Abstract
In 1976–1992 245 new cases of asthma induced by diisocyanates were diagnosed, caused by hexamethylene diisocyanate (HDI) in 39%, diphenylmethane diisocyanate (MDI) in 39%, and toluene diisocyanate (TDI) in 17% of the cases. Our aim was to study the clinical outcome of diisocyanate-induced asthma. A questionnaire was sent to the 235 patients alive in 1995, and validated by reexamining clinically 91 of them. The study was carried out on average 10 (3-19) yr after the diagnosis. Of the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients having displayed immunoglobulin E (IgE) antibodies to isocyanates used less medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR 0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and duration of exposure (p = 0.0008) than the IgE-negative patients. This did not, however, entirely explain the more favourable outcome of the IgE-positive patients. Patients with HDI-induced asthma used less medication (OR 0.412; CI 0.229, 0.739) than patients with MDI- and TDI-induced asthma. The results confirm the generally rather poor medical outcome of diisocyanate-induced asthma; the persistence of symptoms and unspecific bronchial reactivity were pronounced in TDI-induced asthma. A more favourable outcome was associated with IgE mediation and HDI inducement.
Diisocyanates, toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), and hexamethylene diisocyanate (HDI) are the most common chemicals that cause asthma. The pathogenesis of diisocyanate-induced asthma has not been solved yet. The symptomless latency period and the reactions in specific challenge tests indicate immunological mechanisms. In diisocyanate-induced asthma, immunoglobulin E (IgE) antibodies to isocyanates have been detected usually in 14–20% of the cases (1, 2), suggesting that IgE mediation is not the major mechanism of diisocyanate-induced asthma. Other immunological or nonimmunological mechanisms have also been suggested (3).
The studies on the outcome of diisocyanate-induced asthma have usually dealt with TDI-induced asthma (4-11), and only a few with MDI- (10-12) or HDI-induced (11, 12) asthma. Comparisons of the outcome of asthma among the causative diisocyanates are lacking. Usually the material on patients has included fewer than 60 subjects, and the longest follow-up periods have ranged from a couple of months to 5 yr (5, 10, 13). One longer follow-up period involving 114 subjects was published by Tarlo and coworkers (11). In most studies the respiratory symptoms have persisted for years in a majority of the patients (5, 10, 12) in spite of discontinued exposure to diisocyanate, and nonspecific bronchial hyperresponsiveness has persisted (6, 7).
During 1976–1992, 245 cases of diisocyanate-induced asthma were evaluated at the Finnish Institute of Occupational Health. In 89% of the cases, the evaluation was confirmed by specific challenge testing. The causative diisocyanates were MDI, HDI, or TDI. Our aim was to study the clinical outcome of diisocyanate-induced asthma.
Patients with diisocyanate-induced asthma diagnosed in 1976–1992 were studied. The isocyanates causing asthma were MDI in 96 (39%), HDI in 95 (39%), TDI in 42 (17%), TDI combined with HDI in 8 (3.3%), TDI combined with MDI in 3 (1.2%), TDI combined with naphthalene diisocyanate (NDI), and MDI in 1 person (0.4%). They worked in the production or handling of polyurethane foams in 44% of the cases, spray painting in 30%, car repair work in 4%, painting in 5%, and several other tasks involving exposure to diisocyanates: mechanics, welders, foremen, etc. In 58 cases, information on exposure levels at work was available, varying from 0.00017 to 0.69 (mean 0.023) mg/m3 as NCO. The anthropometric data on the patients from the year of diagnosis are presented in Table 1. The protocols have been approved by the institutional ethical committee, and the informed written consent of the subjects was obtained.
In 1995, a questionnaire was sent to 235 patients in whom diisocyanate-induced asthma was previously diagnosed. Of the responders (n = 213, 91%), 167 patients (78%) volunteered for the control studies. Of these 121 were called for control examinations: all IgE-positive patients and IgE-negative patients randomly selected from those with a positive bronchial provocation test. Fifty-two patients with an immediate reaction and 62 with a late reaction in the challenge tests were selected. In 7 of the 21 IgE-positive patients, the diagnosis of asthma had been based on peak expiratory flow (PEF) variation. The final clinical material comprised 91 patients, 52 immediate reactors and 37 late reactors; 19 cases were IgE positive. Clinical examinations, lung function studies including spirometry, bronchodilation test, histamine challenge and diffusing capacity tests, as well as the total IgE level and the diisocyanate-specific IgE measurements were performed.
The challenge tests were carried out in a 6-m3 challenge chamber according to the modified method of Newman Taylor and coworkers (2, 14) and they lasted for 15 min. During the 17-yr period the methods of isocyanate challenges have changed slightly, but the basic procedure with increasing challenge concentrations and the concentration levels have been essentially the same. The first tests with a TDI were carried out by spraying the paint with TDI-containing hardener; since 1980 the tests were carried out mostly by evaporating a calculated amount of pure isocyanate (toluene-2,4-diisocyanate 80% and toluene-2,6-diisocyanate 20%, Merck 808264) in a toluene solution. In the first MDI challenges the patient was exposed to MDI reacting with polyol to form a rigid foam. Since 1980, most MDI challenge tests were done by spraying an MDI–toluene solution (diphenylmethandiisocyanate zur Synthese, Merck 820797) into the exposure chamber. Challenge testing with TDI and MDI was done with rising nominal concentrations from 0.0069 mg/m3 (NCO) (0.002 ppm) to 0.069 mg/m3 (0.02 ppm), one test per day, corresponding to one-tenth of the 15-min occupational exposure limit (OEL) values of Finland or the level of the OEL value. The challenge tests with HDI were carried out during simulating work tasks, for example, by spraying the hardener of the lacquer or paint, containing mainly the prepolymers (15). We also challenged 15 cases to an HDI monomer but could not induce an asthmatic reaction. The air concentrations of TDI and MDI have been measured with a TDI detector (Model 7005; MDA Scientific, UK), and those of HDI monomer as reported earlier (15). In 126 challenge tests the mean isocyanate monomer concentration leading to diagnosis was 0.044 (range 0.0017–0.69) mg/m3 as NCO. The prepolymer concentration during HDI challenge test was measured (15) during 10 challenge tests: mean 3.90, range 0.062–9.5 mg/m3 (NCO). As a negative test, polyol (the inert component of the polyurethane foam) was used in 107 cases, lactose was used in 17, or in work-simulating challenge testing the paint or lacquer without isocyanates or welding of black iron was used.
Until 1984, only PEF was followed up with a Wright peak flow meter. Since then also FEV1 measurements were performed with a Vitalograph S bellow spirometer (Vitalograph, Buckingham, UK) according to a method reported earlier (16). Since 1993, FEV1 and PEF were followed up with a Micro Plus Spirometer (Micro Medical, UK) (17). Reduction of 20% of PEF or FEV1 was regarded as significant. A reduction of 15–19% was regarded as significant in an immediate reaction as well as in a late reaction provided that other supporting findings had been found, such as wheezing lung sounds or a dose– effect relationship in challenge tests (2, 18). The reactions of the skin were examined by a dermatologist and those of nasal mucosa by an otorhinolaryngologist. The reaction was regarded as immediate when the strongest PEF or FEV1 reduction was registered during the first hour after the challenge test. Because several patients had received medication for asthma in the follow-up, the dual reactions are not dealt with separately here.
Until 1987, spirometry was performed with a 3000 Kifa Bernstein spirometer (Instrumenta, Sweden), and FVC, FEV1, and maximal mid-expiratory flow (MMEF) were measured, and the FEV1/FVC ratio was calculated in volume–time display. The reference values of Berglund and coworkers (19) were used. Since 1988, a rolling-seal spirometer (Mijnhardt, Vicatest 3) connected to a microcomputer (Medicro MR-3) has been used, using Viljanen's spirometry reference values (20). The flow–volume curve was formed with the envelope method by using the standards of the European Respiratory Society (21). Vital capacity (VC), FVC, FEV1, FEV1/FVC ratio, MMEF, and maximal expiratory flow at the volume level of 50% of FVC (MEF50) were measured. A bronchodilator test was performed with three puffs of rimiterol hydrobromide, 0.2 mg per puff at 1 min intervals. Spirometry was controlled 5 min later and an increase in FEV1 of 15% or 200 ml, an increase in MMEF of 33%, or at least 0.4 L/s was considered significant. In control examinations, a bronchodilation test was not always performed, if the spirometry result was normal.
In the histamine challenge testing, a modified method of Laitinen (22) using 1% histamine diphosphate was used until 1991; PEF was followed up with a Wright peak flow meter (Clement Clarke M286; Ferraris Medical). Since 1992, the Sovijärvi method (23) has been used, and the FEV1 values were followed up with a Vitalograph S bellow spirometer (Vitalograph). A 15% reduction in FEV1 was considered significant and the provocative dose of 1.6% histamine diphosphate causing a 15% reduction in FEV1 (provocative dose, PD15) was measured. The hyperresponsiveness was graded as strong with PD15 < 0.10 mg, moderate with 0.11–0.40 mg, and slight with 0.41–1.6 mg. The histamine challenge test was not performed if FEV1 was < 70% of predicted value. The single breath diffusing capacity for carbon monoxide (Dl CO) and specific diffusing capacity (Dl CO/Va) was measured by the Morgan transfer test (Morgan, UK) until 1994, after which a Masterlab Transfer or a Compact Lab Transfer device was used (Erich Jaeger, Würzburg, Germany) using Viljanen's reference values (20). In the control examinations, the condition of asthma was studied also by monitoring the peak expiratory flow in the morning and in the afternoon. The long-term PEF recordings at home and at work were made according to the method of Burge (24) with a mini-Wright peak flow meter.
In control examinations, the decision to start or increase medication for asthma was made based on the anamnestic symptoms, finding in spirometry, histamine challenge test result, or PEF variation. The use of medication was checked from the prescriptions of medication for asthma.
Twenty common environmental allergens were scratch chamber tested until 1978 (Bencard, UK and Dome, Division of Miles Laboratories Ltd., UK), and since 1979 were skin prick tested (Allergologisk Laboratorium A/S, ALK, Copenhagen, Denmark) with a standard technique (25). Histamine hydrochloride (10 mg/ml) was used as a positive control. MDI, TDI (the diisocyanate solutions were the same as those used in challenge testing, above), and HDI (hexamethylene diisocyanate [HDI], Fluka 52649) were prick tested as human serum albumin (HSA) conjugates, as previously described (25, 26). Certificated HSA for the conjugates was obtained from the Finnish Red Cross Blood Transfusion Service (albumin SPR 200 mg/ml, human serum albumin 20%; SPR Helsinki, Finland). The hapten conjugates of HSA were prepared according to the method of Belin and Wass (27). A 1% (wt/vol) hapten–HSA conjugate in Coca's solution containing 50% glycerol (27) was used for prick testing. Skin reactions 3 mm or larger were regarded as positive, in addition to a negative reaction with the diluent.
The total IgE values were determined by the enzyme immunoassay technique (Phadezym PRIST kit; Pharmacia Diagnostics, Uppsala, Sweden) until 1993; since then a Pharmacia CAP system IgE RIA (Kabi Pharmacia Diagnostics, Uppsala, Sweden) has been used. Since 1997, the total IgE values have been measured with the UniCAP system (Pharmacia & Upjohn). The determination of specific IgE antibodies to diisocyanates was performed by enzyme immunoassay with commercial kits (Pharmacia Diagnostics) as reported earlier (2) from 1983 to 1993, after which they were done using a Pharmacia CAP system RAST RIA (Pharmacia, Sweden) and the isocyanate binding was related to HSA binding. Since 1997, the isocyanate-specific IgE has been measured with the UniCAP system (Pharmacia & Upjohn).
Two different definitions were used for atopy in the data analysis: (1) one or more positive skin prick reactions after testing with 20 common environmental allergens, and (2) earlier infantile eczema, atopic dermatitis, or hay fever or other allergic rhinitis, here called atopic history.
The questionnaire based on the Tuohilampi question series (available only in Finnish) was sent to patients. The questions queried the subjects' present working situation, exposure to diisocyanate, smoking habits, symptoms of asthma, and use of medication for asthma. The following questions compared with the clinical and laboratory data were asked. The question on the symptoms of asthma was: Have you suffered from symptoms of asthma or felt episodes of shortness of breath with wheezing (1) not at all, (2) only during respiratory infections, or (3) also unrelated to respiratory infections? The question concerning the need for medication for asthma was: Have you used medication for asthma during the past 12 months (1) not at all, (2) only on demand, or (3) regularly?
The associations of self-reported data with clinical variables (atopy, spirometry, histamine challenge results, etc.) and other risk factors were analyzed using logistic regression models. Odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated. Dependent variables were self-reported variables (occurrence of symptoms of asthma, and use of medication for asthma), and clinical variables were independent variables. In the comparison of the self-reported data, patients answering having no symptoms or symptoms only during re-spiratory infections were combined, as well as patients using no medication or medication only on demand. Patients with an immediate reaction were compared with those with a late reaction, patients with specific IgE antibodies were compared with those without antibodies, and atopic persons were compared with nonatopic ones. Possible differences in the duration of symptoms between the IgE-positive and IgE-negative patients were tested with an ordinary t-test. In the comparison of the lung function test results between the primary and the control examinations, the following tests were used: pairwise t-tests with spirometry parameters (VC, FVC, MMEF, maximal expiratory flow [MEF50]) and diffusing capacity results, Bowker's Test of Symmetry with grading of ventilatory function impairment, and the McNemar test with bronchodilation test results.
Isocyanate-specific IgE was positive in 32 patients (21.9% of those 146 cases studied). The isocyanates having caused a specific IgE response were HDI in 12, MDI in 18, TDI and HDI in 1, TDI and MDI in 1, and pure TDI exposure in no cases. In most cases when antibodies to MDI or HDI were present, a cross-reaction to TDI was also present. Skin prick tests to isocyanates had been performed in 52% of the cases, and 11 (8.7%) were positive. The patients with IgE antibodies had significantly more immediate reactions in challenge testing (p = 0.002, χ2 test). The total IgE concentration was 119.9 ± 223.4 kU/L, in the IgE positive 238.71 ± 331.74 kU/L, and in the IgE negative 85.67 ± 127.35 kU/L (p = 0.002, χ2 test).
The specific inhalation challenge test was the main diagnostic criteria for occupational asthma in 216 (88.5%) cases, PEF monitoring in 14 cases, IgE positivity and occupational effect in PEF monitoring in 2 cases, and a significant increase in bronchial hyperreactivity after exposure in 3 cases. In 9 cases the asthma was so labile that the challenge test could not be performed. Most patients felt symptoms of dyspnea during the challenge testing. All HDI-induced cases of asthma were predominantly caused by prepolymers and most of the TDI- and MDI-induced asthma cases were caused by monomers. In 10% of MDI- and 36% of TDI-induced asthma, prepolymers may also be involved, because asthma had been diagnosed in work-simulating challenge testing. Elevated body temperature during the challenge test was measured in 39 (17.7%) cases. The reaction in the challenge test was immediate or dual in 101 cases (46%) and late in 118 cases (54%). In addition to asthma, the following additional diagnoses were confirmed: occupational allergic rhinitis in 19 cases (7.8%), allergic alveolitis (MDI) in one case based on symptoms and reduced diffusing capacity, allergic eczema in 1 case, and urticaria caused by isocyanates in 1 case. After the diagnosis of occupational asthma, in 231 cases (94.7%) the patient was told to avoid isocyanate exposure, and in 13 cases (5.3%) the present work was allowed, but only with respiratory protection. Medication for asthma was started in 183 cases (75.6%).
The follow-up duration from the baseline studies to the questionnaire was 10.4 ± 4.41 yr (mean ± SD) (range 3.0–19.0). There were 130 (60.5%) smokers and 76 (36%) ex-smokers. Of patients 32 (15 %) reported some isocyanate exposure in their present work and 18 reported using isocyanates on their days off, 15 once a year on average, 2 once a week, and 1 once a month. All the numbers do not match because of inaccuracies in answers.
Of patients 36 (17%) reported they had no symptoms of asthma, 63 (30%) only during respiratory infections, and 109 (52%) unrelated to respiratory infections. About 60% of the patients reported having symptoms from various nonspecific stimuli. Of patients 72 (34%) reported not using any medication for asthma, 66 (31%) only on demand, and 74 (35%) regularly. Forty persons (26%) had used peroral steroids. The patients not using medication for asthma reported having stopped medication a mean of 3.6 (range 2–13) yr after the diagnosis.
Of patients 75 (36%) had suffered from cough of long duration, 123 (58%) reported expectorations daily or almost daily at least for 3 mo during 1 yr, and 43 (24%) reported having chronic bronchitis, 8 (5%) emphysema, 3 (1.9 %) bronchiectases, and 50 (29%) allergic rhinitis.
A persisting need for medication was associated with the presence of baseline ventilatory impairment, as well as with bronchial hyperreactivity (Table 2). An atopic tendency in relatives, an earlier atopic history, or atopy in skin prick tests did not influence either the duration of the symptoms or the need for medication. There was no association between persistence of symptoms or need of medication with duration of exposure, duration of symptoms before diagnosis, or the latency period in all patients. Those who continued in their primary work place did not report more symptoms than those working in new work places. Smoking was not related to persisting symptoms or to persisting need for medication.
Patients with IgE mediation used significantly less medication and had fewer symptoms of asthma than patients who had not shown isocyanate-specific IgE (Table 2). When IgE positivity and HDI exposure were used simultaneously in a multiple regression model with the clinical outcome parameters, no accentuation or weakening of the associations was found. The IgE-positive patients had a significantly shorter duration of symptoms, latency period, and duration of exposure before diagnosis compared to the IgE-negative patients (Table 3).
Patients with HDI-induced asthma used less medication (72% were using no medication or only on demand, 28% regularly) than patients with TDI- (54% and 46%, respectively) and MDI-induced asthma (63% and 37%, respectively) (OR 0.412; CI 0.229, 0.739). The continuation of symptoms was most strongly associated with TDI exposure (OR 2.533; CI 1.080, 5.939). When HDI-induced asthma was compared with TDI- and MDI-induced asthma, excluding those with specific IgE antibodies, the symptoms were significantly associated with TDI-induced asthma, whereas the use of medication was associated both with TDI- and MDI-induced asthma (Table 4). This comparison included patients in whom IgE antibodies were not studied. Exclusion of those not studied for specific IgE caused an increase of the OR values; however, the confidence intervals widened due to the decline in the number of patients.
Of patients 91 (71 men, 21 women; 20 with TDI-, 36 with MDI-, and 35 with HDI-induced asthma) came to control examinations, 43 (48%) of whom were still working. The follow-up time after the diagnostic baseline studies was 12.42 ± 4.68 (mean ± SD) yr (range 4–22 yr). Thirty patients (33%) reported isocyanate exposure after the diagnosis of occupational asthma, 6 (12.2%) in their present work place.
The diurnal PEF variation was less than 10% in 53 persons (58%), 10–20% in 29 patients (31.9%), and more than 20% in 9 patients (9.9%). They had significantly more slight, moderate, and strong ventilatory function impairment in spirometry than in the baseline studies (Table 5). The percentages of VC, FEV1, MMEF, and diffusing capacity values of the predicted values were significantly lower in the control examinations. The FEV1 value had decreased on average 39.6 ml a year between the primary and control examinations. In nonsmokers (n = 40) the yearly reduction in FEV1 was 33.8 ml, and in smokers 51.8 ml (Table 6). Total IgE was 168.5 ± 334.3 (2– 2,070) kU/L; specific IgE was still positive in three patients in earlier IgE-positive ones.
In control examinations, those who in the questionnaire reported having symptoms of asthma also had a need of medication (p = 0.029, χ2 test) based on lung function results, and those who reported using medication also had prescriptions for asthma medication (p = 0.001, χ2 test). Those who reported using medication for asthma had significantly more ventilatory impairment in spirometry (p = 0.004, χ2 test) and also more bronchial hyperreactivity (p = 0.054, χ2 test). According to the questionnaire the occurrence of symptoms was not significantly associated with ventilatory impairment in spirometry, bronchial hyperreactivity, or PEF variation. However, 19 (22%) of those who reported being symptomless had ventilatory impairment in spirometry, 24 (25%) were hyperreactive, and 16 (18%) showed increased PEF variation.
The outcome of, especially, TDI- and to some extent MDI- induced asthma has been investigated earlier (4-12). By comparison, the present material is rather large and the follow-up time is long; the diagnosis has been ascertained by specific challenge testing in 89% of the cases. The material comprises 95 cases of HDI-induced asthma, of which only little information is available. Thus, the study offers a comparison of the outcome of different diisocyanate-caused cases of asthma.
According to the questionnaire study, more than 80% of the patients still felt symptoms of asthma and used medication for asthma, which is in accordance with earlier studies on the poor outcome of isocyanate-induced asthma (4-10). In Finland, compensation for cases of occupational asthma is comparatively advantageous. This may have caused an exaggeration of symptoms of asthma in the questionnaire study in order to ensure the continuity of the compensation. Therefore, we wanted to validate the results of the questionnaire by calling some of the patients for control examinations. The results of the control examinations confirmed the results of the questionnaire. About 60% of the patients used inhaled steroids after the control examinations, and there was progression of lung function impairment. Half of them were hyperreactive. However, the FEV1 reduction did not exceed the decline reported by Fletcher and Peto (28) in smoking and nonsmoking subjects. The yearly reduction of FEV1 and FVC was similar, and that of MEF50 and MMEF less than reported by Diem and coworkers (29), who followed up workers with continuing negligible isocyanate exposure.
Patients with IgE-mediated asthma had a significantly better outcome than patients without demonstrable IgE mediation. Earlier, Park and Nahm (13) in a smaller study comprising cases of TDI-induced asthma found a similar tendency. In our study, the duration of the asymptomatic latency period was usually rather long, 174 patients (71%) had a latency period longer than 1 yr, which is in agreement with earlier findings (10, 13, 30). However, symptoms of asthma developed after a shorter exposure period in the IgE-positive than in the IgE-negative patients, which is in agreement with a study of Pezzini and coworkers (9). Also when cases of TDI-induced asthma were excluded, those with IgE antibodies had fewer symptoms and used significantly less medication. This shows that the more unfavorable prognosis of the IgE-negative cases does not depend merely on TDI inducement. The better outcome of IgE-mediated asthma may be related to nonmechanistic factors. The early onset of symptoms leading to shorter exposure times may be a simple explanation. However, an interesting question is why the symptoms develop earlier in the IgE-positive than the IgE-negative patients. Different mechanisms in the IgE-positive and IgE-negative patients with asthma could explain the differences in the onset of the disease and further influence on the prognosis.
Probably by chance we did not find any TDI antibodies in TDI reactors, whereas 20% of the patients with HDI- and 29% with MDI-induced asthma were IgE positive. The commercial test method for determination of specific IgE against TDI showed, however, positive reaction as cross-reactivity in cases of MDI- and HDI-induced asthma. Therefore, it is not likely that the IgE negativity of cases of TDI-induced asthma would depend on the low sensitivity of the test. The skin prick tests to TDI–HSA conjugate were also negative. The prevalence of specific IgE antibody to TDI–HSA conjugate has also been low in some other studies (31-33). Pezzini and coworkers (9) suggested that MDI could be a more effective hapten than TDI. The presence of specific IgE has been suggested to be associated with heavy episodic exposure to TDI (9, 33). It is possible that the IgE production in TDI-induced asthma, indeed, needs higher exposure levels than in MDI- or HDI-induced asthma, possibly depending on the characteristics of the iso-cyanate molecule, TDI occurring in occupational exposure mostly in the vapor phase, MDI and spray painted HDI as aerosols (34).
Patients with HDI-induced asthma had a better outcome than those with TDI- and MDI-induced asthma. Despite the comparatively small TDI-induced material, multiple regression analyses showed the least favorable prognosis for patients with TDI-induced asthma. The poor outcome of TDI-induced asthma has been confirmed repeatedly (4-9). Multiple regression analyses indicated that the better outcome of HDI-induced asthma did not depend only on IgE positivity. In addition, when we compared the outcome, exluding the IgE-positive cases, we still found that patients with HDI-induced asthma had the best outcome. In this comparison, those whose antibodies were not studied were included, implying that some IgE-positive cases in fact may be present. When also excluding those not studied for specific IgE antibodies, the result remained significant; however, the smaller number of patients caused widening of the confidence interval.
The total IgE level was higher in the IgE-positive patients than in the IgE-negative ones, which has also been reported earlier (2, 35). The high total IgE correlated with atopy neither in our study nor in the studies reported by Keskinen and coworkers (2) or Tee and coworkers (35). The finding remains unexplained; it has, however, been considered unlikely to interfere with the analytics of isocyanate-specific antibodies (2).
Bronchial hyperreactivity has not been consistently found in diisocyanate-induced asthma. Particularly patients who display a late reaction in a specific challenge test have been reported to show bronchial hyperreactivity (9). Bronchial hyperreactivity occurred in about half of our patients, with no distinction between immediate or late reactors. In some cases the bronchial hyperreactivity may have disappeared or diminished during long sick leaves prior to the diagnostic examinations. During the 20-yr follow-up period of our study the methods used in lung function studies have been modernized. This may have influenced comparisons of nonspecific bronchial hyperreactivity; the number of the initially hyperreactive patients may have been too small as a lower concentration of histamine (1%) was used prior to 1992.
The participation in the questionnaire study was satisfactory (91%). The answers in the outcome questions (use of medication and occurrence of symptoms of asthma) did not differ between those who did and who did not volunteer for clinical studies; neither were there any differences between those who participated and those who did not. We, therefore, believe that the clinically studied patients were fairly representative of the entire population of patients with asthma.
The use of medication according to the prescriptions was in line with the results of the questionnaire. Some patients (n = 19) who in the questionnaire reported that they were symptomless still had ventilatory impairment in spirometry and bronchial hyperreactivity (n = 24), indicating that the patients did not recognize their symptoms. In addition, the use of medication for asthma may have masked their symptoms. A questionnaire study alone obviously is not sufficient for follow-up studies of the condition of asthma; if practical, lung function studies should be preferred.
The study design did not allow evaluation of the use of medication for asthma on the prognosis. In several cases the medication was either inadequate or had been discontinued. Also the praxis of medication for asthma changed profoundly during the follow-up; the early use of inhaled steroids became common practice in the 1990s. Exposure levels may also have been higher in the 1970s and the early 1980s. The material was studied by dividing the patients into two groups: before and after the median year (1984) of diagnosis setting. There was no difference in the outcome variables between the groups, indicating that neither conceivable changes in isocyanate exposure levels nor changes in treatment praxis over the years influenced the results.
Atopy did not prove to be a prognostic factor, although according to some studies atopy might be one risk factor for the persistence of symptoms of asthma (12). We did not find the reaction type to have a prognostic value. Also in earlier literature, the results of the challenge test reaction as an outcome variable have been controversial: immediate reactions have been claimed to forecast both a poor (10) and a good prognosis (5).
Baseline ventilatory impairment and bronchial hyperreactivity are associated with continuing use of medication. Use of medication possibly has influenced the occurrence of symptoms. A poor outcome of asthma has been associated with baseline bronchial hyperreactivity and disturbance of ventilatory function (4, 8). The results were in concordance with this. We did not find an association between the duration of isocyanate exposure before diagnosis and the outcome variables as in several earlier studies (8, 10, 12), which may be due to inaccuracies in old patient documents. Persisting symptoms of asthma have also been associated with continuing isocyanate exposure (4, 8, 31). Because of the poor reply rate to questions on continuance of exposure (about 60%), we were unable to study these associations. There may have been a reluctance to answer these particular questions as all of them had been explicitly advised to avoid all further exposure to isocyanates.
In conclusion, our study corroborated earlier reports showing a rather poor prognosis of diisocyanate-induced asthma. The long-term follow-up revealed certain new aspects. HDI-induced asthma was associated with a better outcome than MDI- and TDI-induced asthma. This may depend on individual characteristics of the isocyanate molecules. Patients with IgE-mediated asthma had a significantly better prognosis than the IgE-negative patients. It proved to be partly, but not entirely, due to shorter exposure and symptomatic periods before the diagnosis; it also once more focuses interest on the mechanism of isocyanate-induced asthma. Neither surveillance nor treatment had been satisfactory in our patients. Our results emphasize the need for medical surveillance and adequate treatment of patients suffering from diisocyanate-induced asthma. Early diagnosis and adequate medical surveillance, including active treatment and swift vocational rehabilitation, are equally essential for the patient's overall prognosis.
The authors wish to thank Mrs. Lea Aalto for coding the questionnaire results, Dr. Brita Grenquist-Norden for supervising the control examinations, Mrs. Terttu Kaustia for revising the manuscript, Riitta Rühr and Tuula Suomela for searching the patient's addresses, Irmeli Koskinen for advice on social questions, Outi Tupasela for help in laboratory problems, and the whole staff of the Department of Work Medicine in the Finnish Institute of Occupational Health for their cooperation and help during the study.
Supported by the Finnish Work Environment Fund and Biomarkers for the assessment of health risk from occupational exposure to isocyanates, Grant BMHT4-CT95-0559. No part of the research presented has been funded by tobacco industry sources.
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