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(Chest. 2002;121:1223-1230.)
© 2002 American College of Chest Physicians

Bronchial Hyperreactivity in Patients Who Inhale Heroin Mixed With Cocaine Vaporized on Aluminum Foil*

Ana Boto de los Bueis, MD; Antonio Pereira Vega, MD; José Luis Sánchez Ramos, MD; José Antonio Maldonado Pérez, MD; Rut Ayerbe García, MD; Domingo García Jiménez, MD and Emilio Pujol de La Llave, MD

* From the Sección de Respiratorio (Drs. Boto de los Bueis, Pereira Vega, Maldonado Pérez, Ayerbe García, García Jiménez, and Pujol de La Llave), and Unidad Docente de Medicina Familiar y Comunitaria de Huelva (Dr. Sánchez Ramos), Hospital Juan Ramón Jiménez, Huelva, Spain.

Correspondence to: Antonio Pereira Vega, MD, Comisión de Docencia, Hospital Juan Ramón Jiménez, Ronda Norte, s/n 21005, Huelva, Spain; e-mail: apv01h{at}nacom.es/docencia@hjrj.sas.cica.es


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Background: In our area, inhaling heroin mixed with cocaine vaporized on aluminum foil, known as rebujo, is becoming more and more common.

Aim: To define the prevalence and the characteristics of bronchial disease (wheezing, bronchial hyperreactivity [BHR], and asthma) present in subjects inhaling heroin mixed with cocaine vaporized on aluminum foil.

Materials and methods: Ninety-one subjects who inhaled the drug mixture were included in the study: 62 subjects were from a drug rehabilitation center (INH-I group), and 29 subjects were among patients admitted to our hospital for a variety of reasons (INH-II group). A questionnaire was completed in both groups, as well as IgE determination and lung function tests (spirometry and methacholine challenge). The control group consisted of 122 individuals who did not inhale the drug mixture, and were chosen randomly from the general population (NO-INH group). All subjects were tobacco smokers.

Results: In the INH-I group, there was a 41.9% prevalence of wheezing over the past 12 months, a 44.4% prevalence of BHR, and a 22.02% prevalence of asthma, defined as wheezing plus BHR. In the NO-INH group, these values were 32.78% (p = 0.22), 15.57% (p < 0.0001), and 8.19% (p < 0.01), respectively. Of the subjects who inhaled the drug mixture and denied having symptoms prior to the use of the drug mixture, 31.4% had wheezing develop after commencing use of the drug, following a mean latency of 4.09 months. Wheezing remitted in only 7.6% after discontinuation of the drug.

Conclusions: (1) There is a real increase in BHR in subjects who inhale heroin mixed with cocaine vaporized on aluminum foil; and (2) this BHR is associated with wheezing that develops after a variable period of latency, once drug inhalation begins, and persists despite discontinuation of the drug.

Key Words: cocaine • heroin • hyperreactivity • inhaled • wheezing

Pulmonary disease associated with illicit drug use is being reported more often, and varies according to the drug used in each area and the route of administration.1 While white heroin is usually injected IV in the Northeast stretch of Spain, brown heroin, often mixed with cocaine, vaporized and inhaled2 is more common in Andalusia (southern Spain). In certain areas of the South, there is a rapidly growing, consolidated market for this product.

The inhalation of illicit drugs has been associated with respiratory symptoms since the 1980s. Several studies have linked the inhalation of freebase cocaine ("crack") with an exacerbation of bronchial asthma,3 4 5 6 while inhaled heroin vapors ("chasing the dragon") may trigger bronchospasm.7 8 To date, results are controversial and a causal relationship has not yet been established between these drugs and bronchial asthma and bronchial hyperreactivity (BHR).9

In our area, the metropolitan district of Huelva, where the inhalation of vapors released by burning heroin mixed with freebase cocaine on aluminum foil (known as rebujo) is widespread, there are an increasing number of reports of severe episodes of bronchospasm developing in young adults following this type of drug abuse. It is unclear whether the pulmonary disease derived from the use of this drug mixture is similar to pulmonary disease caused by the inhalation of cocaine and heroin vapors separately, whether the mixture of the two drugs causes additive effects or, quite the contrary, whether deleterious effects on the airway are counteracted by the combination of the two drugs. Our study aims to define the prevalence of pulmonary disease in subjects who inhale the drug mixture, and to describe the respiratory disease, mainly involving the airways, that develops.


   Materials and Methods
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 Materials and Methods
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Data Collection
The data for the 91 subjects included in the study who inhaled the drug mixture were collected in two different ways. First, all subjects who inhaled the drug mixture and had just begun a drug rehabilitation program at a drug rehabilitation center in Huelva were studied between January and March 1998. A sample of 63 subjects was thus obtained, with the exclusion of 1 HIV-positive subject. The tests performed on these subjects included a detailed respiratory questionnaire, peripheral eosinophil count, total IgE, as well as a skin-prick testing, chest radiography, and lung function testing.

Subjects with cough and/or dyspnea, and/or wheezing over > 3 months a year during the past 2 years were classified as having chronic respiratory symptoms. The questionnaire specified whether the symptoms had presented prior to use of the drug mixture. A history of family asthma was defined as a medically confirmed diagnosis of asthma in a first-degree relative, while childhood asthma was defined as when the subject had had asthma attacks during childhood, but with no further crises occurring during adulthood prior to exposure to the drug mixture. The presence of elevated total IgE and/or positive skin-prick result was defined as atopy, while BHR was confirmed by a positive bronchial challenge response to methacholine. Wheezing during the past 12 months was termed "symptoms suggestive of asthma." All subjects reporting wheezing and BHR over the past 12 months were considered to be asthmatics.

On completion of the questionnaire, those subjects fulfilling any of the following conditions were excluded from the study: (1) regular parenteral drug use over the past 5 years, (2) HIV infection, (3) history of chronic airway disease or chest disease, or (4) active tuberculosis or residual pulmonary fibrosis.

Total IgE tests were performed at the Juan Ramón Jiménez Hospital in Huelva, using the Kallested Total IgE Microplate method (Sanofi Diagnostics Pasteur; Chaska, MN). Results from 0 to 145 IU/mL were considered normal adult values, while results > 145 IU/mL were considered elevated. Skin-prick tests were performed with extracts from 11 pneumoallergens normally present in our area (Dermatophagoides pteronyssinus, trees, Gramineae, grasses, Alternaria, olive, Cynodon, Phragmites, Artemisia, dog and cat dander). Readings were recorded 20 min after completion of the procedure. We considered a result to be positive if the allergen reading was greater than that for histamine, provided the control result was negative.

Lung function tests included spirometric measurements, including calculation of FVC, FEV1, flow between 25% and 75% of FVC (MEF), forced expiratory flow at 25% of FVC, forced expiratory flow at 50% of FVC (FEF50), forced expiratory flow at 75% of FVC, peak expiratory flow (PEF), and methacholine bronchial challenge. Spirometry was performed according to the recommendations of the Spanish Society for Respiratory Pathology, using the best of at least three reproducible measurements for the calculations.10 A nonspecific bronchial challenge was performed with adaptation of our protocol to the latest standards set by the Spanish Society for Respiratory Pathology.10 11 Both tests were conducted with a portable spirometer (Vitalograph 2120; Vitalograph; Ennis, Ireland) connected to a portable computer (Ascentia A series; AST Research; Dublin, Ireland). For administration of the methacholine solution, nebulizers (Oxineb; Proclinics; Barcelona, Spain) were filled with 3 mL of varying concentrations of methacholine (from 0 to 25 mg/mL) and then connected to an electric airflow generator. This system ensured delivery of the drug at a continuous flow of 6 to 8 L/min and consecutive inhalation, breathing a 3-min tidal volume. Any subject with a drop of 20% over initial FEV1 percentage (postdiluent) was considered hyperreactive. All this material was transferred to the drug rehabilitation center for the days on which the protocol was to be performed. After each test day, the spirometer was calibrated with a 3-L syringe. Spirometric measurements were not obtained using the method of the European Respiratory Health Study,12 the method used at our hospital, because the subjects from the drug rehabilitation center (the INH-I group) could not come to our hospital.

In the second format, the same questionnaire was applied to 29 subjects who had been admitted to either the Internal Medicine or the Respiratory Disease Departments over the past 2 years for a variety of reasons, and who were found to be smokers of the heroin and cocaine mixture (the INH-II group). Because the majority of subjects in the INH-II group had been admitted to the hospital for airway symptoms, their respiratory symptoms are described with no indication as to the prevalence of asthma. Accurate information was not available for two of the subjects.

The control group (the NO-INH group) was from the European Community Respiratory Health Survey,12 conducted in 44 European cities, including several Spanish provinces.13 Two hundred twenty-nine subjects from Huelva were included in this survey (age range, 20 to 44 years) and were randomly chosen from the general population. A respiratory questionnaire focusing on symptoms suggesting asthma, spirometry, and BHR measurements were administered. As in the INH-II group, spirometry was performed with the bell spirometer at our hospital (Biomedin 9000; Biomedin; Padua, Italy), and the methacholine challenge had a long or a short protocol, according to whether the subject presented with asthma-related symptoms or not, up to a maximum accumulative dose of 1 mg of methacholine.13 Because all of the subjects who inhaled the drug mixture were tobacco smokers, tobacco smokers were selected for comparison. We thus obtained a control group with 122 individuals.

Statistical Analysis
All variables for analysis were processed in a Microsoft Access (Microsoft; Redmond, WA)-format database and were then searched to eliminate any possible contradictory data. The statistical significance of the differences in lung function results among the groups was determined by analysis of variance. The {chi}2 test was used to compare the groups in terms of qualitative variables. Statistical software (SPSS 10.0 Windows; SPSS; Chicago, IL) was used, with 95% confidence intervals (CIs), and bilateral levels of p < 0.05 considered as significant.


   Results
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Sample Characteristics
Details of age, gender, and substance abuse are provided in Table 1 . The 62 subjects in the INH-I group were white (age range, 19 to 42 years). All subjects reported inhaling heroin mixed with cocaine vaporized on aluminum foil, and they all also claimed to be regular tobacco smokers. The age range for the INH-II group was 20 to 45 years. The age range for the NO-INH group was 20 to 44 years.


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  		Table 1.. Patient and Drug Use Characteristics*

 
The comparison made between INH-I group and INH-II group subjects on the amount and duration of use of the drug mixture showed no significant differences. All of the INH-I subjects had discontinued use of the drug mixture prior to entering the study (mean duration since last use of the drug, 6.7 months [SD, 5.5 months]). Of the 27 INH-II group subjects, 19 subjects continued to smoke the drug mixture and only 8 subjects had discontinued use of the drug prior to the study (mean duration since last use of the drug, 2.7 months [SD, 5.7 months]). The majority of the INH-I group subjects (71%) had smoked cannabis at some time in their lives but had not been regular cannabis users for > 2 years. No evidence of cannabis use could be found for the INH-II group or the NO-INH group.

The prevalence of a history of childhood asthma was statistically different in the three groups (p = 0.002): 22.2% in the INH-II group, 14.5% in the INH-I group, and 3.3% in the NO-INH group. A family history of asthma was also more frequent in the INH-II group (37%) than in both the INH-I and NO-INH groups (p = 0.004). The presence of chronic respiratory symptoms (cough and wheezing), however, was similar in all three groups (Fig 1 , Table 2 ).



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  		Figure 1.. Wheezing, BHR, and asthma in smokers of heroin and cocaine (INH-1) and in the control group (NO-INH).

 

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  		Table 2.. Prevalence of Chronic Respiratory Symptoms in the NO-INH Group and in Subjects Prior to Use of the Drug Mixture (INH-I and INH-II Groups)*

 
Prevalence of Pulmonary Disease in Subjects Who Inhaled the Drug Mixture
Only the 62 subjects in the INH-I group in whom the prevalence of wheezing, BHR, and asthma was confirmed were included. These results were later compared with data collected for the NO-INH group (Fig 1) . The prevalence of wheezing over the past 12 months was 41.93% (95% CI, 29.51 to 55.15%) in the INH-I group and 32.78% (95% CI, 24.56 to 41.86%) in the NO-INH group (p = 0.22). The prevalence of BHR assessed by methacholine challenge was 44.44% (95% CI, 30.91 to 58.6%) in the INH-I group and 15.57% (95% CI, 9.64 to 23.24%) in the NO-INH (p < 0.0001). Table 3 shows the comparison of the percentage of subjects with BHR at different cutoff points for the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) or provocative dose of methacholine causing a 20% fall in FEV1 (INH-I and NO-INH groups, respectively). Of the 44.44% of the subjects in the INH-I group who had BHR, 79.1% occurred at doses of <= 10 mg/mL. The differences in the prevalence of BHR between both groups remained significant even when not considering those with PC20 > 10 mg/mL (p = 0.006) to be hyperreactive. Lastly, the prevalence of asthma in the INH-I group was 22.03% (95% CI, 12.28 to 34.72%), and 8.19% (95% CI, 4.0 to 14.12) in the NO-INH group (p < 0.01).


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  		Table 3.. Comparison of the Prevalence of BHR at Different Cutoff Points Between the INH-I Group and the NO-INH Group*

 
Respiratory Manifestations in the INH-I and INH-II Groups
Of all the subjects who inhaled the drug mixture and denied having respiratory symptoms prior to their addiction to the drug mixture, 33.7% had a cough develop when they started smoking the drug, while 31.4% presented with wheezing and 25.8% had dyspnea develop. Among the subjects who had wheezing develop once they began to inhale the drug mixture, 39.32% continued to wheeze even after discontinuation of the drug, while wheezing disappeared in 7.6% following discontinuation. The mean time from commencement of use of the drug mixture to the onset of wheezing was 4.09 months (SD, 2.2 months). Most subjects reported a perceived improvement in one or more of their respiratory symptoms immediately after inhaling the drug mixture. These subjects noticed the same symptoms reappearing with the onset of withdrawal symptoms. The mean time to onset of wheezing after each inhalation was 5.75 h (SD, 4.19 h). For those who reporting wheezing prior to inhaling the drug mixture (n = 22; 24.71%), 31.81% reported a worsening of their condition with use of the drug, while 45.45% noticed no change. The overall presence of wheezing as the study was being conducted (wheezing prior to inhalation and/or wheezing triggered by the inhalation) was 72% in the INH-II group (n = 18) and 41.9% in the INH-I group (n = 26).

Of the 29 subjects in the INH-II group, 12 subjects (41.9%) had been admitted to hospital for bronchospasm, with a mean number of 12 hospital admissions per patient (minimum of 2 and maximum of 14 hospital admissions). In the INH-I group, four subjects (6.4%) had been admitted to the hospital for bronchospasm (mean, 1.7 hospital admissions; minimum of one and maximum of three hospital admissions). The subjects in the INH-II group had the lowest lung function results, especially MEF (mean, 49.21% over theoretical value), and FEF50 (mean, 47.50%), PEF (mean, 61.94%), and FEV1 (mean, 75.37%; Table 4 ).


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  		Table 4.. Hospital Admissions and Lung Function in the Study Groups*

 
Differential Aspects Between Asthma-Symptomatic Subjects Who Inhaled the Drug Mixture and Subjects Who Did Not
There were 44 asthma-symptomatic subjects among those who inhaled the drug mixture (50.57%) and 40 asthma-symptomatic subjects in the NO-INH group (32.78%). All of the patients in both groups were tobacco smokers. No differences were found in the history of family asthma or positive skin prick test results between the two groups, although childhood asthma and increased levels of IgE were greater among the subjects who inhaled the drug mixture (Table 5 ).


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  		Table 5.. Differences Between Asthma-Symptomatic Subjects Who Inhaled or Did Not Inhale the Drug Mixture*

 
Subjects who inhaled the drug mixture presenting with asthma symptoms showed significantly lower values of FEF50, MEF, and PEF (as percentage of the theoretical value) than asthma-symptomatic subjects in the NO-INH group (Table 6 ). Finally, 11 of 19 symptomatic subjects who inhaled the drug mixture had a positive response to methacholine challenge, compared with 10 of the 40 symptomatic subjects in the NO-INH group (p = 0.014).


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  		Table 6.. Lung Function Among Asthma-Symptomatic Subjects Who Inhaled or Did Not Inhale the Drug Mixture*

 

   Discussion
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The association of inhaled illicit drugs and asthma is controversial. To date, the few studies published on the topic have focused on "crack" smokers14 15 16 17 or heroin inhalation.18 19 However, these are not the usual drug abuse patterns found in our area. According to the latest National Drug Prevention Scheme, the most prevalent use in Andalusia (southern Spain) is inhalation of vaporized brown heroin mixed with freebase cocaine.2 This mixture also has specific features in our area, such as the use of ammonia in the preparation of freebase cocaine, and the inhalation of the drugs on aluminum foil, which is known in the streets as rebujo. Cocaine and heroin, ammonia,20 and aluminum21 22 have all been associated with asthma and BHR.

In our study, we found a 41.93% prevalence of wheezing, a 44,44% prevalence of BHR, and a 22.03% prevalence of asthma among subjects who inhaled a mixture of heroin and cocaine vaporized on aluminum foil. When these results are compared with those for the general population in our city13 (32.78%, 15.57%, and 8.19%, respectively), we find a clear difference in BHR and the diagnosis of asthma, in the sense that inhaling the drug mixture seems not only to cause symptoms, but also produces objective BHR data.

BHR is associated with wheezing23 and is present in almost all asthma patients, at least during symptomatic periods.24 BHR is also present in approximately 10% of asymptomatic subjects.25 26 This asymptomatic BHR is currently understood to be an intermediate state between normality and asthma.

The differences in BHR results may be accounted for by the fact that the methacholine tests were performed according to different protocols and at different laboratories. However, several standardized surveys confer a high degree of validity to BHR determination as a dichotomous characteristic for any of the methods used (continuous methacholine administration in drug inhalers or pulsed administration in the European Community Survey).11 Even when admitting that our results may be influenced to a certain extent by the methodology used, the fact that almost 50% of our subjects who inhaled the drug mixture presented with BHR is nonetheless striking. This percentage would still be 35.1% if we were only to include INH-I group subjects who had PC20 at lower methacholine doses (<= 10 mg/mL), values generally accepted as more characteristic of asthma. With this cutoff point, the differences between the INH-I group and the NO-INH group continued to be significant (p = 0.006), underlining a clear difference between the two groups in relation to BHR.

The INH-II group was not included in the asthma prevalence study, since bronchospasm had been the cause for hospital admission in most of these cases. Inclusion of this group would have considerably biased the comparison of asthma prevalence.

We have also seen that previously asymptomatic inhalers of the drug mixture have asthma symptoms develop after a variable period of latency (mean, 5.7 months) after commencement of use of the drug. This marks a difference with the reactive airway dysfunction syndrome (RADS),27 where the onset of symptoms occurs during the first 24 h following a single exposure to high concentrations of a gas, smoke, or vapor that causes an insult on the bronchial epithelium. When inhaling the heroin and cocaine mixture, there is not a single exposure to high concentration of vapors; instead, there is repeated exposure to irritants at moderately low or "tolerable" levels that may correspond to the term "low dose or low concentration RADS" as described by Kipen et al.28 This condition seems to be caused by an irritant mechanism similar to RADS that may have a set period of latency. The physiopathogenic mechanism underlying RADS is thought to bring about an anomalous re-epitethialization and reinnervation of the bronchial mucosa after the epithelial damage sustained by the first exposure to the toxic substance. This may give rise to hypersensitivity of subepithelial receptors and, consequently, to maintained airway hyperresponsiveness.28 Persistent asthma symptoms were noted as a further characteristic in inhalers of the drug mixture, even after discontinuation of the drug. In our study, all the subjects in the INH-I group and eight subjects in the INH-II group had discontinued use of the drug several months previously. Workers developing asthma from aluminum salt21 22 characteristically suffer persistent asthma symptoms despite discontinued contact with aluminum, as in the cases described for "low concentration RADS."28

In the comparison of characteristics among asthma-symptomatic inhalers of the drug mixture (44 subjects) with symptomatic subjects in the NO-INH group (40 subjects), we were able to show a greater number of histories of childhood asthma and raised total IgE levels among inhalers of the drug mixture. In their study on 20 subjects who inhaled of heroin vaporized on aluminum foil and 20 asthmatics, Otero et al19 found that, contrary to our results, significantly fewer of the subjects had both a history of atopy and positive skin-prick test results, as well as lower levels of IgE than asthmatic subjects who did not inhale the drug. This suggests that this kind of substance abuse would not act as a single triggering mechanism in predisposed subjects. Instead, it is a causal factor of pulmonary obstruction and BHR, and the aluminum vapors inhaled during the combustion of heroin may be the causal irritant. There are many differences between these two studies, ie, our control subjects were taken from a populational study and not from diagnosed asthmatics and, unlike the article by Otero et al,19 all our subjects were tobacco smokers. Furthermore, in the study by Otero et al,19 heroin was the substance inhaled on aluminum foil, while our study includes subjects who inhaled a mixture of heroin and cocaine. Brooks et al29 stated that even though atopy and/or previous asthma do not contribute to the pathogenesis of RADS, 88% of individuals with not-so-sudden irritant-induced asthma exhibited an allergy/atopy status and 30% of subjects with new-onset irritant-induced asthma were really manifesting an exacerbation of a preexisting asthmatic state. Thus, preexisting atopy and asthma do indeed seem to be major risk factors for asthma developing following low levels of exposure to irritants, as in the case of these subjects who inhaled the drug mixture.

Small (FEF50, MEF) and large (PEF) airway function was mildly impaired in asthma-symptomatic subjects who inhaled the drug mixture, with normal values for FEV1 and FVC. The asthma symptomatic subjects in the populational study showed consistently normal lung function test results. This suggests that, in spite of the slight functional impairment, inhaling heroin and cocaine vaporized on aluminum foil may act as an allergen or irritant with prolonged effect even in the absence of clinical findings (spirometry was performed in the intercritical period). In this respect, functional impairment was greater in the subjects who inhaled heroin vapors in the study by Otero et al,19 with FEV1/FVC < 70% in 11 of 20 subjects who inhaled the drug, and in none of the asthmatic subjects who did not inhale the drug.

The pathogenesis of heroin mixed with cocaine and vaporized on aluminum foil may be the result of the synergy of both drugs in combination. As indicated by some authors,30 31 BHR may be caused by a cocaine-induced immune mechanism, while an irritating factor similar to low-dose or low-concentration RADS28 may be responsible for heroin-induced BHR.

Subjects in the INH-II group showed more severe symptoms, with a greater percentage of wheezing, a higher number of hospital admissions per patient, and worse lung function parameters than subjects in the other two groups. The INH-II group also had a higher number of subjects with a history of childhood asthma, a family history of asthma, and higher IgE than in the other two groups. These data suggest that atopy and/or family predisposition may not only influence the likelihood of symptoms, but also contribute to their severity.

The synergistic effect of other allegedly toxic substances on the airway, such as tobacco or marijuana, has not yet been clearly established. We found no positive relationship between smoking, whatever the intensity of tobacco use, and the prevalence of wheezing or BHR. Even though concomitant use of cannabis was slightly more frequent in symptomatic subjects than in asymptomatic subjects, this was not associated to BHR.

{Delta}-9-tetrahydrocannabinol, the principal psychoactive component of cannabis, can under experimental conditions cause either bronchial obstruction (when inhaled by asthmatics as a pure aerosol of {Delta}-9-tetrahydrocannabinol in ethanol30 ) or bronchodilatation (when smoked by either healthy subjects or by asthmatics32 33 ). However, it has not yet been proven that cannabis has any harmful effect on the peripheral small airway, or that it compounds the damage caused by tobacco in this same area. The influence of HIV infection on the presence of BHR is currently under review.34 35 In our study, this factor has not been taken into account, given that no HIV-infected subjects were included in the sample.

In our case, the subjects who had wheezing develop were heavier users of the drug mixture than were asymptomatic and nonhyperresponsive subjects, although the difference was not significant, perhaps due to the size of the sample. As commented above, rebujo is a mixture of heroin and cocaine that is placed on aluminum foil and heated, and the resulting vapors are inhaled. According to reports by users of this drug mixture, the aluminum foil is generally burned prior to placing the drug to avoid inhaling the vapors released from the foil. Even bearing this "safety" practice in mind, it is difficult to determine the role played by the vapors released from the aluminum foil in wheezing and BHR in our sample. It is also extremely difficult to know whether the vapors from the ammonia used to prepare freebase cocaine or "bazuco" may also affect the airway in these subjects. Furthermore, the action of heroin and cocaine is consistent with bronchospasm.

This study has shown for the first time that there is a real increase in BHR in subjects who inhale mixed heroin and cocaine vaporized on aluminum foil. Following a variable period of latency, this BHR is often accompanied by wheezing that begins after inhalation of the drug and persists even after discontinuation. Although further studies are needed to fully understand the pathogenic mechanism underlying the asthma seen in these subjects, our results point toward the idea that the drug mixture acts as an irritant capable of triggering asthma in predisposed healthy subjects, ie, with either atopy or, in particular, a history of childhood asthma. Concomitant use of cannabis or heavy smoking does not boost the presence of BHR in inhalers of the drug mixture.


   Footnotes
 
Abbreviations: BHR = bronchial hyperreactivity; CI = confidence interval; FEF50 = forced expiratory flow at 50% of FVC; MEF = flow between 25% and 75% of FVC; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1; PEF = peak expiratory flow; RADS = reactive airway dysfunction syndrome

This research has been supported by a grant from the Department of Health of the Andalusian Regional Government.

Received for publication March 8, 2000. Accepted for publication November 29, 2001.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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