The Value of Precipitating Antibodies in Screening for Hypersensitivity Pneu mon it is~-· GUILLERMO A. doPICO, WILLIAM G. REDDAN, FRANK CHMELIK, MARY ELLEN PETERS, CHARLES E. REED, and JOHN RANKIN
SUMMARY ________________________________________________________ To evaluate the usefulness of preCipitm tests as a screening method to detect hypersensitivity pneumonitis, we compared persons with precipitins to organic antigens with precipitin-negative subjects from the same population of 1,072 office workers participating in a health survey examination. Thirty-three of the 53 persons with precipitins to Micropolyspora faeni, Thermoactinomyces vulgaris, T. candidus, pigeon serum, aspergillus, alternaria, pullularia, penicillium, Cephalosporium, trichoderma, and phoma were matched according to age, sex, height, and smoking habits with precipitin-negative subjects. The subjects completed a self-administered standard questionnaire, they were interviewed and examined, chest radiograms were taken, and pulmonary functions were evaluated at rest and during mild and moderate exercise. No significant differences were found between the 2 populations in any of the pulmonary function measurements. In addition, clinical and radiologic evidence failed to distinguish between the 2 groups. No cases of hypersensitivity pneumonitis were found. In this population, precipitins had no apparent relationship to lung disease. The frequency of precipitins was considerably higher than the frequency of hypersensitivity pneumonitis. We concluded that the detection of hypersensitivity pneumonitis in population surveys attempting to establish prevalence of the disease cannot be accomplished by the simple analysis of serum precipitating antibodies but requires, in addition, a more complex analysis of historical, radiologic, and immunologic data.
Introduction A major problem in attempting to establish the still unknown prevalence of hypersensitivity pneumonitis is the lack of a simple, sensitive, and reasonably specific survey instrument. The presence of precipitating antibodies to inhaled (Received in original form May 5, 1975 and in revised form December 13, 1975) 1 From the Pulmonary and Allergy-Immunology Sections of the Departments of Medicine, Preventive Medicine, and Radiology, University of Wisconsin Center for Health Sciences, Madison, Wise. 2 Supported by a Specialized Center of Research (SCOR) Grant No. 1-P17-HL-15389 from the Natiomi1 Heart and Lung Institute of the National Institutes of Health. 3 Presented at the Annual Meeting of the Ameri-
organic antigens is useful evidence in confirming the diagnosis of hypersensitivity pneumonitis when the characteristic clinical, radiologic, and functional features are present. However, the usefulness of the precipitin tests as a reliable screening method to determine the prevalence of hypersensitivity pneumonitis should be questioned, because many persons with no apparent lung disease have precipitins (l-4). Precipitins against Micropolyspora faeni and Thermoactinomyces vulgaris, for example, have been reported in farm workers without respiratory symptoms, and otherwise classic cases of farcan Thoracic Society, May 18-21, in Montreal, Quebec, Canada. 4 Requests for reprints should be addressed to Dr. G. A. doPico, Pulmonary Division, Department of Medicine, 504 Walnut Street, Madison, Wise.
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 113, 1976
451
452
ooPICO, REDDAN, CHMELIK, PETERS, REED, AND RANKIN
mer's lung disease may lack precipitins detectable with currently available antigens (3). For these reasons, Grant and associates (2) have questioned and criticized the validity of using precipitin tests in survey studies to determine the prevalence of farmer's lung disease. Fink and co-workers (I) found no correlation between respiratory symptoms, roentgenographic abnormalities, pulmonary function abnormalities, and precipitating antibodies against pigeon serum in a selected sample of pigeon breeders attending a breeders' convention. Faux and associates (5), on the other hand, found that all budgerigar breeders with precipitins to budgerigar serum had lung disease. This study was undertaken to evaluate the usefulness of precipitin tests as a screening method for hypersensitivity pneumonitis. We examined office workers with positive precipitins to inhaled organic antigens and compared them with precipitin-negative workers matched for age, sex, height, and smoking habits. Materials and Methods Fifty·three persons with precipitins were identified from a population of 1,072 State of Wisconsin office workers participating in a health survey examination. Each of the 53 was matched with a precipitin-negative subject from the same large population according to sex, age (± I year), height (± 1.5 inches), and smoking habits. The 106 persons were then invited to participate in a clinical, radiologic, and physiologic study. None of the subjects, physicians, or technicians involved in the study was aware of the precipitin test results. Of the 53 subjects with positive precipitins, 5 refused to participate, 4 were eliminated because of the presence of hemiplegia, recent myocardial infarction, pregnancy, or cerebral palsy, and 11 could not participate for other non-health-related reasons (vacation, leave of absence, move to another city, or marriage). Of the 33 matched pairs, 17 pairs were men and 16 were women. Eleven pairs were smokers and 22 were nonsmokers. Mean age was 39.8 years (range: 19 to 62), with a mean of 37.4 years for women (range: 19 to 62) and 42 years for men (range: 26 to 62). The detection of precipitating antibodies was done by the gel immunodiffusion technique of Flaherty and co-workers (6) modified for semi-automation (4). Fungal extracts were prepared according to the methods of Flaherty and co-workers (6, 7) and pigeon serum by the method of Fink and associates (8). Six separate antigenic pools (table I) were prepared by combining lyophilized extracts of 2 strains of M. faeni and T. candid us isolated from an air conditioner (Pool I), 2 strains of T. vulgaris (Pool II), pigeon serum (Pool III), 3 strains of Aspergillus
TABLE 1 FREQUENCY OF PRECIPITATING ANTIBODIES IN 33 PRECIPITIN-POSITIVE SUBJECTS Precipitating Antibodies Antigen Pool*
(no.)
1. Micropolyspora faeni
16
(%) 48
(2 strains)
Thermoactinomyces candidus II. T. vulgaris (2 strains) Ill. Pigeon serum
8
24
9
27
14
45
8
24
17
51
33
100
1v. Aspergillus fumigatus (3 strains) V. Alternaria Pullularia
Penicillium rubrum P. casei VI. Trichoderma Phoma Cephalosporium Reactive to one or more pools
• One strain of each fungus was used unless otherwise indicated.
fumigatus (Pool IV), one strain each of alternaria, pullularia, Penicillium casei, and P. rubrum (Pool V), and one strain each of trichoderma, Cephalosporium, and phoma (Pool VI). The last 6 molds were included because they have been reported as occasional causes of hypersensitivity pneumonitis (7, 9-13). The concentration of each antigen was 10 mg per ml of lyophilized nondialyzed solids. The reproducibility, reliability, and sensitivity of the technique and the panel of extracts used in this study have been determined and reported previously (6). All subjects completed a self-administered, standardized questionnaire concerning respiratory symptoms, smoking habits, and occupational and other exposures, as well as past and present personal and family histories of pulmonary or nonpulmonary diseases. All subjects were interviewed and examined. Posteroanterior and lateral chest radiograms were obtained and interpreted by 2 observers independently. Pulmonary function studies included forced expiratory volume in I sec (FEV 1), forced vital capacity (FVC), maximal mid-expiratory flow (MMEF 25 _75), maximal flow at 50 and 75 per cent of vital capacity (FEF 50 and FEF 75 ), closing volume as a percentage of vital capacity, and diffusing capacity (DLco) at rest and during mild and moderate exercise. Five FVC tracings per subject were recorded on a 13.5-liter Collins spirometer by the same technician. The 2 highest FEV 1 and FVC values corrected for BTPS were averaged and recorded (14). The MMEF 25 _75 value was taken from the highest FVC tracing
453
SCREENING FOR HYPERSENSITIVITY PNEUMONITIS
according to a standard technique (15). The FEF 50 and FEF 75 were measured from 3 reproducible maxi· mal expiratory flow-volume curves obtained on a Wedge spirometer and displayed on an X-Y recorder and averaged. Closing volumes were obtained by the nitrogen method and the mean of 3 acceptable tracings was recorded (16). DLco was measured by the single-breath method of Ogilvie and associates (17), at rest and during mild and moderate exercise; alveolar volume (VA) was calculated from the helium dilution measurement. Minute ventilation (VE:), frequency, tidal volume, 0 2 consumption (Vo 2), respiratory quotient, heart rate, arterial systemic blood pressure, VEjVo 2 , and DLco were measured during mild and moderate exercise on a motor-driven treadmill by methods described previously (18). The significance of the difference in pulmonary function between precipitin-positive and precipitinnegative subjects was tested by the t test for paired variables. P < 0.05 was considered significant.
precipitin-positive and preCipltm-negative subjects in the incidence and character of periodicity of respiratory symptoms, past history of pulmonary disease and chest physical findings, or family history of asthma. There was a higher incidence (P < 0.05) of family history of hay fever among precipitin-positive subjects. Pulmonary function. There were no significant differences between the groups in any of the resting pulmonary function measurements (table 2). Both precipitin-positive and precipitin-negative groups closely approximated predicted values for diffusing capacity (106 per cent predicted), FVC (99 per cent predicted), and ventilatory flow measurements (FEV 1' MMEF 25 . 75 , FEF 50 ; 80 to 89 per cent predicted). Although there was considerable variation, regression analysis of the increase in pulmonary diffusing capacity from rest through mild and moderate exercise {Vo2, 0.900 and 1.45 liter per min, respectively) failed to distinguish the 2 groups. As expected, smokers of both groups had a lower DLco than did nonsmokers (P < 0.02). Chest radiograms. Minimal abnormalities of interstitial or alveolar pulmonary disease compatible with hypersensitivity pneumonitis were found in a precipitin-negative middle-aged man who was a heavy smoker. All other chest radiograms were considered normal. There was no significant clinical or physiologic difference between those subjects with precipitins to only antigen pools I, II, III, or IV and their matched controls.
Results
Clinical findings. The frequency of preCipiUns to each antigenic pool is presented in table 1. Of the 33 subjects with positive precipitins, 18 had precipitating antibodies to a single antigenic pool: 10 to Pool I, 6 to Pool VI, and 2 to Pool IV. The serum of the other 15 had precipitins to 2 or more of the antigenic pools. Twelve of the 15 included precipitins to A. fumigatus and 6 included precipitins toM. faeni. There were no single reactions to Pools II, III, or V. The syndrome characteristic of hypersensitivity pneumonitis (fever, malaise, dyspnea, cough, and leukocytosis 4 to 6 hours after exposure to the antigen) was not identified in any of the subjects. There were no significant differences among
Discussion
The precipitating antibodies for which we
TABLE
2
PULMONARY FUNCTION IN 33 MATCHED PAIRS OF PRECIPITIN-POSITIVE AND PRECIPITIN-NEGATIVE SUBJECTS Precip itin~Positive Subjects
FEV1. ml FVC, ml MMEF2s-?s. liter/min FEFso. liter/sec FEF75, liter/sec CV,% OLeo. ml/min/mm Hg OLIVA
Precipitin-Negative Subjects
(mean)
(SE)
(mean)
(SE)
p
3,486 4,252 251.6 3.9 1.32 15.5 29.7 6.8
156 227 36 0.27 0.13 1.4 1.15 0.25
3,494 4,083 296.4 4.1 1.37 16.8 29.6 6.9
146 225 74 0.22 0.12 1.2 1.16 0.26
> 0.20 > 0.20 > 0.20 > 0.20 > 0.20 > 0.20 > 0.20 > 0.20
Definition of abbreviations: FEV 1 = forced expiratory volume in 1 sec; FVC = forced vital capacitY; MMEF2s- 75 = maximal mid-expiratory flow; FEFso = maximal instantaneous flow at 50 per cent of vital capacity; FEF75 =maximal instantaneous flow at 75 per cent of vital capacitY; CV =closing volume as a percentage of vital capacitY; OLeo= diffusing capacity for CO; DL/VA =diffusion per unit of alveolar volume.
454
DOPICO, REDDAN, CHMELIK, PETERS, REED, AND RANKIN
screened in this study have all been associated with hypersensitivity pneumonitis (l-3, 9-13, 19). With the exception of farmer's lung disease, pigeon breeder's disease, and allergic aspergillosis, the other forms of hypersensitivity pneumonitis for which we sought evidence have not been studied extensively. They have appeared mostly as outbreaks after heavy occupational exposure or as single case reports (7, 9-13, 19). The characteristic syndrome of hypersensitivity pneumonitis has been described among office workers exposed to air control systems contaminated with thermophilic actinomycetes (19). No such syndromes were identified among the office employees examined by us. The exposure and development of precipitins against thermophilic actinomycetes, pigeon serum, and other ubiquitous fungi and organic materials is not limited to high-risk occupations (4, 19). Precipitins to T. vulgaris, A. fumigatus, pigeon serum, and M. faeni have been found in persons with symptoms related to their home environment as well as in asymptomatic members of the same household (19). From our study we concluded that (1) in this population of office workers, the occurrence of precipitins had no apparent relationship to lung disease; (2) in urban dwellers the frequency of serum precipitins was considerably higher than the frequency of hypersensitivity pneumonitis; (.3) the presence of precipitins seemed to reflect exposure to common airborne antigens rather than to indicate a burden of lung disease; (4) the detection of hypersensitivity pneumonitis in population surveys attempting to establish prevalence of the disease cannot be accomplished by the simple analysis of serum precipitating antibodies but requires, in addition, a more complex analysis of historical, radiologic, and immunologic data. Acknowledgment The writers thank the director of the Division of Health, Department of Health and Social Services, and the Office of the Governor of the State of Wisconsin for their cooperation, and Dr. Donn D'Alessio, Dr. John Gianunzio, and Dr. Warren Dennis for the sta· tistical analysis and the epidemiologic design of this study. References I. Fink, J. N., Schlueter, D.P., Sosman, A., Unger, G. F., Barboriak, J. J., Rimm, A. A., Arkins, J. A., and Dhalioval, K. S.: Clinical survey of pigeon breeders, Chest, 1972,62,277.
2. Grant, I. W., Blyth, W., Wardrop, V. E., Gordon, R. M., Pearson, J. C., and Mair, A.: Prevalence of farmer's lung in Scotland. A pilot survey, Br Med J, 1972,1,530. 3. Pepys, J.: Immunologic approaches in pulmonary disease caused by inhaled materials, Ann NY Acad Sci, 1974, 221, 27. 4. Chmelik, F., Flaherty, D. K., and Reed, C. E.: Precipitating antibodies in working and hospitalized populations directed toward antigens causing hypersensitivity pneumonitis, Am Rev Respir Dis, 1975,111,201. 5. Faux, J. A., Wide, L., Hargreave, F. E., Longbottom, J. L., and Pepys, J.: Immunological aspects of respiratory allergy in Budgerigar (Meloprittacus undulatus) fanciers, Clin Allergy, 1971,1, 149. 6. Flaherty, D. K., Barboriak, J. J., Emmanuel, D., Fink, J., Marx, J., Moore, V., Reed, C. E., and Roberts, R.: Multilaboratory comparison of the three immunodiffusion methods used for the detection of precipitating antibodies in hypersensitivity pneumonitis, J Lab Clin Med, 1974, 84, 298. 7. Flaherty, D. K., Murray, H. D., and Reed, C. E.: Cross reactions to antigens causing hypersensitivity pneumonitis, J Allergy Clin lmmunol, 1974, 53, 329. 8. Fink, J. N., Barboriak, J. J., and Sosman, A. J.: Immunologic studies of pigeon breeder's disease, J Allergy, 1967,39, 1214. 9. Schlueter, D. P., Fink, J. N., and Hensley, G. T.: Wood pulp workers disease: Hypersensitivity pneumonitis caused by alternaria, Ann Intern Med, 1972, 77,904 .. 10. deWelch, A. L., Gutersohm, J., and Bijtikofer, E.: La maladie des laveurs de fromage ("Kiisewascher Krankheit'') une forme particuliere du syndrome du poumon du fermier, Schweiz Med Wochenschr, 1969, 99, 872. II. Sahn, S. A., and Lakshminarayan, S.: Allergic bronchopulmonary penicilliosis, Chest, 1973, 6J, 286. 12. Green, W. F.: Precipitins against a fungus, phoma violacea, isolated from a moldy shower curtain in sera from patients with suspected allergic interstitial pneumonitis, Med J Aust, 1972,1, 696. 13. Cohen, H. 1., Merigan, T. C., and Losek, J. C.: Sequoiosis: A granulomatous pn~umonitis associated with redwood sawdust inhalation, Am J Med, 1967,43,785. 14. Recommended Standardized Procedure for NHIL Lung Programs, Report of Workshop on Epidemiology of Respiratory Diseases, Sept. 1819, 1971, Bethesda, Md .. 1972. 15. Leuallen, F. C., and Fowler, W. S.: Maximum mid-expiratory flow, Am Rev Tuberc, 1955, 72, 783. 16. Suggested Standardized Procedures for Closing Volume Determinations (Nitrogen Method), Division of Lung Diseases, NHLI, July 1973.
SCREENING FOR HYPERSENSITIVITY PNEUMONITIS
17. Ogilvie, C. M., Forster, R. E., Blakemore, W. S., and Morton, J. W.: A standardization of breath· holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide, J Clin Invest, 1957,36, l. 18. doPico, G. A.: Pulmonary stress testing, J Car-
455
diovasc Pulm Tech, 1974,2, 37. 19. Banaszak, E., Barboriak, J., Fink, J., Scanlon, G., Schlueter, D., Sosman, G., Thiede,W.,and Unger, G.: Epidemiologic studies relating thermophillie fungi and hypersensitivity lung syndromes, Am Rev Respir Dis, 1974, 110, 585.
SUMMARY ________________________________________________________ To evaluate the usefulness of preCipitm tests as a screening method to detect hypersensitivity pneumonitis, we compared persons with precipitins to organic antigens with precipitin-negative subjects from the same population of 1,072 office workers participating in a health survey examination. Thirty-three of the 53 persons with precipitins to Micropolyspora faeni, Thermoactinomyces vulgaris, T. candidus, pigeon serum, aspergillus, alternaria, pullularia, penicillium, Cephalosporium, trichoderma, and phoma were matched according to age, sex, height, and smoking habits with precipitin-negative subjects. The subjects completed a self-administered standard questionnaire, they were interviewed and examined, chest radiograms were taken, and pulmonary functions were evaluated at rest and during mild and moderate exercise. No significant differences were found between the 2 populations in any of the pulmonary function measurements. In addition, clinical and radiologic evidence failed to distinguish between the 2 groups. No cases of hypersensitivity pneumonitis were found. In this population, precipitins had no apparent relationship to lung disease. The frequency of precipitins was considerably higher than the frequency of hypersensitivity pneumonitis. We concluded that the detection of hypersensitivity pneumonitis in population surveys attempting to establish prevalence of the disease cannot be accomplished by the simple analysis of serum precipitating antibodies but requires, in addition, a more complex analysis of historical, radiologic, and immunologic data.
Introduction A major problem in attempting to establish the still unknown prevalence of hypersensitivity pneumonitis is the lack of a simple, sensitive, and reasonably specific survey instrument. The presence of precipitating antibodies to inhaled (Received in original form May 5, 1975 and in revised form December 13, 1975) 1 From the Pulmonary and Allergy-Immunology Sections of the Departments of Medicine, Preventive Medicine, and Radiology, University of Wisconsin Center for Health Sciences, Madison, Wise. 2 Supported by a Specialized Center of Research (SCOR) Grant No. 1-P17-HL-15389 from the Natiomi1 Heart and Lung Institute of the National Institutes of Health. 3 Presented at the Annual Meeting of the Ameri-
organic antigens is useful evidence in confirming the diagnosis of hypersensitivity pneumonitis when the characteristic clinical, radiologic, and functional features are present. However, the usefulness of the precipitin tests as a reliable screening method to determine the prevalence of hypersensitivity pneumonitis should be questioned, because many persons with no apparent lung disease have precipitins (l-4). Precipitins against Micropolyspora faeni and Thermoactinomyces vulgaris, for example, have been reported in farm workers without respiratory symptoms, and otherwise classic cases of farcan Thoracic Society, May 18-21, in Montreal, Quebec, Canada. 4 Requests for reprints should be addressed to Dr. G. A. doPico, Pulmonary Division, Department of Medicine, 504 Walnut Street, Madison, Wise.
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 113, 1976
451
452
ooPICO, REDDAN, CHMELIK, PETERS, REED, AND RANKIN
mer's lung disease may lack precipitins detectable with currently available antigens (3). For these reasons, Grant and associates (2) have questioned and criticized the validity of using precipitin tests in survey studies to determine the prevalence of farmer's lung disease. Fink and co-workers (I) found no correlation between respiratory symptoms, roentgenographic abnormalities, pulmonary function abnormalities, and precipitating antibodies against pigeon serum in a selected sample of pigeon breeders attending a breeders' convention. Faux and associates (5), on the other hand, found that all budgerigar breeders with precipitins to budgerigar serum had lung disease. This study was undertaken to evaluate the usefulness of precipitin tests as a screening method for hypersensitivity pneumonitis. We examined office workers with positive precipitins to inhaled organic antigens and compared them with precipitin-negative workers matched for age, sex, height, and smoking habits. Materials and Methods Fifty·three persons with precipitins were identified from a population of 1,072 State of Wisconsin office workers participating in a health survey examination. Each of the 53 was matched with a precipitin-negative subject from the same large population according to sex, age (± I year), height (± 1.5 inches), and smoking habits. The 106 persons were then invited to participate in a clinical, radiologic, and physiologic study. None of the subjects, physicians, or technicians involved in the study was aware of the precipitin test results. Of the 53 subjects with positive precipitins, 5 refused to participate, 4 were eliminated because of the presence of hemiplegia, recent myocardial infarction, pregnancy, or cerebral palsy, and 11 could not participate for other non-health-related reasons (vacation, leave of absence, move to another city, or marriage). Of the 33 matched pairs, 17 pairs were men and 16 were women. Eleven pairs were smokers and 22 were nonsmokers. Mean age was 39.8 years (range: 19 to 62), with a mean of 37.4 years for women (range: 19 to 62) and 42 years for men (range: 26 to 62). The detection of precipitating antibodies was done by the gel immunodiffusion technique of Flaherty and co-workers (6) modified for semi-automation (4). Fungal extracts were prepared according to the methods of Flaherty and co-workers (6, 7) and pigeon serum by the method of Fink and associates (8). Six separate antigenic pools (table I) were prepared by combining lyophilized extracts of 2 strains of M. faeni and T. candid us isolated from an air conditioner (Pool I), 2 strains of T. vulgaris (Pool II), pigeon serum (Pool III), 3 strains of Aspergillus
TABLE 1 FREQUENCY OF PRECIPITATING ANTIBODIES IN 33 PRECIPITIN-POSITIVE SUBJECTS Precipitating Antibodies Antigen Pool*
(no.)
1. Micropolyspora faeni
16
(%) 48
(2 strains)
Thermoactinomyces candidus II. T. vulgaris (2 strains) Ill. Pigeon serum
8
24
9
27
14
45
8
24
17
51
33
100
1v. Aspergillus fumigatus (3 strains) V. Alternaria Pullularia
Penicillium rubrum P. casei VI. Trichoderma Phoma Cephalosporium Reactive to one or more pools
• One strain of each fungus was used unless otherwise indicated.
fumigatus (Pool IV), one strain each of alternaria, pullularia, Penicillium casei, and P. rubrum (Pool V), and one strain each of trichoderma, Cephalosporium, and phoma (Pool VI). The last 6 molds were included because they have been reported as occasional causes of hypersensitivity pneumonitis (7, 9-13). The concentration of each antigen was 10 mg per ml of lyophilized nondialyzed solids. The reproducibility, reliability, and sensitivity of the technique and the panel of extracts used in this study have been determined and reported previously (6). All subjects completed a self-administered, standardized questionnaire concerning respiratory symptoms, smoking habits, and occupational and other exposures, as well as past and present personal and family histories of pulmonary or nonpulmonary diseases. All subjects were interviewed and examined. Posteroanterior and lateral chest radiograms were obtained and interpreted by 2 observers independently. Pulmonary function studies included forced expiratory volume in I sec (FEV 1), forced vital capacity (FVC), maximal mid-expiratory flow (MMEF 25 _75), maximal flow at 50 and 75 per cent of vital capacity (FEF 50 and FEF 75 ), closing volume as a percentage of vital capacity, and diffusing capacity (DLco) at rest and during mild and moderate exercise. Five FVC tracings per subject were recorded on a 13.5-liter Collins spirometer by the same technician. The 2 highest FEV 1 and FVC values corrected for BTPS were averaged and recorded (14). The MMEF 25 _75 value was taken from the highest FVC tracing
453
SCREENING FOR HYPERSENSITIVITY PNEUMONITIS
according to a standard technique (15). The FEF 50 and FEF 75 were measured from 3 reproducible maxi· mal expiratory flow-volume curves obtained on a Wedge spirometer and displayed on an X-Y recorder and averaged. Closing volumes were obtained by the nitrogen method and the mean of 3 acceptable tracings was recorded (16). DLco was measured by the single-breath method of Ogilvie and associates (17), at rest and during mild and moderate exercise; alveolar volume (VA) was calculated from the helium dilution measurement. Minute ventilation (VE:), frequency, tidal volume, 0 2 consumption (Vo 2), respiratory quotient, heart rate, arterial systemic blood pressure, VEjVo 2 , and DLco were measured during mild and moderate exercise on a motor-driven treadmill by methods described previously (18). The significance of the difference in pulmonary function between precipitin-positive and precipitinnegative subjects was tested by the t test for paired variables. P < 0.05 was considered significant.
precipitin-positive and preCipltm-negative subjects in the incidence and character of periodicity of respiratory symptoms, past history of pulmonary disease and chest physical findings, or family history of asthma. There was a higher incidence (P < 0.05) of family history of hay fever among precipitin-positive subjects. Pulmonary function. There were no significant differences between the groups in any of the resting pulmonary function measurements (table 2). Both precipitin-positive and precipitin-negative groups closely approximated predicted values for diffusing capacity (106 per cent predicted), FVC (99 per cent predicted), and ventilatory flow measurements (FEV 1' MMEF 25 . 75 , FEF 50 ; 80 to 89 per cent predicted). Although there was considerable variation, regression analysis of the increase in pulmonary diffusing capacity from rest through mild and moderate exercise {Vo2, 0.900 and 1.45 liter per min, respectively) failed to distinguish the 2 groups. As expected, smokers of both groups had a lower DLco than did nonsmokers (P < 0.02). Chest radiograms. Minimal abnormalities of interstitial or alveolar pulmonary disease compatible with hypersensitivity pneumonitis were found in a precipitin-negative middle-aged man who was a heavy smoker. All other chest radiograms were considered normal. There was no significant clinical or physiologic difference between those subjects with precipitins to only antigen pools I, II, III, or IV and their matched controls.
Results
Clinical findings. The frequency of preCipiUns to each antigenic pool is presented in table 1. Of the 33 subjects with positive precipitins, 18 had precipitating antibodies to a single antigenic pool: 10 to Pool I, 6 to Pool VI, and 2 to Pool IV. The serum of the other 15 had precipitins to 2 or more of the antigenic pools. Twelve of the 15 included precipitins to A. fumigatus and 6 included precipitins toM. faeni. There were no single reactions to Pools II, III, or V. The syndrome characteristic of hypersensitivity pneumonitis (fever, malaise, dyspnea, cough, and leukocytosis 4 to 6 hours after exposure to the antigen) was not identified in any of the subjects. There were no significant differences among
Discussion
The precipitating antibodies for which we
TABLE
2
PULMONARY FUNCTION IN 33 MATCHED PAIRS OF PRECIPITIN-POSITIVE AND PRECIPITIN-NEGATIVE SUBJECTS Precip itin~Positive Subjects
FEV1. ml FVC, ml MMEF2s-?s. liter/min FEFso. liter/sec FEF75, liter/sec CV,% OLeo. ml/min/mm Hg OLIVA
Precipitin-Negative Subjects
(mean)
(SE)
(mean)
(SE)
p
3,486 4,252 251.6 3.9 1.32 15.5 29.7 6.8
156 227 36 0.27 0.13 1.4 1.15 0.25
3,494 4,083 296.4 4.1 1.37 16.8 29.6 6.9
146 225 74 0.22 0.12 1.2 1.16 0.26
> 0.20 > 0.20 > 0.20 > 0.20 > 0.20 > 0.20 > 0.20 > 0.20
Definition of abbreviations: FEV 1 = forced expiratory volume in 1 sec; FVC = forced vital capacitY; MMEF2s- 75 = maximal mid-expiratory flow; FEFso = maximal instantaneous flow at 50 per cent of vital capacity; FEF75 =maximal instantaneous flow at 75 per cent of vital capacitY; CV =closing volume as a percentage of vital capacitY; OLeo= diffusing capacity for CO; DL/VA =diffusion per unit of alveolar volume.
454
DOPICO, REDDAN, CHMELIK, PETERS, REED, AND RANKIN
screened in this study have all been associated with hypersensitivity pneumonitis (l-3, 9-13, 19). With the exception of farmer's lung disease, pigeon breeder's disease, and allergic aspergillosis, the other forms of hypersensitivity pneumonitis for which we sought evidence have not been studied extensively. They have appeared mostly as outbreaks after heavy occupational exposure or as single case reports (7, 9-13, 19). The characteristic syndrome of hypersensitivity pneumonitis has been described among office workers exposed to air control systems contaminated with thermophilic actinomycetes (19). No such syndromes were identified among the office employees examined by us. The exposure and development of precipitins against thermophilic actinomycetes, pigeon serum, and other ubiquitous fungi and organic materials is not limited to high-risk occupations (4, 19). Precipitins to T. vulgaris, A. fumigatus, pigeon serum, and M. faeni have been found in persons with symptoms related to their home environment as well as in asymptomatic members of the same household (19). From our study we concluded that (1) in this population of office workers, the occurrence of precipitins had no apparent relationship to lung disease; (2) in urban dwellers the frequency of serum precipitins was considerably higher than the frequency of hypersensitivity pneumonitis; (.3) the presence of precipitins seemed to reflect exposure to common airborne antigens rather than to indicate a burden of lung disease; (4) the detection of hypersensitivity pneumonitis in population surveys attempting to establish prevalence of the disease cannot be accomplished by the simple analysis of serum precipitating antibodies but requires, in addition, a more complex analysis of historical, radiologic, and immunologic data. Acknowledgment The writers thank the director of the Division of Health, Department of Health and Social Services, and the Office of the Governor of the State of Wisconsin for their cooperation, and Dr. Donn D'Alessio, Dr. John Gianunzio, and Dr. Warren Dennis for the sta· tistical analysis and the epidemiologic design of this study. References I. Fink, J. N., Schlueter, D.P., Sosman, A., Unger, G. F., Barboriak, J. J., Rimm, A. A., Arkins, J. A., and Dhalioval, K. S.: Clinical survey of pigeon breeders, Chest, 1972,62,277.
2. Grant, I. W., Blyth, W., Wardrop, V. E., Gordon, R. M., Pearson, J. C., and Mair, A.: Prevalence of farmer's lung in Scotland. A pilot survey, Br Med J, 1972,1,530. 3. Pepys, J.: Immunologic approaches in pulmonary disease caused by inhaled materials, Ann NY Acad Sci, 1974, 221, 27. 4. Chmelik, F., Flaherty, D. K., and Reed, C. E.: Precipitating antibodies in working and hospitalized populations directed toward antigens causing hypersensitivity pneumonitis, Am Rev Respir Dis, 1975,111,201. 5. Faux, J. A., Wide, L., Hargreave, F. E., Longbottom, J. L., and Pepys, J.: Immunological aspects of respiratory allergy in Budgerigar (Meloprittacus undulatus) fanciers, Clin Allergy, 1971,1, 149. 6. Flaherty, D. K., Barboriak, J. J., Emmanuel, D., Fink, J., Marx, J., Moore, V., Reed, C. E., and Roberts, R.: Multilaboratory comparison of the three immunodiffusion methods used for the detection of precipitating antibodies in hypersensitivity pneumonitis, J Lab Clin Med, 1974, 84, 298. 7. Flaherty, D. K., Murray, H. D., and Reed, C. E.: Cross reactions to antigens causing hypersensitivity pneumonitis, J Allergy Clin lmmunol, 1974, 53, 329. 8. Fink, J. N., Barboriak, J. J., and Sosman, A. J.: Immunologic studies of pigeon breeder's disease, J Allergy, 1967,39, 1214. 9. Schlueter, D. P., Fink, J. N., and Hensley, G. T.: Wood pulp workers disease: Hypersensitivity pneumonitis caused by alternaria, Ann Intern Med, 1972, 77,904 .. 10. deWelch, A. L., Gutersohm, J., and Bijtikofer, E.: La maladie des laveurs de fromage ("Kiisewascher Krankheit'') une forme particuliere du syndrome du poumon du fermier, Schweiz Med Wochenschr, 1969, 99, 872. II. Sahn, S. A., and Lakshminarayan, S.: Allergic bronchopulmonary penicilliosis, Chest, 1973, 6J, 286. 12. Green, W. F.: Precipitins against a fungus, phoma violacea, isolated from a moldy shower curtain in sera from patients with suspected allergic interstitial pneumonitis, Med J Aust, 1972,1, 696. 13. Cohen, H. 1., Merigan, T. C., and Losek, J. C.: Sequoiosis: A granulomatous pn~umonitis associated with redwood sawdust inhalation, Am J Med, 1967,43,785. 14. Recommended Standardized Procedure for NHIL Lung Programs, Report of Workshop on Epidemiology of Respiratory Diseases, Sept. 1819, 1971, Bethesda, Md .. 1972. 15. Leuallen, F. C., and Fowler, W. S.: Maximum mid-expiratory flow, Am Rev Tuberc, 1955, 72, 783. 16. Suggested Standardized Procedures for Closing Volume Determinations (Nitrogen Method), Division of Lung Diseases, NHLI, July 1973.
SCREENING FOR HYPERSENSITIVITY PNEUMONITIS
17. Ogilvie, C. M., Forster, R. E., Blakemore, W. S., and Morton, J. W.: A standardization of breath· holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide, J Clin Invest, 1957,36, l. 18. doPico, G. A.: Pulmonary stress testing, J Car-
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diovasc Pulm Tech, 1974,2, 37. 19. Banaszak, E., Barboriak, J., Fink, J., Scanlon, G., Schlueter, D., Sosman, G., Thiede,W.,and Unger, G.: Epidemiologic studies relating thermophillie fungi and hypersensitivity lung syndromes, Am Rev Respir Dis, 1974, 110, 585.
