Effects of Deep Inhalation during Early and Late Asthmatic Reactions to Allergen 1-3

RICCARDO PELLEGRINO, BENEDETTO VIOLANTE, EMANUELE CRIMI, and VITO BRUSASCO

Introduction

Experimental inhalation of allergen often determines a biphasic obstructive response in the asthmatic lung (1). The early phase reaction does not last long and reverses spontaneously, whereas the late phase reaction lasts longer and is more difficult to reverse with bronchodilators (2). Studies on bronchoalveolar lavage have shown that the late phase reaction, like natural asthma, is accompanied by an inflammatory reaction in the periphery of the lung (3, 4). Therefore, late phase reaction has been regarded as a more appropriate model of natural asthma than has early phase reaction, which is mainly characterized by smooth muscle contraction. Despite these differences, pulmonary function studies generally failed to identify differences between early and late phase asthmatic reactions (5, 6). The effect of deep inhalation on bronchial caliber in stable asthma has been found to vary from bronchoconstriction (7, 8) to bronchodilatation (9). According to an analysis by Froeb and Mead (10), the different response to deep breath depends on a different balance between airway and parenchymal hysteresis.It has been suggested that the bronchoconstriction after deep inhalation, which has been frequently observed during severe spontaneous obstruction (7, 11-14), is caused by a prevailing parenchymal hysteresis secondary to airway inflammation, whereas the bronchodilatation, which is usually observed during acutely induced bronchoconstriction (9, 12, 15, 16), reflects a prevailing airway hysteresis caused by smooth muscle spasms in large airways. In planning this study, we reasoned that if early and late asthmatic reactions to inhaled allergen rely on different mechanisms, i.e., smooth muscle spasm versus airway inflammation, the effect of deep inhalation on airway caliber would be qualitatively or quantitatively different during these two conditions. 822

SUMMARY Eighteen asthmatic patients with a biphasic asthmatic reaction to house dust mite were studied. The effect of deep inhalation (01) was quantitated by comparing the maximal expiratory flow at 40% (MEF40) of vital capacity from partial (P) and maximal (M) flow-volume curves, and specific airway conductance (SGaw) before and after 01 (SGawDI).At baseline, the ratio MEF40M/P was significantly larger than unity (1.45 ± 0.26 SO), whereas the ratio SGawDl/SGaw was not significantly different from unity (0.92 ± 0.24). During early phase reaction, both MEF40M/P and SGawol/SGaw were significantly increased to 2.66 ± 0.97 and 1.96 ± 0.47, respectively. During late phase reaction, when the FEV1 values were similar to those observed during early phase reaction, MEF40MIP and SGawol/SGaw were 1.86 ± 0.46 and 1.43 ± 0.29, respectively, significantly higher than the values at baseline but significantly lower than those during early phase reaction. Similar results were obtained in a subgroup of nine patients when SGaw values during the late phase reaction were similar to those during the early phase reaction. We conclude that 01 has a different effect during early and late asthmatic reactions, suggesting a different ratio of airway to parenchymal hysteresis. This may result from an increased parenchymal hysteresis (more peripherally located bronchial obstruction) or a decreased airway hysteresis (prominent airway inflammation) during the late phase reaction. AM REV RESPIR DIS 1990; 142:822-825

Methods

Subjects Fourteen male and four female asthmatic patients with a mean age of 27 yr (range, 15 to 42 yr) who fulfilled the diagnostic criteria of the American Thoracic Society (17) participated in the study. All patients were sensitized to house dust mite as demonstrated by skin test and were known to have biphasic asthmatic reactions after inhalation of an allergen extract of Dermatophagoidespteronyssinus. At the time of study, they were in a stable phase and did not report acute exacerbation of asthma during the previous 4 wk. To be admitted in the study, patients had to have an FEV 1 larger than 75070 of predicted (18) and to not be on steroid treatment. Theophylline preparations, aerosol 1l2-stimulants, and cromolyn sodium were withheld for 48, 24, and 72 h before the study, respectively. Only one patient was a smoker. Patients were informed of the nature and the purpose of the study and gave their consent.

Measurements The effect of deep inhalation on bronchial caliber was estimated by comparing the values of specific airway conductance (SGaw) before and after a deep breath, and the maximal expiratory flows during forced expiratory maneuvers started from full inflation and from 60 to 65070 of vital capacity. Airway resistance (Raw) and thoracic gas volume (Vtg) were measured by the method

of Dubois and colleagues (19) in a constantvolume body plethysmograph (Jaeger, Wurzburg, FRG) while the subjects were breathing spontaneously. Specific airway conductance was then calculated as SGaw = Rawl Vtg. After approximately 60 s, during which patients breathed quietly without taking deep breaths, five measurements of SGaw were taken and their average retained for analysis. Patients were then asked to inhale to full inflation and to exhale spontaneously to functional residual capacity. The average of the first five technically acceptable SGaw measurements after deep inhalation was taken within 10 to 15 s and called SGawDI. To determine FEV 1 and flow-volumecurves, respiratory flow was measured at the mouth through a screen-type pneumotachograph (Jaeger), linear up to 16 Lis, and volume was obtained by electrical integration of the flow signal. Special attention was paid to elimi(Received in original form November 11, 1989 and in revised form March 26, 1990) 1 From the Servizio di Fisiopatologia Respiratoria, Ospedale A. Carle, and from the Istituto di Medidna dello Sport, Cattedra di Fisiopatologia Respiratoria, Universita di Genova, Genoa, Italy. 2 Supported in part by a grant from the Italian Ministry of Public Education. 3 Correspondence and requests for reprints should be addressed to Vito Brusasco,M.D., Istituto di Medidna dello Sport, Viale Benedetto XV, 10, 16132 Genoa, Italy.

DEEP INHALATION DURING ALLERGEN-INDUCED ASTHMA

823 TABLE 1

nate any drift of the integrator. After several quiet breaths through the pneumotachograph, patients were asked to exhale forcefully from the end of a spontaneous inspiration to residual volume. Immediately after the completion of this maneuver, they were asked to inhale to full inflation and, without holding their breath, to exhale again forcefully in order to measure residual volume. Maximal (M) and partial (P) flow-volume curves were displayed on a x-y recorder, and flows at 40070 of forced vital capacity (MEF4o) were taken . Volume was also plotted against time to measure FEV r - Only flow-volume curves with sharp peak flows were retained for analysis. In all instances, tests of forced expirat ion were made after tests of Raw.

Protocol Baseline pulmonary function and the effect of deep inhalation on both SGaw and maximal expiratory flow were determined at 9:00 A .M . Immediately after, patients underwent a bronchial inhalation challenge with allergen according to a method previously described (20). Briefly, twofold incremented solutions of D. pteronyssinus dosed in arbitrary units by RAST inhibition (Lofarma, Milan, Italy) were inhaled during quiet breathing through an ampul-dosimeter device that, according to the manufacturing firm (MEFAR, Brescia, Italy), delivers particles with a median mass diameter between 1.53 and 1.61 11m. Challenge was stopped when the FEV" measured 15min after inhalation, decreased below 80% of the control value measured after inhalation of saline solution. At this point , SGaw and SGawm were measured, and partial and maximal f1owvolume curves were recorded. Patients were then monitored hourly until a late asthmatic reaction occurred. In each patient, the effect of deep inhalation during late reaction was evaluated when the value of FEV. was closest to that observed during early asthmatic reaction. Generally, at the time when FEV. values matched for early and late asthmatic reactions, SGaw values did not match. In a subgroup of nine patients, the observation time was prolonged in order to obtain measurements of the values of SGaw during late reaction when they matched with those measured during early reaction.

PULMONARY FUNCTION DATA AT BASELINE AND DURING EARLY AND LATE ASTHMATIC REACTIONS'

At matched FEV" n = 18 FEV" L SGaw, cm H20-' s-' Vtg , L At matched SGaw, n = 9 FEV" L SGaw, cm H20-' s-' Vtg, L

Baseline

EAR

LAR

3.74 ± 0.83 0.140 ± 0.037 3.81 ± 0.77

2.42 ± 0.52t 0.027 ± O.Q1ot 4.93 ± 1.26t

2.48 ± 0.71t 0.041 ± 0.013tt 4.57 ± 0.98t§

3.39 ± 0.90 0.148 ± 0.038 3.41 ± 0.73

2.23 ± 0.58t 0.031 ± 0.007t 4.05 ± 0.8311

1.95 ± 0.58t 0.034 ± 0.007t 4.09 ± 0.8211

Definition of abbreviations: EAR = early asthmatic reaction ; LAR = late asthmatic reaction. • Values are mean ± SO. t Significantly different from baseline ; p < 0.001. Significantly different from EAR; p < 0.001. § Significantly different from EAR; P < 0.05. II Significantly different from baseline; p < 0.01.

*

the other hand, when in the subgroup of nine patients the values of SGaw were similar during early and late reactions, FEV 1 values tended (p ::::: 0.05) to be lower during late reaction.

Effect of Deep Inhalation on A irway Caliber The values of maximal to partial flow ratio (MEF4 0M/P) observed at baseline and during allergen-induced bronchoconstriction are shown in figure 1. At baseline, MEF40M/P was 1.45 ± 0.26 SD in the whole group and 1.44 ± 0.32 in the subgroup. These values were significantly different from unity (p < 0.001 and p < 0.01, respectively). During early reaction, MEF 4 0M/P was 2.66 ± 0.97 in the

whole group and 2.61 ± 0.66 in the subgroup. These values were significantly different from unity (p < 0.001) and from those at baseline (p < 0.001). During late reaction, MEF 40M/P was 1.86 ± 0.46 in the whole group and 1.85 ± 0.47 in the subgroup. These values weresignificantly different from unity (p < 0.001), significantly higher than those observed at baseline (p < 0.01 and p < 0.05, respectively), but significantly lower than those during early reaction (p < 0.01 and p < 0.001, respectively). The effect of a previous deep inspiration on specific airway conductance is shown in figure 2. At baseline, the ratio SGawm/SGaw was 0.92 ± 0.24 in the whole group and 0.94 ± 0.15 in the sub3

4

3

Statistical Analysis Paired t test was used and p values < 0.05 were accepted as significant. Results

Effect of Allergen Challenge on Pulmonary Function Pulmonary function data observed at baseline and during allergen-induced asthmatic reactions are shown in table 1. In the whole group, when the values of FEV. were similar during early and late reaction, SGaw values were significantly (p < 0.001)lower during the early reaction than during the late reaction. On

o o

BEAR

LAR

Fig. 1. Maximal to partial flow ratio (MEF4.M/P) at baseline (B) and during early (EAR) and late (LAR) asthmatic reactions. Results for EAR and LAR were obtained at similar values of FEY, or SGaw (see table 1). Data are mean ± SO. Hatched bars = matched FEV, (n = 18); open bars = matched SGaw (n = 9).

BEAR

LAR

Fig. 2. Ratio of specific airway conductance after to before deep inhalation (SGawoI/SGaw) at baseline (B) and during early (EAR) and late (LAR) asthmatic reactions. Results for EAR and LAR were obtained at similar values of FEY, or SGaw (see table 1). Data are mean ± SO. Hatched bars = matched FEV, (n = 18); open bars = matched SGaw (n = 9).

824

PELLEGRINO, VIOLANTE, CRIMI, AND BRUSASCO

group. These values werenot significantly different from unity. During early reaction, SGawDI/SGaw was 1.96 ± 0.47 in the whole group and 1.95 ± 0.53 in the subgroup. These values were significantly (p < 0.(01) different from unity and from those at baseline (p < 0.001). During late reaction, SGawDI/SGaw was 1.43 ± 0.29 in the whole group and 1.39 ± 0.26 in the subgroup. These values were significantly different from unity (p < 0.001 and p < 0.01, respectively), significantly higher than at baseline (p < 0.001 and p < 0.01, respectively), but significantly lower than during early reaction (p < 0.001 and p < 0.01, respectively). Discussion

The results of the present study confirmed and extended those previously published on the effect of volume history in asthmatic patients. Like others (9, 12, 15, 16), we have found that lung inflation has a bronchodilator effect on airway caliber during acutely induced bronchoconstriction. The new finding of this study is that this effect is reduced during the late phase asthmatic reaction to inhaled allergen. In normal subjects, deep inhalation has been found to cause slight bronchodilatation (10,21-24), which lasts for several seconds. This effect is more evident during induced bronchoconstriction (21, 23, 24). In asthmatic patients, either bronchodilatation (9) or bronchoconstriction (7, 8) has been reported as a response to a deep breath in the baseline state, whereas dilatation was the most frequently (9, 12, 15, 16) yet not invariably (23, 25) observed response with induced bronchoconstriction. Lim and coworkers (12) found that deep inhalation caused bronchoconstriction in most asthmatics during spontaneous obstruction, as opposed to bronchodilatation during acutely induced obstruction. . According to the analysis proposed by Froeb and Mead (10), the magnitude and the direction of changes induced by volume history are determined by the balance between airway and parenchymal hystereses. If airway hysteresis exceeds parenchymal hysteresis, airway caliber at a given lung volume is larger when this volume is reached during deflation than during inflation, Le., deep inhalation has a bronchodilator effect. On the other hand, a volume history of full inflation results in a reduction of bronchial caliber if parenchymal hysteresis is larger than airway hysteresis and has no effect if these are equal. Several pieces of evi-

dence show that this analysis may be appropriate to explain the variability of the effect of deep inhalation in asthma. Burns and associates (15) found that during bronchoconstriction induced by methacholine, patients who bronchodilate less after deep inhalation are those with a greater parenchymal hysteresis. Moreover, in stable asthmatic patients previously challenged with cold air, administration of {32- agonists or ipratropiurn by aerosol, which are likely to reduce hysteresis of airways more than that of lung parenchyma (26), reversed the effect of deep inhalation from bronchodilatation to bronchoconstriction (16). During recovery from severe asthmatic attacks, which are commonly characterized by inflammatory reaction in the peripheral airways, the bronchoconstrictor effect of deep inhalation decreases proportionally to the degree of bronchial obstruction (14). In addition, in stable asthmatics, the bronchodilator effect of full inflation has been found to correlate negatively with the amounts of eosinophils, proteins, and histamine in bronchoalveolar lavage fluid (13). In this study, we found that a volume history of deep inhalation determines greater bronchodilatation during early asthmatic reactions than during late asthmatic reactions. This difference can explain the apparent (table 1)underestimation of the severity of early reactions if FEV 1 instead of Raw is used as an index of bronchial airway caliber. The similarity of results observed at matched values of FEV 1 and SGaw makes unlikely the possibility that the different effect of deep inhalation during early and late reaction was due to a different severity of bronchoconstriction. Webelieve, therefore, that the different response to deep inhalation during early and late reactions to allergen was specifically connected with different mechanisms and/or sites of airway obstruction. Our results can be interpreted on the framework of the analysis by Froeb and Mead (10)as suggesting that during late reaction either lung parenchymal hysteresis is increased or airway hysteresis is decreased compared to early reaction. During the late reaction, a widespread inflammatory cellular infiltration and an increased level of inflammatory mediators in the periphery of the lung may determine contraction of respiratory bronchioles, alveolar ducts, or septal contractile cells (27), with an ensuing increase in parenchymal hysteresis. On the other hand, inflammatory changes with ede-

rna of the airway may diminish the interdependence between airway and parenchyma, which will result in less airway hysteresis. None of our patients demonstrated, during late reactions, bronchoconstriction in response to deep inhalation as it has been reported to occur during spontaneous asthma attacks. This does not invalidate the assumption that late reactions mimic the natural asthma attack more closely than do early reactions. It seems likely that the late reaction represents an intermediate situation of a continuum where the two extremes are the early reaction and the natural attack. A reduced release of bronchodilating prostaglandins (28, 29) or an enhanced, vagally mediated bronchoconstrictor reflex during late reaction might also have contributed to the outcome of our results; however, the failure of the cyclooxygenase inhibitor indomethacin (24) and atropine (23) to alter the bronchomotor effects of deep inhalation makes these possibilities unlikely. A less homogeneous distribution of ventilation during late responses might have decreased the MEF4oM/P ratio (22) but not the SGawDI/SGaw ratio. On the other hand, variable changes in glottic size after a deep breath (30) would have affected more measurements of airway conductance than of maximal flows (31). The similarity of results obtained with maximal flow ratio and airway conductance also makes these explanations unlikely. In conclusion, we have shown that deep inhalation has a bronchodilator effect in asthma induced by inhaled allergen. This bronchodilator effect is maximum during early asthmatic reaction, likely because this is mainly characterized by spasms of bronchial smooth muscle, and is blunted during the late phase reaction, which is characterized by prominent inflammatory changes. For practical purposes, we must emphasize that using pulmonary function tests requiring different volume histories to assess the severity of bronchospasm may give different results, depending, even in the same patient, on the phase of the disease. Determination of the effect of deep inhalation may constitute a sensitive method to monitor the time course of inflammatory events in the asthmatic lung. References 1. Herxheimer H. The late bronchial reaction in induced asthma. Int Arch Allergy 1952; 3:323-8.

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Effects of deep inhalation during early and late asthmatic reactions to allergen.

Eighteen asthmatic patients with a biphasic asthmatic reaction to house dust mite were studied. The effect of deep inhalation (DI) was quantitated by ...
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