Different Effects of Nasal and Bronchial Glucocorticosteroid Administration on Bronchial Hyperresponsiveness in Patients with Allergic Rhinitis1 •2
MICHEL AUBIER, JEAN LEVY, CHRISTINE CLERICI,
FRAN~OISE
NEUKIRCH, and DENIS HERMAN
Introduction
Disorders of the upper respiratory tract, particularly allergic rhinitis, are commonly associated with bronchial hyperresponsiveness (1, 2). The latter may play an important role in the development and progression of airflow limitation (3, 4). Thus, appropriate drug therapy of chronic increased airway responsiveness may represent an important therapeutic intervention in patients with allergic rhinitis. In patients with asthma without allergic rhinitis, the development of bronchial hyperresponsiveness is associated with the presence of an inflammatory process in the lower respiratory tract (5, 6), and inhaled steroids produce marked improvement in airway reactivity (7,8). Inflammation is also a common feature of allergic rhinitis (9, 10), and topical nasal steroids are very effective in treating this upper airway disease (11, 12). However, little is known about the pathogenesis of the bronchial hyperresponsiveness associated with allergic rhinitis. In particular, it is not known whether in this situation the increased bronchial reactivity is, as in asthma, associated with airway inflammation or if it is linked to postnasal drip of mediators that directly alter airway reactivity. In the latter case, bronchial hyperreactivity in patients with allergic rhinitis should be treated with topical nasal anti-inflammatory agents, whereas in the former the anti-inflammatory drugs should be administered directly into the lowerairways.Therefore, our investigation was designed to ascertain the effect of either nasal (topical) or bronchial (inhaled) steroid administration on airway hyperresponsiveness in patients with nonseasonal allergic rhinitis associated with increased bronchial reactivity in response to carbachol challenge. Our data clearly demonstrate that nasal glucocorticosteroids have a much more potent effect on bronchial hyperreactivity than bronchial inhalation, which gives some insight into the patho122
SUMMARY Disorders of the upper respiratory tract, particularly allergic rhinitis, are commonly associated with bronchial hyperresponslveness. The latter may be due to postnasal drip or to mediator or chemotactic factors Into the lower airways that either directly alter airway reactivity or cause airway Inflammation. The aim of this study was to compere the effect of an Identical dose of nasel or bronchial corticosteroid administration on bronchial hyperresponslveness In patients with allergic rhinitis. Eleven patients ware studied. All of them ware Judged atopic on the basis of positive skin testa to common allergens. During control, spirometry, flow-volume curves, and specific airway conductance (SGaw) ware measured. Bronchial challenges ware then performed with Increasing concentrations of carbachol, and dose-response curves ware constructed. The concentration of carbachol that decreased SGaw by 35% from baseline (PO,,) was determined by Interpolating from the dose-response curve. Control measurements ware repeated at 1-wk Intarvals to ensure that PO" was stable In all the patlenta. Then the patients received for 2 wk, In a double-blind randomized crossover fashion, a topical administration of either an aerosol of 400 J.lg of beclamethasone dlproplonate (B) Into the nose (100 J.lg four times per day) or Into the bronchi. During each trial period, Identical sprays of placebo ware used, the latter being administered Into the nose when B was ad· ministered Into the bronchi and vice veraa. Measurements ware then performed aftar 2 wk of Intranasel administration and after 2 wk of Intrabronchlal administration. During both control periods all patients had normal baseline function data and showed markad and atable bronchial hyperrespon. slveness, PD•• amounting to 30 :l: 7 and 31 :l: 6 J.lg of carbachol at first and second control periods, respectively (normal velue > 160 I1g).After 2 wkof Intranasel B, PO.. Increased markedly, averaging 75 :l: 12 I1g(p < 0.001),whereas no significant change In PO" wes noted after 2 wk of Intrabronchlal B. No significant change In baseline lung function and SGaw (I.e., before bronchial challenge) was noted efter Intranasal or Intrabronchlal B administration. Thesa data show that toplcallntranassl administration of B hss an Important protective effect on carbachol responsiveness In patients with allergic rhinitis, whereas the same dosa of B administered Into the lower airways had no effect. AM REV RESPIR DIS 1112; 141:122-128
genesis of the increased airway reactivity commonly observed in these patients. Methods
Patients Eleven patients (nine men and five women with a mean ± SD age of 33 ± 9 yr) attending the chest and allergy unit with symptoms of perennial rhinitis (lasting for at least 2 yr) were prospectively studied. None of the patients had clinical history of asthma (absence of dyspnea. chest tightness, or wheezing), and physical examination as well as spirometry were normal at the time of their visit to the outpatient clinic. All patients showed bronchial hyperresponsiveness to inhaled carbachol, and they were judged atopic on the basis of positive skin prick tests for common allergens (house dust mites in all of them and ragweed pollens in six). Careful examination of sinus radiographs (absence of opacification of both maxillary sinuses,mucosal thickening, or air-fluid level on occipital-mental
view) eliminated sinusitis in all of them. All patients were nonsmokers. None of the patients wasusing regular medication, and none had used inhaled steroids in the past. Vasoconstrictor agents (pseudoephedrine) that were used occasionally for nasal congestion by three of them were withheld at least 48 h prior to the study sessions. Each subject was in clinical steady state and did not report upper or lower respiratory tract infection during the previous 2 months or during the study period. Exposure to allergens (except for house dust) to which immediate skin reactions were (Received in originalform September 19, 1991 and in revisedform January 3, 1992) 1 From the Unite de Pneumologie, INSERM U 226, Servicesde Medecine Interne et d'Explorations Fonctionnelles, Hepital Bichat, Paris, France. 2 Correspondence and requests for reprints should be addressed to Michel Aubier, M.D., Unite de Pneumologie 8e etage Sud, Hopital Biehat, 46 rue Henri Huchard, 75018 Paris, France.
123
EFFECT OF NASAL AND BRONCHIAL GWCOCORTICOSTEROIDS IN ALLERGIC RHINITIS
elicited was avoided for at least 2 wk before and during the trial period, the study being performed between November 1990 and February 1991. The investigation was approved by our local ethics committee, and signed informed consent was obtained.
Lung Function Measurements All measurements were made with the subjects in the sitting position. In each subject several flow-volume curves were obtained with a Hewlett-Packard spirometer (HewlettPackard, Waltham, MA) in order to determine FEV" FVC, and maximal midexpiratory flow rate (MMEF). Airway resistance (Raw) was determined during quiet breathing, and thoracic gas volume was measured at functional residual capacity (13) using a constant-volume body plethysmograph (Gould system 2800; Gould Instruments, Cleveland, OH) connected to a computer. Airway resistance was averaged for those four breathing cycles preceding the determination ofthe corresponding thoracic gas volume. Mean airway resistance was multiplied by the thoracic gas volume to give specific airway conductance (SGaw). Carbachol Inhalation Challenges Bronchial provocation tests were performed following the guidelines of the SEPCR working group: bronchial hyperreactivity of the European Society for Clinical Respiratory Physiology (14) and of the American Thoracic Society. Carbachol challenges were performed sequentially with a MEFAR dosimeter. The latter is derived from the Rosenthal-French dosimeter (Johns Hopkins University, Baltimore, MD) in which the opening of a solenoid valve is triggered by the patient's inhaling. The dosimeter makes it possible to preset the delivery time, the pause between deliveries, and the number of breaths. In our laboratory, we selected a delivery time between 0.3 and 1.2 s and a pause between deliveries of 15 s. We used a carbachol solution prepared with carbachol powder (Sigma Chemical Co., St. Louis, MO) diluted with saline and sodium bicarbonate to obtain a neutral pH. The concentration of the solution was 0.50/0. Patients wore noseclips and inhaled via mouthpieces from functional residual capacity to total lung capacity, first saline and then carbachol solution in a cumulative fashion starting at a concentration equivalent to 10 ILg, the dose then being doubled until the SGaw decreased by 50% or a 16O-lLg dose of carbachol was reached. 1\vo minutes after each step, five measurements of SGaw were obtained. Each step was separated by a 5-min interval, completion of all the measurements lasting 25 min for each patient. Dose-response curves were constructed by plotting SGaw against increasing doses of carbachol. The provocation dose (in micrograms) was defined as the dose of carbachol necessary to decrease SGaw by 35% (PD35) as compared with baseline values. PD 3S was determined by interpolation from the doseresponse curve.
Experimental Procedure This was a randomized, crossover, doubleblind study. 1\vo baseline measurements separated by a week were performed as described above to ensure the stability of the bronchial hyperresponsiveness. After the second baseline the patients were treated with beclomethasone dipropionate (Glaxo Laboratories, Paris, France) administered either as a nasal spray or as a bronchial aerosol inhalation over 2 wk. After 2 wk, the measurements were repeated, and the patients received once again for 2 wk beclomethasone dipropionate administered either by nasal sprays or by bronchial aerosol inhalation depending on the mode of administration they had during the first 2 wk of the trial. For nasal administration, the patients were asked to spray each nostril with beclomethasone dipropionate four times a day. The same protocol of administration was performed for bronchial inhalation. Each puff of the beclomethasone dipropionate spray delivered 50 ILg of the drug, giving the patients 400 ILg daily into the nose or into the bronchi for each study period. Identical sprays of placebo were used at the same time in each patient during each trial period, placebo being administered into the nose when beclomethasone dipropionate was administered in the bronchi and vice versa. Furthermore, the physician who performed the measurements was unaware of which trial period the patient was in. In order to assure that the intended dose was actually received by the patient, the bottles of beclomethasone dipropionate and placebo were weighed before and after treatment. The measurements suggested that all the patients had complied with the instructions for taking the medications. No other medications were allowed during the study. At each study period, the two baseline measurements and the two treatment measurements, the tests were always conducted at the same time of the day (3:00 P.M.). To determine a systemic effect of beclomethasone dipropionate, measurements of resting early morning (8:00 A.M.) plasma cortisol concentration were performed in each patient at first baseline and at the end of each study period. The serum cortisol levelwas determined by fluorescence polarization immunoassay, an immunofluorimetric method using TDX system cortisol from Abbott Diagnostics Division (North Chicago, IL).
Statistical Analysis The results are expressed as mean ± SEM, and the statistical analysis was performed using Student's t test for paired data in a comparison of the values obtained at baseline, after 2 wk of nasal, and 2 wk of oral beclomethasone dipropionate administration. Results
Plasma Cortisol Concentration At the first baseline measurement, plasma cortisol concentration averaged 8 ± 2 J.1g/IOO ml for the 11 patients. No significant change was noted after daily administration of 400 J.1g of beclomethasone dipropionate for 2 wk, plasma cortisol concentrations amounting to 9 ± 2 J.1g/IOO ml and 8 ± I J.1g/IOO ml after nasal and bronchial administration, respectively. Pulmonary Function The mean values in pulmonary mechanics measured at first and second baselines and after 2 wk of nasal and bronchial beclomethasone dipropionate administration in the 11 patients are shown in table 1. When entering the study, i.e., at the first baseline measurement, pulmonary function was normal in all the patients. It should be noted that no significant change in any of the measured parameters, including SGaw, occurred during the experiment. Indeed, no statistical difference in the measurements performed during the second baseline, after 2 wk of nasal, or after 2 wk ofbronchial beclomethasone administration was observed as compared with the first baseline measurement. Inhalation Carbachol Challenge All patients exhibited marked bronchial hyperresponsiveness during the first baseline measurement, mean PD 3 5 amounting to 30 ± 7 J.1g of carbachol, the dose necessary to decrease SGaw by 35010 in normal subjects being alwaysgreater than 160 J.1g of carbachol in our laboratory. As shown in figure I, bronchial hyper-
TABLE 1 PULMONARY FUNCTION DATA FOR 11 PATIENTS WITH CHRONIC ALLERGIC RHINITIS, MEASURED AT FIRST BASELINE (B1), SECOND BASELINE (B2), AND AFTER 2 WEEKS OF NASAL (N) AND BRONCHIAL (B) BECLOMETHASONE DIPROPIONATE ADMINISTRATION· B1 FEV" % pre .3 50 LO Cl 40 0~ 30 ro
C')
I
I
u
0
Fig. 1. Individual (closed circles) valuesof SGawPO.. (provocative doseof carbachol causinga 35% decrease in SGaw)after carbachol challenge performed during the first baseline (B1) and second (B2) baseline measurement. Each patlenrs response is shown by lines connectingthe two baseline values. Open circles representthe mean valuesfor the group. Bars represent 1 SE.
0 si: u
140
~
60 40 20 0
?
I :>< (
8
18
Fig. 3. Individual(closed circles) valuesof SGawPD•• In the 11 patients measuredat baseline(B) and after 2 wk of bronchial administration of beclomethasone dipropionate (lB). Each patient's response Is shownby lines connectingthe baseline value (left) to the beclomethasone diproplonatevalue(right). Opencirclesrepresent the mean value for the group. Bars represent 1 SE.
responsiveness is shown in figure 2 for the 11 patients. Intranasal beclomethasone dipropionate markedly decreased bronchial hyperresponsiveness, mean P03S for the 11 patients amounting to 30 ± 7 to 31 ± 6 IJ.g and 75 ± 12 J.1g of carbachol (p < 0.(01) at first and second baseline and after 2 wk of intranasal beclomethasone, respectively. By contrast, 2 wk of intrabronchial beclomethasone dipropionate administration had no significant effect on bronchial hyperresponsiveness (figure 3), P0 3S after the 2 wk of beclomethasone dipropionate administration amounting to 44 ± 12 J.1g of carbachol, a mean value for the group, which was not significantly different from the mean P03S measured at two baselines. However, a significant difference (p < 0.01) was still observed between the mean P03S measured after 2 wk of intranasal and intrabronchial beclomethasone administration.
IN
Fig. 2. Individual(closed circles) valuesof SGawPO.. in the 11 patients measured at baseline (B) and after 2 wk of nasaladministration of beclomethasone dlpropl· onate (IN). Each patlenrs response Is shown by lines connectingthe baselinevalue (left) to the beclornethasonedlproplonate value (right). Open circles represent the mean values for the group. Bars represent1 SE.
Discussion Our results clearly demonstrate that 2 wk of treatment with topical nasal glucocorticosteroids markedly decreased bronchial hyperresponsiveness associated with allergic rhinitis. Another interest-
ing result of the present study is that an identical dose of glucocorticosteroids administered via bronchial inhalation had no significant effect on airway hyperresponsiveness. The difference between the effect of nasal and bronchial glucocorticosteroid administration observed in our patients should be first discussed in view of the study design. We chose to compare the effect of an identical dose of intranasal beclomethasone dipropionate as that administered by bronchial inhalation in order to ensure that the nasal sprays did not pass through the nose and into the bronchi to exert a topical beneficial effect, which would have explained the decreased bronchial hyperresponsiveness. The fact that no change in airway reactivity was observed when the subjects received the drug by bronchial inhalation strongly suggests that this was not the case. This is further supported by the fact that the patients who had nasal administration the first 2 wk, which led to a marked reduction in bronchial hyperresponsiveness, exhibited again, after the second trial period during which they received beclomethasone dipropionate via bronchial inhalation, a degree of airway responsiveness close to the one measured during the two baselines. It is possible, however, that the amount of beclomethasone dipropionate that reached the bronchi may have been smaller than in the nose despite the fact that a similar dose of 400 IJ.g was administered during each study period. Indeed, several studies have shown that with use of bronchial inhalation techniques, approximately 70 to 80070 of the aerosol dose is deposited in the oropharynx, and 15 to 20% is deposited in the lung and small airways (15, 16). The lack of effect on airway responsiveness of bronchial administration of beclomethasone in our study may therefore be attributed to the fact that the amount of the drug that reached the bronchi was not high enough. This, however, appears unlikely, as several studies (17, 18) have clearly demonstrated a decrease in bronchial hyperresponsiveness in patients with pure asthma (i.e.,not associated with upper airway disease) with a dose of inhaled steroids of 400 IJ.g per day. Thus, although we cannot exclude that a higher dose of beclomethasone dipropionate would have decreased bronchial hyperresponsiveness in our patients, our data suggest that the abnormalities underlying the increased airway reactivity in patients with allergic rhinitis are essentially located in the nose. Nasal inflammation has been well
125
EFFECT OF NASAL AND BRONCHIAL GWCOCORTICOSTEROIDS IN ALLERGIC RHINITIS
demonstrated in allergic rhinitis (10), many different stimuli being capable of producing inflammation of the nasal mucosa. During inflammatory responses, preformed and/or newlygenerated inflammatory mediators may be released from resident cells in the nasal mucosa (mast cells, goblet cells, lymphocytes, macrophages, etc.)(19). These mediators such as leukotrienes, prostaglandins, and platelet-activating factor will increase vascular permeability with local tissue edema, secretion of mucus, and glandular proteins (rhinorrhea) (10). These nasal secretions, as previously shown (20), may be aspirated into the lower airways in patients with upper airway diseases. Thus, an attractive hypothesis linking nasal disease and increased airway responsiveness could be a postnasal drip of mucus, mediators, or chemotactic factors into the lower airways, which either directly alter reactivity or cause airway inflammation. Our data, which clearly demonstrate that bronchial hyperresponsiveness in our patients was decreased during nasal administration of steroids, whereas it was unaffected during bronchial inhalation, strongly favor the first hypothesis, i.e., postnasal drip of mediator directly altering bronchial reactivity. In this connection, it has been shown that prolonged treatment with topical glucocorticosteroids reduces the release of mediator in the nasal cavity (21). This hypothesis is also supported by a recent study that showed that natural antigenic exposure in subjects with pollen-induced rhinitis was not accompanied by changes in cell differential on bronchoalveolar lavage at the time of maximal symptoms of allergic rhinitis (22), contrary to what has been reported in patients with asthma not associated with upper airwaydisease (23). However, the nasal inflammation and the increased vascular permeability of the nasal mucosa that have been reported in patients with allergic rhinitis (10) may have led to an increased absorption of dipropionate beclomethasone from the nose into the bloodstream. As a result, the decreased airway hyperresponsiveness observed in our patients during nasal administration could have been secondary to a systemic effect of the drug. This, however, is unlikely, as plasma cortisol concentration did not change significantly in our patients throughout the study. Although airway responsiveness decreased in all our patients during nasal glucocorticosteroid administration, it should be noted (figure 2) that large decreases were seen in five of the 11 pa-
tients, whereas six had relatively small decreases. It may therefore be questioned whether there is more than one population included in our study group. In this connection, it should be noted that the percentage of patients with allergic rhinitis who demonstrate aspecificbronchial hyperreactivity varies in the literature from 24 to 73070 (2, 24). This discrepancy may reflect the fact that different populations were studied, although it is difficult to compare the two above studies because of differences in surveys and methods. Our patients wereprospectively selected on the basis of a positive response to carbachol challenge. All had allergicrhinitis as described in METHODS, and we were unable after reviewing the inclusion criteria to find any difference between the high and low responders to nasal glucocorticosteroids. In particular, it should be noted that no correlation between PD 3 5 before and the increase in PD 35 after 2 wk of nasal glucocorticosteroids was found in the 11 patients. Although our study was directed toward bronchial hyperreactivity rather than toward nasal symptoms, topical glucocorticoids administration had, as previously shown (12), a marked effect on the symptoms of allergic rhinitis in our patients. Indeed, in all of them a dramatic reduction of sneezing, rhinorrhea (mucus discharge), and nasal blockage was observed during nasal glucocorticosteroid administration. Thus, another hypothesis to explain the benefit of nasal glucocorticosteroids administration on bronchial hyperresponsiveness in our patients is that the intranasally administered drug had restored normal nasal physiologic conditions, including warming, humidification, and filtration of airborne allergens. Because a large proportion of allergens is contained in particles small enough to penetrate the bronchi (25),these aeroallergensare more likely to deposit in the airways during mouth breathing when the nose is obstructed, leading to increased bronchial reactivity. Finally,it has been proposed that bronchial hyperresponsiveness in patients with allergic rhinitis may be secondary to "nasobronchial" reflex (26). This hypothesis, however, also appears unlikely because it has been shown that topical anesthesia with lidocaine applied in the . nasal cavity did not prevent any of the nasal symptoms elicited after allergen challenge (27). Furthermore, in three of our subjects, topical nasal anesthesia did not influence the degree of bronchial hyperresponsiveness (personal data).
Regardless, the mechanisms underlying the strong protective effect of nasal glucocorticosteroids on bronchial hyperresponsiveness, the present study is, to our knowledge, the first one comparing the effects on airway reactivity in patients with allergic rhinitis of an identical dose of glucocorticosteroids administered in the nose and in the bronchi. The presented data clearly show that bronchial hyperresponsiveness in patients with allergic rhinitis can be improved by nasal steroid administration. References 1. Adinoff AD, Irvin GL. Upper respiratory tract disease and asthma. Semin Respir Med 1987; 8:308-14. 2. Ramsdale DH, Burns MW. Asymptomatic bronchial hyperresponsiveness in rhinitis. J Allergy Clin Immunol 1985; 75:573-8. 3. Lam S, Wong R, Young M. Nonspecific bronchial reactivity in occupational asthma. J Allergy Clin Immunol 1979; 63:28-33. 4. Cokcroft DN, Gotten DJ, Mink JT. Nonspecific bronchial reactivity after exposure to western red cedar. Am Rev Respir Dis 1977; 119:429-34. 5. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985; 131:599-606. 6. Jeffrey PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma: an ultrastructural quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989; 140: 1745-53. 7. Ryan G, Latimer KM, Juniper EF, Roberts RS, Hargreave FE. Effect of beclomethasone dipropionate on bronchial responsiveness to histamine in controlled nonsteroid-dependent asthma. J Allergy Clin Immunol 1985; 75:25-30. 8. Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O'Byrne PM, Hargreave FE. Effect of long-term treatment with inhaled corticosteroids on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990; 142:832-6. 9. Naclerio RM, Proud D, Togias AG, et al. Inflammatory mediators in late antigen-induced rhinitis. N Eng! J Med 1985; 313:65-70. 10. Raphael GD, Baraniuk IN, Kaliner MA. How and why the nose runs. J Allergy Clin Immunol 1991; 87:457-67. 11. Pipkorn U, Norman P, Middleton E Jr. Topical steroids. In: Mygind N, Weeke B, eds. Clinical aspects of allergic and vasomotor rhinitis. Copenhagen: Munksgaard, 1985; 165-79. 12. Mygind N. Topical steroid treatment for allergic rhinitis and allied conditions. Clin Otolaryngol 1982; 7:343-52. 13. Dubois AB, Botelho SY, Bedell GN, Marshall R, Comroe JH Jr. A rapid plethysmographic method for measuring thoracic gas volume: a comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. J Clin Invest 1956; 35:222-6. 14. Eiser NM, Kerreliyn KF, Quanjer PH. Guidelines for standardization of bronchial challenges with (non specific) bronchoconstrieting agents. Bull Eur Physiopathol Respir 1983; 19:495-501. 15. Newman SP, Pavia D, Moren F, Sheahan NF, Clarke SW. Deposition of pressurised aerosols in the human respiratory tract. Thorax 1981; 36:52-5. 16. Newhouse MT, Dolovich MB. Control of asth-
126 rna by aerosols. N Engl J Med 1986; 315:870-4. 17. Brompton Hospital Medical Research Council Collaborative 'Irial, Double-blind trial comparing two dosages schedules of beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma: preliminary report. Cancer 1974; 2:303-7. 18. Toogood JH, Lefcoe NM, Haines DJM, et al. A graded dose assessment of the efficacy of beclomethasone dipropionate aerosol for severe chronic asthma. J Allergy Clin Immunol 1977; 59:298-308. 19. Andersson M, Svensson C, Andersson P, Pipkorn U. Objective monitoring of the allergic inflammatory response of the nasal mucosa in patients with hay fever during natural allergen challenge. Am Rev Respir Dis 1989; 911-4.
AUBIER, LEVY, CLERIC', NEUKIRCH, AND HERMAN
20. HuwleyEJ, Viroslav J, GrayWR, PierceAK. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 1978; 64:564-8. 21. Pipkorn U, Proud D, Lichtenstein LM, KageySobotka A, Normal PS, Naclerio RM. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids, N Engl J Med 1987; 316:1506-10. 22. Boulet LP, Thrcotte H, Lampron N, Laviolette M. Influence of natural antigenic exposure on bronchoalveolar lavage in subjects with pollen-induced rhinitis. J Allergy Clin Immunol 1990; 86:19-25. 23. Metzger WJ, Zavala D, Richerson HB, et al. Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs. Am Rev Respir Dis 1987; 135:433-40.
24. Stevens WJ, Vermeire PA. Bronchial responsiveness to histamine and allergen in patients with asthma, rhinitis, and cough. Eur J Respir Dis 1980; 203:61-5. 25. Agarwall MK, Swanson MC, Reed CE, Yunginger JW. Airborne ragweed allergens: association with various particles sizes and short ragweed plants parts. J Allergy Clin Immunol 1984; 74: 687-93. 26. Paintal AS. Vagal sensory receptors and their reflex effects. Physiol Rev 1973; 52:159-82. 27. Holmberg K, Bake B, Pipkorn U. The effect of topical nasal anesthesia on allergen-induced symptoms, obstruction and blood flow. Clin Exp Allergy 1989; 19:443-7.
MICHEL AUBIER, JEAN LEVY, CHRISTINE CLERICI,
FRAN~OISE
NEUKIRCH, and DENIS HERMAN
Introduction
Disorders of the upper respiratory tract, particularly allergic rhinitis, are commonly associated with bronchial hyperresponsiveness (1, 2). The latter may play an important role in the development and progression of airflow limitation (3, 4). Thus, appropriate drug therapy of chronic increased airway responsiveness may represent an important therapeutic intervention in patients with allergic rhinitis. In patients with asthma without allergic rhinitis, the development of bronchial hyperresponsiveness is associated with the presence of an inflammatory process in the lower respiratory tract (5, 6), and inhaled steroids produce marked improvement in airway reactivity (7,8). Inflammation is also a common feature of allergic rhinitis (9, 10), and topical nasal steroids are very effective in treating this upper airway disease (11, 12). However, little is known about the pathogenesis of the bronchial hyperresponsiveness associated with allergic rhinitis. In particular, it is not known whether in this situation the increased bronchial reactivity is, as in asthma, associated with airway inflammation or if it is linked to postnasal drip of mediators that directly alter airway reactivity. In the latter case, bronchial hyperreactivity in patients with allergic rhinitis should be treated with topical nasal anti-inflammatory agents, whereas in the former the anti-inflammatory drugs should be administered directly into the lowerairways.Therefore, our investigation was designed to ascertain the effect of either nasal (topical) or bronchial (inhaled) steroid administration on airway hyperresponsiveness in patients with nonseasonal allergic rhinitis associated with increased bronchial reactivity in response to carbachol challenge. Our data clearly demonstrate that nasal glucocorticosteroids have a much more potent effect on bronchial hyperreactivity than bronchial inhalation, which gives some insight into the patho122
SUMMARY Disorders of the upper respiratory tract, particularly allergic rhinitis, are commonly associated with bronchial hyperresponslveness. The latter may be due to postnasal drip or to mediator or chemotactic factors Into the lower airways that either directly alter airway reactivity or cause airway Inflammation. The aim of this study was to compere the effect of an Identical dose of nasel or bronchial corticosteroid administration on bronchial hyperresponslveness In patients with allergic rhinitis. Eleven patients ware studied. All of them ware Judged atopic on the basis of positive skin testa to common allergens. During control, spirometry, flow-volume curves, and specific airway conductance (SGaw) ware measured. Bronchial challenges ware then performed with Increasing concentrations of carbachol, and dose-response curves ware constructed. The concentration of carbachol that decreased SGaw by 35% from baseline (PO,,) was determined by Interpolating from the dose-response curve. Control measurements ware repeated at 1-wk Intarvals to ensure that PO" was stable In all the patlenta. Then the patients received for 2 wk, In a double-blind randomized crossover fashion, a topical administration of either an aerosol of 400 J.lg of beclamethasone dlproplonate (B) Into the nose (100 J.lg four times per day) or Into the bronchi. During each trial period, Identical sprays of placebo ware used, the latter being administered Into the nose when B was ad· ministered Into the bronchi and vice veraa. Measurements ware then performed aftar 2 wk of Intranasel administration and after 2 wk of Intrabronchlal administration. During both control periods all patients had normal baseline function data and showed markad and atable bronchial hyperrespon. slveness, PD•• amounting to 30 :l: 7 and 31 :l: 6 J.lg of carbachol at first and second control periods, respectively (normal velue > 160 I1g).After 2 wkof Intranasel B, PO.. Increased markedly, averaging 75 :l: 12 I1g(p < 0.001),whereas no significant change In PO" wes noted after 2 wk of Intrabronchlal B. No significant change In baseline lung function and SGaw (I.e., before bronchial challenge) was noted efter Intranasal or Intrabronchlal B administration. Thesa data show that toplcallntranassl administration of B hss an Important protective effect on carbachol responsiveness In patients with allergic rhinitis, whereas the same dosa of B administered Into the lower airways had no effect. AM REV RESPIR DIS 1112; 141:122-128
genesis of the increased airway reactivity commonly observed in these patients. Methods
Patients Eleven patients (nine men and five women with a mean ± SD age of 33 ± 9 yr) attending the chest and allergy unit with symptoms of perennial rhinitis (lasting for at least 2 yr) were prospectively studied. None of the patients had clinical history of asthma (absence of dyspnea. chest tightness, or wheezing), and physical examination as well as spirometry were normal at the time of their visit to the outpatient clinic. All patients showed bronchial hyperresponsiveness to inhaled carbachol, and they were judged atopic on the basis of positive skin prick tests for common allergens (house dust mites in all of them and ragweed pollens in six). Careful examination of sinus radiographs (absence of opacification of both maxillary sinuses,mucosal thickening, or air-fluid level on occipital-mental
view) eliminated sinusitis in all of them. All patients were nonsmokers. None of the patients wasusing regular medication, and none had used inhaled steroids in the past. Vasoconstrictor agents (pseudoephedrine) that were used occasionally for nasal congestion by three of them were withheld at least 48 h prior to the study sessions. Each subject was in clinical steady state and did not report upper or lower respiratory tract infection during the previous 2 months or during the study period. Exposure to allergens (except for house dust) to which immediate skin reactions were (Received in originalform September 19, 1991 and in revisedform January 3, 1992) 1 From the Unite de Pneumologie, INSERM U 226, Servicesde Medecine Interne et d'Explorations Fonctionnelles, Hepital Bichat, Paris, France. 2 Correspondence and requests for reprints should be addressed to Michel Aubier, M.D., Unite de Pneumologie 8e etage Sud, Hopital Biehat, 46 rue Henri Huchard, 75018 Paris, France.
123
EFFECT OF NASAL AND BRONCHIAL GWCOCORTICOSTEROIDS IN ALLERGIC RHINITIS
elicited was avoided for at least 2 wk before and during the trial period, the study being performed between November 1990 and February 1991. The investigation was approved by our local ethics committee, and signed informed consent was obtained.
Lung Function Measurements All measurements were made with the subjects in the sitting position. In each subject several flow-volume curves were obtained with a Hewlett-Packard spirometer (HewlettPackard, Waltham, MA) in order to determine FEV" FVC, and maximal midexpiratory flow rate (MMEF). Airway resistance (Raw) was determined during quiet breathing, and thoracic gas volume was measured at functional residual capacity (13) using a constant-volume body plethysmograph (Gould system 2800; Gould Instruments, Cleveland, OH) connected to a computer. Airway resistance was averaged for those four breathing cycles preceding the determination ofthe corresponding thoracic gas volume. Mean airway resistance was multiplied by the thoracic gas volume to give specific airway conductance (SGaw). Carbachol Inhalation Challenges Bronchial provocation tests were performed following the guidelines of the SEPCR working group: bronchial hyperreactivity of the European Society for Clinical Respiratory Physiology (14) and of the American Thoracic Society. Carbachol challenges were performed sequentially with a MEFAR dosimeter. The latter is derived from the Rosenthal-French dosimeter (Johns Hopkins University, Baltimore, MD) in which the opening of a solenoid valve is triggered by the patient's inhaling. The dosimeter makes it possible to preset the delivery time, the pause between deliveries, and the number of breaths. In our laboratory, we selected a delivery time between 0.3 and 1.2 s and a pause between deliveries of 15 s. We used a carbachol solution prepared with carbachol powder (Sigma Chemical Co., St. Louis, MO) diluted with saline and sodium bicarbonate to obtain a neutral pH. The concentration of the solution was 0.50/0. Patients wore noseclips and inhaled via mouthpieces from functional residual capacity to total lung capacity, first saline and then carbachol solution in a cumulative fashion starting at a concentration equivalent to 10 ILg, the dose then being doubled until the SGaw decreased by 50% or a 16O-lLg dose of carbachol was reached. 1\vo minutes after each step, five measurements of SGaw were obtained. Each step was separated by a 5-min interval, completion of all the measurements lasting 25 min for each patient. Dose-response curves were constructed by plotting SGaw against increasing doses of carbachol. The provocation dose (in micrograms) was defined as the dose of carbachol necessary to decrease SGaw by 35% (PD35) as compared with baseline values. PD 3S was determined by interpolation from the doseresponse curve.
Experimental Procedure This was a randomized, crossover, doubleblind study. 1\vo baseline measurements separated by a week were performed as described above to ensure the stability of the bronchial hyperresponsiveness. After the second baseline the patients were treated with beclomethasone dipropionate (Glaxo Laboratories, Paris, France) administered either as a nasal spray or as a bronchial aerosol inhalation over 2 wk. After 2 wk, the measurements were repeated, and the patients received once again for 2 wk beclomethasone dipropionate administered either by nasal sprays or by bronchial aerosol inhalation depending on the mode of administration they had during the first 2 wk of the trial. For nasal administration, the patients were asked to spray each nostril with beclomethasone dipropionate four times a day. The same protocol of administration was performed for bronchial inhalation. Each puff of the beclomethasone dipropionate spray delivered 50 ILg of the drug, giving the patients 400 ILg daily into the nose or into the bronchi for each study period. Identical sprays of placebo were used at the same time in each patient during each trial period, placebo being administered into the nose when beclomethasone dipropionate was administered in the bronchi and vice versa. Furthermore, the physician who performed the measurements was unaware of which trial period the patient was in. In order to assure that the intended dose was actually received by the patient, the bottles of beclomethasone dipropionate and placebo were weighed before and after treatment. The measurements suggested that all the patients had complied with the instructions for taking the medications. No other medications were allowed during the study. At each study period, the two baseline measurements and the two treatment measurements, the tests were always conducted at the same time of the day (3:00 P.M.). To determine a systemic effect of beclomethasone dipropionate, measurements of resting early morning (8:00 A.M.) plasma cortisol concentration were performed in each patient at first baseline and at the end of each study period. The serum cortisol levelwas determined by fluorescence polarization immunoassay, an immunofluorimetric method using TDX system cortisol from Abbott Diagnostics Division (North Chicago, IL).
Statistical Analysis The results are expressed as mean ± SEM, and the statistical analysis was performed using Student's t test for paired data in a comparison of the values obtained at baseline, after 2 wk of nasal, and 2 wk of oral beclomethasone dipropionate administration. Results
Plasma Cortisol Concentration At the first baseline measurement, plasma cortisol concentration averaged 8 ± 2 J.1g/IOO ml for the 11 patients. No significant change was noted after daily administration of 400 J.1g of beclomethasone dipropionate for 2 wk, plasma cortisol concentrations amounting to 9 ± 2 J.1g/IOO ml and 8 ± I J.1g/IOO ml after nasal and bronchial administration, respectively. Pulmonary Function The mean values in pulmonary mechanics measured at first and second baselines and after 2 wk of nasal and bronchial beclomethasone dipropionate administration in the 11 patients are shown in table 1. When entering the study, i.e., at the first baseline measurement, pulmonary function was normal in all the patients. It should be noted that no significant change in any of the measured parameters, including SGaw, occurred during the experiment. Indeed, no statistical difference in the measurements performed during the second baseline, after 2 wk of nasal, or after 2 wk ofbronchial beclomethasone administration was observed as compared with the first baseline measurement. Inhalation Carbachol Challenge All patients exhibited marked bronchial hyperresponsiveness during the first baseline measurement, mean PD 3 5 amounting to 30 ± 7 J.1g of carbachol, the dose necessary to decrease SGaw by 35010 in normal subjects being alwaysgreater than 160 J.1g of carbachol in our laboratory. As shown in figure I, bronchial hyper-
TABLE 1 PULMONARY FUNCTION DATA FOR 11 PATIENTS WITH CHRONIC ALLERGIC RHINITIS, MEASURED AT FIRST BASELINE (B1), SECOND BASELINE (B2), AND AFTER 2 WEEKS OF NASAL (N) AND BRONCHIAL (B) BECLOMETHASONE DIPROPIONATE ADMINISTRATION· B1 FEV" % pre .3 50 LO Cl 40 0~ 30 ro
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Fig. 1. Individual (closed circles) valuesof SGawPO.. (provocative doseof carbachol causinga 35% decrease in SGaw)after carbachol challenge performed during the first baseline (B1) and second (B2) baseline measurement. Each patlenrs response is shown by lines connectingthe two baseline values. Open circles representthe mean valuesfor the group. Bars represent 1 SE.
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Fig. 3. Individual(closed circles) valuesof SGawPD•• In the 11 patients measuredat baseline(B) and after 2 wk of bronchial administration of beclomethasone dipropionate (lB). Each patient's response Is shownby lines connectingthe baseline value (left) to the beclomethasone diproplonatevalue(right). Opencirclesrepresent the mean value for the group. Bars represent 1 SE.
responsiveness is shown in figure 2 for the 11 patients. Intranasal beclomethasone dipropionate markedly decreased bronchial hyperresponsiveness, mean P03S for the 11 patients amounting to 30 ± 7 to 31 ± 6 IJ.g and 75 ± 12 J.1g of carbachol (p < 0.(01) at first and second baseline and after 2 wk of intranasal beclomethasone, respectively. By contrast, 2 wk of intrabronchial beclomethasone dipropionate administration had no significant effect on bronchial hyperresponsiveness (figure 3), P0 3S after the 2 wk of beclomethasone dipropionate administration amounting to 44 ± 12 J.1g of carbachol, a mean value for the group, which was not significantly different from the mean P03S measured at two baselines. However, a significant difference (p < 0.01) was still observed between the mean P03S measured after 2 wk of intranasal and intrabronchial beclomethasone administration.
IN
Fig. 2. Individual(closed circles) valuesof SGawPO.. in the 11 patients measured at baseline (B) and after 2 wk of nasaladministration of beclomethasone dlpropl· onate (IN). Each patlenrs response Is shown by lines connectingthe baselinevalue (left) to the beclornethasonedlproplonate value (right). Open circles represent the mean values for the group. Bars represent1 SE.
Discussion Our results clearly demonstrate that 2 wk of treatment with topical nasal glucocorticosteroids markedly decreased bronchial hyperresponsiveness associated with allergic rhinitis. Another interest-
ing result of the present study is that an identical dose of glucocorticosteroids administered via bronchial inhalation had no significant effect on airway hyperresponsiveness. The difference between the effect of nasal and bronchial glucocorticosteroid administration observed in our patients should be first discussed in view of the study design. We chose to compare the effect of an identical dose of intranasal beclomethasone dipropionate as that administered by bronchial inhalation in order to ensure that the nasal sprays did not pass through the nose and into the bronchi to exert a topical beneficial effect, which would have explained the decreased bronchial hyperresponsiveness. The fact that no change in airway reactivity was observed when the subjects received the drug by bronchial inhalation strongly suggests that this was not the case. This is further supported by the fact that the patients who had nasal administration the first 2 wk, which led to a marked reduction in bronchial hyperresponsiveness, exhibited again, after the second trial period during which they received beclomethasone dipropionate via bronchial inhalation, a degree of airway responsiveness close to the one measured during the two baselines. It is possible, however, that the amount of beclomethasone dipropionate that reached the bronchi may have been smaller than in the nose despite the fact that a similar dose of 400 IJ.g was administered during each study period. Indeed, several studies have shown that with use of bronchial inhalation techniques, approximately 70 to 80070 of the aerosol dose is deposited in the oropharynx, and 15 to 20% is deposited in the lung and small airways (15, 16). The lack of effect on airway responsiveness of bronchial administration of beclomethasone in our study may therefore be attributed to the fact that the amount of the drug that reached the bronchi was not high enough. This, however, appears unlikely, as several studies (17, 18) have clearly demonstrated a decrease in bronchial hyperresponsiveness in patients with pure asthma (i.e.,not associated with upper airway disease) with a dose of inhaled steroids of 400 IJ.g per day. Thus, although we cannot exclude that a higher dose of beclomethasone dipropionate would have decreased bronchial hyperresponsiveness in our patients, our data suggest that the abnormalities underlying the increased airway reactivity in patients with allergic rhinitis are essentially located in the nose. Nasal inflammation has been well
125
EFFECT OF NASAL AND BRONCHIAL GWCOCORTICOSTEROIDS IN ALLERGIC RHINITIS
demonstrated in allergic rhinitis (10), many different stimuli being capable of producing inflammation of the nasal mucosa. During inflammatory responses, preformed and/or newlygenerated inflammatory mediators may be released from resident cells in the nasal mucosa (mast cells, goblet cells, lymphocytes, macrophages, etc.)(19). These mediators such as leukotrienes, prostaglandins, and platelet-activating factor will increase vascular permeability with local tissue edema, secretion of mucus, and glandular proteins (rhinorrhea) (10). These nasal secretions, as previously shown (20), may be aspirated into the lower airways in patients with upper airway diseases. Thus, an attractive hypothesis linking nasal disease and increased airway responsiveness could be a postnasal drip of mucus, mediators, or chemotactic factors into the lower airways, which either directly alter reactivity or cause airway inflammation. Our data, which clearly demonstrate that bronchial hyperresponsiveness in our patients was decreased during nasal administration of steroids, whereas it was unaffected during bronchial inhalation, strongly favor the first hypothesis, i.e., postnasal drip of mediator directly altering bronchial reactivity. In this connection, it has been shown that prolonged treatment with topical glucocorticosteroids reduces the release of mediator in the nasal cavity (21). This hypothesis is also supported by a recent study that showed that natural antigenic exposure in subjects with pollen-induced rhinitis was not accompanied by changes in cell differential on bronchoalveolar lavage at the time of maximal symptoms of allergic rhinitis (22), contrary to what has been reported in patients with asthma not associated with upper airwaydisease (23). However, the nasal inflammation and the increased vascular permeability of the nasal mucosa that have been reported in patients with allergic rhinitis (10) may have led to an increased absorption of dipropionate beclomethasone from the nose into the bloodstream. As a result, the decreased airway hyperresponsiveness observed in our patients during nasal administration could have been secondary to a systemic effect of the drug. This, however, is unlikely, as plasma cortisol concentration did not change significantly in our patients throughout the study. Although airway responsiveness decreased in all our patients during nasal glucocorticosteroid administration, it should be noted (figure 2) that large decreases were seen in five of the 11 pa-
tients, whereas six had relatively small decreases. It may therefore be questioned whether there is more than one population included in our study group. In this connection, it should be noted that the percentage of patients with allergic rhinitis who demonstrate aspecificbronchial hyperreactivity varies in the literature from 24 to 73070 (2, 24). This discrepancy may reflect the fact that different populations were studied, although it is difficult to compare the two above studies because of differences in surveys and methods. Our patients wereprospectively selected on the basis of a positive response to carbachol challenge. All had allergicrhinitis as described in METHODS, and we were unable after reviewing the inclusion criteria to find any difference between the high and low responders to nasal glucocorticosteroids. In particular, it should be noted that no correlation between PD 3 5 before and the increase in PD 35 after 2 wk of nasal glucocorticosteroids was found in the 11 patients. Although our study was directed toward bronchial hyperreactivity rather than toward nasal symptoms, topical glucocorticoids administration had, as previously shown (12), a marked effect on the symptoms of allergic rhinitis in our patients. Indeed, in all of them a dramatic reduction of sneezing, rhinorrhea (mucus discharge), and nasal blockage was observed during nasal glucocorticosteroid administration. Thus, another hypothesis to explain the benefit of nasal glucocorticosteroids administration on bronchial hyperresponsiveness in our patients is that the intranasally administered drug had restored normal nasal physiologic conditions, including warming, humidification, and filtration of airborne allergens. Because a large proportion of allergens is contained in particles small enough to penetrate the bronchi (25),these aeroallergensare more likely to deposit in the airways during mouth breathing when the nose is obstructed, leading to increased bronchial reactivity. Finally,it has been proposed that bronchial hyperresponsiveness in patients with allergic rhinitis may be secondary to "nasobronchial" reflex (26). This hypothesis, however, also appears unlikely because it has been shown that topical anesthesia with lidocaine applied in the . nasal cavity did not prevent any of the nasal symptoms elicited after allergen challenge (27). Furthermore, in three of our subjects, topical nasal anesthesia did not influence the degree of bronchial hyperresponsiveness (personal data).
Regardless, the mechanisms underlying the strong protective effect of nasal glucocorticosteroids on bronchial hyperresponsiveness, the present study is, to our knowledge, the first one comparing the effects on airway reactivity in patients with allergic rhinitis of an identical dose of glucocorticosteroids administered in the nose and in the bronchi. The presented data clearly show that bronchial hyperresponsiveness in patients with allergic rhinitis can be improved by nasal steroid administration. References 1. Adinoff AD, Irvin GL. Upper respiratory tract disease and asthma. Semin Respir Med 1987; 8:308-14. 2. Ramsdale DH, Burns MW. Asymptomatic bronchial hyperresponsiveness in rhinitis. J Allergy Clin Immunol 1985; 75:573-8. 3. Lam S, Wong R, Young M. Nonspecific bronchial reactivity in occupational asthma. J Allergy Clin Immunol 1979; 63:28-33. 4. Cokcroft DN, Gotten DJ, Mink JT. Nonspecific bronchial reactivity after exposure to western red cedar. Am Rev Respir Dis 1977; 119:429-34. 5. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985; 131:599-606. 6. Jeffrey PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma: an ultrastructural quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989; 140: 1745-53. 7. Ryan G, Latimer KM, Juniper EF, Roberts RS, Hargreave FE. Effect of beclomethasone dipropionate on bronchial responsiveness to histamine in controlled nonsteroid-dependent asthma. J Allergy Clin Immunol 1985; 75:25-30. 8. Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O'Byrne PM, Hargreave FE. Effect of long-term treatment with inhaled corticosteroids on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990; 142:832-6. 9. Naclerio RM, Proud D, Togias AG, et al. Inflammatory mediators in late antigen-induced rhinitis. N Eng! J Med 1985; 313:65-70. 10. Raphael GD, Baraniuk IN, Kaliner MA. How and why the nose runs. J Allergy Clin Immunol 1991; 87:457-67. 11. Pipkorn U, Norman P, Middleton E Jr. Topical steroids. In: Mygind N, Weeke B, eds. Clinical aspects of allergic and vasomotor rhinitis. Copenhagen: Munksgaard, 1985; 165-79. 12. Mygind N. Topical steroid treatment for allergic rhinitis and allied conditions. Clin Otolaryngol 1982; 7:343-52. 13. Dubois AB, Botelho SY, Bedell GN, Marshall R, Comroe JH Jr. A rapid plethysmographic method for measuring thoracic gas volume: a comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. J Clin Invest 1956; 35:222-6. 14. Eiser NM, Kerreliyn KF, Quanjer PH. Guidelines for standardization of bronchial challenges with (non specific) bronchoconstrieting agents. Bull Eur Physiopathol Respir 1983; 19:495-501. 15. Newman SP, Pavia D, Moren F, Sheahan NF, Clarke SW. Deposition of pressurised aerosols in the human respiratory tract. Thorax 1981; 36:52-5. 16. Newhouse MT, Dolovich MB. Control of asth-
126 rna by aerosols. N Engl J Med 1986; 315:870-4. 17. Brompton Hospital Medical Research Council Collaborative 'Irial, Double-blind trial comparing two dosages schedules of beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma: preliminary report. Cancer 1974; 2:303-7. 18. Toogood JH, Lefcoe NM, Haines DJM, et al. A graded dose assessment of the efficacy of beclomethasone dipropionate aerosol for severe chronic asthma. J Allergy Clin Immunol 1977; 59:298-308. 19. Andersson M, Svensson C, Andersson P, Pipkorn U. Objective monitoring of the allergic inflammatory response of the nasal mucosa in patients with hay fever during natural allergen challenge. Am Rev Respir Dis 1989; 911-4.
AUBIER, LEVY, CLERIC', NEUKIRCH, AND HERMAN
20. HuwleyEJ, Viroslav J, GrayWR, PierceAK. Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 1978; 64:564-8. 21. Pipkorn U, Proud D, Lichtenstein LM, KageySobotka A, Normal PS, Naclerio RM. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids, N Engl J Med 1987; 316:1506-10. 22. Boulet LP, Thrcotte H, Lampron N, Laviolette M. Influence of natural antigenic exposure on bronchoalveolar lavage in subjects with pollen-induced rhinitis. J Allergy Clin Immunol 1990; 86:19-25. 23. Metzger WJ, Zavala D, Richerson HB, et al. Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs. Am Rev Respir Dis 1987; 135:433-40.
24. Stevens WJ, Vermeire PA. Bronchial responsiveness to histamine and allergen in patients with asthma, rhinitis, and cough. Eur J Respir Dis 1980; 203:61-5. 25. Agarwall MK, Swanson MC, Reed CE, Yunginger JW. Airborne ragweed allergens: association with various particles sizes and short ragweed plants parts. J Allergy Clin Immunol 1984; 74: 687-93. 26. Paintal AS. Vagal sensory receptors and their reflex effects. Physiol Rev 1973; 52:159-82. 27. Holmberg K, Bake B, Pipkorn U. The effect of topical nasal anesthesia on allergen-induced symptoms, obstruction and blood flow. Clin Exp Allergy 1989; 19:443-7.
