give incorrect advice to patients and their families if one does not have the full facts. Occupational allergy is important to recognize clinically, but it also has the potential to shed considerable light on
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the mechanisms of other forms of allergic disease. Inevitably, collecting data on patients with occupational disorders presents some difficulty, because cases occur sporadically and one must take immediate action to minimize the affected person’s exposure. Nevertheless, it should be possible to construct prospective frameworks that will allow investigation of the key immunologic questions as and when these patients become available. In most cases it would be appropriate to form clinical networks to address such questions within a reasonable period. It is clear that environmental and occupational disorders deserve our attention and have the potential to give us much useful information about key scientific issues within our specialty. The new Editorial Board hopes to encourage publication of relevant articles in these two areas and encourages anyone with clinical or experimental programs in this area to consider submitting their work to the Journal. REFERENCES 1. Solomon WR. Airborne pollen: a brief life. J Allergy Clin Immunol 2002;109:895-900. 2. Zock JP, Jarvis D, Luczynska C, Sunyer J, Burney P. Housing characteristics, reported mold exposure, and asthma in the European Community Respiratory Health Survey. J Allergy Clin Immunol 2002;110:285-92. 3. Morkjaroenpong V, Rand CS, Butz AM, Huss K, Eggleston P, Malveaux FJ, et al. Environmental tobacco smoke exposure and nocturnal symptoms among inner-city children with asthma. J Allergy Clin Immunol 2002;110:147-53. 4. Mitakakis TZ, Mahmic A, Tovey ER. Comparison of vacuuming procedures for reservoir dust mite allergen on carpeted floors. J Allergy Clin Immunol 2002;109:122-4. 5. McFadden ER. Natural rubber latex sensitivity seminar: conference summary. J Allergy Clin Immunol 2002;110(2 Suppl):S137-40.
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6. Poulos LM, O’Meara TJ, Hamilton RG, Tovey ER. Inhaled latex allergen (Hev b 1). J Allergy Clin Immunol 2002;109:701-6. 7. Wagner B, Buck D, Hafner C, Sowka S, Niggemann B, Scheiner O, et al. Hev b 7 is a Hevea brasiliensis protein associated with latex allergy in children with spina bifida. J Allergy Clin Immunol 2001;108:621-7. 8. Rihs HP, Chen Z, Rueff F, Cremer R, Raulf-Heimsoth M, Baur X, et al. HLA-DQ8 and the HLA-DQ8-DR4 haplotype are positively associated with the hevein-specific IgE immune response in health care workers with latex allergy. J Allergy Clin Immunol 2002;110:507-14. 9. Allmers H, Schmengler J, Skudlik C. Primary prevention of natural rubber latex allergy in the German health care system through education and intervention. J Allergy Clin Immunol 2002;110:318-23. 10. Tarlo SM, Easty A, Eubanks K, Parsons CR, Min F, Juvet S, et al. Outcomes of a natural rubber latex control program in an Ontario teaching hospital. J Allergy Clin Immunol 200;108:628-33. 11. Vandenplas O, Jamart J, Delwiche JP, Evrard G, Larbanois A. Occupational asthma caused by natural rubber latex: outcome according to cessation or reduction of exposure. J Allergy Clin Immunol 2002;109:125-30. 12. Charous BL, Blanco C, Tarlo S, Hamilton RG, Baur X, Beezhold D, et al. Natural rubber latex allergy after 12 years: recommendations and perspectives. J Allergy Clin Immunol 2002;109:31-4. 13. Hoffman DR, El-Choufani SE, Smith MM, de Groot H. Occupational allergy to bumblebees: allergens of Bombus terrestris. J Allergy Clin Immunol 2001;108:855-60. 14. Park HS, Frew AJ. Genetic markers for occupational asthma. J Allergy Clin Immunol 2002;109:774-6. 15. Mapp CE, Fryer AA, De Marzo N, Pozzato V, Padoan M, Boschetto P, et al. Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates. J Allergy Clin Immunol 2002;109:867-72. 16. Herrick CA, Xu L, Wisnewski AV, Das J, Redlich CA, Bottomly K. A novel mouse model of diisocyanate-induced asthma showing allergictype inflammation in the lung after inhaled antigen challenge. J Allergy Clin Immunol 2002;109:873-8. 17. Lee YC, Song CH, Lee HB, Oh JL, Rhee YK, Park HS, et al. A murine model of toluene diisocyanate-induced asthma can be treated with matrix metalloproteinase inhibitor. J Allergy Clin Immunol 2001;108:1021-6. 18. Marks GB. What should we tell allergic families about pets? J Allergy Clin Immunol 2001;108:500-2.