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Airway Inflammation after Cessation of Exposure to Agents Causing Occupational Asthma

Department of Chest Medicine, Sacré-Coeur Hospital, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to Jean-Luc Malo, M.D., Department of Chest Medicine, Sacré-Coeur Hospital, 5400 W. Gouin Blvd., Montreal, PQ, H4J 1C5, Canada. E-mail: malojl{at}meddir.umontreal.ca

	ABSTRACT

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Subjects with occupational asthma (OA) generally present asthma symptoms and airway hyperresponsiveness after cessation of exposure. We hypothesized that they are also left with airway inflammation. We assessed 133 subjects with OA at a mean interval of 8.7 years (0.5–20.8 years) after cessation of exposure by questionnaire, airway caliber, and responsiveness to methacholine. Satisfactory samples of induced sputum were obtained from 98 subjects. We defined three groups of subjects: (1) cured: normalization of the concentration of methacholine provoking a 20% decrease in FEV₁ (PC₂₀), (2) improved: increase in PC₂₀ by 3.2-fold or more but PC₂₀ still abnormal, and (3) not improved: no significant change in PC₂₀. In all, 9/28 subjects (32.1%) with no improvement versus 6/56 (10.7%) subjects with partial and complete improvements had sputum eosinophils equal to or greater than 2% and 11/28 (39.3%) subjects versus 11/56 (19.6%) subjects showed sputum neutrophils equal to or greater than 61%. Levels of interleukin-8 and of the neutrophil-derived myeloperoxidase were significantly more elevated in sputum of subjects with no improvement. Those in the cured or improved groups had a significantly longer time lapse since diagnosis and a higher PC₂₀ at the time of diagnosis. We conclude that failure to improve after cessation of exposure to an agent causing OA is associated with airway inflammation at follow-up.

Key Words: asthma • occupational diseases • sputum • interleukin-8 • myeloperoxidase

Numerous follow-up studies have shown that subjects with occupational asthma (OA) are generally left with permanent disability, even after cessation of exposure (1). This concept—rather revolutionary at the time it was documented (it was assumed that subjects with OA would be "cured" after cessation of exposure)—was initially supported by follow-up studies by Chan-Yeung and associates (2, 3) in workers with Western red cedar–induced OA. It was later found that the maximum improvement occurs in the first 2 years after cessation of exposure (4), and this supported guidelines in the assessment of disability for OA (5). These conclusions were more recently modulated by findings showing that improvement does continue over the long term, although at a slower rate than in the first 2 years after cessation of exposure. Elapsed time since cessation of exposure has indeed been significantly associated with improvement at the follow-up visits in two recent studies, one that includes workers exposed to various agents (6) and another that examines workers exposed to toluene diisocyanate (7).

Several hypotheses can be proposed for this lack of cure. Several follow-up studies that have been reviewed elsewhere (1) have shown that duration of exposure with symptoms, which reflects the intensity of the immunologic and inflammatory burden, is consistently associated with a poorer prognosis. Airway inflammation and remodeling have been found in bronchial biopsies of workers removed from exposure for a relatively short interval (6–18 months) (8, 9). The IgE-related immunologic response disappears or diminishes with time after end of exposure (4, 10, 11). However, workers removed from exposure for long intervals can still react on exposure to the offending agent (11). Although concomitant sensitization to ubiquitous allergens is frequent in subjects acquiring sensitization to an agent they are exposed to in their occupation (12), levels of specific IgE to these common allergens are similar at the time of diagnosis and years after cessation of exposure (13).

We hypothesized that the persistence of asthma in subjects with OA after the end of exposure could be explained by the presence of airway inflammation that can be documented even years after cessation of exposure. To test this, we performed a study with the following original characteristics: (1) a long follow-up interval of subjects with OA seen after the end of exposure, (2) a large number (n = 133) of subjects with OA due to various high– and low–molecular weight agents, and (3) assessment of cells and relevant cytokines (interleukin [IL]-8, eotaxin, neutrophil-derived myeloperoxidase [MPO]) in induced sputum in the majority of subjects.

	METHODS

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All subjects with a diagnosis of OA who had been investigated at Sacré-Coeur Hospital 6 months or more before the beginning of the study were solicited to participate.

A questionnaire was administered to ensure that the worker was no longer exposed to the agent that caused OA and to get information on the control of asthma symptoms at the time of the visit as well as the current and past need for corticosteroids as set by the treating physician. Subjects needed to be in a stable, symptomatic situation (no nocturnal awakenings due to asthma, minimal use of rescue bronchodilator). The type and dose of antiasthma medication that was prescribed by the subject's treating physician was not changed unless the subject's asthma was considered uncontrolled, in which case the medication was modified and the subject reassessed at a later visit. Spirometry was performed (14) and responsiveness to methacholine assessed (15) using a Wright's nebulizer (output = 0.14 ml/minute) with doubling concentrations of methacholine up to 32 mg/ml. At the end of the test, albuterol was administered before the induction of sputum with saline according to the methodology proposed by Pizzichini and coworkers (16), and the collected sputum samples were treated with a 4% solution of the mucolytic agent dithiothreitol to facilitate total cell counts, differential cell counts, and inflammatory mediator recovery as described previously (17). There is evidence that the inflammatory influx in terms of sputum cells (18, 19) and cytokines (19) is not altered by previous methacholine testing.

Sputum supernatants were concentrated by centrifugation on Centricon centrifugal filter device YM-3 (Millipore; FisherScientific, Montreal, PQ, Canada) with a 3,000 molecular weight cutoff according to the manufacturer's instructions. The Centricon centrifugal filter device YM-3 was selected because (1) the efficiency of the anisotropic membrane is not altered by a 4% dithiothreitol solution (manufacturer's information) and (2) it makes it possible to eliminate dithiothreitol from the concentrated fractions, which is essential, because this mucolytic agent has been reported to interfere with the determination of MPO in sputum-treated samples (20). Sample volumes before and after concentration on Centricon centrifugal filter device YM-3 were measured to determine the factor of concentration. Protein concentrations in the top concentrated fractions and the lower filtered fractions were determined using the reducing compatible–detergent compatible protein assay from Bio-Rad (Bio-Rad Laboratories, Montreal, PQ, Canada), designed for samples containing dithiothreitol. Protein determination indicated that the upper fractions contained more than 98% of the total proteins. The upper fractions were then used for the determination of inflammatory markers by ELISA using commercially available kits for human IL-8 (BD Biosciences, Mississauga, Ontario, Canada), human eotaxin (BioSource, MediCorp, Montreal, PQ, Canada), and human MPO (Calbiochem, San Diego, CA) according to the manufacturer's instructions. Optical densities were determined using the ELISA reader Elx 808iu (Bio-Tek Instruments, Inc., Richmond, VA), and calculations were performed using the KC4 software (Bio-Tek Instruments, Inc.). Data are the mean values of duplicate measurement and were expressed as picograms per milliliter after data were adjusted from the factor of concentration.

Subjects were separated into three groups according to their outcome in terms of responsiveness to methacholine: (1) "cured subjects," i.e., those with improvement in the concentration of methacholine provoking a 20% decrease in FEV₁ (PC₂₀) of 3.2-fold or greater difference (21) from baseline and a PC₂₀ more than 16 mg/ml (22); (2) "improved subjects," i.e., those with improvement in PC₂₀ as for the "cured" group but still with an abnormal PC₂₀; (3) subjects with no significant improvement (changes in PC₂₀ < a 3.2-fold difference and a PC₂₀ 16 mg/ml) at follow-up.

Analysis of Results
Anthropometric, clinical, functional, and induced sputum results were compared in the three groups of subjects (see above) using analysis of variance with contrasts or Wilcoxon test (in case the distribution of data was not normal) or ² distribution in the case of proportions. Logistic regressions were used to examine factors associated with functional and inflammatory outcomes: (1) follow-up PC₂₀ results, (2) cure and improvement, and (3) presence of eosinophils and/or neutrophils in induced sputum at the follow-up visit.

	RESULTS

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Table 1 lists selected variables for participants and nonparticipants. We contacted 484 subjects by mail: of these, 44 refused to participate, 24 were stated to be deceased by family members, and we got no formal reply from 283 subjects. There were fewer males and fewer smokers among the 133 participants than among the nonparticipants. The durations of symptoms while at work were similar. The time lapse since diagnosis and end of exposure was longer for nonparticipants, which could be one of several reasons for their nonparticipation. FEV₁ and baseline PC₂₀ were similar in the two groups. The proportions of subjects exposed to high– and low–molecular weight agents were slightly different in participants and nonparticipants. Among participants, 35 were on inhaled fluticasone (dose range of daily dose = 200–2,000 µg), 11 on budesonide (dose range of daily dose = 400–800 µg), and 1 on beclomethasone (500 µg daily).

	DISCUSSION

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This study shows that lack of improvement in airway responsiveness in subjects with OA after removal from exposure is associated with the magnitude of functional impairment at the time of diagnosis, the time lapse since diagnosis, and the presence of an inflammatory influx.

Our series represents one of the largest follow-up series and one with a long follow-up. Our results confirm those obtained in a relatively smaller group of subjects seen for a shorter follow-up (6). In the latest follow-up from our group, we showed that subjects removed from exposure for 5 years of more had a more favorable outcome than those seen at a shorter interval. The current study extends those results to 10 years or more. Factors associated with a more favorable outcome were, as in the previous series (6), the time lapse since diagnosis and the PC₂₀ value at the time of diagnosis. The only difference is that the current work did not show significant differences in outcome according to the nature of the agent (high– vs. low–molecular weight), whereas our previous work showed a tendency for subjects with OA due to low–molecular weight agents to experience a more satisfactory outcome. Also, there was a tendency for the duration of exposure and the duration of exposure with symptoms to be longer in the group without improvement, but this failed to reach statistical significance in the current study, whereas it did so in the previous one (6). Padoan and coworkers recently confirmed these results in workers previously exposed to toluene diisocyanate (7). These authors found that the principal predictor of responsiveness to methacholine at follow-up was PC₂₀ at the time of diagnosis and other, less significant predictors included duration of exposure, the interval since removal from exposure, and current treatment with inhaled steroids (7). Although the initial results had suggested a plateau of improvement 2 years or more after cessation of exposure (4), the clear message from current and recent (6, 7) works is that improvement continues even after a long time has lapsed since cessation of exposure. Previous results applied in the case of workers exposed seasonally to snow crab (4), which is a different context of exposure from the one encountered in the current series.

There were differences in the characteristics of participants and nonparticipants in our follow-up observational study: fewer males, longer duration of exposure, lower proportion of high–molecular weight agents, and shorter time lapse since diagnosis in participants (Table 1). The participation was also low (133/484 or 27.5%). Duration of exposure was longer among participants, although duration of exposure with symptoms that has been consistently found in many studies to be related to poorer prognosis (1) was similar in participants and nonparticipants. The proportion of subjects exposed to high–molecular weight agents was slightly lower in participants. The prognosis has generally been found to be similar in subjects exposed to high– and low–molecular weight agents (1), although we recently showed that the prognosis was less satisfactory in subjects exposed to high–molecular weight agents (6). Finally, recruiting more nonparticipants would have allowed us to include subjects with a longer time lapse since diagnosis, which would have further improved the significance of the study.

Thirty of the 133 subjects (22.6%) could not be included in the specific analysis performed by categorizing the subjects according to the outcome of PC₂₀ because the latter assessment was normal at baseline or was not performed at the time of diagnosis or at follow-up. As a whole, these subjects had a lower FEV₁. The results of the analysis that associates functional outcome to the presence of baseline characteristics and inflammatory features at the time of follow-up therefore apply to subjects who were generally left with milder asthma.

There were nine subjects in the cured group (32%) who were on inhaled steroids. The subjects included in our study were treated for asthma by their physicians. No attempt was made to change their medication unless they were in an unstable clinical status, at which time the treatment was changed and the assessment postponed. We preferred to base the analysis of outcome on a functional parameter (PC₂₀) rather than on clinical criteria.

Our study shows that inflammation is present years after cessation of exposure to an occupational agent causing asthma. Indeed, 15 of the 98 subjects (15.3%) from whom we obtained satisfactory sputum for cell examination had eosinophils more than or equal to 2% and 22/98 (22.4%) had neutrophils more than or equal to 60%. The presence of airway inflammation after disappearance of asthmatic symptoms was recently shown in children who had "outgrown asthma" for a mean interval of 21 months (at least 12) and who underwent bronchoalveolar lavage (23). Six of 25 children (24%) had increased eosinophil levels. In our study, subjects with no significant change in airway hyperresponsiveness were shown to have more airway inflammation. However, in the "not improved" category of subjects, only 32% had significant sputum eosinophilia and 39% had significant neutrophilia. In most studies, airway inflammation has been associated with airway hyperresponsiveness, but the association is generally loose (24). It has more recently been shown that other factors related to airway remodeling can also contribute to airway hyperresponsiveness (24).

The role of eosinophils as effector cells in asthmatic airways has recently been challenged (25). Neutrophils can also be implicated in asthma (26). Increased neutrophils have mainly been associated with OA due to isocyanates (27). Significant increase in sputum neutrophils has been documented by Anees in subjects with OA due to low–molecular weight agents, including six subjects exposed to isocyanates, at the time of exposure to the causal agent (28). Only 14 of these 38 workers (37%) had significant sputum eosinophilia (28).

In this study, we specifically addressed the question of whether the absence of functional improvement was associated with the presence of airway inflammation. We found that one third of uncured subjects, twice the number of subjects who were cured or improved, had significant eosinophilia and even more had significant neutrophilia. The presence of airway inflammation is puzzling, as subjects were no longer exposed to the agent causing OA. New sensitization to a ubiquitous allergen since removal from exposure can be excluded on the ground that skin tests to common aeroallergens were repeated in the 54 workers without evidence of atopy at the time of diagnosis. Only three subjects developed skin reactivity to one common allergen or another. Ongoing immunologic process within the airways is probable. Lemière and coworkers showed that even in the absence of significant nonspecific bronchial hyperresponsiveness, subjects with OA can still develop an asthmatic reaction on exposure to the causal agent years after cessation of exposure (11); this points out the importance of memory cells. The presence of airway inflammation in subjects who improve or were apparently cured is interesting. It is not excluded that these subjects are at increased risk of asthmatic flare-ups in the course of a viral infection or after exposure to nonspecific stimuli. In addition to assessing airway caliber and responsiveness, it may be worthwhile to assess airway inflammation through noninvasive means such as induced sputum to assess disability in subjects with asthma and OA once they have been removed from exposure to an etiologic agent (5). Finally, it might be interesting to assess airway inflammation before starting exposure to an agent that can cause OA to know if subjects with airway inflammation are more at risk of enhancement and persistence of inflammation after the end of exposure. This can only be done in a prospective study in apprentices or in entry into a workforce such as the one in which Gautrin and coworkers showed that having a measurable PC₂₀ before starting exposure makes apprentices more at risk of developing OA (29).

We found that the potent neutrophil chemoattractant IL-8 and the neutrophil-derived MPO were more elevated in subjects without functional improvement. IL-8 and MPO have been reported to be increased in chronic atopic and nonatopic asthma (30, 31), suggesting an active role for the neutrophils in this condition. IL-8 is a chemokine that acts as a chemoattractant and is an activating agent for both neutrophils and IL-5–primed eosinophils (31). This might explain the increase in both neutrophils and eosinophils in our workers who showed no functional improvement. The strong correlation between the levels of IL-8 and the percentage neutrophils and/or the levels of MPO strongly suggests a role for IL-8 in the recruitment and activation of neutrophils in the airways. We found no difference in eotaxin levels in the three groups of subjects. Although eotaxin is believed to be involved in the pathogenesis of tissue eosinophilia in allergic airways (32), Scheerens and coworkers have recently shown that eotaxin is only involved in eosinophil recruitment shortly after allergen challenge but not in later stages (33). It would be relevant to examine the presence of other factors related to airway and smooth muscle remodeling such as matrix metalloproteases, fibronectin, and growth factors (34). It would also be most interesting to study cells and factors related to inflammation and remodeling not only in induced sputum but also in bronchial biopsies in selected subjects. This would allow for direct assessment of basement membrane and airway muscle that can contribute to persisting airway hyperresponsiveness.

In conclusion, this study shows that airway inflammation is present in subjects with OA years after cessation of exposure to the causal agent, suggesting that this is the cause of persisting airway hyperresponsiveness and asthmatic symptoms. This study also provides evidence that the model of OA offers a unique opportunity to examine the long-term consequences of exposure to a sensitizing agent in the apparent absence of ongoing challenge due to the persistence of exposure.

	Acknowledgments

 
The authors thank Carole Trudeau, R.T., Simone Chaboillez, R.T., Katia Desbiens M.Sc., and Jocelyne L'Archevêque, R.T., for collecting and examining data and Lori Schubert for reviewing the manuscript.

	FOOTNOTES

 
Catherine Lemière, M.D., and Karim Maghni, Ph.D., are recipients of a scholarship from the Institut de Recherché en Santé du Canada and the Fonds de la Recherche en Santé du Québec (FRSQ), respectively.

Conflict of Interest Statement: K.M. has no declared conflict of interest; C.L. has no declared conflict of interest; H.G. has no declared conflict of interest; W.Y. has no declared conflict of interest; J-L.M. has no declared conflict of interest.

Received in original form September 7, 2003; accepted in final form October 18, 2003

	REFERENCES

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1. Chan-Yeung M, Malo JL. Natural history of occupational asthma. In: Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI, editors. Asthma in the workplace. New York: Marcel Dekker Inc.; 1999. p. 129–143.
2. Chan-Yeung M. Fate of occupational asthma: a follow-up study of patients with occupational asthma due to western red cedar (thuja plicata). Am Rev Respir Dis 1977;116:1023–1029.[Medline]
3. Chan-Yeung M, Lam S, Koerner S. Clinical features and natural history of occupational asthma due to western red cedar (thuja plicata). Am J Med 1982;72:411–415.[CrossRef][Medline]
4. Malo JL, Cartier A, Ghezzo H, Lafrance M, Mccants M, Lehrer SB. Patterns of improvement of spirometry, bronchial hyperresponsiveness, and specific IgE antibody levels after cessation of exposure in occupational asthma caused by snow-crab processing. Am Rev Respir Dis 1988;138:807–812.[Medline]
5. American Thoracic Society. Guidelines for the evaluation of impairment/disability in patients with asthma. Am Rev Respir Dis 1993;147:1056–1061.[Medline]
6. Perfetti L, Cartier A, Ghezzo H, Gautrin D, Malo JL. Follow-up of occupational asthma after removal from or diminution of exposure to the responsible agent. Chest 1998;114:398–403.[Abstract/Free Full Text]
7. Padoan M, Pozzato V, Simon M, Zedda L, Milan G, Bononi J, Piola C, Maestrelli P, Boschetto P, Mapp CE. Long-term follow-up of toluene diisocyanate-induced asthma. Eur Respir J 2003;21:637–640.[Abstract/Free Full Text]
8. Saetta M, Di Stefano A, Maestrelli P, De Marzo N, Milani GF, Pivirotto F, Mapp CE, Fabbri LM. Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate. Am Rev Respir Dis 1992;145:160–168.[Medline]
9. Boulet LP, Boutet M, Laviolette M, Dugas M, Milot J, Leblanc C, Paquette L, Côté J, Cartier A, Malo JL. Airway inflammation after removal from the causal agent in occupational asthma due to high and low molecular weight agents. Eur Respir J 1994;7:1567–1575.[Abstract]
10. Merget R, Caspari C, Kulzer SA, Dierkes-Globisch R, Breitsadt R, Kniffka A, Degens P, Schultze-Werninghaus G. Effectiveness of a medical surveillance program for the prevention of occupational asthma caused by platinum salts: a nested case-control study. J Allergy Clin Immunol 2001;107:707–712.[CrossRef][Medline]
11. Lemière C, Cartier A, Malo JL, Lehrer SB. Persistent specific bronchial reactivity to occupational agents in workers with normal nonspecific bronchial reactivity. Am J Respir Crit Care Med 2000;162:976–980.[Abstract/Free Full Text]
12. Nguyen B, Ghezzo H, Malo JL, Gautrin D. Time course of onset of sensitization to common and occupational inhalants in apprentices. J Allergy Clin Immunol 2003;111:807–812.[CrossRef][Medline]
13. Perfetti L, Hébert J, Lapalme Y, Ghezzo H, Gautrin D, Malo JL. Changes in IgE-mediated allergy to ubiquitous inhalants after removal from or diminution of exposure to the agent causing occupational asthma. Clin Exp Allergy 1998;28:66–73.[CrossRef][Medline]
14. American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med 1995;152:1107–1136.[Medline]
15. Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977;7:235–243.[CrossRef][Medline]
16. Pizzichini MMM, Popov TA, Efthimiadis A, Hussack P, Pizzichini S, Evans E, Dolovich J, Hargreave FE. Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med 1996;154:866–869.[Abstract]
17. Lemière C, Chaboillez S, Malo JL, Cartier A. Changes in sputum cell counts after exposure to occupational agents: what do they mean? J Allergy Clin Immunol 2001;107:1063–1068.[CrossRef][Medline]
18. Maestrelli P, Calcagni PG, Saetta M, Di Stefano A, Hosselet JJ, Santonastaso A, Fabbri LM, Mapp CE. Sputum eosinophilia after asthmatic responses induced by isocyanates in sensitized subjects. Clin Exp Allergy 1994;24:29–34.[CrossRef][Medline]
19. Spanevello A, Vignola AM, Bonanno A, Confalonieri M, Crimi E, Brusasco V. Effect of methacholine challenge on cellular composition of sputum induction. Thorax 1999;54:37–39.[Abstract/Free Full Text]
20. Woolhouse IS, Bayley DL, Stockley RA. Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis. Thorax 2002;57:667–671.[Abstract/Free Full Text]
21. Dehaut P, Rachiele A, Martin RR, Malo JL. Histamine dose–response curves in asthma: reproducibility and sensitivity of different indices to assess response. Thorax 1983;38:516–522.[Abstract/Free Full Text]
22. Malo JL, Pineau L, Cartier A, Martin RR. Reference values of the provocative concentrations of methacholine that cause 6% and 20% changes in forced expiratory volume in one second in a normal population. Am Rev Respir Dis 1983;128:8–11.[Medline]
23. Warke TJ, Fitch PS, Brown V, Taylor R, Lyons JDM, Ennis M, Shields MD. Outgrown asthma does not mean no airways inflammation. Eur Respir J 2002;19:284–287.[Abstract/Free Full Text]
24. Barnes PJ, Drazen JM. Pathophysiology of asthma. In: Barnes PJ, Drazen JM, Rennard S, Thomson NC, editors. Asthma and COPD. Amsterdam: Academic Press; 2002. p. 343–359.
25. Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti-interleukin-S only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:199–204.[Abstract/Free Full Text]
26. Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002;57:643–648.[Abstract/Free Full Text]
27. Boschetto P, Mapp CE, Picotti G, Fabbri LM. Neutrophils and asthma. Eur Respir J 1989;2:456s–459s.
28. Anees W, Huggins V, Pavord ID, Robertson AS, Burge PS. Occupational asthma due to low molecular weight agents: eosinophilic and non-eosinophilic variants. Thorax 2002;57:231–236.[Abstract/Free Full Text]
29. Gautrin D, Infante-Rivard C, Ghezzo H, Malo JL. Incidence and host determinants of probable occupational asthma in apprentices exposed to laboratory animals. Am J Respir Crit Care Med 2001;163:899–904.[Abstract/Free Full Text]
30. Amin K, Ludviksdottir D, Janson C, Nettelbladt O, Bjornsson E, Roomans GM, Boman G, Sevéus L, Venge P. Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. Am J Respir Crit Care Med 2000;162:2295–2301.[Abstract/Free Full Text]
31. Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001;119:1329–1336.[Abstract/Free Full Text]
32. Yamada H, Yamaguchi M, Yamamoto K, Nakajima T, Hirai K, Morita Y, Sano Y, Yamada H. Eotaxin in induced sputum of asthmatics: relationship with eosinophils and eosinophil cationic protein in sputum. Allergy 2000;55:392–397.[CrossRef][Medline]
33. Scheerens J, van Gessel SBE, Nijkamp FP, Folkerts G. Eotaxin protein levels and airway pathology in a mouse model for allergic asthma. Eur J Pharmacol 2002;453:111–117.[CrossRef][Medline]
34. O'Donnell RA, Davies DE, Holgate ST. Airway remodeling. In: Barnes PJ, Drazen JM, Rennard S, Thomson NC, editors. Asthma and COPD. Amsterdam: Academic Press; 2002. p. 67–78.

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				J.-L. Malo and H. Ghezzo Recovery of Methacholine Responsiveness after End of Exposure in Occupational Asthma Am. J. Respir. Crit. Care Med., June 15, 2004; 169(12): 1304 - 1307. [Abstract] [Full Text] [PDF]

				P. Maestrelli Natural History of Adult-Onset Asthma: Insights from Model of Occupational Asthma Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 331 - 332. [Full Text] [PDF]

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