- Email: [email protected]
Outcome of asthma induced by isocyanates
Br. J. Dis. Chest (1987) 81, 14
OUTCOME
OF ASTHMA ISOCYANATES
INDUCED
BY
S. LOZEWICZ, B. K. ASSOUFI, R. HAWKINS AND A. J. NEWMAN TAYLOR Department
of Occupational London
Medicine, Brompton SW3 6HP
Hospital,
Summary
Isocyanates are widely used in industry for the manufacture of polyurethanes. Although they are recognized as an important cause of occupational asthma, it is unclear whether asthma persists after avoidance of exposure. We have followed up 50 cases, all of whom had avoided exposure for at least 4 years. At follow-up, 82% continued to have respiratory symptoms and approximately half of these required treatment at least once per week. These results indicate that a significant proportion of those with isocyanate-induced asthma are likely to have persisting symptoms for at least several years after exposure is avoided. INTRODUCTION Isocyanates are important causes of occupational asthma (l-3). It is unclear if avoidance of exposure to isocyanates leads to remission of asthma. We have followed up a group of patients with isocyanate-induced asthma, diagnosed by inhalation testing, who have subsequently avoided further exposure for at least 4 years. Not all patients who had measurement of bronchial reactivity at diagnosis were available for testing at follow-up and we have studied outcome using questionnaire assessment of symptoms of asthma and treatment requirement in addition to measurement of bronchial reactivity in those available for testing. Methods
A total of 56 cases of isocyanate-induced asthma (IA) were diagnosed at the Brompton Hospital between 1971 and 1979, of whom we followed up 50 (89%). In each case: 1. Symptoms of asthma had developed after exposure to isocyanates. Two caseshad histories of asthma preceding occupational exposure to isocyanates. One was a man who had persistent asthma between the ages of 5 and 16 years after which he only wheezed at times of respiratory tract infections. His first severe attack followed occupational exposure to TDI at the age of 32. The other was a woman who had been told that she had asthma as a child but who had no recollection of childhood respiratory symptoms. 2. Inhalation testing with the isocyanate(s) used at work reproducibly provoked an asthmatic reaction.
LOZEWICZ,
ASSOUFI,
HAWKINS
ET AL.:
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ASTHMA
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3. Exposure to isocyanates had been avoided for at least 4 years. Some remained in the same factory but were relocated to an area not using isocyanates or the use of isocyanates was discontinued. Others left the factory to work elsewhere. At the time of diagnosis measurements were made of lung function and, in some cases, bronchial reactivity to histamine. At the time of follow-up patients answered an interviewer-administered modified Medical Research Council respiratory questionnaire (4). Where possible, those unable to attend the hospital were interviewed by telephone or postal questionnaire. The presence of continuing symptoms was assessedby asking patients whether they still had chest tightness or difficulty in breathing. Patients who were able to attend at follow-up also had lung function tests and measurement of bronchial reactivity to inhaled histamine or cold air. The proportion of the study population attending for lung function at outpatient follow-up became lesswith increasing time from diagnosis; in order to increase the number of lung function test results available for analysis, we included the results of tests made after a period of less than 4 years from diagnosis. Thirty-eight patients had measurements of lung function made both at diagnosis and one or more years later when attending for outpatient followup. The numbers of these 38 subjects providing their most recent results of lung function studies at given intervals from diagnosis are shown below: l-2 years: 3 2-3 years: 9 PI years: 8 4+ years: 18 A subgroup of 12 patients who developed asthma while exposed to TDI in one printing factory was analysed separately. These patients probably represent all the caseswhich developed in this factory. Lung function
tests
Forced expiratory volume in one second (FEV,) and forced vital capacity (FVC) were measured using a regularly calibrated dry wedge spirometer (Vitalograph). Inhalation
testing
Isocyanates. Single-blind occupational type inhalation tests were made with toluene di-isocyanate (TDI), diphenylmethane di-isocyanate (MDI), hexamethylene di-isocyanate (HDI), and naphthylene di-isocyanate (NDI). The methods used for inhalation testing and measurement of atmospheric concentrations of TDI and MD1 have been described previously (1, 2). Histamine. Airway reactivity to histamine was measured by the method of de Vries (1960) as modified by O’Brien et al. (2). A fall in FEV, of 10% obtained with this method was taken to indicate the presence of bronchial hyper-reactivity. lsocapnic hyperventilation of cold air (IHCA). The method used was that of Assoufi et al. (5). Using this test, asthmatic but not normal subjects demonstrate a fall in FEV, of IO%, which was taken to indicate the presence of bronchial hyper-reactivity in the present study. Skin prick
tests
Skin prick tests were made with a control solution and extracts of common inhalant allergens, grass pollen, Aspergillus fumigatus, cat hair, dog hair, house dust, and Dermatophagoidespteronyssinus (Bencard). A positive reaction was defined as a weal diameter of 3 mm or more greater than that provoked by the control solution. Atopy was regarded as present when one or more positive reactions was elicited. Assessment of outcome
Assessment of outcome was based on answers to the questions relating to treatment requirement and symptoms of asthma in addition to measurements of lung function and airway reactivity. Patients
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were regarded as having symptoms of asthma if they had chest tightness or difficulty with breathing. Treatment included inhaled or oral bronchodilators, inhaled disodium cromoglycate, and inhaled or oral corticosteroids. In order to investigate which factors might be associated with a poor outcome, patients were divided into two groups in relation to frequency of treatment requirement at followup: Group 1: 22 patients who required any of the above treatments once per week or more often. Group 2: 27 patients who required only bronchodilator treatment less often than once per week. One patient was known to have continuing symptoms of asthma after more than 4 years of avoidance of exposure, but his treatment requirements were not known.
RESULTS Patient details We were able to follow up 50 (89%) of the total 56 cases of IA. Twenty-five responded to an interviewer-administered questionnaire at hospital, nine responded to a postal questionnaire, and 13 responded by telephone. There was no response to questionnaire from six subjects although in three of these cases it was possible to obtain information from outpatient follow-up notes. Three died between the time of diagnosis and follow-up. There was no significant difference in outcome (in terms of treatment requirement) between those interviewed in hospital and those responding to questionnaire by telephone or post (Table I). There were 47 males and nine females, and their ages at diagnosis ranged from 23 to 62 years (mean 46.1). Thirty-nine per cent (20) of 51 patients tested at diagnosis were atopic. Twelve of the 50 seen at follow-up currently smoked cigarettes, 15 had never smoked and 23 were ex-smokers. At diagnosis, 32 patients had measurement of airway reactivity by inhalation testing with histamine. At follow-up, 21 patients had measurement of airway reactivity: 11 patients (not all from the 32 tested at diagnosis) had inhalation testing with histamine, and 19 were tested with cold air. Nine subjects were tested with both histamine and cold air. Work exposure Occupations of patients at the time of diagnosis are shown in Table II. The mean latent interval of exposure before the development of symptoms was 6.5 years (range 0.5-30). The mean period of symptomatic exposure was 2.7 years (range 0.5-9). Table 1. Method of questionnaire administration and outcome Treatment
at follow-up
Once per week or more often
Less than once per week
14 13
11 9
Type of questionnaire Interviewer administered Response by post or telephone
Chi squared 2.22 P>O.lO
In three caseswhere it was not possible to administer the questionnaire, information was obtained from the patients’ hospital notes.
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ASTHMA
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Table II. Occupations of patients at diagnosis; classification by type to exposure Printing and/or laminating of flexible packaging Polyurethane foam production Soldering and coil winding Paint manufacture or use Symthetic rubber manufacture (NDI) Indirect exposure (to TDI vapour emitted from adjacent factory) Other Total
Inhalation
27 8 5 5 3 3 5 56
tests at diagnosis
Zsocyanates. Twelve patients had positive inhalation tests to more than one type of isocyanate and consequently the total number of positive inhalation tests (70) was greater
than the study population (56). Measurement of di-isocyanate concentrations was made during 42 of the positive inhalation tests. The maximum atmospheric concentration of TDI ranged between an estimated 0.001-0.002 and 0.02 ppm (n=32). A concentration of 0.02 ppm was reached during only two tests. The range of concentrations of MD1 was between 0.001-0.002 and 0.02 ppm (n=lO). A concentration of 0.02 ppm was reached during only one test. The most frequent sensitizing isocyanate was TDI (45 patients, 64% of positive reactions), followed by MD1 (16 patients, 23% of positive reactions). The majority of reactions were late (28 patients, 40% of reactions) or dual (31 patients, 44% of reactions). An isolated immediate reaction occurred in only 9% of positive tests. Histamine. Sixteen of the 32 patients tested with histamine at diagnosis had bronchial hyper-reactivity. Outcome after diagnosis
At the time of follow-up, 4 years or more from the time of diagnosis, 412 (82% of the patients followed up) continued to have difficulty in breathing or chest tightness. In 19 (46%), this occurred more than once per week, and 22 (54%) required treatment at least once per week. The mean values of FEV, and FVC at follow-up indicate an obstructive ventilatory defect of similar degree to that at diagnosis (Table III). Of the 19 patients who had measurement of bronchial reactivity to cold air at follow-up, 12 were hyper-reactive. Five of the 11 patients who underwent inhalation testing with histamine at follow-up had bronchial hyper-reactivity. Of the total of 21 patients who were tested at follow-up, 14 demonstrated bronchial hyper-reactivity. Nine patients underwent inhalation tests with histamine at both diagnosis and followup: three were hyper-reactive at diagnosis of whom one was hyper-reactive at follow-up; three were hyper-reactive at follow-up of whom one had been hyper-reactive at diagnosis. In only one patient was it possible to calculate paired values of the provocative concentra-
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Table III. Lung function at diagnosis and one or more years later At diagnosis
One or more years later
FEV, (% predicted normal)
82.5 (+3.42)
78.0 (+3.69)
FVC (% predicted normal)
98.8 (+2.99)
96.4 (+2.61)
FEVJFVC (%)
63.1 (+1.97)
60.2 (+2.20)
Results are given asthe mean value reference 13.
+SEM,
n=38.
Predicted normal values from
tion of histamine causing a 10% fall in FEV,, since in the remainder one or both of the paired tests had produced a less than 10% fall in FEV,. Factors
associated
with a poor
outcome
At follow-up, bronchial hyper-reactivity to cold air was present in seven of eight patients tested in group 1 (who required treatment once per week or more often), and in five of 11
patients tested in group 2 (who required treatment less often than once per week). Table IV. Prognostic factors Group
Treatment at follow-up
1
Group 2
Once per week or more often 22
Less than once per week 27
Histamine Increased Normal
10 3
2 13
Chi squared=9.049 P
Isocyanate Immediate or dual Late
16 4
12 13
Chi squared=3.58 SO.10
77.1 (+5.3@ n=21
93.6 (+2.90) n=22
PCO.02
Number available Inhalation test reaction at diagnosis
FEV, (70 predicted at diagnosis
Meant-sEM
normal)
(unpaired t-test)
Details of treatment requirement at follow-up were available for 49 patients. In some of these, results of inhalation tests and/or lung function measurements were not available and the number of patients in each analysis is less than 49.
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Table V. Prognostic factors
Treatment at follow-up Number available Mean duration
of exposure
Group 1
Group 2
Once per week or more often 22
Less than once per week 27
(years+sEM)
Before onset of symptoms After onset of symptoms
6.8 (+1.31) n=22 3.0 (+0.76) n=21
5.17 (+1.26)
P>O.lO
n=26
2.19 (+0.54)
P>O.lO
n=26
(t-test) Atopy at diagnosis
Atopic Non-atopic Cigarette smoking
5 12
12 15
Chi squared=0.461 P>O. 10
3 11 7
9 10 8
P>O. 10
13 9
1.5 12
Chi squared=0.00172 P>O.lO
at follow-up
Current smoker Ex-smoker Non-smoker
Chi squared=2.402
Place of work after diagnosis
Same factory Left factory
Details of treatment requirement at follow-up were available for 49 patients. In some casesdetails relating to the prognostic factors listed above were not available and the total number of patients in the respective analyses is less than 49. More individuals diagnosis (RO.01).
in group 1 had bronchial hyper-reactivity to histamine at the time of More individuals in this group had an immediate reaction (either
isolated or as part of a dual reaction) than an isolated late reaction to inhalation testing with isocyanates at the time of diagnosis (Table IV). FEV, at diagnosis was significantly lower in this group (RO.02) ( mean FEV, 77.1% predicted normal) compared with the group requiring treatment less than once per week (mean FEV, 93.6% predicted normal) (Table IV). The duration of exposure before the onset of symptoms and the duration of continuing exposure after the onset of symptoms were longer in the group requiring more treatment at follow-up, but again the difference did not achieve statistical significance. There was a higher proportion of atopic individuals and cigarette smokers in the group with a better outcome, although in neither case did the difference achieve statistical significance (Table V). There was no difference in outcome between patients who were relocated at work, and
those who left the factory (Table V). All of the subgroup of 12 patients who developed asthma while exposed to TDI in one printing
factory
continued
to have symptoms of asthma despite avoidance of further
exposure. One patient died during a severe asthmatic episode one year after diagnosis, and the remaining 11 had symptoms of asthma at follow-up. Five (45% of those followed
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up) had symptoms once per week or more often, and seven (64%) took treatment this often. Six of these 12 patients were tested with cold air, and each demonstrated bronchial hyper-reactivity. DISCUSSION Isocyanates are widely used in industry in the manufacture and use of polyurethanes. Some 5% (6) to 15% (7) of those exposed in their work to isocyanates develop asthma, usually during the first year of exposure. The number in the United Kingdom at risk of developing asthma from this cause is unknown, but it has been estimated that in the United States between 50,000 and 100,000 persons are currently exposed in their work to isocyanates (8). The outcome of those who develop asthma from this cause is therefore a matter of some importance. Our aim in this study was to determine if asthma induced by inhaled isocyanates remits with avoidance of exposure. We were able to follow up 50 of a total of 56 patients in whom the diagnosis had been confirmed by inhalation testing with isocyanates and who had avoided further isocyanate exposure for at least 4 years. Asthmatic symptoms persisted in 41 of these 50 patients (82%), and were sufficiently frequent in about one-half to require treatment more than once per week. We found no evidence that those who had left employment in the factories where they had been exposed to isocyanates had subsequent isocyanate exposure and we observed no difference in outcome between those who were relocated at their original place of work and those who left the factory. In all cases controlled inhalation testing with isocyanates to which exposure occurred at work provoked an asthmatic reaction. It is unlikely that this represented an irritant response in individuals with previously increased airway reactivity; asthmatic reactions are not provoked by exposure to concentrations of TDI similar to those used in the present study in subjects with bronchial hyper-reactivity which has not been induced by isocyanates (9). Only two patients had ever had significant respiratory symptoms prior to exposure to isocyanates, and eight patients with bronchial hyper-reactivity to inhaled histamine (not from our group of 56) did not have an asthmatic reaction provoked by inhalation testing with isocyanates. Furthermore it has been shown that the relationship between the threshold concentration of isocyanate and histamine is weak, so that increased reactivity to isocyanates cannot be explained on the basis of non-specific bronchial reactivity (10). It seems very unlikely that the asthmatic reactions which followed controlled inhalation testing with isocyanates were a consequence of pre-existing bronchial hyper-reactivity and the persistence of symptoms cannot reasonably be explained as the continuation of asthma which was present before exposure to isocyanates. We were concerned that our study patients might not be representative of cases of isocyanate-induced asthma. Cases referred to a hospital may be from the more severely affected. Furthermore, those with continuing symptoms may be more likely than those without to be available for follow-up investigation, although this is not supported by the findings in our group (Table I). We examined a subgroup of 12 patients in our study population who were all employed in one printing factory and who probably represent all of those who developed asthma in this factory. The severity of their symptoms influenced neither their inclusion into the study nor their availability for follow-up. All had continu-
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ing symptoms when seen at follow-up, and more than half required treatment more than once per week. These results are comparable to those found in the total study group and suggest that our study population is not unrepresentative of cases of isocyanate asthma generally. In determining what factors might be associated with a poor outcome, patients were divided into two groups according to the frequency of treatment requirement at follow-up. It would have been more satisfactory to determine outcome on the basis of bronchial reactivity, but testing was possible in only 21 patients at follow-up. The greater prevalence of bronchial hyper-reactivity in the group requiring more treatment at follow-up provides some validation of our assessment of outcome on the basis of treatment requirement. Those with a poor outcome were more likely at the time of diagnosis to have bronchial hyper-reactivity to histamine, lower values of FEV, and an immediate reaction to inhalation testing with isocyanates. These results agree with those from Chan Yeung’s study of patients with occupational asthma due to western red cedar (11); poor outcome was associated with a greater degree of bronchial reactivity to histamine, more abnormal results of lung function studies, and a dual (rather than isolated late) reaction to inhalation testing with red cedar extract or plicatic acid at the time of diagnosis. An important factor which determined outcome in their study was duration of exposure after the development of asthma: those with evidence of continuing asthma had remained exposed for significantly longer. We also found that those with a poor outcome had on average remained longer in employment exposed to isocyanates; the difference was not significant at the 5% level, but the number examined in our study was smaller. Parkes comments that recovery from asthma due to isocyanates ‘commonly takes several days, occasionally as long as 10 weeks’ after leaving exposure (3). The results of Adam’s study (7) suggest that symptoms might continue after cessation of exposure in patients sensitized to TDI, but it was not stated if the patients had respiratory symptoms prior to exposure to isocyanates, and the diagnosis was not confirmed by inhalation testing. Paggiaro et al. (12) studied 12 patients with TDI asthma proven by inhalation testing and found that 2 years after cessation of exposure, 67% continued to have dyspnoea and wheezing. It was not stated whether these patients had respiratory symptoms prior to exposure to isocyanates, and the number of cases was too small to determine prognostic factors. Eighty-two per cent of the 50 patients we were able to follow up continued to have respiratory symptoms 4 or more years after avoidance of exposure, and approximately half of these required treatment at least once per week. Our results imply that a significant proportion of those with isocyanate-induced asthma are likely to have persisting symptoms for at least several years after exposure is avoided. The nature of the continuing asthma in these patients seems no different from asthma without an identifiable initiating cause. ACKNOWLEDGEMENTS We are grateful to Dr K. M. Venables for her advice on the preparation of the manuscript. REFERENCES 1. Harries MG, Burge PS, Samson M, Newman Taylor AJ, Pepys J. Isocyanate asthma: respiratory symptoms due to 1, 5naphthylene di-isocyanate. Thorax 1979; 34: 762-6.
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2. O’Brien IM, Harries MG, Burge PS, Pepys J. Toluene di-isocyanate induced asthma. I. Reactions to TDI, MD1 and histamine. Clin Allergy 1979; 9: 1-6. 3. Parkes RW. Occupational lung disorders. London: Butterworths and Co., 1982. 4. Medical Research Council. Questionnaire on respiratory symptoms. London: Publications Group, Medical Research Council, 1976. 5. Assoufi BK, Dally MB, Newman Taylor AJ, Denison DM. Cold air test: a simplified standard method for airway reactivity. Bull Eur Physiopath Resp 1986; 22: 349-57. 6. Butcher BT, Karr RM, O’Neil CE et al. Inhalation challenge and pharmacologic studies of toluene di-isocyanate (TDI) sensitive workers. J Allergy Clin Immunol 1979; 64: 146-52. 7. Adams WGF. Long term effects on the health of men engaged in the manufacture of tolylene di-isocyanate. Br J Ind Med 1975; 32: 72-8. 8. Occupational exposure to di-isocyanates. NIOSH Criteria Document for a Recommended Standard. Publication no. 78-215. Washington, DC: US Department of Health, Education and Welfare, 1978: 18. 9. Chester EH, Marinez-Catinchi FL, Schwartz HJ et al. Patterns of airway reactivity to asthma produced by exposure to toluene di-isocyanate. Chest 1979; 75 (supplement): 229-31. 10. Burge PS. Non-specific bronchial hyperreactivity in workers exposed to toluene di-isocyanate, diphenyl methane di-isocyanate and colophony. Eur J Resp Dis 1982; 63 (supplement 123): 91-6. 11. Chan-Yeung M, Lam S, Koener S. Clinical features and natural history of occupational asthma due to western red cedar (Thuja plicata). Am J Med 1982; 72: 411-15. 12. Paggiaro PL, Loi AM, Rossi 0 et al. Follow-up study of patients with respiratory diseasedue to toluene diisocyanate (TDI). Clin Allergy 1984; 14; 463-9. 13. Cotes JE. Lung function. Oxford: Blackwell Scientific Publications, 1979: 369-80.
Date accepted 7 May 1986
OUTCOME
OF ASTHMA ISOCYANATES
INDUCED
BY
S. LOZEWICZ, B. K. ASSOUFI, R. HAWKINS AND A. J. NEWMAN TAYLOR Department
of Occupational London
Medicine, Brompton SW3 6HP
Hospital,
Summary
Isocyanates are widely used in industry for the manufacture of polyurethanes. Although they are recognized as an important cause of occupational asthma, it is unclear whether asthma persists after avoidance of exposure. We have followed up 50 cases, all of whom had avoided exposure for at least 4 years. At follow-up, 82% continued to have respiratory symptoms and approximately half of these required treatment at least once per week. These results indicate that a significant proportion of those with isocyanate-induced asthma are likely to have persisting symptoms for at least several years after exposure is avoided. INTRODUCTION Isocyanates are important causes of occupational asthma (l-3). It is unclear if avoidance of exposure to isocyanates leads to remission of asthma. We have followed up a group of patients with isocyanate-induced asthma, diagnosed by inhalation testing, who have subsequently avoided further exposure for at least 4 years. Not all patients who had measurement of bronchial reactivity at diagnosis were available for testing at follow-up and we have studied outcome using questionnaire assessment of symptoms of asthma and treatment requirement in addition to measurement of bronchial reactivity in those available for testing. Methods
A total of 56 cases of isocyanate-induced asthma (IA) were diagnosed at the Brompton Hospital between 1971 and 1979, of whom we followed up 50 (89%). In each case: 1. Symptoms of asthma had developed after exposure to isocyanates. Two caseshad histories of asthma preceding occupational exposure to isocyanates. One was a man who had persistent asthma between the ages of 5 and 16 years after which he only wheezed at times of respiratory tract infections. His first severe attack followed occupational exposure to TDI at the age of 32. The other was a woman who had been told that she had asthma as a child but who had no recollection of childhood respiratory symptoms. 2. Inhalation testing with the isocyanate(s) used at work reproducibly provoked an asthmatic reaction.
LOZEWICZ,
ASSOUFI,
HAWKINS
ET AL.:
ISOCYANATE-INDUCED
ASTHMA
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3. Exposure to isocyanates had been avoided for at least 4 years. Some remained in the same factory but were relocated to an area not using isocyanates or the use of isocyanates was discontinued. Others left the factory to work elsewhere. At the time of diagnosis measurements were made of lung function and, in some cases, bronchial reactivity to histamine. At the time of follow-up patients answered an interviewer-administered modified Medical Research Council respiratory questionnaire (4). Where possible, those unable to attend the hospital were interviewed by telephone or postal questionnaire. The presence of continuing symptoms was assessedby asking patients whether they still had chest tightness or difficulty in breathing. Patients who were able to attend at follow-up also had lung function tests and measurement of bronchial reactivity to inhaled histamine or cold air. The proportion of the study population attending for lung function at outpatient follow-up became lesswith increasing time from diagnosis; in order to increase the number of lung function test results available for analysis, we included the results of tests made after a period of less than 4 years from diagnosis. Thirty-eight patients had measurements of lung function made both at diagnosis and one or more years later when attending for outpatient followup. The numbers of these 38 subjects providing their most recent results of lung function studies at given intervals from diagnosis are shown below: l-2 years: 3 2-3 years: 9 PI years: 8 4+ years: 18 A subgroup of 12 patients who developed asthma while exposed to TDI in one printing factory was analysed separately. These patients probably represent all the caseswhich developed in this factory. Lung function
tests
Forced expiratory volume in one second (FEV,) and forced vital capacity (FVC) were measured using a regularly calibrated dry wedge spirometer (Vitalograph). Inhalation
testing
Isocyanates. Single-blind occupational type inhalation tests were made with toluene di-isocyanate (TDI), diphenylmethane di-isocyanate (MDI), hexamethylene di-isocyanate (HDI), and naphthylene di-isocyanate (NDI). The methods used for inhalation testing and measurement of atmospheric concentrations of TDI and MD1 have been described previously (1, 2). Histamine. Airway reactivity to histamine was measured by the method of de Vries (1960) as modified by O’Brien et al. (2). A fall in FEV, of 10% obtained with this method was taken to indicate the presence of bronchial hyper-reactivity. lsocapnic hyperventilation of cold air (IHCA). The method used was that of Assoufi et al. (5). Using this test, asthmatic but not normal subjects demonstrate a fall in FEV, of IO%, which was taken to indicate the presence of bronchial hyper-reactivity in the present study. Skin prick
tests
Skin prick tests were made with a control solution and extracts of common inhalant allergens, grass pollen, Aspergillus fumigatus, cat hair, dog hair, house dust, and Dermatophagoidespteronyssinus (Bencard). A positive reaction was defined as a weal diameter of 3 mm or more greater than that provoked by the control solution. Atopy was regarded as present when one or more positive reactions was elicited. Assessment of outcome
Assessment of outcome was based on answers to the questions relating to treatment requirement and symptoms of asthma in addition to measurements of lung function and airway reactivity. Patients
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were regarded as having symptoms of asthma if they had chest tightness or difficulty with breathing. Treatment included inhaled or oral bronchodilators, inhaled disodium cromoglycate, and inhaled or oral corticosteroids. In order to investigate which factors might be associated with a poor outcome, patients were divided into two groups in relation to frequency of treatment requirement at followup: Group 1: 22 patients who required any of the above treatments once per week or more often. Group 2: 27 patients who required only bronchodilator treatment less often than once per week. One patient was known to have continuing symptoms of asthma after more than 4 years of avoidance of exposure, but his treatment requirements were not known.
RESULTS Patient details We were able to follow up 50 (89%) of the total 56 cases of IA. Twenty-five responded to an interviewer-administered questionnaire at hospital, nine responded to a postal questionnaire, and 13 responded by telephone. There was no response to questionnaire from six subjects although in three of these cases it was possible to obtain information from outpatient follow-up notes. Three died between the time of diagnosis and follow-up. There was no significant difference in outcome (in terms of treatment requirement) between those interviewed in hospital and those responding to questionnaire by telephone or post (Table I). There were 47 males and nine females, and their ages at diagnosis ranged from 23 to 62 years (mean 46.1). Thirty-nine per cent (20) of 51 patients tested at diagnosis were atopic. Twelve of the 50 seen at follow-up currently smoked cigarettes, 15 had never smoked and 23 were ex-smokers. At diagnosis, 32 patients had measurement of airway reactivity by inhalation testing with histamine. At follow-up, 21 patients had measurement of airway reactivity: 11 patients (not all from the 32 tested at diagnosis) had inhalation testing with histamine, and 19 were tested with cold air. Nine subjects were tested with both histamine and cold air. Work exposure Occupations of patients at the time of diagnosis are shown in Table II. The mean latent interval of exposure before the development of symptoms was 6.5 years (range 0.5-30). The mean period of symptomatic exposure was 2.7 years (range 0.5-9). Table 1. Method of questionnaire administration and outcome Treatment
at follow-up
Once per week or more often
Less than once per week
14 13
11 9
Type of questionnaire Interviewer administered Response by post or telephone
Chi squared 2.22 P>O.lO
In three caseswhere it was not possible to administer the questionnaire, information was obtained from the patients’ hospital notes.
LOZEWICZ,
ASSOUFI,
HAWKINS
ET AL.:
ISOCYANATE-INDUCED
ASTHMA
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Table II. Occupations of patients at diagnosis; classification by type to exposure Printing and/or laminating of flexible packaging Polyurethane foam production Soldering and coil winding Paint manufacture or use Symthetic rubber manufacture (NDI) Indirect exposure (to TDI vapour emitted from adjacent factory) Other Total
Inhalation
27 8 5 5 3 3 5 56
tests at diagnosis
Zsocyanates. Twelve patients had positive inhalation tests to more than one type of isocyanate and consequently the total number of positive inhalation tests (70) was greater
than the study population (56). Measurement of di-isocyanate concentrations was made during 42 of the positive inhalation tests. The maximum atmospheric concentration of TDI ranged between an estimated 0.001-0.002 and 0.02 ppm (n=32). A concentration of 0.02 ppm was reached during only two tests. The range of concentrations of MD1 was between 0.001-0.002 and 0.02 ppm (n=lO). A concentration of 0.02 ppm was reached during only one test. The most frequent sensitizing isocyanate was TDI (45 patients, 64% of positive reactions), followed by MD1 (16 patients, 23% of positive reactions). The majority of reactions were late (28 patients, 40% of reactions) or dual (31 patients, 44% of reactions). An isolated immediate reaction occurred in only 9% of positive tests. Histamine. Sixteen of the 32 patients tested with histamine at diagnosis had bronchial hyper-reactivity. Outcome after diagnosis
At the time of follow-up, 4 years or more from the time of diagnosis, 412 (82% of the patients followed up) continued to have difficulty in breathing or chest tightness. In 19 (46%), this occurred more than once per week, and 22 (54%) required treatment at least once per week. The mean values of FEV, and FVC at follow-up indicate an obstructive ventilatory defect of similar degree to that at diagnosis (Table III). Of the 19 patients who had measurement of bronchial reactivity to cold air at follow-up, 12 were hyper-reactive. Five of the 11 patients who underwent inhalation testing with histamine at follow-up had bronchial hyper-reactivity. Of the total of 21 patients who were tested at follow-up, 14 demonstrated bronchial hyper-reactivity. Nine patients underwent inhalation tests with histamine at both diagnosis and followup: three were hyper-reactive at diagnosis of whom one was hyper-reactive at follow-up; three were hyper-reactive at follow-up of whom one had been hyper-reactive at diagnosis. In only one patient was it possible to calculate paired values of the provocative concentra-
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Table III. Lung function at diagnosis and one or more years later At diagnosis
One or more years later
FEV, (% predicted normal)
82.5 (+3.42)
78.0 (+3.69)
FVC (% predicted normal)
98.8 (+2.99)
96.4 (+2.61)
FEVJFVC (%)
63.1 (+1.97)
60.2 (+2.20)
Results are given asthe mean value reference 13.
+SEM,
n=38.
Predicted normal values from
tion of histamine causing a 10% fall in FEV,, since in the remainder one or both of the paired tests had produced a less than 10% fall in FEV,. Factors
associated
with a poor
outcome
At follow-up, bronchial hyper-reactivity to cold air was present in seven of eight patients tested in group 1 (who required treatment once per week or more often), and in five of 11
patients tested in group 2 (who required treatment less often than once per week). Table IV. Prognostic factors Group
Treatment at follow-up
1
Group 2
Once per week or more often 22
Less than once per week 27
Histamine Increased Normal
10 3
2 13
Chi squared=9.049 P
Isocyanate Immediate or dual Late
16 4
12 13
Chi squared=3.58 SO.10
77.1 (+5.3@ n=21
93.6 (+2.90) n=22
PCO.02
Number available Inhalation test reaction at diagnosis
FEV, (70 predicted at diagnosis
Meant-sEM
normal)
(unpaired t-test)
Details of treatment requirement at follow-up were available for 49 patients. In some of these, results of inhalation tests and/or lung function measurements were not available and the number of patients in each analysis is less than 49.
LOZEWICZ.
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19
Table V. Prognostic factors
Treatment at follow-up Number available Mean duration
of exposure
Group 1
Group 2
Once per week or more often 22
Less than once per week 27
(years+sEM)
Before onset of symptoms After onset of symptoms
6.8 (+1.31) n=22 3.0 (+0.76) n=21
5.17 (+1.26)
P>O.lO
n=26
2.19 (+0.54)
P>O.lO
n=26
(t-test) Atopy at diagnosis
Atopic Non-atopic Cigarette smoking
5 12
12 15
Chi squared=0.461 P>O. 10
3 11 7
9 10 8
P>O. 10
13 9
1.5 12
Chi squared=0.00172 P>O.lO
at follow-up
Current smoker Ex-smoker Non-smoker
Chi squared=2.402
Place of work after diagnosis
Same factory Left factory
Details of treatment requirement at follow-up were available for 49 patients. In some casesdetails relating to the prognostic factors listed above were not available and the total number of patients in the respective analyses is less than 49. More individuals diagnosis (RO.01).
in group 1 had bronchial hyper-reactivity to histamine at the time of More individuals in this group had an immediate reaction (either
isolated or as part of a dual reaction) than an isolated late reaction to inhalation testing with isocyanates at the time of diagnosis (Table IV). FEV, at diagnosis was significantly lower in this group (RO.02) ( mean FEV, 77.1% predicted normal) compared with the group requiring treatment less than once per week (mean FEV, 93.6% predicted normal) (Table IV). The duration of exposure before the onset of symptoms and the duration of continuing exposure after the onset of symptoms were longer in the group requiring more treatment at follow-up, but again the difference did not achieve statistical significance. There was a higher proportion of atopic individuals and cigarette smokers in the group with a better outcome, although in neither case did the difference achieve statistical significance (Table V). There was no difference in outcome between patients who were relocated at work, and
those who left the factory (Table V). All of the subgroup of 12 patients who developed asthma while exposed to TDI in one printing
factory
continued
to have symptoms of asthma despite avoidance of further
exposure. One patient died during a severe asthmatic episode one year after diagnosis, and the remaining 11 had symptoms of asthma at follow-up. Five (45% of those followed
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up) had symptoms once per week or more often, and seven (64%) took treatment this often. Six of these 12 patients were tested with cold air, and each demonstrated bronchial hyper-reactivity. DISCUSSION Isocyanates are widely used in industry in the manufacture and use of polyurethanes. Some 5% (6) to 15% (7) of those exposed in their work to isocyanates develop asthma, usually during the first year of exposure. The number in the United Kingdom at risk of developing asthma from this cause is unknown, but it has been estimated that in the United States between 50,000 and 100,000 persons are currently exposed in their work to isocyanates (8). The outcome of those who develop asthma from this cause is therefore a matter of some importance. Our aim in this study was to determine if asthma induced by inhaled isocyanates remits with avoidance of exposure. We were able to follow up 50 of a total of 56 patients in whom the diagnosis had been confirmed by inhalation testing with isocyanates and who had avoided further isocyanate exposure for at least 4 years. Asthmatic symptoms persisted in 41 of these 50 patients (82%), and were sufficiently frequent in about one-half to require treatment more than once per week. We found no evidence that those who had left employment in the factories where they had been exposed to isocyanates had subsequent isocyanate exposure and we observed no difference in outcome between those who were relocated at their original place of work and those who left the factory. In all cases controlled inhalation testing with isocyanates to which exposure occurred at work provoked an asthmatic reaction. It is unlikely that this represented an irritant response in individuals with previously increased airway reactivity; asthmatic reactions are not provoked by exposure to concentrations of TDI similar to those used in the present study in subjects with bronchial hyper-reactivity which has not been induced by isocyanates (9). Only two patients had ever had significant respiratory symptoms prior to exposure to isocyanates, and eight patients with bronchial hyper-reactivity to inhaled histamine (not from our group of 56) did not have an asthmatic reaction provoked by inhalation testing with isocyanates. Furthermore it has been shown that the relationship between the threshold concentration of isocyanate and histamine is weak, so that increased reactivity to isocyanates cannot be explained on the basis of non-specific bronchial reactivity (10). It seems very unlikely that the asthmatic reactions which followed controlled inhalation testing with isocyanates were a consequence of pre-existing bronchial hyper-reactivity and the persistence of symptoms cannot reasonably be explained as the continuation of asthma which was present before exposure to isocyanates. We were concerned that our study patients might not be representative of cases of isocyanate-induced asthma. Cases referred to a hospital may be from the more severely affected. Furthermore, those with continuing symptoms may be more likely than those without to be available for follow-up investigation, although this is not supported by the findings in our group (Table I). We examined a subgroup of 12 patients in our study population who were all employed in one printing factory and who probably represent all of those who developed asthma in this factory. The severity of their symptoms influenced neither their inclusion into the study nor their availability for follow-up. All had continu-
LOZEWICZ,
ASSOUFI,
HAWKINS
ET AL.:
ISOCYANATE-INDUCED
ASTHMA
21
ing symptoms when seen at follow-up, and more than half required treatment more than once per week. These results are comparable to those found in the total study group and suggest that our study population is not unrepresentative of cases of isocyanate asthma generally. In determining what factors might be associated with a poor outcome, patients were divided into two groups according to the frequency of treatment requirement at follow-up. It would have been more satisfactory to determine outcome on the basis of bronchial reactivity, but testing was possible in only 21 patients at follow-up. The greater prevalence of bronchial hyper-reactivity in the group requiring more treatment at follow-up provides some validation of our assessment of outcome on the basis of treatment requirement. Those with a poor outcome were more likely at the time of diagnosis to have bronchial hyper-reactivity to histamine, lower values of FEV, and an immediate reaction to inhalation testing with isocyanates. These results agree with those from Chan Yeung’s study of patients with occupational asthma due to western red cedar (11); poor outcome was associated with a greater degree of bronchial reactivity to histamine, more abnormal results of lung function studies, and a dual (rather than isolated late) reaction to inhalation testing with red cedar extract or plicatic acid at the time of diagnosis. An important factor which determined outcome in their study was duration of exposure after the development of asthma: those with evidence of continuing asthma had remained exposed for significantly longer. We also found that those with a poor outcome had on average remained longer in employment exposed to isocyanates; the difference was not significant at the 5% level, but the number examined in our study was smaller. Parkes comments that recovery from asthma due to isocyanates ‘commonly takes several days, occasionally as long as 10 weeks’ after leaving exposure (3). The results of Adam’s study (7) suggest that symptoms might continue after cessation of exposure in patients sensitized to TDI, but it was not stated if the patients had respiratory symptoms prior to exposure to isocyanates, and the diagnosis was not confirmed by inhalation testing. Paggiaro et al. (12) studied 12 patients with TDI asthma proven by inhalation testing and found that 2 years after cessation of exposure, 67% continued to have dyspnoea and wheezing. It was not stated whether these patients had respiratory symptoms prior to exposure to isocyanates, and the number of cases was too small to determine prognostic factors. Eighty-two per cent of the 50 patients we were able to follow up continued to have respiratory symptoms 4 or more years after avoidance of exposure, and approximately half of these required treatment at least once per week. Our results imply that a significant proportion of those with isocyanate-induced asthma are likely to have persisting symptoms for at least several years after exposure is avoided. The nature of the continuing asthma in these patients seems no different from asthma without an identifiable initiating cause. ACKNOWLEDGEMENTS We are grateful to Dr K. M. Venables for her advice on the preparation of the manuscript. REFERENCES 1. Harries MG, Burge PS, Samson M, Newman Taylor AJ, Pepys J. Isocyanate asthma: respiratory symptoms due to 1, 5naphthylene di-isocyanate. Thorax 1979; 34: 762-6.
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2. O’Brien IM, Harries MG, Burge PS, Pepys J. Toluene di-isocyanate induced asthma. I. Reactions to TDI, MD1 and histamine. Clin Allergy 1979; 9: 1-6. 3. Parkes RW. Occupational lung disorders. London: Butterworths and Co., 1982. 4. Medical Research Council. Questionnaire on respiratory symptoms. London: Publications Group, Medical Research Council, 1976. 5. Assoufi BK, Dally MB, Newman Taylor AJ, Denison DM. Cold air test: a simplified standard method for airway reactivity. Bull Eur Physiopath Resp 1986; 22: 349-57. 6. Butcher BT, Karr RM, O’Neil CE et al. Inhalation challenge and pharmacologic studies of toluene di-isocyanate (TDI) sensitive workers. J Allergy Clin Immunol 1979; 64: 146-52. 7. Adams WGF. Long term effects on the health of men engaged in the manufacture of tolylene di-isocyanate. Br J Ind Med 1975; 32: 72-8. 8. Occupational exposure to di-isocyanates. NIOSH Criteria Document for a Recommended Standard. Publication no. 78-215. Washington, DC: US Department of Health, Education and Welfare, 1978: 18. 9. Chester EH, Marinez-Catinchi FL, Schwartz HJ et al. Patterns of airway reactivity to asthma produced by exposure to toluene di-isocyanate. Chest 1979; 75 (supplement): 229-31. 10. Burge PS. Non-specific bronchial hyperreactivity in workers exposed to toluene di-isocyanate, diphenyl methane di-isocyanate and colophony. Eur J Resp Dis 1982; 63 (supplement 123): 91-6. 11. Chan-Yeung M, Lam S, Koener S. Clinical features and natural history of occupational asthma due to western red cedar (Thuja plicata). Am J Med 1982; 72: 411-15. 12. Paggiaro PL, Loi AM, Rossi 0 et al. Follow-up study of patients with respiratory diseasedue to toluene diisocyanate (TDI). Clin Allergy 1984; 14; 463-9. 13. Cotes JE. Lung function. Oxford: Blackwell Scientific Publications, 1979: 369-80.
Date accepted 7 May 1986