Airway responses mild asthmatics
to exercise
in
E. Neil Schachter, M.D., Harvey Kreisman, M.D., Michael Littner, Gerald J. Beck, Ph.D., and Frans Voncken New Haven, Conn.
M.D.,
Measurements of flow on maximal and partial expiratoryflow-volume (MEFV and PEFV) curves offer a simple, sensitive, and safe method for studying the prevalence, clinical characteristics, and airway changes of exercise-induced bronchospasm (EIB). These methods show that asthmatic individuals with even mild disease clearly difser from nonasthmatic persons in terms of their airway response to exercise, Nineteen asthmatic and fourteen nonasthmatic volunteers underwent graded exercise testing to elicit exercise-induced bronchospasm. Pulmonary function was measured using MEFV and PEFV curves before and after exercise. Exercise-induced bronchospasm was demonstrated in 17 of 19 asthmatic subjects without inducing marked degrees of airway constriction. The most sensitive index of EIB was changes in Jrow rates measured at low lung volumes, particularly those measured on PEFV curves. Analysis of flow-volume curves suggested two patterns of airway response to exercise among asthmatics, involving, respectively, small and larger airways. No signiJicant changes in pulmonary function were demonstrated in the nonasthmatic subjects. The degree of EIB measured by changes in Jopowrates on the PEFV curve correlated with airway reactivity to nonspeciJic irritants such as cold weather, tobacco smoke, and respiratory tract infections, but not with a history of specific allergies. We suggest that EIB is a general feature of asthma, rejecting the increased reactivity of asthmatics to a wide variety of airway irritants.
Many asthmatics complain of dyspnea and have objective changes in lung function indicating progressive airway obstruction during the first 10 min following exercise. Both objective and subjective changes subside after 30 to 60 min.le4 This exerciseinduced bronchospasm (EIB) must be carefully distinguished from effort-associated dyspnea reported by patients with other underlying pulmonary disorders. The forced vital capacity (FVC), the forced expiratory volume in one second (FEV J, and the peak expiratory flow rate (PEFR) are most frequently used to follow this response. The accuracy and reproducibility of such effort-dependent measurements, however, have been questioned particularly in situations involving mild degrees of airway obstruction.5 In circumstances involving submaximal effort, patient fatigue could contribute to further inaccuracies of these measurements . In severe asthmatics,6 exercise-induced bronchoFrom the Department of Medicine, Yale University School of Medicine. Received for publication Sept. 28, 1977. Accepted for publication Feb. 8, 1978. Reprint requests to: E. Neil Schachter, M.D., Department of Medicine, Yale University School of Medicine, New Haven, Conn. 06510. Vol. 61, No. 6, pp. 390-398
spasm (EIB) occurs in up to 90% of subjects. In other studies, using subjects with less severe asthma, &e prevalence has been as low as 19%.? We won&red whether more sensitive, less effort-dependent stu&s might not show a higher prevalence of EIB among asthmatic subjects with mild disease. Maximal and partial expiratory flow volwnt (MEFV and PEFV) curves are a very sensitive method for detecting airway responses to constrictor stimuli.*-” We used these tests to study the effect of exercise challenge in both asthmatic and normal subjects. We also investigated the clinical hist&s of those studied to better delineate those at risk. SUBJECTS
AND METHODS
Exercise challenge studies were performed in 19 asahmatic subjects(I 7 male and 2 female) and 14 subjeds without any clinical history of wheezing or asthma(I 2 mrk and 2 female). Ages and baseline pulmonary function of these subjects are shown in Table 1. Becausewe were in&rested in studying responsesin asthmaticswith mild disease, our subjects were recruited from the University community. Clinic and hospitalized patients were not selected &use these individuals tend to have more severe disease. AU subjects had a past history of asthma as defined by the Amaican Thoracic Society. None of the subjects thus sekcted required steroid therapy or disodium cromoglycate for con-
0091-6749/7810661-0390$00.90/O
63 1978 The C. V. Mosby Co.
VOLUME NUMBER
61 6
Airway
responses to exercise
391
MEFV-CURVES
l>
2
-
Pre-exercise
---
Post-exercise
TLC
-60%
PEFV-CURVES
2
I
3
of Vital
Capacity+
VOLUME
MEASURED
4 FROM
6
5 TLC
7
(liters)
FIG.1. Pre- and post-exercisemaximal and partial expiratoryfiow volume curves. ThsTtC points have been superimposed in order to determine MEF,s/, and MEF,,, (P). As pointed out in the text, the total lung capacity may increasefollowing exercise.
Nortasthmatic Stair climbing (n = 7) Cycloergometer (n = 7) Asthmatic Cycloergometer (n = 19)
26.3 f 1.2
109.7 ?I 3.8
115.45 5.2
84.7 Ifr 5.4
120.1 -c 5.5
108.0+- 11.2
23.0 r 1.8
107.0 k 4.5
110.3r 3.6
84.0 r
1.3
119.3 t 7.9
113.7 -r- 4.8
24.5 2 0.7
104.5-t 2.3
84.3 k 4.5
66.9 +- 14.8
87.5 rt 6.2
S9.4 r
6.5
expressed as a percentof predicted with the exceptionof FEVIS expressed as FEV,/FVC x 100(mean+ SEM). *All measurements tF’redict&values:Bouhuys,A., andSchoenberg, J.: Personal communication.
trol of their disease.Their attacks,althoughvarying in frequency, respondedto outpatient treatment and none had requinedhospitalizationfor asthma.Presenceor absenceof a history of EIB was not a selectioncriterion. As a consequence,although a majority of subjects(17/19) did complain of wheezingafter exercise, only 3 felt that minimal exercisewas sufficient to elicit asthma.The other subjects required what they described as moderate or strenuous exerciseto elicit EIB, again confirming the relatively mild degreeof their clinical illness. Finally, the baselinepulmonary function of the asthmaticsubjectswas relatively normal ITable I). Healthy subjectswere volunteersfrom our laboratorystaff. In all instances,informed consentwas obtained. A detailed questionnaireincluding questionsrelated to respiratory symptoms, prior pulmonary disease,allergies, andEIB was administeredto eachsubject. Seventeenof the
19 asthmatic subjects noted dyspnea or wheezing after exercise; none of the normal subjectscomplainedof any wheezingor prolongeddyqmea following exmcise. Exercise studies were performed only if the subject’s usual asthmaticmedicationswere omitted in t?+e24 hr preceding testing. Exercise was performed at mimrdely the same time of day for each individual Fo avoid the possibleeffect of diurnal variarion. The asthmatic subjectsexercisedon a Cyclaergometer (Monark), on a maximum of four separatedays during which fixed exerciseloads were used. They p&led for 8 min, at a constantspeedof 50 cycleslsec,agstinsta con&ant work load. The workload on the initial study day was 300 kilopoad meters per minute (kpmlmin) and was increased up to a maximum of 900 kpm/min, in successivesessions. A steadystate, as judged by cardiacfrequency,was usually reachedby the fifth minute of exercise.The “threshold”
392
Schachter
J. ALLERGY
et al.
PEFR
FEV,
FVC
r
0
Asthmatics
m
Non-asthmatic
IO-19 20-29
F
o-9
>30
% FALL
PARAMETER
IN
MEF 40%
MEF 40%
o-9
CLIN. IMMUNOL. JUNE 1978
IO-19 20-29
>30
% FALL
o-9
IN
(PI
IO-19 2029
>30
PARAMETER
FIG. 2. Comparison
of the relative incidence of puImonan/ function changes following exercise. Each parameter is expressed as a percent of control. Normal subjects represent the group exercised on the Cycloergometer.
TABLE II. Effect
of exercise
on pulmonary
function
in 19 asthmatic
Pre-exercise FVC (L) FEV, (L) PEFR (L/set) MEF,, (Llsec) MEF,, (P) (L/set)
5.03 3.34 6.46 2.04 1.63
2 k +k ?I
0.18 0.16 0.49 0.22 0.18
0 min 4.92 3.37 6.51 2.19 1.81
+ c r k k
0.20* 0.18 0.48 0.27 0.25
subjects
(mean
6 min 4.86 3.15 6.09 1.83 I.31
+ k -t 2 +
0. I91 0.18t 0.49* 0.24t 0.19t
k
SEMI 16 min 4.83 3.14 5.89 1.85 1.46
+ 2 f + 2
0.18t 0.19t 0.51t 0.25* 0.22*
*p < 0.05. tp < 0.005. exercise load was reached when either a 10% fall in FEV, was found, or a heart rate greater than I50 beats/min for the last 3 min of their exercise was achieved, or if the subject was not able to tolerate greater effort. The mean maximal exercise load performed by the asthmatic subjects was 676 2 55 kpm/min (mean ? SEM). We examined the response to exercise among asthmatic subjects by looking at pulmonary function data of the highest exercise load used. A control group of 7 nonasthmatic subjects was similarly exercised at increasing workloads on a Cycloergometer until a heart rate of at least 150 beats/min was achieved during the last 3 min of exercise. The mean maximal exercise load performed by this group was 600 + 87 kpm/min, and the mean pulse rate achieved by the seventh minute of exercise was I61 -C 12 beats/min.
Because differences have been described among asthmatics (but not among nonasthmatics) in relation to the type of exercise used to elicit EIB, we studied a second nonasthmatic control group in which running up and down a flight of stairs for a total of 8 min was the stress used. This clinically relevant form of stress testing has been used by McNeil and co-workers3 to elicit EIB. Each of the 7 subjects in this group climbed one flight of stairs (I 5 steps) at a pace which induced a heart rate of at least 150 beats/min by the sixth minute of exercise. At least two studies were performed on each of these subjects. Measurements of flow and volume were obtained, using a flowmeter whose signal was electronically integrated to obtain volume, and recorded on a Gould X-Y recorder.‘* The subject inspired to approximately 70% of vital capacity
VOLUME NUMBER
61 6
Aitway responses to exercise
TABLE Hi. Maximum
StJbjfJCtS
post-exercise
fall in pulmonary
function
in 19 asthmatic
subjects*+
AFVC
AFEVI
D. S. P. s. B. D. I. N. W. H. G. G.
10 5 5 1 8 0
9 7 4 2 7 0
54 13 3 7 19 0
-7y i4 ;n I!4 7 :1
F. L. M. K. L. s.
7 0 2
6 0 2
19 0 I
2.; j C) II
Mean t SEM
4.2 c 1.2
4.1 2 I.1
13.6 t 5.6
II 6 10 4 7 12 3 13
21 31 18 13 II 12 17 5
56 57 50 20 0 23 12 6
Mean k SEM Group III E. L. ‘I’. A.
8.31 k 1.3
16.0 + 2.6
28.0 t 7.7
4 I
6 0
0 4
Mean 2 SEM
2.5 k 1.5
3.0 ” 3.0
2.0 + 2.0
Grof4p
393
A=bos
ANI=&
0’)
I
Group II R. D. M. L. G. c. D. L. J. D. D. P. T. G. S. K.
24.7 f_ 6.9 45 ?I Xl 34 0 .iu .3.! 1: 38.4 + 9.1 h 5 5.5 4 0.5
*All &creases are expressed as a percent of control pulmonary function values.
TThreegroupsrepresentdifferent patternsof flow limitation. Group I, flow limitations at low lung volumes; Group II, generalizedH O W limitation; Group III, no flow limitation.
and then expired forcefully to residual volume. He then inspired to total lung capacity and once again expired forcefully to residual volume. The parameters examined from these partial and maximal expiratory flow volume (PEFV and MEFV) curves were flow rates at a lung volume 6 0 % of the control vital capacity below total lung capacity (MEFao% [P] and MEFlocx) as well as FVC, FEV,, and PEFR (Fig. I). These maneuvers were performed IO min before exercise, immediately before exercise, and at 0, 6, 15, and 25 min following exercise. Three PEFV and MEFV maneuvers were done at I -min intervals at each of these times and the mean volumes and flow rates were determined. The postexercise values were expressed as a percent of the mean control values (immediately before exercise). Measurements of flow on MEFV and PEFV curves by the above method reflect flow at an absolute lung volume only if total lung capacity (TLC) remains unchanged.In normal subjects challenged with aerosol bronchoconstrictor agents?or exercise, It3changesin TLC have beenabsentor minimal. However, in asthmatics undergoing such challenges, increases in TLC may occur.‘a* I4 Such increases in TLC would tend to minimize the changesin flow measured by our method compared to those measured at an absolute lung volume. Therefore, our measurements probably under-
estimatethe decreasein lung function after exercise,when TLC increases in some subjects.
Pulmonary function studies performed before exercise challenge showed no airway obstnrction in the nonasthmatic subjects. Mild airway obstruction was seen in the asthmatic group (Table I). In both control groups of nonasthmatic subjects, lung function did not change significantly after exercise, suggesting that the type of provocation used in nonasthmatics does not affect the stability of their airways. For the group of asthmatic subjects, there was no significant change in any of the measured pulmonary function immediately following exercise with the exception of a small but significant fall in FVC. At 6 and 15 min, all function (Table II) had significantly decreased. W e examined the maximum percent decrease in
J. ALLERGY
394 Schachter et al.
TABLE IV. Pre-exercise
variation (mean r SEM) in asthmatics
compared
NC Pre-exerciset Post-exercise t r
2.7 L 0.48 5.78 + 1.00 4.6 (p < 0.001) 0.64 (p < 0.01)
to maximal
FEVI
2.94 9.56 3.28 0.05
xt 0.71 2 1.93 (p < 0.005) (NS)
post-exercise
PEFR
6.11 9.83 I .26 0.08
+ 1.43 k 2.49 (NS) (NS)
fall in pulmonary
MEF,,
7.83 k 1.58 19.80 k 4.88 2.7 (p < 0.025) 0.4 (NS)
CLIN. IMMUNOL. JUNE 1978
function*
MEF,,,,% (PI
10.4 -c 2.29 28.7 k 5.13 2.4 (p < 0.005) 0.34 (NS)
*These variations are expressedas a percentof pre-exercisecontrol values. tAbsolute values.
each pulmonary function parameter following exercise. These maximal changes have been described as a more sensitive index of EIB.’ When these maximum percent decreases in pulmonary function (compared to control and grouped by 10% intervals) were examined in the asthmatic and nonasthmatic groups exercising on the Cycloergometer, the MEFawc (P) discriminated best between these two groups (Fig. 2). Using a 10% or greater change in a given parameter to indicate response, none of the nonasthmatics showed a response. Similarly, the nonasthmatic stair climbing group also showed no response. On the other hand, 16 of 19 asthmatics demonstrated a response by MEF,o% (P), whereas only 7 of 19 showed a response by FEV, . Similarly, fewer asthmatics were identified by FVC, PEFR, or MEFIOQ than by MEFIOR (P). These results indicate that MEF4,,% (P) is the most sensitive of these measurements for distinguishing airway changes following exercise in these two groups. Two patterns of airway obstruction were noted when measurements of pulmonary function were separated into effort-dependent and independent parameters. In one instance airway obstruction was primarily manifested by a decrease in flow rates at low lung volumes, and in the second a more general decrease in flow rates was observed. As can be seen in Table III, 9 asthmatic subjects had maximal postexercise decreases in both FVC and FEVl which were less than lo%, but their maximal fall in MEFNRor MEF,,%(P) were greater than 10%; in 8 subjects decreases in FVC or FEVr exceeded 10%; and in the remaining 2 subjects all flows failed to decrease by more than 10%. Individual subjects showed marked differences between the fall in FEVl and FVC and the fall in flow rates at low lung volumes (Fig. 3), but many gradations are apparent. Because pulmonary function in asthmatics had been evaluated twice in the pre-exercise period over an interval of 10 min, we could obtain an index of the variability of pulmonary function over a short period, during which repeated forced vital capacity maneu-
vers were obtained. We examined the absolute change in a given parameter, on the day of maximum effect, pre-exercise (e.g., IFEV, [at 0 min pre-exercise] FEV, [at 10 min pre-exercise]/). This absolute change was expressed as a percent of the control parameter (immediately pre-exercise), and was compared by the paired t test to the maximum percent change (always a fall) post-exercise (Table IV). For all the parameters, with the notable exception of PEFR, the decrease in pulmonary function was significantly greater than their pre-exercise variation. The magnitude of the decrease in function after exercise did not correlate, in general, with the degree of pre-exercise variation.
Clinical history in EIB Detailed histories were available from the questionnaire in 18 of the 19 asthmatic subjects tested. This information was used to characterize the group. Eight had exacerbations of their asthma, on a weekly or daily basis; the others had less frequent attacks. These attacks were mild, and none of the subjects had received corticosteroids. Only 3 subjects felt that minimal exercise precipitated their asthma, and the remainder that either moderate or strenous effort was required. Whereas nearly all subjects were aware of wheezing with exercise (16/l@ , only 7 of the 18 knew how to abort their attacks. We calculated the correlation between the severity of EIB expressed as the maximum percent decrease in MEFIOR (P) and each item in the questionnaire, as well as with FEV, (expressed as a percent of predicted). For continuous characteristics (e.g., age), the usual product-moment correlation was calculated.r5 For discrete characteristics, such as history of hives or bronchitis, the point biserial correlation’6 was used, consolidating when necessary the characteristic into two categories (e.g., dyspnea grades 0 to 3 were consolidated; grades 0 and 1 were associated with 1, and grades 2 and 3 were associated with 2). Table V demonstrates that seven findings correlated with the severity of EIB. These included a rela-
VOLUME 61 NUMBER 6
Airway
100
TABLE V. Correlation between degree of EIB expressed as percent decrease in MEF,% (P) and historical factors associated with asthma in asthmatic subjects
responses to exercise
395
o-e
FVC
.-@
MEF 40%
.-.
MEF 40% (Pf
General
Age* Years of asthma* Frequencyof asthma Bronchitis Other lung disease Smoking Characteristichistory Knows how to abort EIB FEV, (% or predicted)*
-0.04 0.11 0.44 0.541 0.07 -0.18 0.32 0.28
fj
50
L 5 z
ii I 25
r
Exercise I I
SUBJECT.
ML
0.51t
Atop>
Hives Eczema
-0.531 0.03
Foods Drugs Hay fever
0.16 0.11
Family allergies
0.22
0.06
Asthma exacerbated by:
Upper respiratoryinfections Dusts Animals Tobacco Cold
0.57t
-0.04 0.36 0.531
0.38
EIB made worse by:
Amount of exercise Cold weather
0.491 0.471
*Product-moment correlation(othersare point biserialconelations). ?Significanc correlationat the level p < 0.05. tion between the severity of EIB and a history of bronchitis, a history of asthma exacerbated by cigarette smoke, and upper respiratory infections. The severity of EIB also correlated with the degree of baseline airway obstruction as indicated by control FEV, (expressed as a percent of predicted). Severity of EIB correlated with the amount of exercise necessary to induce EIB as elicited by history; in other words, those subjects who were more sensitive to exercise by history were found to be SO by objective exercise testing. A history of EIB aggravated by cold weather also correlated with the severity of EIB. There was no correlation with the patient’s age or the duration of his asthma. Whereas the majority of our subjects complained of allergic symptoms (see Table VI) such as hives (n = 9), eczema (n = 7), food allergies (n = lo), and hay fever (n = 14), there was no correlation between these and the severity of EIB. An exception
CONTROL
0
MINUTES
6
15
AFTER
25
EXERCISE
FIG. 3. Two subjects
illustrating di#ere#~t pqtterne of change in pulmonary fur&on fgtbwkkg BW~*. tn the upper pan& changes occur primarily in tlQwr rates %t kw lung volumes. In the lower panel, changes occur in all measured function.
was the presence of hives in which a negative correlation was established.
Asthmatic subjects clearly differ from ~~~~asthmatic individuals in terms of their airway response to exercise. The form of exercise used to stress nonasthmatic subjects does not influence th,eir resistance to this form of induced broncho8pasm. Our study shows that the frequency with which EIB may be demonstrated in mild astl~matics depends on the sensitivity of the measurements used. This is particularly true at low (threshold) levels of exercise. In 17 of 19 (89%) asthmatic subjects with mikl airway obstruction, we measured some degree of airRow limitation using MEFV and PEFV curves. In contrast, Kiviloog, Imell, and Eklund’ found a decrease in peak flow rate of 10% following maximal exercise in 22 of 116 (19%) asthmatics. Ftrrthermore, whereas the average exercise load used by Kiviloog”s subjects was 861 kDm/min. in our own studv EIB was 1
396
J. ALLERGY
Schachter et al.
TABLE VI. Allergic
history*
and post-exercise
fall in MEF,, Atopic
Subjects
Hives
It. D. P. s. M. L. D. S. G. C. I. N. E. L. W. H. F. L. T. G. A. A. G. G. M. K. D. L. D. P. B. P. J. D. S. K.
0 I 1 I 0 I I 1 I 0 0 1 0 0 1 0 0 0
Eczema
I 0 1 0 0 1 0 I 0 0 0 I 0 0 1, 0 0 1
Food allergy
Drug allergy
1 0 I 1 0 I I 0 I 1 1 1 0 0 1 0 0 0
0 0 0 I 0 0 0 0 0 I 0 1 0 0 0 0 0 1
CLIN. IMMUNOL. JUNE 1978
(P) history Allergic rhinitis
I I I 1 0 1 1 1 I 1 1 I 1 1 0 0 0 I
Family atw
-
1 1 I 1 0 I 1 0 1 1 I 0 0 1 0 0 I I
A MEF-
(P)t
(%I
45 19 71 79 81 24 6 17 23 33 5 12 19 34 30 18 0 13
*0 = absenceof findings; 1 = presenceof findings. t Expressedas a percent decrease(compared to control value).
documented with an average cycling load of 676 kpm/min. Both the methods(cycling) and the subjectsstudied (adults) by Kiviloog resembledour own. As in our group, the baselinepulmonary function of thesesubjects was minimally disturbed. Although other authors, such as Cropp and Schmultzler’and Sly,17 report a high prevalenceof EIB among asthmatics, these studies have usually been performed with subjects exhibiting severe asthma. In addition to the sensitivity of pulmonary function measurementsused to demonstrateEIB, the effects of the forced expiratory maneuversthemselvesmust be considered.It has been suggestedthat in asthmatics, rapid respiratory maneuvers,such as the FVC, may stimulate airway irritant receptorsand causebronchospasm.I* The responseto exercise in our asthmatic subjects was from 2 to 3 times greaterthan the preexercise variation in MEFV and PEFV data (Table IV). Furthermore,there was no consistentcorrelation between this variation and post-exercise response, making it unlikely that EIB was due to repeated forced expiratory maneuvers. Similar results have beenfound by examining airway resistancefollowing exercise,19since the measurementof this parameter does not require forced expiratory maneuvers. The ability to diagnoseEIB is important for patient management.Only 7 of our 17 asthmatic subjects
who demonstratedEIB (16 had symptoms following exercise) knew how to managetheir illness. Awareness of the physician and a sensitive means for documentingEIB should result in early prophylactic therapy. MEFV and PEFV curves probably reflect eventsin both large and small airways. Bouhuys and coworkers*, ‘O have demonstratedthat in both healthy subjects and patients with airway disease, PEFV curves are a very sensitiveindex of airway responseto bronchoconstrictoragentssuch as histamine, methacholine, carbachol, and cotton dust. These findings have been attributed to changesin airways of small caliber. In part, the sensitivity of the PEFV curves may reflect the effects of a deepinspiration on airway tone which obscuresbronchoconstrictorresponses.8, *’ Our data indicate that in EIB changesoccur in both large andsmall airways. The greaterreductionin flow rates at low lung volumes occurring in 9 of 19 asthmatic subjects suggestsprimary limitation of flow in the smaller airways (Fig. 3 and Table III). The more generalizedlimitation in flow seen in the 8 other responding subjects may representlarger or possibly diffuse airway constriction. Supporting evidencefor this interpretationis suggested by the data of Despas, Leroux, and Macklem,** who demonstratedthat two distinct patternsof airway obstruction could be distinguished among otherwise similar asthmaticsby studying the depen-
VOLUME NUMBER
61 6
dence of maximal expiratory airflow on gas density. Although initial observations using these techniques in asthmatics stressed with exercise pointed to a predominance of large airway obstruction,23 most recently McFadden and co-workersZ4 have shown in a group of 12 asthmatics that two patterns of airway obstruction following exercise may exist. The independence of these responses was suggested by a distinct pattern of protection by two pharmacologic agents of different classes, namely, atropine and disodium cromoglycate. Although the relation between flow limitation expressed by variation in density dependence of flow and that expressed as changes of the PEFV curve remains to be defined, our results indicate that similar bronchial events are being measured. The response to exercise in our subjects correlated with baseline pulmonary function, suggesting that airway reactivity to exercise may be influenced by pre-existing bronchospasm. This interpretation is supported by the data of Haynes, Ingram, and McFadden ,I3 who demonstrated that the number and type of post-exercise abnormalities appeared to be related to prechallenge lung function. These findings suggest that the design of asthmatic challenge studies (particularly those involving exercise) must include standardization of baseline pulmonary function. The mechanisms by which EIB is initiated remain unknown. There was no evidence to relate the severity of EIB and a history of allergic phenomenon. Similar results are reported in groups of asthmatics with more pronounced disease.“, 24 The severity of EIB, in our study, however, did correlate with a history of bronchitis and asthmatic responses to upper respiratory infection, tobacco smoke, and cold weather. These correlations, elicited among mild asthmatics, suggest that EIB is a very general feature of asthma, similar to the increased reactivity among asthmatics to a wide variety of airway irritants. The specific physiologic mechanism may further be dependent on the principal site of airway obstruction as suggested by McFadden and co-workers.24 Partial flow volume studies have not been previously reported in the characterization of EIB. Using this sensitive index of airway obstruction, relatively mild degrees of exercise will elicit clear-cut differences between asthmatic and nonasthmatic subjects. This response is widespread and may be demonstrated among a majority of asthmatics with mild disease. The severity of the response may vary from individual to individual but can be related to the degree of abnormality in baseline pulmonary function, as well as the amount of exercise used. Baseline function must thus be carefully assessedin order to interpret
Airway
responses to exercise
397
the severity of the responses. Furthermore, the pattern of airway responsesto exercise may also differ among individuals and may be shown to reflect primarily small or generalized airway obstruction. MEFV and PEFV curves used in combination are thus a simple, safe, and sensitive method for identifying mild and possibly unsuspected asthmatics, quantitating the effect of their baseline pulmonary function on exercise responses, and determining the site of airway obstruction following exercise. W e are indebted to Dr. Arend Bouhuys for his suggestions and critical review of this manuscript. REFERENCES I.
2.
3. 4.
5. 6.
7.
8.
9.
10. I I.
12.
13
I4
15 16
I7
Anderson, S. D., Silverman, M., Konig, P., and Godfrey. S.: Exercise-induced asthma, Br. J. Dis. Chest 69: 1, 1975. Anderson, S. D., McEvoy, J. D. S., and Bianco, S.: Changes in lung volumes and airway resistance after exercise in asthmatic subjects, Am. Rev. Respir. Dis. 10630, 1972. McNeil], R. S., Nairn, J. R., Miller, J. S.) and Ingram. C. G.: Exercise-induces asthma, Q. J. Med. 35:55, 1966. Pierson, W . E., Bierman, C. W ., and Stamm, S. J.: Cycloergometer-induced bronchospasm, J. ALLFRC~Y CLIN. IMMUNOL. 43: 136, 1969. Bouhuys, A.: Breathing, ed. I, New York, 1974. Grune & Stratton, Inc., pp. 188-195. Cropp G. J. A., and Schmultzler, I. J.: Grading, time course, and incidence of exercise-induced airway obstruction and hyperinflation in asthmatic children. Pediatrics I suppI.) 56:868, 1975. Kiviloog, J., Irnell, L., and Eklund, G.: Ventilatory capacity, working capacity and exercise-induced bronchoconstriction in a population sample of subjects with bronchial asthma or chronic bronchitis, Stand. J. Respir. Dis. 56:73, 1975. Bouhuys, A., Hunt, V. R., Kim, B. M., and Zapletai, A.: Maximum expiratory Row rates in induced bronchocrmstriction in man, 1. Clin. Invest. 48: 1159, 1969. Zuskin, E., Lewis, A. J., and Bouhuys, A.. Inhibition of histamine-induced airway constriction by ascorbic acid. J. ALLERGY CLIN. IMMUNOL. 51:218, 1973. Zuskin, E., and Bouhuys, A.: Acute airway responses to hairspray preparations, N. Engl. J. Med. 29&66Q, 1974. Godfrey, S., Silverman, M., and Anderson, S. D.: Problems of interpreting exercise-induced asthma, J. ALLGRG~ CLIN. IMMUN~L. 52: 199, 1973. Virgulto. J., and Bouhuys, A.: Electronic circuits for recording of maximum expiatory flow-volume (MEFV) curves. J. Appl. Physiol. 35:145, 1973. Haynes, R. L., Ingram, R. H., Jr., and McFadden. E. R., Jr.: An assessment of the pulmonary response to exercise in asthma and an analysis of the factors influencing it. Am. Rev. Respir. Dis. 114:739, 1976. Freedman, S., Tattersfield, A. E., and Pride, N. B.: Changes in lung mechanics during asthma induced by exercise, J. Appl. Physiol. 38:974, 1975. Snedcor, G. W ., Co&ran, W . G.: Statistical methods, Ames, Iowa, 1967, Iowa State University Press. pp. L72- 190. Kendall, M. G., and Stuart, A.: The advanced theory of statistics, London. 1967, Charles Griffin & Co.. Ltd.. vol. 2. pp. 311-312. Sly, R. M.: Exercise related changes in airway obstruction:
398
18.
19.
20.
21.
Schachter
et al.
Frequency and clinical correlates in asthmatic children, Ann. Allergy 28: 1, 1970. Nadel, J. A.: Neurophysiologic aspects of asthma, in Austen, K. F., and Lichtenstein, L. M., editors: Asthma, New York, 1973, Academic Press, Inc., p. 31. Fisher, H. K., Holton, P., Buxton, R., and Nadel, J. A.: Resistance to breathing during exercise-induced asthma attacks, Am. Rev. Respi. Dis. 101:885, 1970. Bouhuys, A., Mitchell, C. A., Schilling, R. S. F., andzuskin, E.: A physiological study of byssinosis in colonial America, Trans. N. Y. Acad. Sci. 35:537, 1973. Nadel, J. A., and Tierney, D. F.: Effect of a previous deep inspiration on airway resistance in man, J. Appl. Physiol. I&717, 1961.
J. ALLERGY
CLIN. IMMUNOL. JUNE 1979
22. Despas, P. J., Leroux, M., and Macklem, P. T.: Site of airway obstruction in asthma as determined by measuring maximal expiratory Row breathing air and a helium-oxygen mixture, J. Clin. Invest, 51:3235, 1972. 23. Mildon, A., Leroux, M., Hutcheon, M., and Zamel, N.: The site of airways obstruction in exercise-induced asthma, Am. Rev. Respir. Dis. 110~409, 1974. 24. McFadden, E. R., Jr., Ingram, R. H., Jr., Haynes, R. L., and Wellman, J. J.: Predominant site of flow limitation and mechanisms of postexertional asthma, J. Appl. Physiol. 42:746, 1977. 25. Konig, P., and Godfrey, S.: Prevalence of exercise-induced bronchial lability in families of children with asthma, Arch. Dis. Child. 48:513, 1973.
to exercise
in
E. Neil Schachter, M.D., Harvey Kreisman, M.D., Michael Littner, Gerald J. Beck, Ph.D., and Frans Voncken New Haven, Conn.
M.D.,
Measurements of flow on maximal and partial expiratoryflow-volume (MEFV and PEFV) curves offer a simple, sensitive, and safe method for studying the prevalence, clinical characteristics, and airway changes of exercise-induced bronchospasm (EIB). These methods show that asthmatic individuals with even mild disease clearly difser from nonasthmatic persons in terms of their airway response to exercise, Nineteen asthmatic and fourteen nonasthmatic volunteers underwent graded exercise testing to elicit exercise-induced bronchospasm. Pulmonary function was measured using MEFV and PEFV curves before and after exercise. Exercise-induced bronchospasm was demonstrated in 17 of 19 asthmatic subjects without inducing marked degrees of airway constriction. The most sensitive index of EIB was changes in Jrow rates measured at low lung volumes, particularly those measured on PEFV curves. Analysis of flow-volume curves suggested two patterns of airway response to exercise among asthmatics, involving, respectively, small and larger airways. No signiJicant changes in pulmonary function were demonstrated in the nonasthmatic subjects. The degree of EIB measured by changes in Jopowrates on the PEFV curve correlated with airway reactivity to nonspeciJic irritants such as cold weather, tobacco smoke, and respiratory tract infections, but not with a history of specific allergies. We suggest that EIB is a general feature of asthma, rejecting the increased reactivity of asthmatics to a wide variety of airway irritants.
Many asthmatics complain of dyspnea and have objective changes in lung function indicating progressive airway obstruction during the first 10 min following exercise. Both objective and subjective changes subside after 30 to 60 min.le4 This exerciseinduced bronchospasm (EIB) must be carefully distinguished from effort-associated dyspnea reported by patients with other underlying pulmonary disorders. The forced vital capacity (FVC), the forced expiratory volume in one second (FEV J, and the peak expiratory flow rate (PEFR) are most frequently used to follow this response. The accuracy and reproducibility of such effort-dependent measurements, however, have been questioned particularly in situations involving mild degrees of airway obstruction.5 In circumstances involving submaximal effort, patient fatigue could contribute to further inaccuracies of these measurements . In severe asthmatics,6 exercise-induced bronchoFrom the Department of Medicine, Yale University School of Medicine. Received for publication Sept. 28, 1977. Accepted for publication Feb. 8, 1978. Reprint requests to: E. Neil Schachter, M.D., Department of Medicine, Yale University School of Medicine, New Haven, Conn. 06510. Vol. 61, No. 6, pp. 390-398
spasm (EIB) occurs in up to 90% of subjects. In other studies, using subjects with less severe asthma, &e prevalence has been as low as 19%.? We won&red whether more sensitive, less effort-dependent stu&s might not show a higher prevalence of EIB among asthmatic subjects with mild disease. Maximal and partial expiratory flow volwnt (MEFV and PEFV) curves are a very sensitive method for detecting airway responses to constrictor stimuli.*-” We used these tests to study the effect of exercise challenge in both asthmatic and normal subjects. We also investigated the clinical hist&s of those studied to better delineate those at risk. SUBJECTS
AND METHODS
Exercise challenge studies were performed in 19 asahmatic subjects(I 7 male and 2 female) and 14 subjeds without any clinical history of wheezing or asthma(I 2 mrk and 2 female). Ages and baseline pulmonary function of these subjects are shown in Table 1. Becausewe were in&rested in studying responsesin asthmaticswith mild disease, our subjects were recruited from the University community. Clinic and hospitalized patients were not selected &use these individuals tend to have more severe disease. AU subjects had a past history of asthma as defined by the Amaican Thoracic Society. None of the subjects thus sekcted required steroid therapy or disodium cromoglycate for con-
0091-6749/7810661-0390$00.90/O
63 1978 The C. V. Mosby Co.
VOLUME NUMBER
61 6
Airway
responses to exercise
391
MEFV-CURVES
l>
2
-
Pre-exercise
---
Post-exercise
TLC
-60%
PEFV-CURVES
2
I
3
of Vital
Capacity+
VOLUME
MEASURED
4 FROM
6
5 TLC
7
(liters)
FIG.1. Pre- and post-exercisemaximal and partial expiratoryfiow volume curves. ThsTtC points have been superimposed in order to determine MEF,s/, and MEF,,, (P). As pointed out in the text, the total lung capacity may increasefollowing exercise.
Nortasthmatic Stair climbing (n = 7) Cycloergometer (n = 7) Asthmatic Cycloergometer (n = 19)
26.3 f 1.2
109.7 ?I 3.8
115.45 5.2
84.7 Ifr 5.4
120.1 -c 5.5
108.0+- 11.2
23.0 r 1.8
107.0 k 4.5
110.3r 3.6
84.0 r
1.3
119.3 t 7.9
113.7 -r- 4.8
24.5 2 0.7
104.5-t 2.3
84.3 k 4.5
66.9 +- 14.8
87.5 rt 6.2
S9.4 r
6.5
expressed as a percentof predicted with the exceptionof FEVIS expressed as FEV,/FVC x 100(mean+ SEM). *All measurements tF’redict&values:Bouhuys,A., andSchoenberg, J.: Personal communication.
trol of their disease.Their attacks,althoughvarying in frequency, respondedto outpatient treatment and none had requinedhospitalizationfor asthma.Presenceor absenceof a history of EIB was not a selectioncriterion. As a consequence,although a majority of subjects(17/19) did complain of wheezingafter exercise, only 3 felt that minimal exercisewas sufficient to elicit asthma.The other subjects required what they described as moderate or strenuous exerciseto elicit EIB, again confirming the relatively mild degreeof their clinical illness. Finally, the baselinepulmonary function of the asthmaticsubjectswas relatively normal ITable I). Healthy subjectswere volunteersfrom our laboratorystaff. In all instances,informed consentwas obtained. A detailed questionnaireincluding questionsrelated to respiratory symptoms, prior pulmonary disease,allergies, andEIB was administeredto eachsubject. Seventeenof the
19 asthmatic subjects noted dyspnea or wheezing after exercise; none of the normal subjectscomplainedof any wheezingor prolongeddyqmea following exmcise. Exercise studies were performed only if the subject’s usual asthmaticmedicationswere omitted in t?+e24 hr preceding testing. Exercise was performed at mimrdely the same time of day for each individual Fo avoid the possibleeffect of diurnal variarion. The asthmatic subjectsexercisedon a Cyclaergometer (Monark), on a maximum of four separatedays during which fixed exerciseloads were used. They p&led for 8 min, at a constantspeedof 50 cycleslsec,agstinsta con&ant work load. The workload on the initial study day was 300 kilopoad meters per minute (kpmlmin) and was increased up to a maximum of 900 kpm/min, in successivesessions. A steadystate, as judged by cardiacfrequency,was usually reachedby the fifth minute of exercise.The “threshold”
392
Schachter
J. ALLERGY
et al.
PEFR
FEV,
FVC
r
0
Asthmatics
m
Non-asthmatic
IO-19 20-29
F
o-9
>30
% FALL
PARAMETER
IN
MEF 40%
MEF 40%
o-9
CLIN. IMMUNOL. JUNE 1978
IO-19 20-29
>30
% FALL
o-9
IN
(PI
IO-19 2029
>30
PARAMETER
FIG. 2. Comparison
of the relative incidence of puImonan/ function changes following exercise. Each parameter is expressed as a percent of control. Normal subjects represent the group exercised on the Cycloergometer.
TABLE II. Effect
of exercise
on pulmonary
function
in 19 asthmatic
Pre-exercise FVC (L) FEV, (L) PEFR (L/set) MEF,, (Llsec) MEF,, (P) (L/set)
5.03 3.34 6.46 2.04 1.63
2 k +k ?I
0.18 0.16 0.49 0.22 0.18
0 min 4.92 3.37 6.51 2.19 1.81
+ c r k k
0.20* 0.18 0.48 0.27 0.25
subjects
(mean
6 min 4.86 3.15 6.09 1.83 I.31
+ k -t 2 +
0. I91 0.18t 0.49* 0.24t 0.19t
k
SEMI 16 min 4.83 3.14 5.89 1.85 1.46
+ 2 f + 2
0.18t 0.19t 0.51t 0.25* 0.22*
*p < 0.05. tp < 0.005. exercise load was reached when either a 10% fall in FEV, was found, or a heart rate greater than I50 beats/min for the last 3 min of their exercise was achieved, or if the subject was not able to tolerate greater effort. The mean maximal exercise load performed by the asthmatic subjects was 676 2 55 kpm/min (mean ? SEM). We examined the response to exercise among asthmatic subjects by looking at pulmonary function data of the highest exercise load used. A control group of 7 nonasthmatic subjects was similarly exercised at increasing workloads on a Cycloergometer until a heart rate of at least 150 beats/min was achieved during the last 3 min of exercise. The mean maximal exercise load performed by this group was 600 + 87 kpm/min, and the mean pulse rate achieved by the seventh minute of exercise was I61 -C 12 beats/min.
Because differences have been described among asthmatics (but not among nonasthmatics) in relation to the type of exercise used to elicit EIB, we studied a second nonasthmatic control group in which running up and down a flight of stairs for a total of 8 min was the stress used. This clinically relevant form of stress testing has been used by McNeil and co-workers3 to elicit EIB. Each of the 7 subjects in this group climbed one flight of stairs (I 5 steps) at a pace which induced a heart rate of at least 150 beats/min by the sixth minute of exercise. At least two studies were performed on each of these subjects. Measurements of flow and volume were obtained, using a flowmeter whose signal was electronically integrated to obtain volume, and recorded on a Gould X-Y recorder.‘* The subject inspired to approximately 70% of vital capacity
VOLUME NUMBER
61 6
Aitway responses to exercise
TABLE Hi. Maximum
StJbjfJCtS
post-exercise
fall in pulmonary
function
in 19 asthmatic
subjects*+
AFVC
AFEVI
D. S. P. s. B. D. I. N. W. H. G. G.
10 5 5 1 8 0
9 7 4 2 7 0
54 13 3 7 19 0
-7y i4 ;n I!4 7 :1
F. L. M. K. L. s.
7 0 2
6 0 2
19 0 I
2.; j C) II
Mean t SEM
4.2 c 1.2
4.1 2 I.1
13.6 t 5.6
II 6 10 4 7 12 3 13
21 31 18 13 II 12 17 5
56 57 50 20 0 23 12 6
Mean k SEM Group III E. L. ‘I’. A.
8.31 k 1.3
16.0 + 2.6
28.0 t 7.7
4 I
6 0
0 4
Mean 2 SEM
2.5 k 1.5
3.0 ” 3.0
2.0 + 2.0
Grof4p
393
A=bos
ANI=&
0’)
I
Group II R. D. M. L. G. c. D. L. J. D. D. P. T. G. S. K.
24.7 f_ 6.9 45 ?I Xl 34 0 .iu .3.! 1: 38.4 + 9.1 h 5 5.5 4 0.5
*All &creases are expressed as a percent of control pulmonary function values.
TThreegroupsrepresentdifferent patternsof flow limitation. Group I, flow limitations at low lung volumes; Group II, generalizedH O W limitation; Group III, no flow limitation.
and then expired forcefully to residual volume. He then inspired to total lung capacity and once again expired forcefully to residual volume. The parameters examined from these partial and maximal expiratory flow volume (PEFV and MEFV) curves were flow rates at a lung volume 6 0 % of the control vital capacity below total lung capacity (MEFao% [P] and MEFlocx) as well as FVC, FEV,, and PEFR (Fig. I). These maneuvers were performed IO min before exercise, immediately before exercise, and at 0, 6, 15, and 25 min following exercise. Three PEFV and MEFV maneuvers were done at I -min intervals at each of these times and the mean volumes and flow rates were determined. The postexercise values were expressed as a percent of the mean control values (immediately before exercise). Measurements of flow on MEFV and PEFV curves by the above method reflect flow at an absolute lung volume only if total lung capacity (TLC) remains unchanged.In normal subjects challenged with aerosol bronchoconstrictor agents?or exercise, It3changesin TLC have beenabsentor minimal. However, in asthmatics undergoing such challenges, increases in TLC may occur.‘a* I4 Such increases in TLC would tend to minimize the changesin flow measured by our method compared to those measured at an absolute lung volume. Therefore, our measurements probably under-
estimatethe decreasein lung function after exercise,when TLC increases in some subjects.
Pulmonary function studies performed before exercise challenge showed no airway obstnrction in the nonasthmatic subjects. Mild airway obstruction was seen in the asthmatic group (Table I). In both control groups of nonasthmatic subjects, lung function did not change significantly after exercise, suggesting that the type of provocation used in nonasthmatics does not affect the stability of their airways. For the group of asthmatic subjects, there was no significant change in any of the measured pulmonary function immediately following exercise with the exception of a small but significant fall in FVC. At 6 and 15 min, all function (Table II) had significantly decreased. W e examined the maximum percent decrease in
J. ALLERGY
394 Schachter et al.
TABLE IV. Pre-exercise
variation (mean r SEM) in asthmatics
compared
NC Pre-exerciset Post-exercise t r
2.7 L 0.48 5.78 + 1.00 4.6 (p < 0.001) 0.64 (p < 0.01)
to maximal
FEVI
2.94 9.56 3.28 0.05
xt 0.71 2 1.93 (p < 0.005) (NS)
post-exercise
PEFR
6.11 9.83 I .26 0.08
+ 1.43 k 2.49 (NS) (NS)
fall in pulmonary
MEF,,
7.83 k 1.58 19.80 k 4.88 2.7 (p < 0.025) 0.4 (NS)
CLIN. IMMUNOL. JUNE 1978
function*
MEF,,,,% (PI
10.4 -c 2.29 28.7 k 5.13 2.4 (p < 0.005) 0.34 (NS)
*These variations are expressedas a percentof pre-exercisecontrol values. tAbsolute values.
each pulmonary function parameter following exercise. These maximal changes have been described as a more sensitive index of EIB.’ When these maximum percent decreases in pulmonary function (compared to control and grouped by 10% intervals) were examined in the asthmatic and nonasthmatic groups exercising on the Cycloergometer, the MEFawc (P) discriminated best between these two groups (Fig. 2). Using a 10% or greater change in a given parameter to indicate response, none of the nonasthmatics showed a response. Similarly, the nonasthmatic stair climbing group also showed no response. On the other hand, 16 of 19 asthmatics demonstrated a response by MEF,o% (P), whereas only 7 of 19 showed a response by FEV, . Similarly, fewer asthmatics were identified by FVC, PEFR, or MEFIOQ than by MEFIOR (P). These results indicate that MEF4,,% (P) is the most sensitive of these measurements for distinguishing airway changes following exercise in these two groups. Two patterns of airway obstruction were noted when measurements of pulmonary function were separated into effort-dependent and independent parameters. In one instance airway obstruction was primarily manifested by a decrease in flow rates at low lung volumes, and in the second a more general decrease in flow rates was observed. As can be seen in Table III, 9 asthmatic subjects had maximal postexercise decreases in both FVC and FEVl which were less than lo%, but their maximal fall in MEFNRor MEF,,%(P) were greater than 10%; in 8 subjects decreases in FVC or FEVr exceeded 10%; and in the remaining 2 subjects all flows failed to decrease by more than 10%. Individual subjects showed marked differences between the fall in FEVl and FVC and the fall in flow rates at low lung volumes (Fig. 3), but many gradations are apparent. Because pulmonary function in asthmatics had been evaluated twice in the pre-exercise period over an interval of 10 min, we could obtain an index of the variability of pulmonary function over a short period, during which repeated forced vital capacity maneu-
vers were obtained. We examined the absolute change in a given parameter, on the day of maximum effect, pre-exercise (e.g., IFEV, [at 0 min pre-exercise] FEV, [at 10 min pre-exercise]/). This absolute change was expressed as a percent of the control parameter (immediately pre-exercise), and was compared by the paired t test to the maximum percent change (always a fall) post-exercise (Table IV). For all the parameters, with the notable exception of PEFR, the decrease in pulmonary function was significantly greater than their pre-exercise variation. The magnitude of the decrease in function after exercise did not correlate, in general, with the degree of pre-exercise variation.
Clinical history in EIB Detailed histories were available from the questionnaire in 18 of the 19 asthmatic subjects tested. This information was used to characterize the group. Eight had exacerbations of their asthma, on a weekly or daily basis; the others had less frequent attacks. These attacks were mild, and none of the subjects had received corticosteroids. Only 3 subjects felt that minimal exercise precipitated their asthma, and the remainder that either moderate or strenous effort was required. Whereas nearly all subjects were aware of wheezing with exercise (16/l@ , only 7 of the 18 knew how to abort their attacks. We calculated the correlation between the severity of EIB expressed as the maximum percent decrease in MEFIOR (P) and each item in the questionnaire, as well as with FEV, (expressed as a percent of predicted). For continuous characteristics (e.g., age), the usual product-moment correlation was calculated.r5 For discrete characteristics, such as history of hives or bronchitis, the point biserial correlation’6 was used, consolidating when necessary the characteristic into two categories (e.g., dyspnea grades 0 to 3 were consolidated; grades 0 and 1 were associated with 1, and grades 2 and 3 were associated with 2). Table V demonstrates that seven findings correlated with the severity of EIB. These included a rela-
VOLUME 61 NUMBER 6
Airway
100
TABLE V. Correlation between degree of EIB expressed as percent decrease in MEF,% (P) and historical factors associated with asthma in asthmatic subjects
responses to exercise
395
o-e
FVC
.-@
MEF 40%
.-.
MEF 40% (Pf
General
Age* Years of asthma* Frequencyof asthma Bronchitis Other lung disease Smoking Characteristichistory Knows how to abort EIB FEV, (% or predicted)*
-0.04 0.11 0.44 0.541 0.07 -0.18 0.32 0.28
fj
50
L 5 z
ii I 25
r
Exercise I I
SUBJECT.
ML
0.51t
Atop>
Hives Eczema
-0.531 0.03
Foods Drugs Hay fever
0.16 0.11
Family allergies
0.22
0.06
Asthma exacerbated by:
Upper respiratoryinfections Dusts Animals Tobacco Cold
0.57t
-0.04 0.36 0.531
0.38
EIB made worse by:
Amount of exercise Cold weather
0.491 0.471
*Product-moment correlation(othersare point biserialconelations). ?Significanc correlationat the level p < 0.05. tion between the severity of EIB and a history of bronchitis, a history of asthma exacerbated by cigarette smoke, and upper respiratory infections. The severity of EIB also correlated with the degree of baseline airway obstruction as indicated by control FEV, (expressed as a percent of predicted). Severity of EIB correlated with the amount of exercise necessary to induce EIB as elicited by history; in other words, those subjects who were more sensitive to exercise by history were found to be SO by objective exercise testing. A history of EIB aggravated by cold weather also correlated with the severity of EIB. There was no correlation with the patient’s age or the duration of his asthma. Whereas the majority of our subjects complained of allergic symptoms (see Table VI) such as hives (n = 9), eczema (n = 7), food allergies (n = lo), and hay fever (n = 14), there was no correlation between these and the severity of EIB. An exception
CONTROL
0
MINUTES
6
15
AFTER
25
EXERCISE
FIG. 3. Two subjects
illustrating di#ere#~t pqtterne of change in pulmonary fur&on fgtbwkkg BW~*. tn the upper pan& changes occur primarily in tlQwr rates %t kw lung volumes. In the lower panel, changes occur in all measured function.
was the presence of hives in which a negative correlation was established.
Asthmatic subjects clearly differ from ~~~~asthmatic individuals in terms of their airway response to exercise. The form of exercise used to stress nonasthmatic subjects does not influence th,eir resistance to this form of induced broncho8pasm. Our study shows that the frequency with which EIB may be demonstrated in mild astl~matics depends on the sensitivity of the measurements used. This is particularly true at low (threshold) levels of exercise. In 17 of 19 (89%) asthmatic subjects with mikl airway obstruction, we measured some degree of airRow limitation using MEFV and PEFV curves. In contrast, Kiviloog, Imell, and Eklund’ found a decrease in peak flow rate of 10% following maximal exercise in 22 of 116 (19%) asthmatics. Ftrrthermore, whereas the average exercise load used by Kiviloog”s subjects was 861 kDm/min. in our own studv EIB was 1
396
J. ALLERGY
Schachter et al.
TABLE VI. Allergic
history*
and post-exercise
fall in MEF,, Atopic
Subjects
Hives
It. D. P. s. M. L. D. S. G. C. I. N. E. L. W. H. F. L. T. G. A. A. G. G. M. K. D. L. D. P. B. P. J. D. S. K.
0 I 1 I 0 I I 1 I 0 0 1 0 0 1 0 0 0
Eczema
I 0 1 0 0 1 0 I 0 0 0 I 0 0 1, 0 0 1
Food allergy
Drug allergy
1 0 I 1 0 I I 0 I 1 1 1 0 0 1 0 0 0
0 0 0 I 0 0 0 0 0 I 0 1 0 0 0 0 0 1
CLIN. IMMUNOL. JUNE 1978
(P) history Allergic rhinitis
I I I 1 0 1 1 1 I 1 1 I 1 1 0 0 0 I
Family atw
-
1 1 I 1 0 I 1 0 1 1 I 0 0 1 0 0 I I
A MEF-
(P)t
(%I
45 19 71 79 81 24 6 17 23 33 5 12 19 34 30 18 0 13
*0 = absenceof findings; 1 = presenceof findings. t Expressedas a percent decrease(compared to control value).
documented with an average cycling load of 676 kpm/min. Both the methods(cycling) and the subjectsstudied (adults) by Kiviloog resembledour own. As in our group, the baselinepulmonary function of thesesubjects was minimally disturbed. Although other authors, such as Cropp and Schmultzler’and Sly,17 report a high prevalenceof EIB among asthmatics, these studies have usually been performed with subjects exhibiting severe asthma. In addition to the sensitivity of pulmonary function measurementsused to demonstrateEIB, the effects of the forced expiratory maneuversthemselvesmust be considered.It has been suggestedthat in asthmatics, rapid respiratory maneuvers,such as the FVC, may stimulate airway irritant receptorsand causebronchospasm.I* The responseto exercise in our asthmatic subjects was from 2 to 3 times greaterthan the preexercise variation in MEFV and PEFV data (Table IV). Furthermore,there was no consistentcorrelation between this variation and post-exercise response, making it unlikely that EIB was due to repeated forced expiratory maneuvers. Similar results have beenfound by examining airway resistancefollowing exercise,19since the measurementof this parameter does not require forced expiratory maneuvers. The ability to diagnoseEIB is important for patient management.Only 7 of our 17 asthmatic subjects
who demonstratedEIB (16 had symptoms following exercise) knew how to managetheir illness. Awareness of the physician and a sensitive means for documentingEIB should result in early prophylactic therapy. MEFV and PEFV curves probably reflect eventsin both large and small airways. Bouhuys and coworkers*, ‘O have demonstratedthat in both healthy subjects and patients with airway disease, PEFV curves are a very sensitiveindex of airway responseto bronchoconstrictoragentssuch as histamine, methacholine, carbachol, and cotton dust. These findings have been attributed to changesin airways of small caliber. In part, the sensitivity of the PEFV curves may reflect the effects of a deepinspiration on airway tone which obscuresbronchoconstrictorresponses.8, *’ Our data indicate that in EIB changesoccur in both large andsmall airways. The greaterreductionin flow rates at low lung volumes occurring in 9 of 19 asthmatic subjects suggestsprimary limitation of flow in the smaller airways (Fig. 3 and Table III). The more generalizedlimitation in flow seen in the 8 other responding subjects may representlarger or possibly diffuse airway constriction. Supporting evidencefor this interpretationis suggested by the data of Despas, Leroux, and Macklem,** who demonstratedthat two distinct patternsof airway obstruction could be distinguished among otherwise similar asthmaticsby studying the depen-
VOLUME NUMBER
61 6
dence of maximal expiratory airflow on gas density. Although initial observations using these techniques in asthmatics stressed with exercise pointed to a predominance of large airway obstruction,23 most recently McFadden and co-workersZ4 have shown in a group of 12 asthmatics that two patterns of airway obstruction following exercise may exist. The independence of these responses was suggested by a distinct pattern of protection by two pharmacologic agents of different classes, namely, atropine and disodium cromoglycate. Although the relation between flow limitation expressed by variation in density dependence of flow and that expressed as changes of the PEFV curve remains to be defined, our results indicate that similar bronchial events are being measured. The response to exercise in our subjects correlated with baseline pulmonary function, suggesting that airway reactivity to exercise may be influenced by pre-existing bronchospasm. This interpretation is supported by the data of Haynes, Ingram, and McFadden ,I3 who demonstrated that the number and type of post-exercise abnormalities appeared to be related to prechallenge lung function. These findings suggest that the design of asthmatic challenge studies (particularly those involving exercise) must include standardization of baseline pulmonary function. The mechanisms by which EIB is initiated remain unknown. There was no evidence to relate the severity of EIB and a history of allergic phenomenon. Similar results are reported in groups of asthmatics with more pronounced disease.“, 24 The severity of EIB, in our study, however, did correlate with a history of bronchitis and asthmatic responses to upper respiratory infection, tobacco smoke, and cold weather. These correlations, elicited among mild asthmatics, suggest that EIB is a very general feature of asthma, similar to the increased reactivity among asthmatics to a wide variety of airway irritants. The specific physiologic mechanism may further be dependent on the principal site of airway obstruction as suggested by McFadden and co-workers.24 Partial flow volume studies have not been previously reported in the characterization of EIB. Using this sensitive index of airway obstruction, relatively mild degrees of exercise will elicit clear-cut differences between asthmatic and nonasthmatic subjects. This response is widespread and may be demonstrated among a majority of asthmatics with mild disease. The severity of the response may vary from individual to individual but can be related to the degree of abnormality in baseline pulmonary function, as well as the amount of exercise used. Baseline function must thus be carefully assessedin order to interpret
Airway
responses to exercise
397
the severity of the responses. Furthermore, the pattern of airway responsesto exercise may also differ among individuals and may be shown to reflect primarily small or generalized airway obstruction. MEFV and PEFV curves used in combination are thus a simple, safe, and sensitive method for identifying mild and possibly unsuspected asthmatics, quantitating the effect of their baseline pulmonary function on exercise responses, and determining the site of airway obstruction following exercise. W e are indebted to Dr. Arend Bouhuys for his suggestions and critical review of this manuscript. REFERENCES I.
2.
3. 4.
5. 6.
7.
8.
9.
10. I I.
12.
13
I4
15 16
I7
Anderson, S. D., Silverman, M., Konig, P., and Godfrey. S.: Exercise-induced asthma, Br. J. Dis. Chest 69: 1, 1975. Anderson, S. D., McEvoy, J. D. S., and Bianco, S.: Changes in lung volumes and airway resistance after exercise in asthmatic subjects, Am. Rev. Respir. Dis. 10630, 1972. McNeil], R. S., Nairn, J. R., Miller, J. S.) and Ingram. C. G.: Exercise-induces asthma, Q. J. Med. 35:55, 1966. Pierson, W . E., Bierman, C. W ., and Stamm, S. J.: Cycloergometer-induced bronchospasm, J. ALLFRC~Y CLIN. IMMUNOL. 43: 136, 1969. Bouhuys, A.: Breathing, ed. I, New York, 1974. Grune & Stratton, Inc., pp. 188-195. Cropp G. J. A., and Schmultzler, I. J.: Grading, time course, and incidence of exercise-induced airway obstruction and hyperinflation in asthmatic children. Pediatrics I suppI.) 56:868, 1975. Kiviloog, J., Irnell, L., and Eklund, G.: Ventilatory capacity, working capacity and exercise-induced bronchoconstriction in a population sample of subjects with bronchial asthma or chronic bronchitis, Stand. J. Respir. Dis. 56:73, 1975. Bouhuys, A., Hunt, V. R., Kim, B. M., and Zapletai, A.: Maximum expiratory Row rates in induced bronchocrmstriction in man, 1. Clin. Invest. 48: 1159, 1969. Zuskin, E., Lewis, A. J., and Bouhuys, A.. Inhibition of histamine-induced airway constriction by ascorbic acid. J. ALLERGY CLIN. IMMUNOL. 51:218, 1973. Zuskin, E., and Bouhuys, A.: Acute airway responses to hairspray preparations, N. Engl. J. Med. 29&66Q, 1974. Godfrey, S., Silverman, M., and Anderson, S. D.: Problems of interpreting exercise-induced asthma, J. ALLGRG~ CLIN. IMMUN~L. 52: 199, 1973. Virgulto. J., and Bouhuys, A.: Electronic circuits for recording of maximum expiatory flow-volume (MEFV) curves. J. Appl. Physiol. 35:145, 1973. Haynes, R. L., Ingram, R. H., Jr., and McFadden. E. R., Jr.: An assessment of the pulmonary response to exercise in asthma and an analysis of the factors influencing it. Am. Rev. Respir. Dis. 114:739, 1976. Freedman, S., Tattersfield, A. E., and Pride, N. B.: Changes in lung mechanics during asthma induced by exercise, J. Appl. Physiol. 38:974, 1975. Snedcor, G. W ., Co&ran, W . G.: Statistical methods, Ames, Iowa, 1967, Iowa State University Press. pp. L72- 190. Kendall, M. G., and Stuart, A.: The advanced theory of statistics, London. 1967, Charles Griffin & Co.. Ltd.. vol. 2. pp. 311-312. Sly, R. M.: Exercise related changes in airway obstruction:
398
18.
19.
20.
21.
Schachter
et al.
Frequency and clinical correlates in asthmatic children, Ann. Allergy 28: 1, 1970. Nadel, J. A.: Neurophysiologic aspects of asthma, in Austen, K. F., and Lichtenstein, L. M., editors: Asthma, New York, 1973, Academic Press, Inc., p. 31. Fisher, H. K., Holton, P., Buxton, R., and Nadel, J. A.: Resistance to breathing during exercise-induced asthma attacks, Am. Rev. Respi. Dis. 101:885, 1970. Bouhuys, A., Mitchell, C. A., Schilling, R. S. F., andzuskin, E.: A physiological study of byssinosis in colonial America, Trans. N. Y. Acad. Sci. 35:537, 1973. Nadel, J. A., and Tierney, D. F.: Effect of a previous deep inspiration on airway resistance in man, J. Appl. Physiol. I&717, 1961.
J. ALLERGY
CLIN. IMMUNOL. JUNE 1979
22. Despas, P. J., Leroux, M., and Macklem, P. T.: Site of airway obstruction in asthma as determined by measuring maximal expiratory Row breathing air and a helium-oxygen mixture, J. Clin. Invest, 51:3235, 1972. 23. Mildon, A., Leroux, M., Hutcheon, M., and Zamel, N.: The site of airways obstruction in exercise-induced asthma, Am. Rev. Respir. Dis. 110~409, 1974. 24. McFadden, E. R., Jr., Ingram, R. H., Jr., Haynes, R. L., and Wellman, J. J.: Predominant site of flow limitation and mechanisms of postexertional asthma, J. Appl. Physiol. 42:746, 1977. 25. Konig, P., and Godfrey, S.: Prevalence of exercise-induced bronchial lability in families of children with asthma, Arch. Dis. Child. 48:513, 1973.
