- Email: [email protected]
Sensitivity and specificity of PC20 and peak expiratory flow rate in cedar asthma
Sensitivity expiratory Johanne
and specificity of PC,, and peak flow rate in cedar asthma
C&6, MD,* Susann
Ste-Foy, Quebec, and Vancouver,
Kennedy, British
PhD, and Moira Chan-Yeung,
Columbia,
MB
Canada
The diagnosis of red cedar asthma is usually confirmed by a specihc challenge with plicatic acid, the compound responsible for the disease. We performed this study to determine the sensitivity and specijcity of two other diagnostic tests, prolonged recording of peak expiratory flow rate (PEFR) and measurement of bronchial responsiveness (provocative dose of methacholine causing a 20% fall in FEV, [PC,, methacholine]). Twenty-three patients with suspected cedar asthma participated in the study. The patients recorded PEFR during 2 weeks away from work and 3 weeks at work. PC,, was measured both at the end of the nonworking and working period. An obvious decrease in PEFR in 2 of 3 working weeks, when PEFRs of weekends or holidays were compared (by visual inspection of the PEFR recording), and a decrease in PC,, by more than a twofold dilution, when the patient returned to work, were considered as positive tests for cedar asthma. Plicatic acid challenge test was performed at the end of the study; 14 patients reacted, whereas nine patients did not. With the results of the plicatic acid challenge test as the gold standard, the sensitivity and specificity of PEFR recordings were 84% and 89%; changes in PC,,, 62% and 78%; and 93% and 45% for a positive clinical history. The combination of PEFR and clinical history revealed a 100% sensitivity with a 45% spectficity. Combination of PEFR and PC,, did not improve the diagnostic accuracy. We conclude (1) that the speciftc challenge with plicatic acid is not necessary when both clinical history and PEFR are negative, (2) that, if either the history or PEFR is positive for occupational asthma, the plicatic acid test must be done to rule out false positive cases, and (3) serial measurement of PC,, methacholine is not a valuable test in cedar asthma. (J ALLERGY CUNIMMUNOL
1990;85:592-8.)
In the diagnosis of occupational asthma, specific inhalation challenge testshave often beenusedto confirm the causal relationship between exposure to the offending agent and the respiratory symptoms.’ Very often, such well-standardized, specific challenge tests cannot be performed for various reasons. (1) The offending agent in the workplace has not yet been identified. (2) Facilities and trained personnelare not avail-
From the Respiratory Division, Department of Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada. Supported by the Workers’ Compensation Board of British Columbia. Received for publication Jan. 30, 1989. Revised Aug. 21, 1989. Accepted for publication Oct. 4, 1989. Reprint requests:JohanneC&e, MD, Centrede Pneumologie,Hopital Laval, 2725 Chemin Ste-Roy,QuCbec,CanadaGlV 4G5. *Johanne C&e, MD, is a recipient of a scholarship from the Canadian Lung Association and the QuebecHealth ResearchFoundation. l/1/17557
592
Abbreviations used PC,: Provocativeconcentrationof
methacholine inducinga 20%drop in FEW, PEFR: Peakexpiratoryflow rate
able. (3) Specific challenge test can sometimesinduce a very severeattack of asthma, especially when the air concentration of the offending agent cannot be monitored. In fact, one deathhasbeenreportedduring a specific challenge test with isocyanates.* The diagnostic value of a change in FEV, during one work shift has been assessedpreviously and was found to be a poor diagnostic test for occupational asthma.3Prolonged recording of PEFB at work and away from work was initially proposed by Burge et al.4s5 as a valuable diagnostic test in occupational asthma. These investigators demonstratedthat false negative results with PBFR recording can occur, especially when the patientswere taking inhaled steroids
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or cromoglycate.4 In these studies,4. 5 the sensitivity and specificity of PEFR were calculated with a positive clinical history or a positive specific challenge test as the gold standard for occupational asthma. There are several studies of a decrease in bronchial responsiveness in patients with occupational asthma after a period away from the offending agent or an increase in bronchial responsiveness after resuming exposure to the offending agent.6-9Similar changes in bronchial responsiveness have been observed in patients with asthma and ragweed sensitization during the seasonal pollen exposure. ‘OVery little information exists about the sensitivity and specificity of this test in the diagnosis of occupational asthma. It has been suggested that a combination of prolonged recording of PEFR and serial measurements of bronchial responsiveness during periods at work and away from work could be very useful in the confirmation of the diagnosis of occupational asthma. ‘I In this study, we assessed the sensitivity (ratio of the number of patients with a positive test to the number of patients with cedar asthma) and specificity (ratio of the number of patients with a negative test to the number of patients without cedar asthma) of prolonged recording of PEFR, changes in bronchial responsiveness, and clinical history, individually or in combination, in the diagnosis of red cedar asthma with the specific challenge test with plicatic acid as the “gold standard .‘I MATERIAL AND METHODS Study design Patients were enrolled in the study at the time of their first consultation for occupational asthma at our occupational health unit. All the patients were questioned by the same physician with special inquiries about the presenceof cough, attacks of shortness of breath, and wheezing, the improvement of these symptoms on weekends and long holidays, and the time of onset of these symptoms. The patients recorded their PEFR during 3 weeks at work and 2 weeks away from work. They could either begin by recording their PEFR away from work first, followed by at work, or vice versa, whichever schedule was the most convenient for a given patient. Measurement of bronchial responsiveness (PC,, methacholine) was done on two occasions at approximately the same hour of the day: at the end of the 3 working weeks and at the end of the 2 weeks away from work.
Subjects Twenty-seven consecutive patients participated in this study on a voluntary basis. All the patients were referred to our occupational health unit by their family physicians for respiratory complaints related to work. All the patients were working in sawmills processing western red cedar. All
the workers were asked to keep their antiasthma medications constant throughout the study. Four patients did not com-
plete the study. In three patients, the asthmasymptomswere too severe for them to record PEFR during 3 weeks of work, and another patient forgot to record PEFR while the patient was away on holiday.
Method PEH?. Each patient was provided with a mini-Wright peak flow meter with detailed instructions concerning its proper use. The method of PEFR recording was checked after 1 week of recording. The patients were asked to record their PEFR at least on six occasions during the day: on waking up, during their two coffee breaks, lunch, dinner, and bedtime. On each occasion, they were asked to blow three times into the peak flow meter and to record all readings. Only the best of the three attempts w-as kept fat analysis. Methucholine challenge test. This test was performed with our own protocol as previously described. ” The patients were asked to stop using inhaled salbutamol for 8 hours and methylxanthines for 24 hours. hrhaied steroids could be continued. The test was performed only if the patient’s baseline FEV, was >60% of predicted value and the drop in FEV, after saline inhalation was < 158’. Baseline FEV, and FVC were measured until three reproducible values within 5% were obtained with a Collins 13.5 L watersealed spirometer (Warren E. Collins. Braintree, Mass.). The test solutions were delivered with a Bennett-Twin nebulizer, which has an output of 0.22 ml/min at an oxygen flow rate of 7 Limin. The particle size has a mass-median diameter of 3.1 km. The patients were asked to breathe the aerosol at tidal volume via a face mask loosely applied over the nose and mouth. The first solution to be inhaled was phosphate-buffered saline that served as a control solution, and this solution was followed by twofold increasing concentrations of methacholine from 0.03 to 64 mgiml at 5minute intervals. Each solution was inhaled by the subjects for 2 minutes followed by measurement of FEV, at 30 seconds and 3 minutes. The procedure continued until the FEV , had fallen by at least 20% below the lowest postsaline value or until the highest concentration had been reached. The PC2, methacholine (concentration of methachohne eliciting a 20% fall of the lowest postsaline value) was obtained from interpolation of the noncumulative dose-response curve on a semilogarithmic scale. For the one patient in whom this test could not be done (> 15% decrease in FEV, after saline inhalation), PC, was arbitrarily assigned the value of 0.03 mg/ml. Specific inhalation challenge test. Phcatic acid, the compound responsible for red cedar asthma, was used for specific challenge test with the method described previously. ” Antiasthma medications were withdrawn as for the methacholine test with the exception that inhaled steroids were also stopped 12 hours before the test. Baseline FEV, and FVC were measured until three reproducible values had been obtained. On the first day, phosphate-buffered saline was inhaled for 2 minutes, and FEV, was measured at 30 seconds and IO, 20, 30, and 60 minutes after inhalation. Thereafter,
594 C&g et al.
TABLE I. Characteristics
J. ALLERGY
of the reactors
and nonreactors
Age (yr) mean ? SEM Smoking habits Nonsmokers Exsmokers Current smokers Past history of asthma Duration of exposure to cedar dust (yr) mean ? SEM Symptom duration before initial visit (mo) mean + SEM Antiasthma medication used No medication Inhaled salbutamol only Inhaled salbutamol and steroids Inhaled salbutamol, steroids, and oral methylxanthines No. of holiday weeks taken mean ?SEM
to plicatic
CLIN. IMMUNOL. MARCH 1990
acid
Reactors (N = 14)
Nonreactors (N = 9)
38 2 3
36 r 2
13 (92%) 1 (8%) 0 (0%) 0 (0%) 6?2
8 (89%) 1 (11%) 0 (0%) 2 (22%) 8?2
21 + 8
36 f
0 9 4 1
3 1 3 2
(0%) (64%)* (29%) (7%)
4.5 + 0.8
13
(33%) (11%) (33%) (23%)
3.8 k 1.2
*Difference statistically significant by Fisher’s exact test at p < 0.05 for plicatic acid reactorscomparedto nonreactors.
FEV, was measured hourly for 7 hours. The patient then left the laboratory and continued measuring PEFR hourly up to bedtime, and at night, if awakened by shortness of breath. On the second day, plicatic acid, 5 mg/ml, was administered by inhalation initially for 30 seconds and was then followed by measurement of FEV, at 30 seconds and 10 minutes. Thereafter, the inhalation of plicatic acid was repeated for 1 minute, 1 minute and 30 seconds, 2 minutes, and an additional 2 minutes, at lo-minute intervals until a total of 7 minutes of inhalation had been administered to the patient or when a drop in FEV, of 15% from the lowest postsaline value was observed. After the patient’s last inhalation of plicatic acid, FEV, was measured at 10, 20, 30, and 60 minutes and then hourly for 7 hours. Thereafter, PEFR was recorded after the same schedule as described above for the control day. The patient was observed 24 hours later in the laboratory for measurement of FEV,.
Data analysis Medical questionnaire. The patient was considered to have occupational asthma if he had no previous history of asthma before exposure to red cedar dust and if his cough, wheezing, or attacks of shortness of breath improved on weekends or on long holidays. F/W,. A decrease in prebronchodilator FEV, (expressed as percent of predicted with the predicted formula of Morris et al.“) of >5% from holidays to working days was considered significaiit. PEH?. The six daily PEFR readings from each patient were all plotted on a graph for the whole study period with days at work clearly identified and were then visually analyzed by three physicians unaware of the results of the specific challenge test. When two of three physicians agreed
that the PEFR graph demonstrated a work relationship in 2 of 3 weeks recorded at work, the worker was considered to be positive for occupational asthma.‘* The graph was considered to have a positive “weekend pattern” if, in 2 of 3 working weeks, the PEFRs observed during working days were on average lower than PEFRs observed on weekends. The graph was considered to have a “week-to-week” pattern if, in 2 of 3 working weeks, the PEFRs were much lower than PEFRs on holidays without significant improvement on weekends. The mean PEFR values were calculated for the 15 working days, the 6 weekend days, and the 14 holidays with the six best readings for each day. Methacholine challenge test. If the PC, methacholine measured at the end of 3 working weeks was decreased from PC, measured at the end of holidays by more than twofold, the metbacholine response was considered to have changed significantly.‘* Plicatic acid challenge test. The plicatic acid test was considered positive if the patient’s lowest FEV, after plicatic acid challenge was < 15% of the value recorded at the same hour on the control day with saline. Sensitivity (percent of patients with cedar asthma with a positive test) and specificity (percent of patients without cedar asthma with a negative test) of PEFR recording, changes in PC, methacholine, FEV, changes, and clinical history were determined with the results of the specific challenge test with plicatic acid as the “gold standard” for cedar asthma.
Statistical
analysis
For comparisons within one group, statistical analysis was performed with Student’s paired t tests for normally distributed data.16 Comparisons of the means between two
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TABLE II. Differences
between
P&,
FEV,, and PEFR recorded
value of PEFR arx! PC,,
595
at work and away from work __l.--___-.---_
Reactors Mean -c SEM
Nonreactors (N = 9) ~l_.--l_-Mean f SEM
0.9 k 1.9 1.8 t 1.7t
3.5 I: z.>: 4.Q ‘- I ‘i
(N = 14)
PC, methacholine (mg/ml)* End of working period End of holiday period FEV,, % predicted End of working period End of holiday period Mean PEFR (L/min) Working period Monday to Friday Saturday and Sunday Holiday period
87.0 t 6.1 102.0 -c 5. It
508 * 22$ 556 r 20 564 -+ 23
107.0 tr 3.0 109.6 -3: 4.4
494 2 278 497 rt 26 509 + 28 ____-
*Geometric mean 2 geometric SEM. tDifference between the value recorded at work and the value on holidays statistically significant by Student’s paired f test at p < 0.01. SDifference between values recordedat work (Monday to Friday) and on weekendsor long holidays statistically significant by Student’s paired t test at p < 0.0 I. lDifference between PEFR values of nonreactorsand of reactors statistically significant by Student’s unpaired r test at p s: 0.01
groupsweremadewith Student’sunpairedr testfor normally distributeddata,andthe Mann-Whitneynonparametric test for datahavinga nonnormaldistribution.16 Finally, theFisher’s exacttestwasusedto compareratiosbetweenthe two groupsof patients.
day to Friday) from those recorded on weekendsof the 3 working weeks or long holidays. The mean PEFRsrecordedon long holidays were not higher than the mean PEFRsrecorded on weekendsin this group of patients. Overall, nonreactorsto plicatic acid had lower PEFRsthan reactors. However, nonreactorsto RESULTS plicatic acid demonstratedno difference between the Of the twenty-three male patients who participated mean PEFRsrecorded at work, on weekends,and on in the study, 14 demonstrateda positive reaction to long holidays. Of the 14 reactorsto plicatic acid, 12 plicatic acid challenge and nine patients did not. demonstrated a positive PEFR pattern (compatible with the diagnosis of occupational asthma).Eleven of Among the nine patients who did not react to plicatic thesepatientshad the “weekend pattern,” asillustrated acid, there were four patients with PC,, < 1 mg/ml. As presentedin Table I, the reactorsand nonreactors in Fig. 1. The remaining patient had the “week-toto plicatic acid were similar with respectto age, smok- week” pattern, since the improvement of PEFR was ing habits, duration of symptoms, total number of observed only after the patient had been away from years of exposureto cedardust, and number of weeks work for 2 weeks. Two patients with confirmed cedar away from cedar dust before the initial visit. The asthma by specific challenge test with plicatic acid reactors to plicatic acid were more frequent users of did not have positive PEFR pattern; both patients had antiasthmamedications than the nonreactorsbut were a mild reaction to plicatic acid comparedto patients with positive PEFR pattern on visual assessment. less likely to use inhaled steroids. Among the nine nonreactors to plicatic acid, one The mean PEFR recorded during 3 weeks at work and 2 weeks away from work, PC&, and FEV, mea- patient demonstrated improvement in PEFR after a sured at the end of both periods for the two groups period of 2 weeks of holidays. This patient was not aware of any other type of exposure in his work enof patients are presentedin Table II. Reactorsto plicatic acid demonstrateda significant decreasein the vironment. In addition to plicatic acid challenge in mean PC,, methacholine and FEV, when these were the laboratory, the patient was also challenged with measuredat the end of the 3 weeksof work compared exposureto cedardust for 1 hour without any reaction. Clinical reassessmentof the same patient 2 months to those measuredat the end of the holiday period. No significant change in PC, and FEV, occurred after he returned to work did not reveal any deterioration in his symptoms. among the nonreactors to plicatic acid. Reactors to The sensitivity and specificity of PEFR recording, plicatic acid also demonstrateda significant decrease changesin PC, methacholine, changesin FEV, , and in the mean PEFR measuredon working days (Mon-
596
C&6 et al.
J. ALLERGY
CLIN. IMMUNOL. MARCH 1990
creasedthe specificity by 22%. Combination of PEFR and clinical history as a diagnostic test was analyzed in the sameway; the combination had a sensitivity of 100% but a specificity of only 45%.
PEFR ( L/MINI es0 -
FIG. 1. The “weekend pattern” of PEFR that was encountered in 11 of 12 workers with PEFR graph illustrating a work relationship. The PEFR graphs from all 11 patients were simialr to the graph depicted here.
clinical history in the diagnosis of cedar asthmawith the plicatic acid challenge test as the “gold standard” are illustrated in Fig. 2. The recording of PEFR offered the best combination of sensitivity (86%) and specificity (89%), sinceonly one nonreactorto plicatic acid had a PEFR pattern suggestive of a work relationship. Changesin PC,, offered a lower sensitivity (62%) and lower specificity (78%) than PEFR recording. A characteristicclinical history had the highest sensitivity (93%), since only one patient who reacted to plicatic acid did not have a typical clinical history, but it lacked specificity (45%). The measurement of FEVl after holidays and after 3 working weeks proved to be less sensitive (85%) than the clinical history and slightly more specific (56%). We also determined the sensitivity and specificity of combination of PC,, and PEFR (Fig. 3). The test was consideredpositive if either PEFR or PC,, methacholine was positive and was considered negative if the results of both PEFR and PC,, were negative. This combination of P&, and PEFR as “test” had greater sensitivity (92%) than PEER reading alone and de-
DISCUSSION In this study we explored the usefulnessof recording PEFR, a good clinical history, changesin bronchial responsiveness,and, changes in FEV, during periods at work and on holidays in the diagnosis of cedar asthma. The sensitivity and specificity of these “tests” were assessedwith the results of specific challenge test as the “gold standard.” We found that recording of PEFR by the patient six times daily during 3 weeks at work and 2 holiday weeks is the best test for confirming the causal relationship betweenwork exposureand asthmacompared to other “tests” assessedindividually. This study also revealedthat, in assessinga patient suspectedof occupational asthma, careful history is important. In addition to determining the patient’s occupation and the various air contaminants at work to detect a possible sensitizing agent, other questions, such as the time of onset of symptoms in relation to the beginning of exposure and the improvement of symptoms on returning to work, are very useful in eliciting a causal relationship. A compatible clinical history detectsmost of the patients with occupational asthma but it is not specific becausemany patients with asthma complained of worsening of symptoms at work. Neither a positive clinical history nor PEFR recording by itself offered 100% sensitivity and specificity. However, the combination of either a positive clinical history or a positive PEFR pattern was sensitive in detecting all plicatic acid reactors. The combination of a negative clinical history and a negative PEFR pattern correspondedwith a negative plicatic acid test at all time. Therefore, when both clinical history and PEFR measurementsdo not indicate a work relationship, the specific challenge test is not necessary.However, if only the PEFR or the clinical history is positive, it is necessaryto perform specific challenge test to rule out false positive cases. Changesof bronchial responsivenessmeasuredafter 3 weeks of work and after 2 weeks of holidays were not a useful diagnostic test for cedar asthma becauseit detectedfew patients with positive plicatic acid test, as well as eliciting a false diagnosis in 22% of the patients. The poor sensitivity of this test can be explained by the fact that bronchial hyperresponsiveness may take a long time to improve after the patient has left exposure to cedar dust.g Since most patients included in this study only used low-dose inhaled steroids (<400 pg), it is very unlikely that
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Diagnostic
va llue of PEFR and PC,., 597
-
SENSITIVITY
&i-:
SPECtFtCITY
RG. 3. The sensitivity and specificity of two different combinations of tests: (1) either a positive PEFR recording or decrease in PCz, methacholine or (2) either a positive PEFR recording or a positive clinical history. PEFR
PC 20 m
FIG. 2. change clinical test as
HISTORY
SENSITIVITY
FEV 1
@88 SPECIFICITY
The sensitivity and specificity of PEFR recording, in P& methacholine, change in FEV,, and positive history with the results of the specific challenge the “gold standard.”
this medication prevented our observing significant changes in bronchial hyperresponsiveness. The usefulness of this test for the diagnosis of other types of occupational asthma remains to be determined. Burge3 had found that a cross-shift change in FEV, is not a sensitive test to detect the work relationship. Our results demonstrated that the longitudinal change in FEV, between the end of the working weeks and the end of the nonworking weeks is more sensitive than cross-shift change in FEV,, but again nonspecific. In 11 of 12 patients who had positive PEFR pattern for occupational asthma, we observed considerable improvement of PEFR on weekends. Therefore, PEFR measurement can pick up most patients with the disease. Since PEFR measurement is a very effortdependent maneuver, false negative as well as false positive results can be expected with this method if PEFRs are not recorded properly. If a patient has occupational asthma, he/she is going to be advised to cease exposure. Because this recommendation has considerable impact on the patient, the diagnosis should be confirmed with the specific inhalation challenge test if this is available. Specific challenge inhalation tests are very time consuming, and if both the history and PEFR do not suggest an occupational asthma, the specific inhala-
tion challenge test does not need to be performed. PEFR measurement therefore helps screen patients most likely to have occupational-related asthma. In this study, most patients were enrolled at the time they were away from work and then when they returned to work. It is thus difficult to know if the improvement of PEFR on weekends would still be observed if they were asked to start recording PEFR at work without being away from work for a time. If this “weekend pattern” persists, there is no need for patients to record PEFR during 2 weeks away from work. Although plicatic acid is a low-molecularweight compound, as isocyanates are. the pattern of PEFR observed in this study differs from the pattern observed in isocyanate-sensitized patients in which only 36% of the patients demonstrated improvement of PEFR on weekends. 5 There are several possible explanations for the differences in results between this study and studies of Burge et al.‘. 5 that assessed the usefulness of PEFR recording in patients with colophony and isocyanateinduced asthma. First, in this study the seusitivity and specificity of PEFR recordings were determined with the results of the specific challenge test as the “gold standard,” whereas in the studies of Burge et al, .4. ’ the “gold standard’ was the history and timal outcome of asthma when the patients returned to work. Second. the PEFR was measured every 2 hours mstead of hourly. The duration of recording was 5 weeks for all the patients in this study. In the study by Burge et al. ,“. 5 recordings varied from 14 days up to 72 days. The above differences may explain why the recording of PEFR in this study proved to be a more sensitive test (considering that patients continued to take inhaled steroids) but less specific.
598 C8t6 et al.
The results of this study demonstratethe importance of specific challenge test in the diagnosis of occupational asthma. As stated earlier, the use of PEFR recording alone underdiagnosedthe diseasein two of 14 of the cases,and overdiagnosedone of nine cases. The use of a more specific test is important since the diagnosisof occupational asthmahasconsiderableimplications for the future of the patient. Moreover, since almost half the patients with cedar asthma recover after leaving the industry, a sensitive test is also of prime importance. Finally, it should be rememberedthat a positive PEFR pattern ony indicates causal relationship between exposure at work and asthma.It doesnot allow the precise identification of the causal agent that may be important if relocation in the same industry is a possible solution to the patient’s health problem. Specific challenge tests are necessary for the latter purpose. In summary, when a patient is being investigated with occupational asthma, a good questionnaire as well as PEFR measurementsshould be done. If both tests are negative, the specific challenge test does not need to be conducted. However, if one of these two testssuggestsoccupational asthma, specific challenge should be performed to rule out false positive cases. When specific challenge test is not available, either becauseof lack of facilities or when a new agent is suspectedof causing asthma, prolonged recording of PEFR at work and away from work is a very valuable diagnostic test. REFERENCES
1. Chan-YeungM, Lam S. Occupationalasthma.Am Rev Respir Dis 1986;133:686-703. 2. Fabbri LM, Danieli D, Crescioli S, et al. Fatal asthma in a subject sensitized to TDI. Am Rev Respir Dis 1988;137: 1494-8.
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3. Burge PS. Single and serial measurementsof lung function in the diagnosisof occupationalasthma.Eur J Respir Dis [Suppl] 1982;123:47-59. 4. Burge PS, O’Brien IM, Harries MG. Peak flow rate records in the diagnosis of occupational asthma due to colophony. Thorax 1979;34:308-16. 5. Burge SP, O’Brien IM, Harries MG. Peak flow rates in the diagnosis of asthma caused by isocyanate. Thorax 1979; 34:317-23. 6. Gheysens B, Auwerx J, Vanden Eckhout A, Demedts M. Cobalt-inducedbronchial asthmain diamond polishers. Chest 1985;88:740-4. 7. Cartier A, Pineau L, Malo JL. Monitoring of maximum peak expiratoty flow rates and histamine inhalation tests in the investigation of occupational asthma. Clin Allergy 1984;14: 193-6. 8. Bardy ID, Malo JL, Seguin P, et al. Occupational asthmaand IgE sensitizationin a pharmaceuticalcompanyprocessingpsylbum. Am Rev Respir Dis 1987;135:1033-8. 9. Hargreave FE. Occupational asthmawithout bronchial hyperresponsiveness.Am Rev Respir Dis 1984;130:513-5. 10. Boulet LP, Carder A, Thomson NC. Asthma and increasesin nonallergic bronchial responsivenessduring the seasonalpollen exposure. J ALLERGY CLIN IMMUNOL 1983;71:399-406. 11. Moller DR, BaughmanR, Murlas C, Brooks S. New directions in occupational asthmacausedby low molecular weight compounds. Semin Respir Med 1986;7:225-39. 12. Lam S, Wong R, Chan-YeungM. Nonspecific bronchial reactivity in occupational asthma. J ALLERGY CLIN IMMUNOL 1979;63:28-34.
13. Chan-Yeung M, Barton GM, Mac Lean L, Grzybowski S. Occupational asthma and rhinitis due to western red cedar (Thuya plicafu). Am Rev Respir Dis 1973;108:1094-1102. 14. Morris JF, Koski A, JohnsonLC. Spirometric standardsfor healthy nonsmoking adults. Am Rev Respir Dis 1971;103:5765. 15. VenablesKM, Burge PS, Davidson N, Taylor AJN. Peak flow rate records in surveys: reproducibility of observers report. Thorax 1984;39:828-32. 16. Zar JH. Biostatistical analysis. 2nded. EnglewoodCliffs, N.J.: Prentice Hall, 1984.
and specificity of PC,, and peak flow rate in cedar asthma
C&6, MD,* Susann
Ste-Foy, Quebec, and Vancouver,
Kennedy, British
PhD, and Moira Chan-Yeung,
Columbia,
MB
Canada
The diagnosis of red cedar asthma is usually confirmed by a specihc challenge with plicatic acid, the compound responsible for the disease. We performed this study to determine the sensitivity and specijcity of two other diagnostic tests, prolonged recording of peak expiratory flow rate (PEFR) and measurement of bronchial responsiveness (provocative dose of methacholine causing a 20% fall in FEV, [PC,, methacholine]). Twenty-three patients with suspected cedar asthma participated in the study. The patients recorded PEFR during 2 weeks away from work and 3 weeks at work. PC,, was measured both at the end of the nonworking and working period. An obvious decrease in PEFR in 2 of 3 working weeks, when PEFRs of weekends or holidays were compared (by visual inspection of the PEFR recording), and a decrease in PC,, by more than a twofold dilution, when the patient returned to work, were considered as positive tests for cedar asthma. Plicatic acid challenge test was performed at the end of the study; 14 patients reacted, whereas nine patients did not. With the results of the plicatic acid challenge test as the gold standard, the sensitivity and specificity of PEFR recordings were 84% and 89%; changes in PC,,, 62% and 78%; and 93% and 45% for a positive clinical history. The combination of PEFR and clinical history revealed a 100% sensitivity with a 45% spectficity. Combination of PEFR and PC,, did not improve the diagnostic accuracy. We conclude (1) that the speciftc challenge with plicatic acid is not necessary when both clinical history and PEFR are negative, (2) that, if either the history or PEFR is positive for occupational asthma, the plicatic acid test must be done to rule out false positive cases, and (3) serial measurement of PC,, methacholine is not a valuable test in cedar asthma. (J ALLERGY CUNIMMUNOL
1990;85:592-8.)
In the diagnosis of occupational asthma, specific inhalation challenge testshave often beenusedto confirm the causal relationship between exposure to the offending agent and the respiratory symptoms.’ Very often, such well-standardized, specific challenge tests cannot be performed for various reasons. (1) The offending agent in the workplace has not yet been identified. (2) Facilities and trained personnelare not avail-
From the Respiratory Division, Department of Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada. Supported by the Workers’ Compensation Board of British Columbia. Received for publication Jan. 30, 1989. Revised Aug. 21, 1989. Accepted for publication Oct. 4, 1989. Reprint requests:JohanneC&e, MD, Centrede Pneumologie,Hopital Laval, 2725 Chemin Ste-Roy,QuCbec,CanadaGlV 4G5. *Johanne C&e, MD, is a recipient of a scholarship from the Canadian Lung Association and the QuebecHealth ResearchFoundation. l/1/17557
592
Abbreviations used PC,: Provocativeconcentrationof
methacholine inducinga 20%drop in FEW, PEFR: Peakexpiratoryflow rate
able. (3) Specific challenge test can sometimesinduce a very severeattack of asthma, especially when the air concentration of the offending agent cannot be monitored. In fact, one deathhasbeenreportedduring a specific challenge test with isocyanates.* The diagnostic value of a change in FEV, during one work shift has been assessedpreviously and was found to be a poor diagnostic test for occupational asthma.3Prolonged recording of PEFB at work and away from work was initially proposed by Burge et al.4s5 as a valuable diagnostic test in occupational asthma. These investigators demonstratedthat false negative results with PBFR recording can occur, especially when the patientswere taking inhaled steroids
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Diagnostic value of PEFR aml PC?, 993
85 3
or cromoglycate.4 In these studies,4. 5 the sensitivity and specificity of PEFR were calculated with a positive clinical history or a positive specific challenge test as the gold standard for occupational asthma. There are several studies of a decrease in bronchial responsiveness in patients with occupational asthma after a period away from the offending agent or an increase in bronchial responsiveness after resuming exposure to the offending agent.6-9Similar changes in bronchial responsiveness have been observed in patients with asthma and ragweed sensitization during the seasonal pollen exposure. ‘OVery little information exists about the sensitivity and specificity of this test in the diagnosis of occupational asthma. It has been suggested that a combination of prolonged recording of PEFR and serial measurements of bronchial responsiveness during periods at work and away from work could be very useful in the confirmation of the diagnosis of occupational asthma. ‘I In this study, we assessed the sensitivity (ratio of the number of patients with a positive test to the number of patients with cedar asthma) and specificity (ratio of the number of patients with a negative test to the number of patients without cedar asthma) of prolonged recording of PEFR, changes in bronchial responsiveness, and clinical history, individually or in combination, in the diagnosis of red cedar asthma with the specific challenge test with plicatic acid as the “gold standard .‘I MATERIAL AND METHODS Study design Patients were enrolled in the study at the time of their first consultation for occupational asthma at our occupational health unit. All the patients were questioned by the same physician with special inquiries about the presenceof cough, attacks of shortness of breath, and wheezing, the improvement of these symptoms on weekends and long holidays, and the time of onset of these symptoms. The patients recorded their PEFR during 3 weeks at work and 2 weeks away from work. They could either begin by recording their PEFR away from work first, followed by at work, or vice versa, whichever schedule was the most convenient for a given patient. Measurement of bronchial responsiveness (PC,, methacholine) was done on two occasions at approximately the same hour of the day: at the end of the 3 working weeks and at the end of the 2 weeks away from work.
Subjects Twenty-seven consecutive patients participated in this study on a voluntary basis. All the patients were referred to our occupational health unit by their family physicians for respiratory complaints related to work. All the patients were working in sawmills processing western red cedar. All
the workers were asked to keep their antiasthma medications constant throughout the study. Four patients did not com-
plete the study. In three patients, the asthmasymptomswere too severe for them to record PEFR during 3 weeks of work, and another patient forgot to record PEFR while the patient was away on holiday.
Method PEH?. Each patient was provided with a mini-Wright peak flow meter with detailed instructions concerning its proper use. The method of PEFR recording was checked after 1 week of recording. The patients were asked to record their PEFR at least on six occasions during the day: on waking up, during their two coffee breaks, lunch, dinner, and bedtime. On each occasion, they were asked to blow three times into the peak flow meter and to record all readings. Only the best of the three attempts w-as kept fat analysis. Methucholine challenge test. This test was performed with our own protocol as previously described. ” The patients were asked to stop using inhaled salbutamol for 8 hours and methylxanthines for 24 hours. hrhaied steroids could be continued. The test was performed only if the patient’s baseline FEV, was >60% of predicted value and the drop in FEV, after saline inhalation was < 158’. Baseline FEV, and FVC were measured until three reproducible values within 5% were obtained with a Collins 13.5 L watersealed spirometer (Warren E. Collins. Braintree, Mass.). The test solutions were delivered with a Bennett-Twin nebulizer, which has an output of 0.22 ml/min at an oxygen flow rate of 7 Limin. The particle size has a mass-median diameter of 3.1 km. The patients were asked to breathe the aerosol at tidal volume via a face mask loosely applied over the nose and mouth. The first solution to be inhaled was phosphate-buffered saline that served as a control solution, and this solution was followed by twofold increasing concentrations of methacholine from 0.03 to 64 mgiml at 5minute intervals. Each solution was inhaled by the subjects for 2 minutes followed by measurement of FEV, at 30 seconds and 3 minutes. The procedure continued until the FEV , had fallen by at least 20% below the lowest postsaline value or until the highest concentration had been reached. The PC2, methacholine (concentration of methachohne eliciting a 20% fall of the lowest postsaline value) was obtained from interpolation of the noncumulative dose-response curve on a semilogarithmic scale. For the one patient in whom this test could not be done (> 15% decrease in FEV, after saline inhalation), PC, was arbitrarily assigned the value of 0.03 mg/ml. Specific inhalation challenge test. Phcatic acid, the compound responsible for red cedar asthma, was used for specific challenge test with the method described previously. ” Antiasthma medications were withdrawn as for the methacholine test with the exception that inhaled steroids were also stopped 12 hours before the test. Baseline FEV, and FVC were measured until three reproducible values had been obtained. On the first day, phosphate-buffered saline was inhaled for 2 minutes, and FEV, was measured at 30 seconds and IO, 20, 30, and 60 minutes after inhalation. Thereafter,
594 C&g et al.
TABLE I. Characteristics
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of the reactors
and nonreactors
Age (yr) mean ? SEM Smoking habits Nonsmokers Exsmokers Current smokers Past history of asthma Duration of exposure to cedar dust (yr) mean ? SEM Symptom duration before initial visit (mo) mean + SEM Antiasthma medication used No medication Inhaled salbutamol only Inhaled salbutamol and steroids Inhaled salbutamol, steroids, and oral methylxanthines No. of holiday weeks taken mean ?SEM
to plicatic
CLIN. IMMUNOL. MARCH 1990
acid
Reactors (N = 14)
Nonreactors (N = 9)
38 2 3
36 r 2
13 (92%) 1 (8%) 0 (0%) 0 (0%) 6?2
8 (89%) 1 (11%) 0 (0%) 2 (22%) 8?2
21 + 8
36 f
0 9 4 1
3 1 3 2
(0%) (64%)* (29%) (7%)
4.5 + 0.8
13
(33%) (11%) (33%) (23%)
3.8 k 1.2
*Difference statistically significant by Fisher’s exact test at p < 0.05 for plicatic acid reactorscomparedto nonreactors.
FEV, was measured hourly for 7 hours. The patient then left the laboratory and continued measuring PEFR hourly up to bedtime, and at night, if awakened by shortness of breath. On the second day, plicatic acid, 5 mg/ml, was administered by inhalation initially for 30 seconds and was then followed by measurement of FEV, at 30 seconds and 10 minutes. Thereafter, the inhalation of plicatic acid was repeated for 1 minute, 1 minute and 30 seconds, 2 minutes, and an additional 2 minutes, at lo-minute intervals until a total of 7 minutes of inhalation had been administered to the patient or when a drop in FEV, of 15% from the lowest postsaline value was observed. After the patient’s last inhalation of plicatic acid, FEV, was measured at 10, 20, 30, and 60 minutes and then hourly for 7 hours. Thereafter, PEFR was recorded after the same schedule as described above for the control day. The patient was observed 24 hours later in the laboratory for measurement of FEV,.
Data analysis Medical questionnaire. The patient was considered to have occupational asthma if he had no previous history of asthma before exposure to red cedar dust and if his cough, wheezing, or attacks of shortness of breath improved on weekends or on long holidays. F/W,. A decrease in prebronchodilator FEV, (expressed as percent of predicted with the predicted formula of Morris et al.“) of >5% from holidays to working days was considered significaiit. PEH?. The six daily PEFR readings from each patient were all plotted on a graph for the whole study period with days at work clearly identified and were then visually analyzed by three physicians unaware of the results of the specific challenge test. When two of three physicians agreed
that the PEFR graph demonstrated a work relationship in 2 of 3 weeks recorded at work, the worker was considered to be positive for occupational asthma.‘* The graph was considered to have a positive “weekend pattern” if, in 2 of 3 working weeks, the PEFRs observed during working days were on average lower than PEFRs observed on weekends. The graph was considered to have a “week-to-week” pattern if, in 2 of 3 working weeks, the PEFRs were much lower than PEFRs on holidays without significant improvement on weekends. The mean PEFR values were calculated for the 15 working days, the 6 weekend days, and the 14 holidays with the six best readings for each day. Methacholine challenge test. If the PC, methacholine measured at the end of 3 working weeks was decreased from PC, measured at the end of holidays by more than twofold, the metbacholine response was considered to have changed significantly.‘* Plicatic acid challenge test. The plicatic acid test was considered positive if the patient’s lowest FEV, after plicatic acid challenge was < 15% of the value recorded at the same hour on the control day with saline. Sensitivity (percent of patients with cedar asthma with a positive test) and specificity (percent of patients without cedar asthma with a negative test) of PEFR recording, changes in PC, methacholine, FEV, changes, and clinical history were determined with the results of the specific challenge test with plicatic acid as the “gold standard” for cedar asthma.
Statistical
analysis
For comparisons within one group, statistical analysis was performed with Student’s paired t tests for normally distributed data.16 Comparisons of the means between two
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TABLE II. Differences
between
P&,
FEV,, and PEFR recorded
value of PEFR arx! PC,,
595
at work and away from work __l.--___-.---_
Reactors Mean -c SEM
Nonreactors (N = 9) ~l_.--l_-Mean f SEM
0.9 k 1.9 1.8 t 1.7t
3.5 I: z.>: 4.Q ‘- I ‘i
(N = 14)
PC, methacholine (mg/ml)* End of working period End of holiday period FEV,, % predicted End of working period End of holiday period Mean PEFR (L/min) Working period Monday to Friday Saturday and Sunday Holiday period
87.0 t 6.1 102.0 -c 5. It
508 * 22$ 556 r 20 564 -+ 23
107.0 tr 3.0 109.6 -3: 4.4
494 2 278 497 rt 26 509 + 28 ____-
*Geometric mean 2 geometric SEM. tDifference between the value recorded at work and the value on holidays statistically significant by Student’s paired f test at p < 0.01. SDifference between values recordedat work (Monday to Friday) and on weekendsor long holidays statistically significant by Student’s paired t test at p < 0.0 I. lDifference between PEFR values of nonreactorsand of reactors statistically significant by Student’s unpaired r test at p s: 0.01
groupsweremadewith Student’sunpairedr testfor normally distributeddata,andthe Mann-Whitneynonparametric test for datahavinga nonnormaldistribution.16 Finally, theFisher’s exacttestwasusedto compareratiosbetweenthe two groupsof patients.
day to Friday) from those recorded on weekendsof the 3 working weeks or long holidays. The mean PEFRsrecordedon long holidays were not higher than the mean PEFRsrecorded on weekendsin this group of patients. Overall, nonreactorsto plicatic acid had lower PEFRsthan reactors. However, nonreactorsto RESULTS plicatic acid demonstratedno difference between the Of the twenty-three male patients who participated mean PEFRsrecorded at work, on weekends,and on in the study, 14 demonstrateda positive reaction to long holidays. Of the 14 reactorsto plicatic acid, 12 plicatic acid challenge and nine patients did not. demonstrated a positive PEFR pattern (compatible with the diagnosis of occupational asthma).Eleven of Among the nine patients who did not react to plicatic thesepatientshad the “weekend pattern,” asillustrated acid, there were four patients with PC,, < 1 mg/ml. As presentedin Table I, the reactorsand nonreactors in Fig. 1. The remaining patient had the “week-toto plicatic acid were similar with respectto age, smok- week” pattern, since the improvement of PEFR was ing habits, duration of symptoms, total number of observed only after the patient had been away from years of exposureto cedardust, and number of weeks work for 2 weeks. Two patients with confirmed cedar away from cedar dust before the initial visit. The asthma by specific challenge test with plicatic acid reactors to plicatic acid were more frequent users of did not have positive PEFR pattern; both patients had antiasthmamedications than the nonreactorsbut were a mild reaction to plicatic acid comparedto patients with positive PEFR pattern on visual assessment. less likely to use inhaled steroids. Among the nine nonreactors to plicatic acid, one The mean PEFR recorded during 3 weeks at work and 2 weeks away from work, PC&, and FEV, mea- patient demonstrated improvement in PEFR after a sured at the end of both periods for the two groups period of 2 weeks of holidays. This patient was not aware of any other type of exposure in his work enof patients are presentedin Table II. Reactorsto plicatic acid demonstrateda significant decreasein the vironment. In addition to plicatic acid challenge in mean PC,, methacholine and FEV, when these were the laboratory, the patient was also challenged with measuredat the end of the 3 weeksof work compared exposureto cedardust for 1 hour without any reaction. Clinical reassessmentof the same patient 2 months to those measuredat the end of the holiday period. No significant change in PC, and FEV, occurred after he returned to work did not reveal any deterioration in his symptoms. among the nonreactors to plicatic acid. Reactors to The sensitivity and specificity of PEFR recording, plicatic acid also demonstrateda significant decrease changesin PC, methacholine, changesin FEV, , and in the mean PEFR measuredon working days (Mon-
596
C&6 et al.
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creasedthe specificity by 22%. Combination of PEFR and clinical history as a diagnostic test was analyzed in the sameway; the combination had a sensitivity of 100% but a specificity of only 45%.
PEFR ( L/MINI es0 -
FIG. 1. The “weekend pattern” of PEFR that was encountered in 11 of 12 workers with PEFR graph illustrating a work relationship. The PEFR graphs from all 11 patients were simialr to the graph depicted here.
clinical history in the diagnosis of cedar asthmawith the plicatic acid challenge test as the “gold standard” are illustrated in Fig. 2. The recording of PEFR offered the best combination of sensitivity (86%) and specificity (89%), sinceonly one nonreactorto plicatic acid had a PEFR pattern suggestive of a work relationship. Changesin PC,, offered a lower sensitivity (62%) and lower specificity (78%) than PEFR recording. A characteristicclinical history had the highest sensitivity (93%), since only one patient who reacted to plicatic acid did not have a typical clinical history, but it lacked specificity (45%). The measurement of FEVl after holidays and after 3 working weeks proved to be less sensitive (85%) than the clinical history and slightly more specific (56%). We also determined the sensitivity and specificity of combination of PC,, and PEFR (Fig. 3). The test was consideredpositive if either PEFR or PC,, methacholine was positive and was considered negative if the results of both PEFR and PC,, were negative. This combination of P&, and PEFR as “test” had greater sensitivity (92%) than PEER reading alone and de-
DISCUSSION In this study we explored the usefulnessof recording PEFR, a good clinical history, changesin bronchial responsiveness,and, changes in FEV, during periods at work and on holidays in the diagnosis of cedar asthma. The sensitivity and specificity of these “tests” were assessedwith the results of specific challenge test as the “gold standard.” We found that recording of PEFR by the patient six times daily during 3 weeks at work and 2 holiday weeks is the best test for confirming the causal relationship betweenwork exposureand asthmacompared to other “tests” assessedindividually. This study also revealedthat, in assessinga patient suspectedof occupational asthma, careful history is important. In addition to determining the patient’s occupation and the various air contaminants at work to detect a possible sensitizing agent, other questions, such as the time of onset of symptoms in relation to the beginning of exposure and the improvement of symptoms on returning to work, are very useful in eliciting a causal relationship. A compatible clinical history detectsmost of the patients with occupational asthma but it is not specific becausemany patients with asthma complained of worsening of symptoms at work. Neither a positive clinical history nor PEFR recording by itself offered 100% sensitivity and specificity. However, the combination of either a positive clinical history or a positive PEFR pattern was sensitive in detecting all plicatic acid reactors. The combination of a negative clinical history and a negative PEFR pattern correspondedwith a negative plicatic acid test at all time. Therefore, when both clinical history and PEFR measurementsdo not indicate a work relationship, the specific challenge test is not necessary.However, if only the PEFR or the clinical history is positive, it is necessaryto perform specific challenge test to rule out false positive cases. Changesof bronchial responsivenessmeasuredafter 3 weeks of work and after 2 weeks of holidays were not a useful diagnostic test for cedar asthma becauseit detectedfew patients with positive plicatic acid test, as well as eliciting a false diagnosis in 22% of the patients. The poor sensitivity of this test can be explained by the fact that bronchial hyperresponsiveness may take a long time to improve after the patient has left exposure to cedar dust.g Since most patients included in this study only used low-dose inhaled steroids (<400 pg), it is very unlikely that
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va llue of PEFR and PC,., 597
-
SENSITIVITY
&i-:
SPECtFtCITY
RG. 3. The sensitivity and specificity of two different combinations of tests: (1) either a positive PEFR recording or decrease in PCz, methacholine or (2) either a positive PEFR recording or a positive clinical history. PEFR
PC 20 m
FIG. 2. change clinical test as
HISTORY
SENSITIVITY
FEV 1
@88 SPECIFICITY
The sensitivity and specificity of PEFR recording, in P& methacholine, change in FEV,, and positive history with the results of the specific challenge the “gold standard.”
this medication prevented our observing significant changes in bronchial hyperresponsiveness. The usefulness of this test for the diagnosis of other types of occupational asthma remains to be determined. Burge3 had found that a cross-shift change in FEV, is not a sensitive test to detect the work relationship. Our results demonstrated that the longitudinal change in FEV, between the end of the working weeks and the end of the nonworking weeks is more sensitive than cross-shift change in FEV,, but again nonspecific. In 11 of 12 patients who had positive PEFR pattern for occupational asthma, we observed considerable improvement of PEFR on weekends. Therefore, PEFR measurement can pick up most patients with the disease. Since PEFR measurement is a very effortdependent maneuver, false negative as well as false positive results can be expected with this method if PEFRs are not recorded properly. If a patient has occupational asthma, he/she is going to be advised to cease exposure. Because this recommendation has considerable impact on the patient, the diagnosis should be confirmed with the specific inhalation challenge test if this is available. Specific challenge inhalation tests are very time consuming, and if both the history and PEFR do not suggest an occupational asthma, the specific inhala-
tion challenge test does not need to be performed. PEFR measurement therefore helps screen patients most likely to have occupational-related asthma. In this study, most patients were enrolled at the time they were away from work and then when they returned to work. It is thus difficult to know if the improvement of PEFR on weekends would still be observed if they were asked to start recording PEFR at work without being away from work for a time. If this “weekend pattern” persists, there is no need for patients to record PEFR during 2 weeks away from work. Although plicatic acid is a low-molecularweight compound, as isocyanates are. the pattern of PEFR observed in this study differs from the pattern observed in isocyanate-sensitized patients in which only 36% of the patients demonstrated improvement of PEFR on weekends. 5 There are several possible explanations for the differences in results between this study and studies of Burge et al.‘. 5 that assessed the usefulness of PEFR recording in patients with colophony and isocyanateinduced asthma. First, in this study the seusitivity and specificity of PEFR recordings were determined with the results of the specific challenge test as the “gold standard,” whereas in the studies of Burge et al, .4. ’ the “gold standard’ was the history and timal outcome of asthma when the patients returned to work. Second. the PEFR was measured every 2 hours mstead of hourly. The duration of recording was 5 weeks for all the patients in this study. In the study by Burge et al. ,“. 5 recordings varied from 14 days up to 72 days. The above differences may explain why the recording of PEFR in this study proved to be a more sensitive test (considering that patients continued to take inhaled steroids) but less specific.
598 C8t6 et al.
The results of this study demonstratethe importance of specific challenge test in the diagnosis of occupational asthma. As stated earlier, the use of PEFR recording alone underdiagnosedthe diseasein two of 14 of the cases,and overdiagnosedone of nine cases. The use of a more specific test is important since the diagnosisof occupational asthmahasconsiderableimplications for the future of the patient. Moreover, since almost half the patients with cedar asthma recover after leaving the industry, a sensitive test is also of prime importance. Finally, it should be rememberedthat a positive PEFR pattern ony indicates causal relationship between exposure at work and asthma.It doesnot allow the precise identification of the causal agent that may be important if relocation in the same industry is a possible solution to the patient’s health problem. Specific challenge tests are necessary for the latter purpose. In summary, when a patient is being investigated with occupational asthma, a good questionnaire as well as PEFR measurementsshould be done. If both tests are negative, the specific challenge test does not need to be conducted. However, if one of these two testssuggestsoccupational asthma, specific challenge should be performed to rule out false positive cases. When specific challenge test is not available, either becauseof lack of facilities or when a new agent is suspectedof causing asthma, prolonged recording of PEFR at work and away from work is a very valuable diagnostic test. REFERENCES
1. Chan-YeungM, Lam S. Occupationalasthma.Am Rev Respir Dis 1986;133:686-703. 2. Fabbri LM, Danieli D, Crescioli S, et al. Fatal asthma in a subject sensitized to TDI. Am Rev Respir Dis 1988;137: 1494-8.
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3. Burge PS. Single and serial measurementsof lung function in the diagnosisof occupationalasthma.Eur J Respir Dis [Suppl] 1982;123:47-59. 4. Burge PS, O’Brien IM, Harries MG. Peak flow rate records in the diagnosis of occupational asthma due to colophony. Thorax 1979;34:308-16. 5. Burge SP, O’Brien IM, Harries MG. Peak flow rates in the diagnosis of asthma caused by isocyanate. Thorax 1979; 34:317-23. 6. Gheysens B, Auwerx J, Vanden Eckhout A, Demedts M. Cobalt-inducedbronchial asthmain diamond polishers. Chest 1985;88:740-4. 7. Cartier A, Pineau L, Malo JL. Monitoring of maximum peak expiratoty flow rates and histamine inhalation tests in the investigation of occupational asthma. Clin Allergy 1984;14: 193-6. 8. Bardy ID, Malo JL, Seguin P, et al. Occupational asthmaand IgE sensitizationin a pharmaceuticalcompanyprocessingpsylbum. Am Rev Respir Dis 1987;135:1033-8. 9. Hargreave FE. Occupational asthmawithout bronchial hyperresponsiveness.Am Rev Respir Dis 1984;130:513-5. 10. Boulet LP, Carder A, Thomson NC. Asthma and increasesin nonallergic bronchial responsivenessduring the seasonalpollen exposure. J ALLERGY CLIN IMMUNOL 1983;71:399-406. 11. Moller DR, BaughmanR, Murlas C, Brooks S. New directions in occupational asthmacausedby low molecular weight compounds. Semin Respir Med 1986;7:225-39. 12. Lam S, Wong R, Chan-YeungM. Nonspecific bronchial reactivity in occupational asthma. J ALLERGY CLIN IMMUNOL 1979;63:28-34.
13. Chan-Yeung M, Barton GM, Mac Lean L, Grzybowski S. Occupational asthma and rhinitis due to western red cedar (Thuya plicafu). Am Rev Respir Dis 1973;108:1094-1102. 14. Morris JF, Koski A, JohnsonLC. Spirometric standardsfor healthy nonsmoking adults. Am Rev Respir Dis 1971;103:5765. 15. VenablesKM, Burge PS, Davidson N, Taylor AJN. Peak flow rate records in surveys: reproducibility of observers report. Thorax 1984;39:828-32. 16. Zar JH. Biostatistical analysis. 2nded. EnglewoodCliffs, N.J.: Prentice Hall, 1984.