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Chronic respiratory disease among nonsmokers in Hagerstown, Maryland
ENVIRONMENTAL
RESEARCH
Chronic
7, 99-109
( 1974)
Respiratory
Disease
in Hagerstown,
Among
Nonsmokers
Maryland
V. Age at Onset of Hay Fever and Pulmonary Function in later Life1 JAMES H. STEBBINGS, JR.~ Division
of Epidemiology,
School Minneapolis, Received
of Public Minnesota May
Health, University 55455
of Minnesota,
25, 1973
In white male nonsmokers of cigarettes the decline of the FEV, between the ages 35 and 55 was significantly less than expected among respondents who reported hay fever or sinusitis, still present, which began before age 21. These respondents, 52 individuals out of 410, showed lower FEV]‘s at age 35 and higher at age 55 than expected. Respondents with a history of asthma were excluded from the analysis. Individuals with hay fever or sinusitis beginning in adult life did not differ from the remainder of the population. The PEFR showed the same, but not statistically significant, pattern as the FEV1. The observed effect of early onset hay fever and sinusitis was very strong. Whether it is due to an age-cohort effect of undetermined origin or may be explained by one of the several biological hypotheses discussed is not clear. Early age at onset of hay fever and sinusitis is associated with higher socioeconomic status in early life. Despite we know
the numerous epidemiological studies of chronic respiratory disease little
of the determinants
of individual
response
to the etiologic
agents.
Alphal-antitrypsin deficiency, secretory immunoglobulin A ( IgA) concentrations, and certain indicators of allergy have been studied, not necessarily adequately, but without yielding clear evidence that they are important in the population as determinants of chronic respiratory disease morbidity or mortality. This paper presents evidence that IgE-mediated upper respiratory allergies, present since childhood, are associated with higher than expected pulmonary function values after age 50, at least among nonsmokers, and suggests some possible interpretations of these unexpected findings. The natural functions of IgE are at present obscure, although considerable attention is being given to its role in parasitic diseases (Kojima et al., 1972). A role in resistance to sinopulmonary infections has been suggested (Ammann 1 Research in Hagerstown, Maryland, was supported by Public Health Service Grants GRS 47-65 and GRS 35-66. The Training Center for Public Health Research in Hagerstown was supported by PHS Grant CD-00001. Support for the investigator was received from the National Heart Institute under Grant TI-HE-5297. Additional support was received from the Washington County (Maryland) Tuberculosis Association. ’ From the Division of Epidemiology, School of Public Health, Mayo Memorial Building Box 197, University of Minnesota, Minneapolis, Minnesota 55455. (Address for reprint requests.) 99 Copyright @ 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.
100
JAMES
H.
STEBBINGS,
JR.
et al., 1969), but this may not be the case (Levy and Chen, 1970) except possibly in highly allergic subjects (Fudenberg, 1971). High serum IgE levels are associated with nonepidemic bronchiolitis in infants (Polmar et al., 1972). Infections of the teeth and sinusesare commonly believed to be related to chronic bronchitis (Joules, 1956). Blood eosinophilia and hyperreactivity of the bronchial tree, but not number of positive skin test reactions, have been related to chronic nonspecific lung disease (van der Lende, 1969): the time relations of these associations have, however, not been adequately defined. Also, associations of hay fever with simple chronic bronchitis among nonsmokers have been reported (Cullen et al., 1$X2$ Stebbings, 1971a). Secretory IgA production has been found to be suppressed by cigarette smoking in normal subjects, but not in patients with chronic respiratory disease, and low concentrations of secretory IgA may predispose to chronic respiratory infections (Lewis et al., 1970). Recent work (Levine et al., 1972; Marsh et al., 1973) indicating the existence of immune response genes, specific for certain ragweed pollen antigens and necessary but not sufficient for the development of hay fever, suggested one biological interpretation of the previously unpublished findings reported here and stimulated their publication. METHODOLOGY
A special census of Washington County, Maryland, was carried out in 1963 by the Johns Hopkins School of Hygiene and Public Health, the National Cancer Institute, and the Washington County Health Department. From these census records all white males aged 35-64 were selected who met certain criteria for smoking and residence histories. The smoking criterion was that the respondent had been a nonsmoker of cigarettes at the time of the census. The residence criteria were that the respondent had lived in the city of Hagerstown or certain contiguous areas at the time of the census and that he had resided outside Washington County for at least 20 years of his life. Of 736 individuals, 81 ( 11.0%) had moved out of the county, and 14 ( 15%) were deceased. Of the 641 still available individuals who met these criteria, 578 (9C%) were interviewed. From those interviewed the study population was defined as those 469 respondents who had never smoked cigarettes or who did not currently smoke and had never smoked as often as once a day. For this analysis 410 individuals from the population were selected on the basis of their medical histories; individuals with a history of asthma, heart disease, and a variety of rarer conditions (Stebbings, 1971a) were excluded for reasons having to do with the original aim of the study, which was to investigate the effect of urban residence on pulmonary function values in nonsmokers of cigarettes. The FEV, was measured using the McKesson Vitalor, the PEFR using the Wright peak flow meter. The maximum values attained in three trials are used in this analysis. Analyses of pulmonary function values were carried out using multiple regression techniques; instrument and interviewer effects were found
HAY
FEVER
AND
PULMONARY
101
FUNCTION
to be significant and were incorporated into the regression equations by the use of dummy variables ( Stebbings, 1971b). A positive history of hay fever or sinusitis was recorded for an affirmative re(sinus sponse to the question “Have you ever had hay fever or rosefever trouble)?” The respondent was questioned further concerning the age at which the condition began and whether it was still present. Coding was by age at onset, in categories O-12, U-21, and 22+ years of age, and by whether or not the respondent still suffered from the condition. Histories of sinusitis and hay fever not still present were infrequent, and are here treated as negative histories. Interviewing took place in the winter and early spring months of 1966, and only a small amount of extended follow-up interviewing extended into the spring polIen season. A full description of the design of the study, the measurement and analysis of the pulmonary function values, and the socioeconomic characteristics and urban residence histories of the population have been published (Stebbings, 1971a,b,c,d). The analyses presented here were carried out in 1966. In retrospect, more detailed coding of the data and some changes in the multiple regression model used in the analysis would have been desirable. The potential benefits of reanalysis, however, were minimal relative to the time and unreimbursable expense involved in retrieving the data. RESULTS
The prevalences of hay fever and sinusitis by age and age at onset are shown in Table 1. The age categories 6-12 and 13-21 were combined, but the adult onset group was split into two categories for tabulation, 2234 and 35+, as the lowest age of the respondents at interview was 35. TABLE PREVALENCE
BY AGB
AND
AGE
1
AT ONSET
OF SINUSITIS Age
35-44 No.
No.
HAY
FEVER
(v-1
45-54
Yo
AND
55-64 %
No.
35-64 %
No.
%
Hay fever Onset age O-21 Onset age 22-34 Onset age 35+ Total
8 12 3 23
6.1 9.1 2.3 17.4
12 5 3 20
6.8 2.8 1.7 11.4
2 0 6 8
2.0 0.0 5.9 7.8
22 17 12 51
5.4 4.1 2.9 12.4
Sinusitis Onset Onset Onset Total
17 10 7 34
12.9 7.6 5.3 25.8
17 8 16 41
9.7 4.5 9.1 23.3
4 5 14 23
3.9 4.9 13.7 22.5
38 23 37 98
9.3 5.6 9.0 23.9
Total
age O-21 age 22-34 age 35+
population
132
176
102
410
I.02
JAMES
H.
STEBBINGS,
JR.
A cohort effect in the prevalence of both hay fever and sinusitis with onset by age 21 appears, and remains when one considers conditions with onset by age 35. This cohort effect remains for all hay fever combined, but the age-specific prevalences of sinusitis are remarkably constant. The relationships of a number of respiratory symptoms and histories of respiratory illness to the FEV, and the PEFR were examined. Respiratory symptoms are, of course, correlated with mild deficits in pulmonary function and such was the case in this study population. As no respondents with a history of daily cigarette smoking were included in the study, histories and symptoms suggestive of chronic respiratory disease were infrequent (Stebbings, Ni’la), and the magnitudes of their effect on the pulmonary function values were small relative to the magnitudes of the effects of sinusitis and hay fever to be described here. The effects of the allergic conditions on puImonary function were analyzed by the addition of variables to the regression equations describing pulmonary function values in the study population. The basic prediction equations are: FEVr
(liters)
= - 1.258 - .0316
X age + .034S X standing height (cm),
and PEFR
(liters/min)
= 155.4 -
1.648
X age X 2.746 X standing height (cm)
plus certain instrument and interviewer effects (Stebbings, 197213) which, although always incorporated in the following analysis, do not need to be shown. The equations presented are correct for the reference instrument and interviewers. Mean values in this study population for the FEV, and PEFR were 3.28 liters and 554 liters/min, respectively. The average difference between individuals with sinusitis and hay fever and persons of the same age and height was estimated by the regression coefficient on a dummy variable (AZ, for allergy, taking the value 1 if the respondent has the condition, 0 otherwise) added to the above equations. These effects were minor, though consistent with the results below, and did not approach statistical significance. The effect of sinusitis and hay fever on the aging of pulmonary function, however, is estimated by the addition of the interaction term of the dummy variable with age (AZ x age) along with the original dummy variable (AZ). The equations so obtained are shown in Table 2, and it will be seen that, for the FEV,, the interaction terms of hay fever and sinusitis, with onset by age 21, are statistically significant and the estimated effects in an unexpected positive direction, while for the adult onset allergies the interaction terms were not significant and the estimated effects either negative or close to zero. Interpretation of these extended equations can be difficult; the information contained is summarized in Table 3, which presents predicted pulmonary function values at age 35 and 55 for individuals with and without the allergic conditions. It will be seen that while individuals with hay fever or sinusitis which began by age 21 show lower FEV,‘s than expected at age 35, the FEVl’s decline much less with age and are distinctly superior at age 55. Results for the PEFR, although not statistically significant, are consistent with those for the FEV,.
HAY
EQUATIONS
PREDICTING
FEVER
AND
PULMONARY
PULMONARY
TABLE FUNCTION
2 BY HISTORY Regression
Age FEVi (liters) Hay fever Onset age O-21 Onset age 22+ Sinusitis Onset age O-21 Onset age 22+ PEFR (liters/minute) Hay fever Onset age O-21 Onset age 22+ Sinusitis Onset O-21 Onset age 22+
Allergy
Height
OF ALLERGIC
(Al)a
.0349
-1.7883 .5980
- .0332 - .0317
.0349 ,034s
-1.1567 - .0161
.0351
2.774 2.761
-1.692 -1.659
2.717 2.750
CONDITIONS
coefficients
- .0330 - ,0304
-1.741 -1.744
103
FUNCTION
-134.305 -54.059 -48.101 3.295
AZ X age
Intercept
.038@ - .0133
-1.2385 -1.3448
.0266* .0005
-1.2155 -1.2540
2.951 ,901
154.805 157.879
1.315 ,001
160.884 154.912
a Variable takes value 1 if respondent has condition, 0 otherwise. b P < 0.025. Significance levels of regression coefficients on age and height (Stebbings, 1971b).
presented
elsewhere
Estimated pulmonary function values for individuals with early onset hay fever (but not sinusitis) are higher at age 55 than at age 35: this is quite unexpected. Individuals with allergic conditions beginning in aduk life show rates of decline of pulmonary function similar to the remainder of the population, although it should be noted that for the better-defined condition, hay fever, and the less
PRIGDICTRD
PULMONARY
FUNCTION FEV,
Onset age O-21 Hay fever Present Absent Sinusitis Present Absent Onset age 22+ Hay fever Present Absent Sinusitis Present Absent D For
a standing
TABLE VALUES
3 RY HISTORY
OF ALLERGIC
at agea
PEFR
CONDITIONS at age”
35
55
35
55
3.11 3.56
3.21 2.90
534 565
559 531
3.33 3.56
3.20 2.89
562 563
554 530
3.66 3.53
2.79 2.92
544 566
527 531
3.55 3.55
2.93 2.91
568 564
535 ,531
height
of 170 cm. From
equations
in Table
2.
104
JAMES
H.
STEBBINGS,
JR.
variable measurement, the FEV, there are indications of an accelerated rate of decline. There were few respondents with allergies above age 55, so it was felt to be safer to estimate the effects in Table 3 only in the age range 35-55. Obviously if the predicted values at age 65 were shown, the results would be much more dramatic. The effects of early onset hay fever and sinusitis are nearly identical; this is not due to the statistical association of these two conditions. Of 60 individuals reporting both hay fever and sinusitis with onset by age 21 only eight reported both; the estimated effects, then, are based on 52 individuals out of the study population of 410. Extreme deviations from expected pulmonary function values which might have accidentally caused these results were sought for among respondents with early onset allergies in the 55-64 age group and among the eight respondents reporting both early onset hay fever and sinusitis, but none was found. DISCUSSION
Before discussion of the meaning of these findings, it is desirable to consider some objections to them having to do with the classification of allergic disorders and with the possibility that certain intervening variables have created spurious associations. Individuals who reported a history of asthma were excluded from this analysis, as chronic respiratory diseases other than asthma were the original concern. History of asthma was, of course, strongly associated with histories of sinusitis and hay fever in the total study population, and diagnosed asthma present for some time would be expected to be found associated with impaired pulmonary function, increasingly so with age, in population surveys of this type (Densen et al., 1969). In this study some preliminary results for the 19 asthmatics among the respondents showed their mean deviation from the predicted FEV, to be - 0.41 liter and from the predicted PEFR - 110 liters/min. No analysis was made of any age effect on these average deviations. It must be emphasized that the results presented here apply only to individuals with hay fever or sinusitis who claim never to have had asthma. This is the great majority of respondents with hay fever and sinusitis: 91%of those with early onset sinusitis and 80% of those with early onset hay fever (adult onset sinusitis and hay fever were not significantly associated with a history of asthma). An objection may be raised as to the meaning of the term “sinusitis” to the respondent. Some positive responses probably do not refer to IgE-mediated allergic responses. However, a positive history of early onset hay fever correlates very highly (P < 0.601) with a positive history of early onset sinusitis in the study population. Further, of 14 persons reporting both hay fever and sinusitis still present, in only one case was the age-at-onset category discordant. Rarely, if ever, would sinusitis coded as still present in this population have referred to sinus infection rather than to an allergic condition (though the allergic condition would not necessarily be IgE-mediated) .
HAY
FEVER
AND
PULMONARY
FUNCTION
105
Possible intervening variables which must be considered are pipe/cigar smoking, social class, and history of urban residence. Each of these may be related to age at onset of hay fever or sinusitis; in all cases, however, the effects of these variables on pulmonary function are too small to account for the findings reported here. Pipe/cigar smoking, with no history of cigarette smoking, was not significantly correlated with the FEV, or the PEFR in this population ( Stebbings, 1971b), and its effect on the FEVl is relatively minor ( Stebbings, 1972), so an association of pipe/cigar smoking with a negative history of early onset allergies could not explain these results. An effect of social class on pulmonary function values in this population exists ( Stebbings, 1971~). However, the social class effect did not vary significantly by age, as do these, and it was determined that it was attained social class rather than the social class of the respondent during his adolescence that was related to his pulmonary function values. History of residence in urban areas of 50,000-tpopulation was related to the prevalence of early onset hay fever and sinusitis. It was not, however, significantly related to the FEV,, and its effect on the PEFR was in the wrong direction to explain these results (Stebbings, 1971d). Early onset hay fever and sinusitis, in this study, affect the FEV, at least as strongly as any environmental variable so far described in the literature. Interpretation of these results may proceed in two distinct, but not mutually contradictory, directions. The first is to postulate a very strong age-cohort effect. The second is to assume that these age trends, estimated from cross-sectional data, do approximate the true longitudinal experience of this population. It is, of course, possible that the effects are statistical accidents, or the results of an unidentified variable. A strong age-cohort effect is suggested by the higher predicted pulmonary function values at age 55 than at age 35 among respondents with early onset hay fever, for the conclusion that pulmonary function increases with age in this group is not likely to be accepted. This is a migrant population, and it might be hypothesized that migration occurred in different decades for different reasons; how such reasons could be so strongly related to pulmonary function values and to age at onset of allergic conditions is not clear. More directly, one might hypothesize that after 1930 some environmental factor, or perhaps treatment regimen, acted to strongly impair lung function in young persons with respiratory allergies. This would not explain a superiority in later adult life relative to the nonallergic, and the evidence to that effect must then be assumed to be due to chance. If the cross-sectional effects found are real and do approximate the longitudinal experience, rather than being an age-cohort effect, one must assume that the apparent increase between age 35 and 55 among those with early onset hay fever is a statistical artifact and that the results for sinusitis are closer to reality. Then one may conclude that IgE does, directly or indirectly, play a role in the defenses of the lung against the agents causing the decline of lung function with age. (The initially lower values will be discussed below,) TO this author the most appealing hypothesis is that IgE-related immunologic
196
JAMES
H.
STEBBINGS,
JR.
responsiveness is protective. In this view age at onset may be taken as a crude index of immunologic responsiveness among those persons susceptible to hay fever in their environment through possession of certain immune response genes (Levine et al., 1972; Marsh et al., 1973). Persons without hay fever or sinusitis are considered as predominantly nonsusceptibles of varying immunologic responsiveness. It must be remembered that virtually everyone is sufficiently responsive to suffer seasonally from one reagin-mediated hypersensitivity reaction, the mosquito bite ( McKiel and West, 1961). One implication of this hypothesis is that a late age at onset of hay fever should be associated with an excessive rate of decline of pulmonary function relative to those members of the population unaffected by hay fever. Such an effect on the FEV, is suggested but certainly not proved in Table 3. Further investigation of this question would require that age at onset be analyzed as a continuous variable. Two alternative hypotheses both imply that persons with adult onset hay fever should have pulmonary function values which decline less rapidly than those in the unaffected population. The first of these is that IgE does play a direct protective role in the lung, and that hay fever stimulates IgE response to other antigens. The second is that hay fever without asthma really means hay fever with asthma but without bronchospasm, and that the hyperemia and mucosal congestion which have been suggested as being the basic indications of asthma (Baker, 1972) are protective against the agents causing long-term decline in lung function. This could be an increased production of secretory IgA, or physical obstruction which reduces the amount of an agent reaching the lung periphery. The latter has been hypothesized to explain a possible protective effect of cigarette smoking on the decline in lung function in workers exposed to asbestos (Becklake et al., 1972). The lower FEV, and PEFR values found at age 35 among respondents with early onset hay fever and sinusitis are difficult to explain, yet it is typical for the persons at greater risk of chronic respiratory disease to show the higher pulmonary function values at an early age. This occurs among cigarette smokers in some populations (Ferris et al., 1965; Ashford et al., 196S), in some study populations exposed to higher air pollution levels (Stebbings, 1971d), and for whites relative to blacks in North America (Stebbings, 1973). Self-selection of persons taking up the smoking habit has been advanced as an explanation for this effect among cigarette smokers; blacks, it is thought, simply begin with a smaller lung for a given body size; the situation with air pollution is obscure. In this study retardation of lung development could be suggested. Epidemiologic studies of pulmonary function, either in children or adults, have emphasized the concept of impairment of function, and no studies have explicitly looked at factors affecting the peak levels of function attained before decline begins. It may be that toward the end of life there is no difference in risk of morbidity attached to a given retardation of development and an equivalent impairment of the lung, but the question has not been raised. Age 35 is only 7-10 years after an individual’s maximum PEFR would have been reached (Stebbings, 1971d); thus, any deficit at age 35 is more a result of the peak value attained than the rate of decline from that point. While one
HAY FEVER AND PULMONARY FUNCTION
107
study has found the vital capacity to peak at age 28 (Berglund et al., 19631, another study has found a decline from the late teens (Ashford et al., 1968>, as has this author (unpublished data) in a New York City population (Stebbings, 1972). Thus, little can be said concerning the relative importance of retarded development and decline in function for the FEV,. Another possible explanation for the lowered values at age 35 is that there is some hyperemia and congestion in the lungs associated with hay fever and sinusitis; this would affect flow rates, lowering the observed PEFR and FEV1. If such an effect were constant with age and additive to the long-term protective effect, it could explain the observed crossing-over of the pulmonary function values. If the hypothesis that IgE-mediated reactions are protective against chronic nonspecific respiratory disease proves valid, then it may partially explain the social class and race differences in morbidity and mortality. American Negroes seem to experience less chronic respiratory morbidity and mortality than whites, and the pulmonary function values of Negro smokers decline less rapidly than those of whites with the same cigarette smoking his1973). Negroes suffer greatly excessive asthma mortality tories (Stebbings, rates, especially in the younger age groups (Dauer et al., 1968); evidence for a higher prevalence of hay fever or an earIier age at onset may not exist. Among New York City postal and transit workers the frequency of a history of hay fever was not significantly different between blacks and whites (Densen et al., 1967), but no data were collected on age at onset or whether the condition was still present. Excess respiratory morbidity and mortality is frequently found in the lower social classes,although this effect is not found in all countries and may disappear in younger cohorts (Stebbings, 1971c). Hay fever, since the time of Osler, has been thought to be related to social class: “Working people or members of uncivilized nations are very rarely attacked by it. Hay fever especially attacks individuals who belong to the higher strata of culture, and particularly those who are exposed to intense intellectual strain or excitement (Dunbar, 1913).” The lower classeshave not yet reached equality in the prevalence of hay fever in this Hagerstown population, but prevalence rates for sinusitis are nearly identical across the social classes. However, both hay fever and sinusitis with onset by age 21 are more frequent in the higher social class categories. The relationship of age at onset to social class is more evident than the relationship of overall prevalence to social class in this population (Stebbings, 197lc). A protective effect against chronic respiratory disease among the upper social classesmight thus exist. Early age at onset of allergies is also related to urban residence in this population, and may explain the interrelationships of urban residence in adult life, age, and pulmonary function described previously ( Stebbings, 1971d). Of ultimate interest, if these findings can be successfully replicated and are found to hold for smokers as well, is that they suggest leads to the investigation of endogenous factors in chronic respiratory disease which may be more profitable than some of those of the past.
108
JAMES
H.
STEBBINGS,
JR.
REFERENCES AMMANN, A. J., CAIN, W. A,, ISHIZAKA, K., HONG, R., AND GOOD, R. A. (1969). Immunoglobulin E deficiency in ataxia-telangiectasia. N. Engl. J. Med. 281, 469472. ASHFORD, J. R., BROWN, S., MORGAN, D. C., AND RAE, S. (1968). The pulmonary ventilatory function of coal miners in the United Kingdom. Amer. Rev. Resp. Dis. 97, 810-826. BAKER, H. (1972). Lack of direct evidence that bronchospasm is a prime factor in the production of asthma. Amer. Rev. Resp. Dis. 105, 839-842. BECKLAKE, M. R., FOURNIER-MASSEY, B., ROSSITER, C. E., AND MCDONALD, J. C. ( 1972). Lung function in chrysotile asbestos mine and mill workers of Quebec. Arch. Environ. Health 24,401-409. BERGLUND, E., BIRATH, G., BJURE, J., GRIMBY, G., K JELLMER, I., SANDQUIST, L., AND SODERHOLM, B. (1963). Spirometric studies in normal subjects. I. Forced expirograms in subjects between 7 and 70 years of age. Acta Med. Stand. 173, 185-192. CULLEN, K. J., STENHOUSE, N. S., WELBORN, T. A., MCCALL, M. G., AND CURNOW, D. H. ( 1968). Chronic respiratory disease in a rural community. Lancet 2, 657460. DAUER, C. C., KORNS, R. F., AND SCHUMAN, L. M. ( 1968 ). “Infectious Diseases.” Harvard Univ. Press, Cambridge. DENSEN, P. M., JONES, E. W., BASS, H. E., AND BREUER, J. (1967). A survey of respiratory disease among New York City postal and transit workers. I. Prevalence of symptoms. Environ. Res. 1, 265-286. DENSEN, P. M., JONES, E. W., BASS, H. E., BREUER, J., AND REED, E. (1969). A survey of respiratory disease among New York City postal and transit workers. 2. Ventilatory function test results. Environ. Res. 2, 277-296. DUNBAR, W. P. (1913). Hay fever. In “Modern Medicine. Its Theory and Practice” (W. Osler and T. McCrae, eds.), ed. 2, Vol. II. Lea & Febiger, Philadelphia. FERRIS, B. G., JR., ANDERSON, D. O., AND ZICKMANTEL, R. ( 1965). Prediction values for screening tests of pulmonary function. Amer. Rev. Resp. Dis. 91, 252-261. FUDENBERG, H. H. ( 1971). Immunoglobulins: structure, function, and genetic control. In “Immunologic Incompetence.” (B. M. Kagan and E. R. Stiehm, eds.). Year Book Medical Publishers, Chicago. JOULES, H. ( 1956). Chronic bronchitis. Proc. Roy. Sot. Med. 41,779-780. KOJIMA, S., YOKOGAWA, M., AND TADA, T. ( 1972). Raised levels of serum IgE in human helminthiases. Amer. I. Trap. Med. Hyg. 21, 913-918. LEVINE, B. B., STEMBER, R. H., AND FOTINO, M. ( 1972). Ragweed hay fever: genetic control and linkage to HL-A haplotypes. Science 178, 1201-1203. LEW, D. A., AND CHEN, J. (19’70). Healthy IgE-deficient person. N. Engl. J. Med. 283, 541-542. LEWIS, D. M., LAPP, N. L., AND BURRELL, R. ( 1970). Quantitation of secretory immunoglobulin A in chronic pulmonary disease. Amer. Rev. Resp. Dis. 101, 55-61. MARSH, D. G., BIAS, W. B., Hsu, S. H., AND GOODFRIEND, L. (1973). Association of the HL-A7 cross-reacting group with a specific reaginic antibody response in allergic man. Science 179,691-693. MCKIEL, J. A., AND WEST, A. S. ( 1961). Nature and causation of insect bite reactions. Pediat. Clin. N. Amer. 8, 795-816. POLMAR, S. H., ROBINSON, L. D., JR., AND MINNEFOR, A. B. (1972). Immunoglobulin E in bronchiolitis. Pediatrics 50, 279-284. STEBBINGS, J. H., JR. (1971a). Chronic respiratory disease among nonsmokers in Hagerstown, Maryland. I. Design of the study and prevalence of symptoms. Environ. Res. 4, 146162. STEBBINGS, J. H., JR. (197Ib). Ch ronic respiratory disease among nonsmokers in Hagerstown, Maryland. II. Problems in the estimation of pulmonary function values in epidemiological surveys. Environ. Res. 4, 163-192. STEBBINGS, J. H., JR. (1971~). Chronic respiratory disease among nonsmokers in Hagerstown, Maryland. III. Social class and chronic respiratory disease. Environ. Res. 4, 213-232.
HAY
STEBBINGS, J. H., town, Maryland.
JR. IV.
(197ld). Effects
FEVER
AND
PULMONARY
FUNCTION
Chronic respiratory disease of urban residence on pulmonary
among nonsmokers function values.
109 in HagersEnoiron. Res.
4,283-304. STEBBINGS, J. H., JR. ( 1972). A survey of respiratory disease among New York City postal and transit workers. III. Anthropometric, smoking, occupational, and ethnic variables affecting the FEVX among white males. Environ. Res. 5, 451-466. STEBBINGS, J. H., JR. ( 1973). A survey of respiratory disease among New York City postal and transit workers. IV. Racial differences in the FEV,. Enuiron. Bes. 6, 147-158. VAN DER LENDE, R. (1969). “Epidemiology of Chronic Non-specific Lung Disease (Chronic Bronchitis ) .” Thomas, Springfield.
RESEARCH
Chronic
7, 99-109
( 1974)
Respiratory
Disease
in Hagerstown,
Among
Nonsmokers
Maryland
V. Age at Onset of Hay Fever and Pulmonary Function in later Life1 JAMES H. STEBBINGS, JR.~ Division
of Epidemiology,
School Minneapolis, Received
of Public Minnesota May
Health, University 55455
of Minnesota,
25, 1973
In white male nonsmokers of cigarettes the decline of the FEV, between the ages 35 and 55 was significantly less than expected among respondents who reported hay fever or sinusitis, still present, which began before age 21. These respondents, 52 individuals out of 410, showed lower FEV]‘s at age 35 and higher at age 55 than expected. Respondents with a history of asthma were excluded from the analysis. Individuals with hay fever or sinusitis beginning in adult life did not differ from the remainder of the population. The PEFR showed the same, but not statistically significant, pattern as the FEV1. The observed effect of early onset hay fever and sinusitis was very strong. Whether it is due to an age-cohort effect of undetermined origin or may be explained by one of the several biological hypotheses discussed is not clear. Early age at onset of hay fever and sinusitis is associated with higher socioeconomic status in early life. Despite we know
the numerous epidemiological studies of chronic respiratory disease little
of the determinants
of individual
response
to the etiologic
agents.
Alphal-antitrypsin deficiency, secretory immunoglobulin A ( IgA) concentrations, and certain indicators of allergy have been studied, not necessarily adequately, but without yielding clear evidence that they are important in the population as determinants of chronic respiratory disease morbidity or mortality. This paper presents evidence that IgE-mediated upper respiratory allergies, present since childhood, are associated with higher than expected pulmonary function values after age 50, at least among nonsmokers, and suggests some possible interpretations of these unexpected findings. The natural functions of IgE are at present obscure, although considerable attention is being given to its role in parasitic diseases (Kojima et al., 1972). A role in resistance to sinopulmonary infections has been suggested (Ammann 1 Research in Hagerstown, Maryland, was supported by Public Health Service Grants GRS 47-65 and GRS 35-66. The Training Center for Public Health Research in Hagerstown was supported by PHS Grant CD-00001. Support for the investigator was received from the National Heart Institute under Grant TI-HE-5297. Additional support was received from the Washington County (Maryland) Tuberculosis Association. ’ From the Division of Epidemiology, School of Public Health, Mayo Memorial Building Box 197, University of Minnesota, Minneapolis, Minnesota 55455. (Address for reprint requests.) 99 Copyright @ 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.
100
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H.
STEBBINGS,
JR.
et al., 1969), but this may not be the case (Levy and Chen, 1970) except possibly in highly allergic subjects (Fudenberg, 1971). High serum IgE levels are associated with nonepidemic bronchiolitis in infants (Polmar et al., 1972). Infections of the teeth and sinusesare commonly believed to be related to chronic bronchitis (Joules, 1956). Blood eosinophilia and hyperreactivity of the bronchial tree, but not number of positive skin test reactions, have been related to chronic nonspecific lung disease (van der Lende, 1969): the time relations of these associations have, however, not been adequately defined. Also, associations of hay fever with simple chronic bronchitis among nonsmokers have been reported (Cullen et al., 1$X2$ Stebbings, 1971a). Secretory IgA production has been found to be suppressed by cigarette smoking in normal subjects, but not in patients with chronic respiratory disease, and low concentrations of secretory IgA may predispose to chronic respiratory infections (Lewis et al., 1970). Recent work (Levine et al., 1972; Marsh et al., 1973) indicating the existence of immune response genes, specific for certain ragweed pollen antigens and necessary but not sufficient for the development of hay fever, suggested one biological interpretation of the previously unpublished findings reported here and stimulated their publication. METHODOLOGY
A special census of Washington County, Maryland, was carried out in 1963 by the Johns Hopkins School of Hygiene and Public Health, the National Cancer Institute, and the Washington County Health Department. From these census records all white males aged 35-64 were selected who met certain criteria for smoking and residence histories. The smoking criterion was that the respondent had been a nonsmoker of cigarettes at the time of the census. The residence criteria were that the respondent had lived in the city of Hagerstown or certain contiguous areas at the time of the census and that he had resided outside Washington County for at least 20 years of his life. Of 736 individuals, 81 ( 11.0%) had moved out of the county, and 14 ( 15%) were deceased. Of the 641 still available individuals who met these criteria, 578 (9C%) were interviewed. From those interviewed the study population was defined as those 469 respondents who had never smoked cigarettes or who did not currently smoke and had never smoked as often as once a day. For this analysis 410 individuals from the population were selected on the basis of their medical histories; individuals with a history of asthma, heart disease, and a variety of rarer conditions (Stebbings, 1971a) were excluded for reasons having to do with the original aim of the study, which was to investigate the effect of urban residence on pulmonary function values in nonsmokers of cigarettes. The FEV, was measured using the McKesson Vitalor, the PEFR using the Wright peak flow meter. The maximum values attained in three trials are used in this analysis. Analyses of pulmonary function values were carried out using multiple regression techniques; instrument and interviewer effects were found
HAY
FEVER
AND
PULMONARY
101
FUNCTION
to be significant and were incorporated into the regression equations by the use of dummy variables ( Stebbings, 1971b). A positive history of hay fever or sinusitis was recorded for an affirmative re(sinus sponse to the question “Have you ever had hay fever or rosefever trouble)?” The respondent was questioned further concerning the age at which the condition began and whether it was still present. Coding was by age at onset, in categories O-12, U-21, and 22+ years of age, and by whether or not the respondent still suffered from the condition. Histories of sinusitis and hay fever not still present were infrequent, and are here treated as negative histories. Interviewing took place in the winter and early spring months of 1966, and only a small amount of extended follow-up interviewing extended into the spring polIen season. A full description of the design of the study, the measurement and analysis of the pulmonary function values, and the socioeconomic characteristics and urban residence histories of the population have been published (Stebbings, 1971a,b,c,d). The analyses presented here were carried out in 1966. In retrospect, more detailed coding of the data and some changes in the multiple regression model used in the analysis would have been desirable. The potential benefits of reanalysis, however, were minimal relative to the time and unreimbursable expense involved in retrieving the data. RESULTS
The prevalences of hay fever and sinusitis by age and age at onset are shown in Table 1. The age categories 6-12 and 13-21 were combined, but the adult onset group was split into two categories for tabulation, 2234 and 35+, as the lowest age of the respondents at interview was 35. TABLE PREVALENCE
BY AGB
AND
AGE
1
AT ONSET
OF SINUSITIS Age
35-44 No.
No.
HAY
FEVER
(v-1
45-54
Yo
AND
55-64 %
No.
35-64 %
No.
%
Hay fever Onset age O-21 Onset age 22-34 Onset age 35+ Total
8 12 3 23
6.1 9.1 2.3 17.4
12 5 3 20
6.8 2.8 1.7 11.4
2 0 6 8
2.0 0.0 5.9 7.8
22 17 12 51
5.4 4.1 2.9 12.4
Sinusitis Onset Onset Onset Total
17 10 7 34
12.9 7.6 5.3 25.8
17 8 16 41
9.7 4.5 9.1 23.3
4 5 14 23
3.9 4.9 13.7 22.5
38 23 37 98
9.3 5.6 9.0 23.9
Total
age O-21 age 22-34 age 35+
population
132
176
102
410
I.02
JAMES
H.
STEBBINGS,
JR.
A cohort effect in the prevalence of both hay fever and sinusitis with onset by age 21 appears, and remains when one considers conditions with onset by age 35. This cohort effect remains for all hay fever combined, but the age-specific prevalences of sinusitis are remarkably constant. The relationships of a number of respiratory symptoms and histories of respiratory illness to the FEV, and the PEFR were examined. Respiratory symptoms are, of course, correlated with mild deficits in pulmonary function and such was the case in this study population. As no respondents with a history of daily cigarette smoking were included in the study, histories and symptoms suggestive of chronic respiratory disease were infrequent (Stebbings, Ni’la), and the magnitudes of their effect on the pulmonary function values were small relative to the magnitudes of the effects of sinusitis and hay fever to be described here. The effects of the allergic conditions on puImonary function were analyzed by the addition of variables to the regression equations describing pulmonary function values in the study population. The basic prediction equations are: FEVr
(liters)
= - 1.258 - .0316
X age + .034S X standing height (cm),
and PEFR
(liters/min)
= 155.4 -
1.648
X age X 2.746 X standing height (cm)
plus certain instrument and interviewer effects (Stebbings, 197213) which, although always incorporated in the following analysis, do not need to be shown. The equations presented are correct for the reference instrument and interviewers. Mean values in this study population for the FEV, and PEFR were 3.28 liters and 554 liters/min, respectively. The average difference between individuals with sinusitis and hay fever and persons of the same age and height was estimated by the regression coefficient on a dummy variable (AZ, for allergy, taking the value 1 if the respondent has the condition, 0 otherwise) added to the above equations. These effects were minor, though consistent with the results below, and did not approach statistical significance. The effect of sinusitis and hay fever on the aging of pulmonary function, however, is estimated by the addition of the interaction term of the dummy variable with age (AZ x age) along with the original dummy variable (AZ). The equations so obtained are shown in Table 2, and it will be seen that, for the FEV,, the interaction terms of hay fever and sinusitis, with onset by age 21, are statistically significant and the estimated effects in an unexpected positive direction, while for the adult onset allergies the interaction terms were not significant and the estimated effects either negative or close to zero. Interpretation of these extended equations can be difficult; the information contained is summarized in Table 3, which presents predicted pulmonary function values at age 35 and 55 for individuals with and without the allergic conditions. It will be seen that while individuals with hay fever or sinusitis which began by age 21 show lower FEV,‘s than expected at age 35, the FEVl’s decline much less with age and are distinctly superior at age 55. Results for the PEFR, although not statistically significant, are consistent with those for the FEV,.
HAY
EQUATIONS
PREDICTING
FEVER
AND
PULMONARY
PULMONARY
TABLE FUNCTION
2 BY HISTORY Regression
Age FEVi (liters) Hay fever Onset age O-21 Onset age 22+ Sinusitis Onset age O-21 Onset age 22+ PEFR (liters/minute) Hay fever Onset age O-21 Onset age 22+ Sinusitis Onset O-21 Onset age 22+
Allergy
Height
OF ALLERGIC
(Al)a
.0349
-1.7883 .5980
- .0332 - .0317
.0349 ,034s
-1.1567 - .0161
.0351
2.774 2.761
-1.692 -1.659
2.717 2.750
CONDITIONS
coefficients
- .0330 - ,0304
-1.741 -1.744
103
FUNCTION
-134.305 -54.059 -48.101 3.295
AZ X age
Intercept
.038@ - .0133
-1.2385 -1.3448
.0266* .0005
-1.2155 -1.2540
2.951 ,901
154.805 157.879
1.315 ,001
160.884 154.912
a Variable takes value 1 if respondent has condition, 0 otherwise. b P < 0.025. Significance levels of regression coefficients on age and height (Stebbings, 1971b).
presented
elsewhere
Estimated pulmonary function values for individuals with early onset hay fever (but not sinusitis) are higher at age 55 than at age 35: this is quite unexpected. Individuals with allergic conditions beginning in aduk life show rates of decline of pulmonary function similar to the remainder of the population, although it should be noted that for the better-defined condition, hay fever, and the less
PRIGDICTRD
PULMONARY
FUNCTION FEV,
Onset age O-21 Hay fever Present Absent Sinusitis Present Absent Onset age 22+ Hay fever Present Absent Sinusitis Present Absent D For
a standing
TABLE VALUES
3 RY HISTORY
OF ALLERGIC
at agea
PEFR
CONDITIONS at age”
35
55
35
55
3.11 3.56
3.21 2.90
534 565
559 531
3.33 3.56
3.20 2.89
562 563
554 530
3.66 3.53
2.79 2.92
544 566
527 531
3.55 3.55
2.93 2.91
568 564
535 ,531
height
of 170 cm. From
equations
in Table
2.
104
JAMES
H.
STEBBINGS,
JR.
variable measurement, the FEV, there are indications of an accelerated rate of decline. There were few respondents with allergies above age 55, so it was felt to be safer to estimate the effects in Table 3 only in the age range 35-55. Obviously if the predicted values at age 65 were shown, the results would be much more dramatic. The effects of early onset hay fever and sinusitis are nearly identical; this is not due to the statistical association of these two conditions. Of 60 individuals reporting both hay fever and sinusitis with onset by age 21 only eight reported both; the estimated effects, then, are based on 52 individuals out of the study population of 410. Extreme deviations from expected pulmonary function values which might have accidentally caused these results were sought for among respondents with early onset allergies in the 55-64 age group and among the eight respondents reporting both early onset hay fever and sinusitis, but none was found. DISCUSSION
Before discussion of the meaning of these findings, it is desirable to consider some objections to them having to do with the classification of allergic disorders and with the possibility that certain intervening variables have created spurious associations. Individuals who reported a history of asthma were excluded from this analysis, as chronic respiratory diseases other than asthma were the original concern. History of asthma was, of course, strongly associated with histories of sinusitis and hay fever in the total study population, and diagnosed asthma present for some time would be expected to be found associated with impaired pulmonary function, increasingly so with age, in population surveys of this type (Densen et al., 1969). In this study some preliminary results for the 19 asthmatics among the respondents showed their mean deviation from the predicted FEV, to be - 0.41 liter and from the predicted PEFR - 110 liters/min. No analysis was made of any age effect on these average deviations. It must be emphasized that the results presented here apply only to individuals with hay fever or sinusitis who claim never to have had asthma. This is the great majority of respondents with hay fever and sinusitis: 91%of those with early onset sinusitis and 80% of those with early onset hay fever (adult onset sinusitis and hay fever were not significantly associated with a history of asthma). An objection may be raised as to the meaning of the term “sinusitis” to the respondent. Some positive responses probably do not refer to IgE-mediated allergic responses. However, a positive history of early onset hay fever correlates very highly (P < 0.601) with a positive history of early onset sinusitis in the study population. Further, of 14 persons reporting both hay fever and sinusitis still present, in only one case was the age-at-onset category discordant. Rarely, if ever, would sinusitis coded as still present in this population have referred to sinus infection rather than to an allergic condition (though the allergic condition would not necessarily be IgE-mediated) .
HAY
FEVER
AND
PULMONARY
FUNCTION
105
Possible intervening variables which must be considered are pipe/cigar smoking, social class, and history of urban residence. Each of these may be related to age at onset of hay fever or sinusitis; in all cases, however, the effects of these variables on pulmonary function are too small to account for the findings reported here. Pipe/cigar smoking, with no history of cigarette smoking, was not significantly correlated with the FEV, or the PEFR in this population ( Stebbings, 1971b), and its effect on the FEVl is relatively minor ( Stebbings, 1972), so an association of pipe/cigar smoking with a negative history of early onset allergies could not explain these results. An effect of social class on pulmonary function values in this population exists ( Stebbings, 1971~). However, the social class effect did not vary significantly by age, as do these, and it was determined that it was attained social class rather than the social class of the respondent during his adolescence that was related to his pulmonary function values. History of residence in urban areas of 50,000-tpopulation was related to the prevalence of early onset hay fever and sinusitis. It was not, however, significantly related to the FEV,, and its effect on the PEFR was in the wrong direction to explain these results (Stebbings, 1971d). Early onset hay fever and sinusitis, in this study, affect the FEV, at least as strongly as any environmental variable so far described in the literature. Interpretation of these results may proceed in two distinct, but not mutually contradictory, directions. The first is to postulate a very strong age-cohort effect. The second is to assume that these age trends, estimated from cross-sectional data, do approximate the true longitudinal experience of this population. It is, of course, possible that the effects are statistical accidents, or the results of an unidentified variable. A strong age-cohort effect is suggested by the higher predicted pulmonary function values at age 55 than at age 35 among respondents with early onset hay fever, for the conclusion that pulmonary function increases with age in this group is not likely to be accepted. This is a migrant population, and it might be hypothesized that migration occurred in different decades for different reasons; how such reasons could be so strongly related to pulmonary function values and to age at onset of allergic conditions is not clear. More directly, one might hypothesize that after 1930 some environmental factor, or perhaps treatment regimen, acted to strongly impair lung function in young persons with respiratory allergies. This would not explain a superiority in later adult life relative to the nonallergic, and the evidence to that effect must then be assumed to be due to chance. If the cross-sectional effects found are real and do approximate the longitudinal experience, rather than being an age-cohort effect, one must assume that the apparent increase between age 35 and 55 among those with early onset hay fever is a statistical artifact and that the results for sinusitis are closer to reality. Then one may conclude that IgE does, directly or indirectly, play a role in the defenses of the lung against the agents causing the decline of lung function with age. (The initially lower values will be discussed below,) TO this author the most appealing hypothesis is that IgE-related immunologic
196
JAMES
H.
STEBBINGS,
JR.
responsiveness is protective. In this view age at onset may be taken as a crude index of immunologic responsiveness among those persons susceptible to hay fever in their environment through possession of certain immune response genes (Levine et al., 1972; Marsh et al., 1973). Persons without hay fever or sinusitis are considered as predominantly nonsusceptibles of varying immunologic responsiveness. It must be remembered that virtually everyone is sufficiently responsive to suffer seasonally from one reagin-mediated hypersensitivity reaction, the mosquito bite ( McKiel and West, 1961). One implication of this hypothesis is that a late age at onset of hay fever should be associated with an excessive rate of decline of pulmonary function relative to those members of the population unaffected by hay fever. Such an effect on the FEV, is suggested but certainly not proved in Table 3. Further investigation of this question would require that age at onset be analyzed as a continuous variable. Two alternative hypotheses both imply that persons with adult onset hay fever should have pulmonary function values which decline less rapidly than those in the unaffected population. The first of these is that IgE does play a direct protective role in the lung, and that hay fever stimulates IgE response to other antigens. The second is that hay fever without asthma really means hay fever with asthma but without bronchospasm, and that the hyperemia and mucosal congestion which have been suggested as being the basic indications of asthma (Baker, 1972) are protective against the agents causing long-term decline in lung function. This could be an increased production of secretory IgA, or physical obstruction which reduces the amount of an agent reaching the lung periphery. The latter has been hypothesized to explain a possible protective effect of cigarette smoking on the decline in lung function in workers exposed to asbestos (Becklake et al., 1972). The lower FEV, and PEFR values found at age 35 among respondents with early onset hay fever and sinusitis are difficult to explain, yet it is typical for the persons at greater risk of chronic respiratory disease to show the higher pulmonary function values at an early age. This occurs among cigarette smokers in some populations (Ferris et al., 1965; Ashford et al., 196S), in some study populations exposed to higher air pollution levels (Stebbings, 1971d), and for whites relative to blacks in North America (Stebbings, 1973). Self-selection of persons taking up the smoking habit has been advanced as an explanation for this effect among cigarette smokers; blacks, it is thought, simply begin with a smaller lung for a given body size; the situation with air pollution is obscure. In this study retardation of lung development could be suggested. Epidemiologic studies of pulmonary function, either in children or adults, have emphasized the concept of impairment of function, and no studies have explicitly looked at factors affecting the peak levels of function attained before decline begins. It may be that toward the end of life there is no difference in risk of morbidity attached to a given retardation of development and an equivalent impairment of the lung, but the question has not been raised. Age 35 is only 7-10 years after an individual’s maximum PEFR would have been reached (Stebbings, 1971d); thus, any deficit at age 35 is more a result of the peak value attained than the rate of decline from that point. While one
HAY FEVER AND PULMONARY FUNCTION
107
study has found the vital capacity to peak at age 28 (Berglund et al., 19631, another study has found a decline from the late teens (Ashford et al., 1968>, as has this author (unpublished data) in a New York City population (Stebbings, 1972). Thus, little can be said concerning the relative importance of retarded development and decline in function for the FEV,. Another possible explanation for the lowered values at age 35 is that there is some hyperemia and congestion in the lungs associated with hay fever and sinusitis; this would affect flow rates, lowering the observed PEFR and FEV1. If such an effect were constant with age and additive to the long-term protective effect, it could explain the observed crossing-over of the pulmonary function values. If the hypothesis that IgE-mediated reactions are protective against chronic nonspecific respiratory disease proves valid, then it may partially explain the social class and race differences in morbidity and mortality. American Negroes seem to experience less chronic respiratory morbidity and mortality than whites, and the pulmonary function values of Negro smokers decline less rapidly than those of whites with the same cigarette smoking his1973). Negroes suffer greatly excessive asthma mortality tories (Stebbings, rates, especially in the younger age groups (Dauer et al., 1968); evidence for a higher prevalence of hay fever or an earIier age at onset may not exist. Among New York City postal and transit workers the frequency of a history of hay fever was not significantly different between blacks and whites (Densen et al., 1967), but no data were collected on age at onset or whether the condition was still present. Excess respiratory morbidity and mortality is frequently found in the lower social classes,although this effect is not found in all countries and may disappear in younger cohorts (Stebbings, 1971c). Hay fever, since the time of Osler, has been thought to be related to social class: “Working people or members of uncivilized nations are very rarely attacked by it. Hay fever especially attacks individuals who belong to the higher strata of culture, and particularly those who are exposed to intense intellectual strain or excitement (Dunbar, 1913).” The lower classeshave not yet reached equality in the prevalence of hay fever in this Hagerstown population, but prevalence rates for sinusitis are nearly identical across the social classes. However, both hay fever and sinusitis with onset by age 21 are more frequent in the higher social class categories. The relationship of age at onset to social class is more evident than the relationship of overall prevalence to social class in this population (Stebbings, 197lc). A protective effect against chronic respiratory disease among the upper social classesmight thus exist. Early age at onset of allergies is also related to urban residence in this population, and may explain the interrelationships of urban residence in adult life, age, and pulmonary function described previously ( Stebbings, 1971d). Of ultimate interest, if these findings can be successfully replicated and are found to hold for smokers as well, is that they suggest leads to the investigation of endogenous factors in chronic respiratory disease which may be more profitable than some of those of the past.
108
JAMES
H.
STEBBINGS,
JR.
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(197ld). Effects
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among nonsmokers function values.
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4,283-304. STEBBINGS, J. H., JR. ( 1972). A survey of respiratory disease among New York City postal and transit workers. III. Anthropometric, smoking, occupational, and ethnic variables affecting the FEVX among white males. Environ. Res. 5, 451-466. STEBBINGS, J. H., JR. ( 1973). A survey of respiratory disease among New York City postal and transit workers. IV. Racial differences in the FEV,. Enuiron. Bes. 6, 147-158. VAN DER LENDE, R. (1969). “Epidemiology of Chronic Non-specific Lung Disease (Chronic Bronchitis ) .” Thomas, Springfield.