Late asthmatic reaction to seasanal Aergens

mid

and

Emanusle Crimi, MD, Piero Gianiorio, MD, Giovanni Orengo, MD, Susanna Voftolini, MD, Paolo Crimi, MD, and Vito Brusesco, MD Genova, Italy Twelve patients with asthma sensitized to Dermatophagoidespteronyssinusand Parietariajudaica were studied. Patients were challenged before (winter), during (summer), and after (aurumn) Parietaria-pollen season. Early asthmatic reaction was positive for both allergens, and the provocative dose causing a 15% decrease of FEV, was similar in all seasons. The provocative dase of methacholine causing a 15% decrease of FEV, and specific IgEs for both allergens were also not significantly different throughout the time of study. Late asthmatic reaction (LAP) to Dermatophagoides occurred in eight of 12 patients in winter, in six of nine in summer, and in five of six patients in autumn. The severity of LAP, expressed as the maximum fall of FEV, 3 to 8 hours after challenge, was not signtficantly dtrerent between seasons. L.AR to Park&aria occurred in only one of 12 patients in winter, in six of 11 in summer, and in one of six patients in autumn. In summer, LAR to Parietaria was significantly more severe than in winter. In both winter and autumn, but not in summer, LAR to Dermatophagoideswas significantly more severe than to Parietaria. We conclude that LAR is allergen specific, and natural exposure has a priming effect on LAP. (J ALLERGY CLIN IMMUNOL 1990;85:885-90.)

The prevalence of LAR varies widely among studies.l4 This variability depends,at least in part, on the concomitant effect of patient-related factors, that is, the degree of bronchial responsiveness,specific IgE serum levels, and baseline airway ftmction.5 It is unclear whether the developmentof LAR may also depend on allergen-relatedfactors, that is, its nature and the environmental exposure to it. The occurrence of LAR to one allergen but not to another in the same patient has been reported by Price et al6 Natural and experimental exposure to allergens have been demonstrated to increase nonspecific bronchial reactivity and specific IgE serum levels.7-13 The relationship between LAR and natural exposure to allergen has not been studied. From Istituto di Medic-ha dell0 Sport, Cattedm di Allergologia Respiratoria, and Istituto di Igiene e Medicina Preventiva, Cattedra di Medlcina di Comuniti Universiti di Genova, and Servizio di Allergologia, Ospedale S. Martino, Genova, Italy. Supportwi in part by a grant from the Italian Ministry of Public Educat&m. Re&vii for publication July 7, 1988. Revised Dec. 1, 1989. Acce@d for publication Dec. 20, 1989. Reprint requests:E. Crimi, MD, Istituto di Medicina dell0 Sport, Vi&e Ihedetto XV 10, 16132Genova, Italy. 1/1/18971

1

Abbreviations used

LAR: Late asthmaticreaction AU: Arbitrary unit PD,,: Provocative dose causing a 15% decreasein mv, OD: Optical density EAR: Early asthmatic reaction

To investigate if LAR is patient specific or rather allergen specific, we studied a group of patients with asthma sensitized to both a perermial al mutolphagoides pteronyssims) and a seasonalal (Parietaria j&&a), which, in our geogra causessymptoms in late spring and summer, To in: vestigateif natural exposureto allergen is an important factor for developmentof CAR, patients wem s&died before, during, and after Parietarbpollm RSSOR. subj#bcts Nine male and three female patbts with aakna (Table I), aged 10 to 23 years, who me-tthe fobwing criteria, were studied: history of rhinitis and a&ma after exposure to house dust and Parietaria pollen and definite positive

886 Crimi et al.

J. ALLERGY

TABLE I. Characteristics

of patients Prick O* (mm)

No.

be (Yd

1

14

2 3 4 5 6 7 8 9 10 11 12

18 21 18 21 22 21 13 19 22 10 23

CLIN. IMMUNOL. MAY 1990

FEV, (% pred

77 91 82 100 81 79 103 84 95 105 110 100

D

11 9 10 8 8 7 8

RAST class P

D

P

12

4 3 4 4 4 3 3 4 4 3 4 3

4 3 4 3 4 2 3 4 3 3 3 3

10

.

12 10 9 10 9

11

11

12 7 10 9

8 8 10 10

D, Dermatophagoiakspteronyssinus; P, Parietaria judaica. *Wheal diameter. skin prick tests and RAST equal to or exceeding the second Pharmaciaclass for both D. pteronyssinus and P. judaica. To enter the study, patients were required to have FEV, higher than 70% of predicWP4without circadian variations exceeding 10% and not to be receiving steroid treatmentor allergen immunotherapy. Beta,-stimulants, if any, were stopped 12 hours before studies. None of the patients was receiving theophylline therapy. Cromolyn sodium was avoided for 1 month at least before studies.

Experimental

procedure

All patients entered the study in winter time when count in our geographic area was constantly Cl0 particles per cubic meter. On the first day of study, patients underwent methacholine bronchial challenge according to a technique previously described.sOn the following day, they were randomly challenged with allergen extract of D. pteronyssinus or P. juahica. After a time interval of 7 days at least, patients were rechallenged with methacholine, and on the following day, with the other allergen. For bronchial challenges we used lyophilized allergens dosed in RAST AUs by RAST-inhibition technique on an in-house (Lofarma, Milan, Italy) standardserapool with a 5000 AU of D. pteronyssinus (0.16 mglml of protein) and a 10,000 AU of Parietaria (0.39 mg/ml of protein) as referenceextracts. Solutions were preparedon each study day by adding distilled water sufficient to obtain 2000 AU per milliliter. A dosimetric technique’ was used to administer aerosolscontaining allergen dosesfrom 2 to 500 AU. Doseresponsecurves were obtained by twofold increments of doses. The bronchial responseto inhaled allergens was inferred from changesin FEV, measuredby a dry-rolling seal spirometer (Mijnhardt BV, Bunnik, The Netherlands) 15 minutes after each inhalation. Challenges were stopped when FEV, was decreased15% of control occurring between the third and the eighth hour after the end of challenge. The severity of the EAR and LAR was estimated from the lowest values of FEV, achievedwithin 1 hour and 3 to 8 hours after the end of challenge, respectively. The aboveprocedurewas repeatedin early summerwhen airborne Parietaria-pollen count in our areawas constantly >lO particles per cubic meter, and in six patients (Nos. 1 to 6, Table I) also in late autumn when pollen count was constantly less than this value. On all occasionsthe same ampule and batches of allergens were used for bronchial challenges.Venousblood sampleswere drawn and serawere frozen for pending analysis. Specific IgE was measuredby ELISA technique (Pharmacia,Uppsala, Sweden)on all seasonal serum samplesat the end,:ofstudy by use of the same batch of allergens for each patient. Results are reported as OD reading at 420 mn.

Statistical analysis Student’s paired t test was used for significance testing. Values of p < 5% were consideredsignificant.

RESULTS On Dermarophagoides-challenge day, baseline values of FEV, (as percent of

predicted) were 90 f 13

(SD) in winter, 101 & 9 in summer, and 90 + 10 in autumn. Allergen PDls (Fig. 1, fop, Zefi) was 26 AU (geometric mean) in winter, 43 AU in summer, and 10 AU in autumn. The maximum fall of FEV, during EAR, that is, within 1 hour after inhalation challenge, was 26 + 8 (percent of control) in winter, 29 k 7 in summer, and 25 + 6 in autumn. The maximum FEV, fall during LAR (Fig. 1, fop, right) was 25 f 13 (percent of control) in winter, 19 f 12 in summer, and 21 k 9 in autumn. LAR occurred in

VOLUME NUMBER

Late asthmatic

85 5

reaction

889

LAR

W

S

A

s

A

Methocholine 10

01 W

Season

W

s Season

A

ffi. 1. Upper m: Bronchial sensitivity to D. pterunyssinus (k&J and severity of LAR (r&&J. Lower pllwb: Nonspecific bronchial sensitivity to methacholine (t&) end serum-epedfk Igi!!s (tight); W, winter; S, summer; and A, autumn. None of these diirences was atetisticaiiy significant.

eight of 12patients in winter, in six of nine in summer, and in five of six patients in autumn. Methacholine PDls (Fig. 1, bofrum, left) was 0.103 mg (geometric mean) in winter, 0.159 mg in summer,and 0.131 mg in autumn. Serum-specificIgEs to Dermatophagoides (Fig. 1, bottom, right) were 1.262 + 0.269 OD in winter, 1.246 ?z 0.320 OD in summer,and 1.310 + 0.147 OD in autumn. None of these differences was statisticaIly significant. On Parieturia-challenge day, baseline values of FEV, (as percent of predicted) were 91 + 12 in winter, 100 & 12 in summer, and 92 + 6 in autumn. Allergen Pa,, (Fig. 2, top, &$I) was 15 AU (geometric mean) in winter, 19 AU in summer, and 16 AU in autumn. The maximum percent fall of FEV, during EAR was 28 +- 8 (percent of control) in winter, 33 2 10 in summer, and 23 f 4 in autumn. The maximum percent FEV, fall during LAB (Fig. 2, top, right) was 6 & 5 in winter, 21 k 19 in summer,and 8 + 7 in autumn. LAB occurred in one of 12 patients in winter, in six of 11 in summer, and in one of six patients in autumn. The only patient who demonstnxttxl LAB to Parietaria in winter and autumn could in summer becauseof a worsening notbechalle of baseline lung function. Methacholine PD,, (Fig. 2, bottom, Zefi)was 0.109 mg in winter, 0.170 mg in

summer, and 0.109 mg in autumn. Serum-qecific IgEs to Purieturia (Fig. 2, bottom, r&I&) were 0.986 2 0.318 OD in winter, 0.894 + 9. summer, and 0.835 + 0.386 OD in creaseof FEV, maximnm fall during with respect to winter was statisticalI (p = 0.02). No other difference was s niticant. The severity of LAB to De ietariu in the different seasonsis Both in winter and autumn, t&t

Parietaria sewxk, the maximum late fal similar after both allergen challenges. Inapreviousstudy,5weh occurrence and severity of dependcmthe severity of the tars predicting LAR were found bronchial reactivity, specific IgE baseline airway function. In that s&kc&WC:did not exconsider if the nature of andthe posureto it were also important deterrnin&ntsof LAB.

888

J. ALLERGY

Crimi et al.

W Msthocholine

31

S

A

s Season

A

CLIN. IMMUNOL. MAY 1990

bE

0’

’ W

A 53&l”

W

FIG. 2. Upper panels: Bronchial sensitivity of Par&aria (left) and severity of LAR (right). Lower panels: Nonspecific bronchial sensitivity to methacholine (/eti) and serum-specific IgEs (right/; W, winter; .S, summer; and4 autumn. Maximum FEV, fall in summer was significantly (p = 0.02) increased compared to winter. No other difference was statistically significant.

The results of the present study demonstratethat the samepatient sensitized to two different allergens may or may not developLAR to both allergens. These data confirm and extend what was previously reported by Price et al6 in a small number of children. From these observations, it might be concluded that LAR is somehow related to the characteristics of the responseto the allergen. However, natural exposure to allergen may modify the patient’s conditions, making the patient more susceptibleto develop LAR. Indeed, the results of our challenges with Par&aria demonstratethat somepatients develop LAR during, but not before and after, pollen season. We could not measurehousedust concentrationsto which patients were exposed.Plans-Mills et all5 have recently reported that patients with asthmaallergic to house dust mites are more likely to have attacks in autumn when dust concentration is higher in their houses. The lack of changesin responseto Dennarophugoidessuggests,however, that natural exposure to the allergen was, in our patients, relatively constant throughout the time of study. Therefore, the different responsein the late phase to Dermatophagoides and Parietaria in winter and autumn can be interpreted as the result of different natural exposure to these allergen. By contrast, the similarity of occurrenceof LAR in summerwas likely the results of exposureto pollen

with a constant exposure to house dust. Any possible difference in the potency of the two allergen preparations used in this study should have resulted in a similar difference in responsein any season. A main finding of this study is that, in patients allergic to more than one allergen, the LAR to a seasonal allergen may occur more frequently and more severely during pollen season,even in the absenceof changesin nonspecific bronchial responsivenessand specific IgE serum levels. The finding of unchanged IgE serum levels during pollen season may appear surprising; however, circulating IgE levels may not accurately reflect the local IgE concentration.16~l7 Moreover, recent results from our laboratory demonstrate that specific IgE levels in bronchial lavage, but not in serum, are higher in patients who develop LAR after challenge than in patients who do not.18 The lack of changein methacholine sensitivity during pollen seasonmay also appear to be an unexpected finding. An increasednonspecific airway responsivenesshas been reported to occur in patients sensitized to only one allergen after pollen season.loThe increase in methacholine sensitivity may not necessarilyoccur during pollen season in patients sensitized to more than one allergen, since in these patients nonspecific bronchial responsivenessreflects the combined speci6c effects of natural exposureto these allergens. In

VOLUME NlJMBER

Late asthmatic

85 5

I

reaction

839

ponwbnb w:

P~O.0003

s: P=O.51 A: p=o.oss

W(n=r

2)

S(n=g)

L

A(n=s)

Season FIG. 3. Severity of LAR (maximum late FEV, fall 3 to 8 hours after challenge) and Parietaria in winter (W), summer (S), and autumn (A) in patients challenges in the same season. Bars represent SE.

our patients an increase in methacholine sensitivity during pollen seasonmay have not occurred because of the already high level of airway hypertesponsiveness likely sustainedby perennial exposure to house dust. In patients sensitized to only one allergen, nonspecifk bronchial hyperreactivity has been demonstrated to be a determinant of LAR5 and appearsto be related to airway inflammation.‘9 Therefore, LAR may be viewed as a consequenceof an increaseddegree of airway inflammation. If nonspecific bronchial inflammation is a main determinant for the development of LAR, it should be expected that the same patient in the same seasonmay or may not develop LAR against any allergen. The observation that some patients sensitized to a perennial and a seasonalallergen develop LAR to the latter during pollen season only, even in the absenceof any increaseof bronchial responsiveness,suggeststhat natural exposure to allergen induces an allergen-specific airway inflammation. Such a specificity of airway inflammation may rely on cellular basis. Metzger et al.*’ demonstratedthat helper T-lymphocytes enter the lung from peripheral blood within 48 hours after local allergen challenge. These cells were also found to be decreasedin blood immediately after inhalation challenge.21These findings indicate that acute exposure to allergen tends to increasethe local amount of immunocompetentcells. It is also plausible that this may also happen during prolonged natural exposure to allergen. Whether

to kmu&~&q&fes who underwent

both

helper T-lymphocytes may contribute to increasethe local IgE level is unknown. Natural exposure to allergens has been demonstratedto increasecirculating eosinophils,~ duces an increase of eos’ lavage.23*24It has also been demonstratedthat late nasal reactions are related to mediatorsreleasedfrom basophils that bear specific IgE on their surface.25 Thesecells are stimulated by chemotactic factors, the releaseof which is dependenton the specific immune response. In summary, our observations indicate that the development of LAR is allergen specific in the sense that the patient’s susceptibility to a given allergen is dependenton the natural exposure to that allergen. RWEREWES e NOM. Late bron1. Booij-Nami H, de Vrbs K, Sl chial obstmctive reaction to ex dust extract. CIiu Allay 1972;2:43-61. 2. Robertwn DG, Keri@anAT, HIU@WM FE, (=balmersR, Dolovich J. Late wtbmatic respowes i&wed by ray3wecd-potlen allergen. J ALLEUGY CUN IMMUFWL1!?74;54:244-54. 3. WarnerJO. Significance of late reactions &.er brouchial cballenge with house dust rpite. kcb I% Child 19%$1:905-l 1. 4. CrimiE,Brsm&wso ha, Villa 0. B~easca V. J3& as&m&c reaction to i&led l.kwa&&a&& pteronyssn’nus: lkquency, reproducAbilify,and antagonismby crom@iynsodium. Alm fdkgy 1986$?183-6. 5. CrimiE,Brwasco V, Losmrlo E, Crimi P. predictive scmacy of late asthmaticrwctio~ to Dem~h@ties p8erotayssinus. J ALLERGY CLANIMMUNOL 1986;78:908-13.

890 Crimi et al.

6. Price JF, Hey EN, Sothil JF. Antigen provocation to the skin, nose, and lung in children with asthma: immediate and dual hypersensitivity reactions.Clin Exp Immunol 1982;47:587-94. 7. Altounyan REC. Changes in histamine and atmpine responsivenessas a guide to diagnosis and evaluation of therapy in obstructive ariways disease. In: Pepys J, Frankland AW, eds. Disodium cromoglycate in allergic airways disease..London: Buttenworth, 196947-53. 8. Platt-Mills TAE, Tovey ER, Mitchell EB, Moszoro H, Neck P, Wilkins SR. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982;2:675-8. 9. Cockcroft DW, Ruffin RE, Dolovich J, Hargreave FE. Allergen-induced increase in nonallergic bronchial reactivity. Clin Allergy 1977;7:503-13. 10. Boulet LP, Cartier A, Thomson NC, Roberts RS, Dolovich, J, Hargreave FE. Asthma and increasesin nonallergic bronchial responsivenessfrom seasonalpollen exposure.J ALLERGYCLIN IMMUNOL1983;71:399-406. 11. Gleich GJ, Jacob JL, Yunginger JW, Henderson LL. Measurement of the absolute levels of IgE antibodies in patients with ragweed hay fever. J ALLERGYCLIN IMMUNOL1978; 60:188-98. 12. Grammer L, Levitz D, Roberts M, Pr&ansky JJ, Zeiss R. Seasonalvariation of IgE antibody specific for ragweedantigen (IgE-a-AgE) from the basophil surfacein patientswith ragweed pollenosis. Int Arch Allergy Immunol 1981;66:179-88. 13. Muto K, Hiratani M, Oshida Y, Ito S, Kasei M, Ueda S. Increased serum IgE antibodies in institutionalized asthmatic children after a transient return home: the role of house dust mite allergens in the home as a trigger of asthmatic attacks in mite-sensitive patients. Ann Allergy 1986;57:249-52. 14. Quanjer PH. Standardized lung function testing: report of working party on standardization of lung function testsEuropeancommunity for coal and steel, ECCS. Bull Eur Physiopathol Respir 1983;19(suppl5):7.

J. ALLERGY

CLIN. IMMUNOL. MAY 1990

15. Platts-Mills TAE, Hayden MRN, ChapmanMD, Wilkins SR. Seasonalvariation in dust mite and grass-pollen allergens in dust from the housesof patients with asthma.J ALLERGYCLM IMMUNOL1987;79:781-91. 16. Huggins KJ, Brostoff J. Local production of specific IgE antibodies in nasal secretion. Lancet 1975;2:148-50. 17. Crimi E, ScordamagliaA, Crimi P, Zupo S, Barocci S. Total and specific IgE in serum, bronchial lavage, and bronchoalveolar lavage of asthmatic patients. Allergy 1983;38:553-9. 18. Crimi E, Rossi GA, Lantero S, et al. Late asthmaticresponse is associatedwith elevated concentration of specific IgE in the respiratory tract [Abstract]. Am Rev Respir Dis 1989; 139(@:461a. 19. Fabbri LM, Aizawa H, Alpert SE, et al. Airways hyperresponsivenessand changes in cell counts in bronchoalveolar lavage after ozone exposure in dogs. Am Rev Respir Dis 1984;129:288-91. 20. Metzger WJ, Zavala D, Richerson HB, et al. Local allergen challenge and bmnchoalveolar lavage of allergic asthmatic lungs. Am Rev Respir Dis 1987;135:433-40. 21. Gerblich AA, Campbell AE, Schuiler MR. Changes in Tlymphocyte subpopulations after antigenic bronchial provocation in asthmatics. N Engl J Med 1984;310:1349-52. 22. Lowell FC. Clinical aspectsof eosinophilia in atopic disease. JAMA 1%7;202:875-8. 23. Durham SR, Kay AB. Eosinophils, bronchial hyperreactivity, and late-phase asthmatic reactions. Clin Allergy 1985;16: 41 l-8. 24. De Monchy JGR, Kauffman HF, Venge P, et al. Bronchoalveolar eosinophilia during allergen-induced late-phase asthmatic reactions. Am Rev Respir Dis 1985;131:373-6. 25. Maclerio RM, Proud D, Togias AG, et al. Inllammatory mediators in late antigen-induced rhinitis. N Engl J Med 1985;313:65-70.

AVAILABLE NOW! The PROCEEDINGS OF THE INTERNATIONAL CONGRESS OF ALLERGOLOGY AND CLINICAL IMMUNOLOGY can be purchased from the Publisher. This collection of “state-of-the-art” presentations from the XII Congress held October 2025, 1985, in Washington, D.C., brings together the current advances in basic and applied aspects of allergy and allergic diseases. It includes 528 pagescovering such topics as IgE,

roles of the different cell types and their products, clinical problems, asthma, rhinitis, and reactions to foods and drugs and occupational agents, collected and reviewed by Editor Charles E. Reed, MD (USA) and Associate Editors JosephBellanti, MD (USA), Robert J. Davies, MD (UK), Sidney Friedlaender, MD (USA), Albert Oehling, MD (Spain), and Raymond G. Slavin, MD (USA). To purchase, call or write: Mosby-Year Book, Inc., 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, or telephone FREE l-800-325-4177, Journal Fulfillment, ext. 7351 (in Missouri call collect at 314-872-8370,Journal Fulfillment, ext. 7351). Prepayment required. Make checks payable to Mosby-Year Book, Inc. (All payments must be in US funds drawn on a US bank.) Price: $36.50 in the US, $40.50 in Canada, and $41.50

international (surface shipping chargesincluded).