Long-term follow-up of toluene diisocyanate-induced asthma

Diisocyanates, widely used and highly reactive industrial chemicals, are among the most frequent causes of occupational asthma (OA) in industrialised countries 1. The most commonly used diisocyanate is toluene diisocyanate (TDI), a mixture of 2,4 and 2,6 isomers (80:20). The precise mechanisms underlying isocyanate-induced asthma are unknown, even though the immunological mechanism remains the likeliest occurrence, with its latency interval between exposure and onset of asthma 2. In terms of long-term outcome, despite complete avoidance of exposure, Park and Nahm 3 showed a spectrum of responses in subjects with isocyanate asthma and proposed that the final outcome depends on which mechanism is predominant in each individual. The majority of the follow-up studies on isocyanate asthma 4–11 emphasised that only one-half of subjects with isocyanate asthma will recover, while one-half of those who do not recover will show some improvement, and one-half will complain of asthmatic symptoms and will require anti-asthma therapy. Short duration of exposure to isocyanates and of symptoms before the diagnosis, immediate cessation of exposure after diagnosis, young age, milder degree of nonspecific airway hyperresponsiveness and presence of specific immunoglobulin (Ig)E antibodies to isocyanates have been found to be associated with a favourable prognosis.

In the present study, the results of a follow-up examination on 87 subjects sensitised to TDI are reported. The phenotype characteristics of the subjects are illustrated in order to investigate the outcome of disease. Since OA is a valid model of adult-onset asthma 12, 13, information on the outcome of OA can also bring new insights into the natural history of non-OA.

Methods

Eighty-seven subjects with a history of asthma induced by exposure to TDI were studied. None of these subjects had symptomatic asthma before occupational exposure to TDI or had been subject to exposure to isocyanate spills in the past. All subjects were asked for a detailed clinical and occupational history, and underwent skin-prick tests with a battery of common allergens and pulmonary function tests. All subjects had been free of respiratory infections or exposure to isocyanates for at least 2 weeks. No subject had taken cromolyn, theophylline, sympathomimetics or antihistamines within 48 h of any study. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁) were measured using a dry bellows spirometer (Model 840; Ohio Air Co., Houston, TX, USA). The isocyanate inhalation test was carried out in all subjects at the time of diagnosis. The methacholine inhalation challenge was performed at diagnosis and at a follow-up visit, as previously described 14. Thirty subjects did not perform the inhalation challenge with methacholine at follow-up for the following reasons: 18 exhibited airway obstruction, two had expiratory wheezes at chest auscultation, seven had hypertension, one was breastfeeding, one had paradoxic bronchoconstrictor response to bronchodilators and one refused to perform the challenge. The instruments, methods and technicians were the same at diagnosis and the follow-up visit.

Results

The clinical features of the subjects at the time of diagnosis and of the follow-up visit are shown in table 1⇓. There were 63 males and 24 females included in the study. A small proportion of the subjects were smokers and atopics, features that did not change at the follow-up visit. The average duration of exposure to TDI was 12 yrs. The majority of workers (>70%) were employed in furniture factories or carpentry shops. At follow-up visit (average duration of follow-up±sem: 11±0.4 yrs), 15% of the subjects continued to remain exposed to TDI, whereas 85% had been removed from exposure. Of those removed from exposure, 34.5% had been removed for >10 yrs. There was a significant difference with regard to the presence of symptoms of asthma and of airway hyperresponsiveness to methacholine between the two visits, with a lower percentage of symptomatic (71 versus 100%) and hyperresponsive subjects (25 versus 62.5%) at follow-up (p<0.001). When subjects were examined according to the interval since removal from exposure, respiratory symptoms occurred in 84.6% of subjects exposed to TDI, in 75% of those removed for <10 yrs (p<0.001) and in 60% of those removed for >10 yrs (p<0.01). PD₂₀ methacholine was lower in subjects exposed to TDI at follow-up (geometric (G) mean (Gsem) 0. 855 mg (1.46) versus 1.045 mg (1.15) in subjects removed for <10 yrs and 1.173 mg (1.18) in those removed for >10 yrs. The degree of airway responsiveness was milder at follow-up examination. At diagnosis, 35.6% of subjects with a positive inhalation challenge to methacholine had a PD₂₀ <0.300 mg, whereas at follow-up the percentage of subjects highly responsive to methacholine was 8.9%. At follow-up visit, 59% of the subjects used inhaled short-acting bronchodilators, 8% used long-acting bronchodilators and 18% used inhaled glucocorticoids. At the time of the diagnosis, specific inhalation challenge with TDI in the laboratory elicited an immediate asthmatic reaction in 20.7%, a late reaction in 54% and a dual reaction in 25.3% of the subjects. At the time of the follow-up examination, there was a significant difference in FVC (% predicted) and PD₂₀ methacholine, as compared with values obtained at diagnosis (table 2⇓) 16. Among subjects exposed to TDI, 33.3% at diagnosis and 37.9% at follow-up exhibited airway obstruction. At follow-up examination, the lung volumes FEV₁ (L) and/or FEV₁ % pred, and FVC (L) and/or FVC % pred, and PD₂₀ methacholine showed a negative correlation with the duration of exposure to TDI, but the correlations were significant only for subjects exposed to TDI. Spearman's rank correlations were −0.70, p<0.01; −0.65, p<0.05; −0.55, p<0.05; −0.49, 1<p<0.05; and −0.60, p<0.05, respectively.

Multiple regression analysis showed that follow-up FEV₁ (% pred) and FVC (% pred) values could be predicted from those at diagnosis. At the time of follow-up examination, FEV₁ and FVC were significantly lower in smokers (B=−6.38, p<0.005 and B=−5.53, p<0.005, respectively), whereas atopy was associated with a better lung function (B=4.64, p<0.05 and B=5.21, p<0.001, respectively). FEV₁ (% pred) was lower in symptomatic subjects (B=−7.61, p<0.005). The results of the stepwise multivariate logistic regression are shown in table 3⇓. In all models, PD₂₀ at diagnosis was a significant predictor of follow-up PD₂₀, a lower degree of airway hyperresponsiveness to methacholine at diagnosis being associated with a lower risk to be hyperresponsive at follow-up. The duration of exposure, the interval since removal from exposure and the current treatment with inhaled glucocorticoids were predictors of the responsiveness to methacholine at the follow-up visit, but the significance was borderline (p=0.06, p=0.08 and p=0.06, respectively).

Discussion

In this study the clinical picture of 87 subjects with TDI-induced asthma and the outcome of the subjects at follow-up examination are described. The outcome of isocyanate-induced asthma has been investigated previously 3–11. However, this study offers additional interest. Indeed, the population was rather large, had been exposed to the same chemical, i.e. TDI, was employed in workplaces with similar characteristics, the diagnosis was made by specific inhalation challenge in 100% of the cases and the follow-up time was long. Thus, the study offers the opportunity to further characterise the natural history of a very common type of OA and to improve the understanding of the natural history of adult-onset asthma.

This study confirms the features of isocyanate asthma. The latent period between onset of exposure and onset of symptoms is prolonged, the proportion of atopic subjects and of current smokers is low, and the late asthmatic reaction is very common. Interestingly, the proportion of atopic subjects and current smokers did not change at follow-up visit, suggesting the absence of an increase in atopic status after many years from the diagnosis of OA caused by a low molecular-weight agent such as TDI. Even though a lower percentage of symptomatic subjects at follow-up examination was observed, they were subjects that had been removed from exposure, not subjects who continued in their primary workplace. However, it should be noted that 60% of subjects removed for >10 yrs complained of asthmatic symptoms and ∼60% of workers needed therapy with bronchodilators, whereas ∼20% of subjects used inhaled glucocorticoids.

These findings confirm the poor clinical outcome of TDI-induced asthma and are in agreement with the results of Piirila et al. 11. Recently, these authors performed a long-term follow-up study on subjects with isocyanate-induced asthma. They examined 95 subjects with hexamethylene diisocyanate (HDI)-, 96 subjects with diphenylmethane diisocyanate (MDI)- and 42 subjects with TDI-induced asthma (17% of the subjects). They found that the persistence of symptoms was mostly associated with TDI-induced asthma, a link confirmed by the finding that TDI patients used more medication than patients with HDI- and MDI-induced asthma. In the study by Piirila et al. 11, the worsening of lung function could be linked to the high percentages (74 and 60.5%) of smokers at diagnosis and at follow-up, whereas in the present study, even though a deleterious effect of smoking on lung volumes at follow-up examination was found, it is emphasised that the percentage of smokers was very low (8 and 6.9% respectively at diagnosis and at follow-up). Another potential mechanism for the worsening in lung function observed by Piirila et al. 11 is the possibility that active cigarette smoking impairs the efficacy of short-term inhaled corticosteroid treatment in mild asthma 17.

In agreement with previously reported findings 18, 19, it was shown that level of airway responsiveness to methacholine at time of diagnosis is a predictor of the persistence of airway hyperresponsiveness. Perfetti et al. 18 examined subjects with OA due to both high and low molecular weight agents and found that subjects removed from exposure for >5 yrs showed better prognostic figures than those reported in most follow-up studies up to 5 yrs after cessation of exposure, showing that the majority of subjects were symptomatic and hyperresponsive to methacholine.

The present study confirms, at least in part, these findings. Even though the level of significance was borderline, it was also shown that the duration of follow-up (for >10 yrs) is a factor that affects airway responsiveness to methacholine. At follow-up examination, a lower proportion of subjects exhibited airway hyperresponsiveness and a lower degree of hyperresponsiveness was observed in the group removed from exposure for >10 yrs. In the present study, the effects of methodological problems were avoided by ensuring instruments, technicians and protocols for delivering methacholine were the same at both diagnosis and follow-up visits. However, it must also be emphasised that a large part (60%) of the group of subjects removed for >10 yrs complained of asthmatic symptoms and that the lung volumes were significantly lower at follow-up after adjusting for age.

The present study did not allow evaluation of the use of anti-inflammatory drugs for asthma and of inhaled long-acting bronchodilators for asthma started at diagnosis. In many cases, the medication had been discontinued and, in addition, the regular use of inhaled steroids and long-acting bronchodilators has become common only in the last decade. The use of these drugs could only be accounted for at the follow-up visit. As expected, subjects who used long-acting bronchodilators had lower lung volumes and subjects who used inhaled steroids had a lower degree of airway hyperresponsiveness to methacholine.

The type of asthmatic reaction did not have a prognostic value in the present study. The influence of the type of reaction on the outcome has been controversial 4, 5. In a previous study, the authors suggested that the late reaction and the severity of the reaction could be related to the persistence of sensitisation to isocyanates 7. At variance with this study, the larger size of the population sample examined here and the long follow-up time allow the authors to conclude that the type of asthmatic reaction is not an important predictor for the persistence of the disease. More recently, evidence has been presented that the outcome of specific airway responsiveness to occupational agents may be different from the outcome of nonspecific airway responsiveness 19.

Among the many risk markers associated with susceptibility for the development of TDI asthma, the ability to cope with oxidative stress has been studied recently 13. Evidence has been presented that TDI exposure might cause oxidative stress at the epithelial surface 20. Defects in antioxidant defences could contribute to both the susceptibility of sensitisation and the persistence of TDI-induced asthma. To support this hypothesis, a critical role for the glutathione-S-transferase locus (GSTP1) gene product has been demonstrated recently 21. Homozygosity for the Val¹⁰⁵-encoding alleles confers protection against the development of the asthma-associated phenotype airway hyperresponsiveness and the protective effect increased in proportion to the duration of exposure to TDI.

In conclusion, the present study showed a poor prognosis of toluene diisocyanate-induced asthma. The long-term follow-up revealed that both asthmatic symptoms and airway hyperresponsiveness to methacholine persisted or improved slowly for >10 yrs after the workers left the workplace and ceased being exposed to isocyanates entirely. A more favourable outcome was associated with a better lung function, a lower degree of airway hyperresponsiveness to methacholine and a longer interval from cessation of exposure.