Increased bronchial responsiveness to exercise and histamine after allergen challenge in children with asthma

Nickelsen

6.

7.

8.

9.

et al.

lergic rhmitis with polymerized ragweed extract. J AI.I.EK(;~ CLIN hMUNO1. 7I:ll8, 1983 (abst) Georgitis JW, Mueller UK, Clayton Wl;, Kane J. Wypych Jl. Reisman RE, Arbesman CE: Local nasal immunotherapy (1,NIT) for treatment of grass pollenosih. J AI.I.I~KGY CLIN I!+ MUNOI. 69:loO. 1982 (abst) Georgitis JW, Clayton WF, Barde SH, Wypych JI. Reisman RE: Local nasal immunotherapy (LNIT) for grass-allergic rhinitis: a second year. J AI.I.ERGY CLIN IMMLXOI. 71:92. 1983 (abst) Wypych JI. Georgitis JW. Tronolone MJ, Barde SH. Mauriello PM, Reisman RE: Local nasal immunotherapy (LNIT) comparing polymerized grass and aqueous grass extracts. J ALI.I!KGY CLIS IMMIXOI. 73:140, 1984 (abst) Norman PS, Winkenwerder WL: Suppression of hay fever symptoms with intranasal dexamethasone aerosol. J AI.I.EKG’~

36:284, 1965 10. Okuda M: Basic study of nasal provocative test. first report: side. site of the nose, size of site. and allergen amount. Arch Otorhinolaryngol 2 14:24 I . 1977

Il. 13.

13. 14.

15.

16.

Siege1 S: Nonparametric statlstich IGr the bebaih)rdi ~c’I~~G:~‘. New York, 1956, McGraw-Hill Book Co. 10~. pp ZO:! ! Lichtenstein LM. lshizaka K. Norman I’S ioh<:?ix. 1481

Increased bon&id reqxb?3ivets to exercise and hyietamine after SW chdlenge in children with asthma Huda Mussaffi, M.D., Chaim Springer, M.D., and Simon Godfrey, M.D., Ph.D, F.R.C.P. Jerusulem, I.srcwl Nonspeci$c bronchial reactivity to e.xercise and histamine was measured in nine children with asthma before and within nine days after allergen inhalation. All patients developed an immediate ,fall in FEV, of 316% after allergen inhalation, and five children also developed a definite late asthmatic response with a fall in peak expiratory,flow qf 214% after 3 to 8 hours. Mean postexercise fall in FEV, (LFEV,) of the whole group was significantly greater after allergen challenge compared with that of control subjects (29 +r 6%, and 16 I~I 4%: p = 0.013). There was no change in refractoriness to repeated exercise after allergen challenge. The mean provocation concentration of histamine causing a decrease in FEV, c$20% of the whole group M’a.sless after allergen challenge compared with that of control subjects (0.47 i- 0. IX and 0.62 2 0.131, but this was not statistically significant (p = 0.19). Of thejva children with late allergen reactions, all demonstrated increased histamine sensitivity, and all ,four children who developed definite exercise-induced asthma ulso detnonstrated increased sensitivity to e.xercise. Of the four children without late allergen reactions, none demonstrated increased histamine sensitivity, but two of the three children with definite exercise-induced asthma demonstrated increased sensitivity to exercise. It may be that sensitivity to exercise is more easily affected by nonspecific reactivity than sensitivity to histamine. It is concluded that increased bronchial responsiveness to both exercise and histamine occur after allergen provocation in patients with usthma. (J ALLERGY CLIN IMMIJNOL 77:48-52, 1986.)

From the Department of Pediatrics and the Pulmonary Laboratory, Hadassah University Hospital, Mount &opus, Jerusalem. Israel. Received for publication Oct. 23, 1984. Accepted for publication June I, 1985. Reprint requests: C. Springer, M.D., Department of Pediatrics, Hadassah University Hospital, Mount Scopus, P.0. Box 24035, Jerusalem 9 1240. Israel.

48

Nonspecific bronchial reactivity to histamine,methacholine, and exercise is characteristic of asthma.’ In general there is a correlation between the responsivenessto histamine and exercise, but this is not always the case.’ It has been observed that patients with asthmahave increasednonspecificbronchial reactivity

VOLUME NUMBER

Increased bronchial responsiveness

77 1, PART 1

Abbreviations used EIA: Exercise-induced asthma RI: Refractory index PC,,: Provocative concentration of histamine causing a decrease in FEV, of 20% PEF: Peak expiratory flow

to histamine after exposure to specific allergens in the laboratory, especially in patients who have late asthmatic response. 3,4 The site of action of histamine on the airway is still the subject of debate. Some studies suggest that histamine acts directly on bronchial smooth muscle, whereas other studies suggest that it may act through a vagally mediated reflex pathway.‘. 6 Exercise induces asthma through complex physiologic pathways that appear to involve the release of chemical mediators from mast cells and that is influenced by the temperature or osmolarity of the airways.‘. 8 To the best of our knowledge, this hyperreactivity after exposure to allergens has not been established for exercise, and we therefore decided to compare the reactivity to exercise and histamine in children with asthma after exposure to allergens. In this way we hoped to shed light on the pathways involved in nonspecific bronchial reactivity. By studying the effect of allergen exposure on the refractoriness that follows EIA,9 we hoped to determine whether allergen acted on the mast cell stores of mediator or on the target organ.

monary calculator system, Hewlett-Packard Co., Palo Alto, Calif.). The best of two to three forced expirations was used to determine the FEV. Lung function was recorded before starting the exercise test, 1, 3, and 5 minutes after its cessation, and then at 5 minute intervals. The severity of EIA was calculated as the maximum percent fall of FEV, after exercise (AFEV, percent). Baseline FEV, lowest postexercise FEV, AFEV,% = x 100 Baseline FEV, In five of the subjects, a second exercise test was performed when FEV returned to 90% of the baseline value after the first test, and the RI was calculated as follows: RI% = AFEV, (first test) - AFEV, (second test) x 1oo AFEV, (first test) Histamine

AND METHODS

Studies were undertaken in nine children with asthma aged 7.8 to 15.5 years (mean 11.7 years) who had previously been found to develop asthma after exercise. All children were atopic and had positive prick skin tests to one or more of seven common allergens. Only one child required continuous prophylaxis with cromolyn sodium (Table I). At the time of the study, all patients were free of symptoms of acute respiratory infections, and baseline lung functions were 70% predicted or more in every case. Antiasthmatic medications were stopped 12 hours before the study. Informed consent was obtained for all the studies that were approved by the hospital ethics committee. Exercise

tests

Exercise tests consisted of 6 minutes of cycling at a fixed load on a cycle ergometer (Lode Instruments N.V., Holland) in such a way as to achieve approximately 60% of maximal oxygen consumption. ” The tests were performed breathing dry air at 22” C (water content 2 mg/L) achieved by passing room air through calcium chloride. Ventilation, heart rate, and gas exchange were recorded during the tests by use of the open circuit method (P. K. Morgan Exercise System, Chatham, England). The FEV, was recorded by means of a Fleish pneumotachograph and integrator (47804, a pul-

inhalation

tests

Histamine challenge was performed with a simple modification of the method of Co&oft et al.” Aerosols were generated by a Hudson nebulizer operated by compressed air to produce an output of 0.16 mlimin. The nose was clipped, and aerosols were inhaled via a mouthpiece by tidal breathing for 1 minute. Buffer phosphate was inhaled first as a control and followed by inhalations of doubling concentrations of histamine acid phosphate from 0.03 to 16 mg/ml at 5-minute intervals until a 20% fall in FEV, was achieved. The results were expressed as PC,, that was determined from the log-dose response curve. ” Allergen

PATIENTS

49

inhalation

tests

Allergen inhalation tests were performed with a simple modification of the method described by Chai et al.‘* The equipment used was the same as that used for histamine inhalation. Allergens were prepared from stock solutions supplied by Hollister-Stier Laboratories (Spokane, Wash.) and diluted with buffer phosphate. Serial fivefold dilutions were prepared and inhaled after a control inhalation of buffer phosphate, starting with the dilution producing a 2 mm wheal reaction in the skin prick test. Inhalations were continued at lo-minute intervals until there was a 20% fall in postbuffer FEV, . The early asthmatic response was recorded as the maximal decrease in FEV, from control value. PEF was measured hourly for 8 hours after the allergen challenge test, and the late asthmatic response was recorded as the maximum fall in PEF from the prechallenge baseline 3 to 8 hours after the allergen challenge. Study

design

Each subject attended the laboratory at 8.00 A.M. On each day of the study, lung function was measured after a rest of 30 minutes, and the study was continued only if the baseline FEV, before each test was >70% predicted. On the first day the patients undertook an exercise test followed by a second exercise test when the FEV, returned to 90% of the baseline value, which was approximately 30 minutes

50 Mussaffi et al TABLE

I. Patient data -Age

No.

hr)

1

IS.5

Albutcrol

10.0 12.5 13.0 14.0 13.0 x.5 10.0

Albuterol PKlV Albuterol PKN Cromolyn Albuterol Albutcrol Albuterol Albuterol

sodium PRN PRN PRN PKN

HIXM HD,Ll HDM HDM HD.M Grass Grass Grass

9

12.0

Albuterol

PRN

HDM

TABLE

Allergen dilution

Maximum immediate fall in FEV, I%)

Maximum late fall in PEF f%)

40 58 40 16 20 21 23 24 30

66 62 49 27 14 10 0 0 0

1.2 x 10 ’ 1.3 x IO 5 7.0 x 10 ” 3.0 x 10 3 1.o x IO rl 6.0 x 10 3 8.0 x 10 .3 1.4 x IO i 1.3 x IO i ____-___-.

analysis

RESULTS response

4 7 3

-~-

Table III. There was a small but significant

Comparisons were made by the use of the t test; differences were considered significant if p < 0.05.

The bronchial

1* \r i

in FEV, of > 16% with low concentrationsof allergen. Five of the nine patients (Nos. 1 through S) developed a definite late asthmatic responsewith a fall in PEF of 2 14%, and one subject(No. 6) developedan equivocal late responsewith a fall in PEF of 10%. The results of the exercise tests are illustrated in

after the end of the first exercise test. Two hours later a histaminechallengetest was performed. The allergen challenge was performed after the return of FEV, to 90% of the baseline value after the histamine test. After the allergen challenge all patients were hospitalized overnight. The postallergen challenge exercise and histamine tests were carried out within 8 days after the first series. In seven patients this was within 2 to 4 days, in one patient, after 6 days, and in the remaining patient, after 8 days. The cause of the delay was to ensure that baseline lung function was 70% predicted on the test day. Published results suggest that postexercise fall in lung function of > 10% is abnormal’” and that the coefficient of variation of repeated testing is 21% if studies are performed within 1 week.” Studies on histamine and methacholine reactivity demonstrated a twofold changein PC, to he significant.’

Statistical

Timing of second challenge (days after allergen challenge)

mite.

II. Allergen provocation tests

No. 1

PKN

used for provocation

2 3 4 5 6 7 8

PRN = as needed: HDM = house dust

2 3 4 5 6 I 8 9

Allergen bronchial

Therapy

to allergen

inhalation

for

each patient is illustrated in Table II. It can be observed that all patients developed an immediate fall

difference

in the meanpreexerciseFEV, before and after allergen challenge. 87 L 3% and 80 t 3% predicted, respectively 0) = 0.03). The postexercisefall in FEV, (AFEV,) of the first test of each pair increased significantly after allergen challenge from 16 t 4% to 29 -t 6% (p = 0.013) (Table III). Similar figures were obtained when only the patients were analyzed with a definite late asthmaticresponse,16 i 5% and 33 ? 8%. respectively (p = 0.027). In the live subjects who completed all four exercise tests, AFEV, of the second test of each pair increased significantly after allergen challenge, 14 -+ 3% and 22 t S%, respectively (p = 0.035); however, in these five patients. there was no significant difference in the refractory index before and after the allergen challenge. 39 -C 11% and 46 -+ 30/c,respectively (I> = 0.28). When the definition and reproducibility of HA is considered (see Methods). all four of the children with late allergenreactionsand EIA developeda significant increasein EIA after allergen challenge but also two of the three children without late allergen mactions. The resultsof the histaminechallengeare illustrated in Table

IV.

Prehistamine

provocation

FEV,

before

and after allergen challenge was similar and did not differ significantly (86 -t 3% and 82 r+ 4%. rcspectively). The mean PC for histamine fell from 0.62 -t 0.13 mg/ml before allergen challenge to 0.47 t 0.18 mg/ml after the allergen challenge. This was not statistically significant (p = 0.19); however. for thosefive subjectswho had a definite late asthmatic response, the mean PC dropped significantly from 0.58 + 0.19 mg/ml to 0.12 rt 0.02 mg/ml. respectively (p = 0.03).

VOLUME NUMBER

increased bronchial

77 1. PART 1

TABLE Ill. Postexercise

AFEV, before Before Exercise

allergen

1

Late APEFR

I 2 3 4 5

66 62 49 27 14

104 87 91 75 90

34 12 9 4 25

6 7 8 9 Mean SEM

10 0 0 0

75 83 89 90 87 3

16 11 28 2 16 4

AFEV,

BL FEV,

= late reaction,

percent

TABLE IV. PC,,: Histamine

before

After Exercise

2 AFEV,

RI

= baseline

and after allergen allergen

53 60 20 9 33

70 96 70 78 80 3

24 29 26 6 29 6

89 70 80

34 32 -

36 47 -

I5

55

70 73 76 4

12

50

15

42

22 5

46 3

= percent

After

allergen

challenge

fall in FEV,.

challenge

lmglml)

BL FEV,

RI

AFEV,

PC*,

PC,,,

(mglml)

KU,

PC,

APEFR

2

AFEV,

BL FEV,

predicted);

challenge

Late

Exercise

88 73 90 14 82

FEV, (percent

challenge

1

AFEV,

Equivocal or no late reaction 70 13 19 85 8 71 85 14 39 4 3 11 BL FEV,

allergen

BL FEV,

Definite late reaction 96 25 26 90 14 17 83 10 60

fall in PEFR;

Before Patient No.

BL FEV,

BL FEV,

1 2 3 4 5

66 62 49 27 14

103 93 86 77 86

Definite late reaction 0.55 1.25 0.04 0.50 0.56

87 73 81 74 82

0.18 0.14 0.04 0.13 0.10

3.10 8.90 (1 .OO) 3.80 5.60

6 7 8 9 Mean SEM

10 0 0 0

70 86 85 92 86 3

Equivocal or no late reaction 0.70 1.10 0.62 0.25 0.62 0.13

73 112 79 78 82 4

0.81 1.50 1.05 0.25 0.47 0.18

0.86 0.73 0.59 1.00

Late APEFR PGW, =

= late reaction,

percent fall in PEFR; BL FEV,

51

challenge

challenge Exercise

Patient No.

Late APEFR

and after allergen

responsiveness

= baseline FEV, (percent

predicted);

PC zIxIj =

PC,, before allergen challenge;

PC,, after allergen challenge.

When the reproducibility of histamine responsivenesswas considered(seeMethods), there was a significant increasein sensitivity in all five patients with late allergenresponseand no increasein thosewithout late response. DISCUSSION We have demonstrated an increase in bronchial reactivity to exerciseafter allergen inhalation and also

confirmed the observation of Cockroft et a1.3and of Cartier et a1.4of an increase in histamine reactivity after allergenchallenge. The increasedresponsiveness to exercise and histamine is probably not due to changesin airway caliber.4, I4 In our exercise study the mean preallergen challenge FEV, was 7% predicted higher than the postallergenchallenge, whereas the absolutepostexerciseFEV, after the allergen challenge was 57% predicted compared with 74% post-

52

Mussaffi

, ALLERGY

et al.

exercise FEV before the allergen challenge. It is therefore most unlikely that the small difference in baseline accounted for the increased response to exercise. Four subjects with definite EIA and a definite late response to allergen challenge (Nos. I , 2, 3, and 5) developed increased responsiveness to exercise. Subjects Nos. 6 and 7 developed an increased responsiveness to exercise in spite of not having a late reaction. The other two subjects without late reactions demonstrated no increased reactivity to exercise. Four out of the five subjects who demonstrated a definite late reaction after allergen challenge (Nos. 1, 2. 3, and 5) developed an increased sensitivity to histamine. Subject 3. who also developed a definite late reaction. had a preallergen and postallergen challenge PC2,, of 0.04 mgiml that was very close to the minimal histamine concentration used so that increased sensitivity to histamine could not possibly be detected after allergen challenge. Subject No. 6 who developed an equivocal late reaction and subjects 7, 8. and 0. who had no late reactions, demonstrated no increased rcsponsiveness to histamine. The lack of any change in the refractory index suggests that the increased responsiveness to exercise after allergen challenge is not due to increased storage of mediators in mast cells. If this were the case, it might be expected that it would be more difficult to deplete the mediators and that refractoriness would be less after allergen challenge. Although allergen challenge increased responsiveness to both exercise and histamine, the two challenges behaved somewhat differently in that a late allergen response appeared to be essential for an increase in histamine sensitivity but not necessarily essential for an increase in exercise sensitivity. It could be that a late allergen response reflects a greater allergenic stimulus and that EIA is more sensitive to an increase in nonspecific reactivity than histamine-induced asthma. The similarity of behavior of exercise and histamine responsiveness suggests that nonspccific responsiveness is increased generally after allergenic stimulation. The early pathways of histamineinduced asthma and HA are unlikely to be the same since EIA but not histamine-induced asthma is followed by a refractory period.‘, I’, and HA but not histamine-induced asthma is associated with the release of neutrophil chemotactic factor.“’ Thus, the present findings would support the concept that the increased responsiveness after allergen is a function of some final common pathways, possibly even the responsiveness of the bronchial smooth muscle itself. Increased reactivity to exercise and histamine after allergen challenge was found in al1 the patients who developed a definite late asthmatic response after al-

(.ilN. IMMUPG iANUAW ?9XB

lergen challenge and persisted for at least up to 8 day\ in patient No. 3 and for 6 days in paticns X(3 ” ft 3, well-known that patients with atopic a\rhrna cxp~ ence more trouble from their asthma during masons of natural allergen exposure. ” Our finding:* that brow: choconstriction after exercise is also inlcrcascd aticr allergen challenge implie:, that such patients may ucii require additional medication to contrail MA \c h~:z! they arc subjected to allergen exposurL~ REFERENCES I. Boushey H.4. Holtzman MJ. Sheller JR, Nadei JA: Bronclnal hypcrrcactivity. Am Rev Respir Dis I? 1289. 1980 2. Mellis CM, Kattan M, Keens TC. Levison ti- (‘omparative study of histamine and exercise challenge\ m asthmatic &ildrcn. Am Rev Respir Dis 117:91 I. 1978 3. Cockroft DW. Ruffm RE. Dolowich J. Hargrcave FE: Aliergcn induced increase in nonallergic bronchial rcactlvity f’lin “rl. lergy 7:503. 1977 4. Cartier A. Thomson NC, Frith PA. Robert; R.. Hargreave I:E: Allergen-induced asthma m bronchial responsiveness to hi\taminc: relationship to the late asthmatic response and change in :urway caliber. J AI I.I’.K(iY CI.IN IMMI!NOI 70: 170. 1982 JM. Ingram RH: Canine pulmonary rc. 5. I,oring GH, hazen sponse to aerosol histamine: direct versus vagal effects. J iZppl Physiol 42946. 1977 6. Shore S, Irvin CG, Shenklcr T. Martm JG: Mcchamsna or histamine-induced contraction of canine airway smooth muscle. J izppl Physioi 55:X. 1983 S: Mechamsms oi cxcrclse-Induced 7. Bar Yichay F.. Godfrey asthma. Lung 162: 195, 1984 8. Hahn A. Anderson SD. Morton AR, Black JL.. Fitch KD: A reinterpretation of the effect of tcmperaturc and water contenr of the inspired air in exercise-induced asthma. Am Rev Respir Dia I .X):575, I984 9 Edmunds AT, Toolcy M. Godfrey S: The refractory pcnod after exercise-induced asthma: its duration and relation to the severit) of exercise. Am Rev Respir Dis I I7:247. 1978 M. Konig P, Godfrey ,S: f