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(Chest. 2002;122:363-368.)
© 2002 American College of Chest Physicians

Bronchial Responsiveness to Eucapnic Hyperventilation and Methacholine Following Exposure to Organic Dust*

Britt-Marie Sundblad, BSc; Lena Palmberg, MD, PhD and Kjell Larsson, MD, PhD, FCCP

* From the Program for Respiratory Health and Climate, National Institute for Working Life, Stockholm, Sweden.

Correspondence to: Britt-Marie Sundblad, BSc, Program for Respiratory Health and Climate, National Institute for Working Life, S-11279 Stockholm, Sweden; e-mail: Britt-Marie.Sundblad{at}niwl.se


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Inhalation of dust in a swine confinement building causes an intense airway inflammatory reaction in the airways and increased bronchial responsiveness to methacholine. The aims of the present study were to investigate whether exposure to organic dust also influences bronchial responsiveness to an indirect stimulus, and to assess the duration of increased postexposure bronchial responsiveness.

Design: Twenty-two healthy nonatopic, nonsmoking subjects were exposed to dust for 3 h in a swine confinement building. Lung function was assessed, and either a methacholine bronchial provocation (n = 11) or a challenge with eucapnic hyperventilation of dry air (n = 11) was performed before exposure and at 7 h, 1 week, 2 weeks, and 4 weeks after exposure.

Results: Vital capacity and FEV1 decreased 3% and 6%, respectively (p < 0.001), and airway resistance increased 15% (p < 0.05) after exposure. The median provocative dose of methacholine causing a 20% decline in FEV1 fell from 1.38 mg (25th to 75th percentiles, 0.75 to 7.20 mg) before exposure to 0.18 mg (0.11 to 0.30 mg) after exposure (p = 0.004). Corresponding values for the dose-response slope were 15.3%/mg (2.88 to 25.3%/mg) and 100.2%/mg (2.1 to 27.3%/mg), respectively (p = 0.01). Bronchial responsiveness to eucapnic hyperventilation was not affected by the exposure: FEV1 fell 4.3% (- 7.2 to - 1.8%) before and 4.8% (- 6.7 to - 1.6%) after exposure (p = 0.72). One week after exposure, the bronchial responsiveness to methacholine was normalized.

Conclusions: The bronchial responsiveness to methacholine but not to dry air increases after exposure to swine house dust. Thus, exposure to organic dust induces increased bronchial responsiveness with different characteristics from that frequently found in asthma.

Key Words: bronchial provocation • dry air • exposure • methacholine • organic dust


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhalation of dust in a swine confinement building causes increased bronchial responsiveness to methacholine and an intense inflammatory reaction in the upper and lower respiratory tract in healthy subjects.1 2 The cellular reaction is characterized by an increase of airway inflammatory cells, predominantly neutrophilic granulocytes,2 and we have demonstrated that mast cells are activated following swine dust exposure.3 Since others4 5 have claimed that mast cells are involved in the bronchoconstriction induced by dry air in asthmatic subjects, we hypothesized that subjects exposed to organic dust react similarly, ie, with increased bronchial responsiveness following inhalation of dry air.

We have developed a standardized methacholine challenge method that enables us to detect small changes of bronchial responsiveness within the normal range.6 7 8 This is a useful method in occupational settings and for detection of small changes in bronchial responsiveness in healthy subjects. The method has been used in a number of previous studies,1 3 9 10 11 in which bronchial responsiveness has been assessed following exposure in swine confinement buildings. In all these studies,1 3 9 10 11 exposure to organic dust in a swine confinement building has yielded an increase in bronchial responsiveness of approximately three dose steps. It is not known how long the increased bronchial responsiveness remains following dust exposure, but there are results indicating that increased responsiveness may still be present 1 week after exposure.9

The aims of the present study were to investigate how exposure to organic dust influences bronchial responsiveness to a direct (methacholine) and an indirect (dry air) stimulus, and to study how long the increased bronchial responsiveness remains after exposure.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Twenty-two healthy, nonsmoking subjects (7 men; mean age, 24 years; range, 21 to 39 years) were exposed to dust for 3 h while weighing pigs in a swine confinement building. The subjects were nonatopic and nonasthmatic as determined by history and a questionnaire, and all denied ongoing respiratory infections. They had not previously been exposed to swine dust. All subjects gave their informed consent, and the study was approved by the ethics committee at the Karolinska Institute.

One week or 2 weeks prior to exposure, lung function measurements and a bronchial provocation test were performed. Eleven subjects were randomized to methacholine challenge, and 11 subjects were randomized to bronchoprovocation with eucapnic hyperventilation of dry air. Baseline data are presented in Table 1 .


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  		Table 1.. Characteristics of the Participating Subjects at Baseline*

 
Exposure took place in a swine confinement building with approximately 300 pigs on four different occasions. Six subjects, three subjects from each group (methacholine and hyperventilation), were exposed on each occasion. Exposure was measured with personal samplers that collected airborne inhalable dust.

Lung function and bronchial responsiveness were measured 7 h after the beginning of the exposure and at 1 week, 2 weeks, and 4 weeks thereafter. On the day of exposure, each subject measured oral temperature every other hour. Symptoms such as shivering, headache, malaise, muscular pain, and nausea were assessed before and after the visit to the swine confinement building.

Spirometry
Vital capacity (VC), FEV1, residual volume (RV), total lung capacity (TLC), and airway resistance were measured using a body plethysmograph (Eric Jaeger; Würzburg, Germany). The best of at least three measurements was chosen. FEV1 was measured with a wedge spirometer (Vitalograph; Buckingham, UK) before and after inhalation of methacholine and dry air.

Methacholine Provocation Test
Bronchial challenge with methacholine was performed with a jet nebulizer (Sidestream; Medic-Aid; Pagham, UK). This nebulizer uses dry compressed air (390 kPa) producing an aerosol of 0.1 L/s to which an additional flow of dry air (0.3 L/s) was added and led through a drying device before inhalation. Because of the evaporative loss, the dose of methacholine administered to the airways is not equal to the weight loss of the nebulizer content. Therefore, a coefficient of 0.75 for the nebulizer was used to correct for the methacholine output.8 The nebulisate was led through a drying device where the aerosol was dried for about 8 s before inhalation. The use of this device increases the methacholine deposition in the lower airways.6 Inhalation time (2 s for a volume of 0.8 L), and number of breaths (n = 15) were controlled using a metronome. The inhalation flow was controlled by the use of a back valve at the outlet of the tube.

Following spirometry, the subjects were asked not to take any deep breaths for 5 min prior to the methacholine test. Methacholine inhalations were performed during 1 min (ie, 30 s of inhalation and 30 s of exhalations at each dose step), and FEV1 was measured 4 min after the start of the inhalation. There was exactly 6 min between the start of the inhalations of two successive concentrations. The subjects inhaled diluent followed by 0.5, 1, 2, 4, 8, 16, and 32 mg/mL of methacholine. Only one FEV1 ( ie, one forced expiration) was allowed at each dose step. If this measure failed, the next dose was administered, provided no symptoms were reported.

The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) and provocative dose of methacholine causing a 20% fall in FEV1 (PD20) calculations were performed by interpolation on a logarithmic scale of concentration or cumulated dose of methacholine, respectively. The dose-response slope (DRS) of change in FEV1 was calculated by linear regression using all the data points, with the percent change of FEV1 (initial value as the average of prediluent and postdiluent value) as a function of the cumulated methacholine dose.12 The reproducibility of the method indicates that the difference between the first and second measurement is plus or minus a doubling concentration.13

Dry-Air Hyperventilation Test
After spirometry, a eucapnic hyperventilation test was performed. Dry, room temperature air with 5% carbon dioxide was hyperventilated through a low-resistance, one-way valve in standing position (Ailos Asthma Test; Ailos; Karlstad, Sweden).14 15 The target ventilation was 35 x FEV1 x 0.75, which was maintained for 4 min. The target minute ventilation (body temperature and pressure, saturated) was measured with a rotameter, and the subjects were asked to breathe to keep a balloon from emptying. Spirometry was then performed at 1, 3, 5, 10, 15, and 20 min after the hyperventilation challenge. Two forced expiratory volume measurements were performed, and the greatest FEV1 measure was chosen. The maximal decrease in FEV1 after hyperventilation was taken as the result of the test.

Symptoms
Symptoms were registered on a visual analog scale (100 mm), where zero represented no symptoms and 100 indicates unbearable or very strong symptoms. The subject was requested to put a cross on the scale. The length between the zero point and the cross was measured, and the difference before and after exposure was calculated.

Exposure Measurement
Twenty-five-mm filter cassettes and suction pumps (IOM; SKC; Dorset, UK) were used to monitor inhalable dust levels, and the cassettes were equipped with polycarbonate filters (pore size 5 µm; Millipore; Sundbyberg, Sweden). The samplers were carried in the breathing zone by each subject. The airflow was measured with a rotameter before and after sampling and adjusted to 2 L/min. Inhalable dust was measured by a standard weighing procedure, after 24 h of conditioning, using a Mettler ME22 balance (Mettler; Greisensee, Switzerland) and reference filter. The filters used for endotoxin analysis were extracted by rotation in 10 mL of endotoxin-free water for 60 min. The extracts were centrifuged for 10 min at 1,000g, and the supernatant was frozen at - 70°C for later analysis with a chromogen version of Limulus amebocyte lysate assay (QCL-1000, Endotoxin; BioWhittaker; Walkersville, MD) with Escherichia coli 0111:B4 as standard.

Statistics
Results are presented as mean ± SD or median values (25th to 75th percentiles). Mean and 95% confidence intervals (CIs) are presented in Figures 1 , 2 . Statistical comparisons were assessed by analysis of variance and Student t test for paired observations (lung function), the Mann-Whitney U test and Wilcoxon signed rank sum test (bronchial responsiveness). A p value < 0.05 was considered significant.



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  		Figure 1.. Bronchial response to methacholine before and after (7 h, 1 week, 2 weeks, and 4 weeks) exposure to dust in a swine confinement building (n = 11), with mean values and 95% CIs for log PD20 and DRS. *** p = 0.003 and ** p = 0.01 compared with pre-exposure values.

 


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  		Figure 2.. Bronchial response to eucapnic hyperventilation of dry air following exposure to dust in a swine confinement building (n = 11), with mean values and 95% CIs for the FEV1 decrease before and after (7 h, 1 week, 2 weeks, and 4 weeks) exposure to dust.

 

   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The oral temperature increased from 36.5°C (range, 35.8 to 37.0°C) prior to exposure to 37.2°C (range, 36.7 to 37.9°C) after exposure (p < 0.001). Maximal temperature was, in most subjects, found between 7 h and 8 h after the beginning of exposure. Symptoms like shivering, headache, and malaise increased significantly (p <= 0.001), while muscle pain and nausea occurred only in exceptional cases. Also, stuffy and runny nose was reported. There were no significant differences between the two groups with regard to temperature reaction or symptoms. The median inhalable dust level was 20.7 mg/m3 (25th to 75th percentiles, 13.2 to 25.4 mg/m3), and the corresponding endotoxin concentration was 176 ng (93 to 242 ng/m3). No differences in exposure were found when the groups were compared.

VC and FEV1 decreased slightly, 3% and 6%, respectively (p < 0.001), after exposure. VC was slightly but still significantly lower than pre-exposure levels 1 week and 2 weeks after exposure (p < 0.05). Airway resistance increased significantly (p < 0.05), but no significant change in RV and TLC was observed after exposure. There was no significant difference between the methacholine and hyperventilation groups in spirometric values (Table 2 ).


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  		Table 2.. Lung Function in Subjects Performing Methacholine Test and Eucapnic Hyperventilation Test Before and 7 h After Exposure to Dust in a Swine Confinement Building.*

 
Exposure increased bronchial responsiveness to methacholine: median PC20 and PD20 fell from 3.38 mg/mL (25th to 75th percentiles, 1.91 to 16.29 mg/mL) and 1.38 mg (0.75 to 7.20 mg) before to 0.67 mg/mL (0.49 to 0.93 mg/mL) and 0.18 mg (0.11 to 0.30 mg) after exposure (p = 0.003), respectively. Corresponding values for DRS were 15.3%/mg (2.88 to 25.3%/mg) before and 100.2%/mg (65.5 to 207.3%/mg) after exposure (p = 0.01). One week after the exposure, bronchial responsiveness had returned to normal (PD20, 1.40 mg [0.65 to 6.21 mg]; and DRS, 16.4%/mg [2.08 to 27.3%/mg]; Fig 1 ).

Exposure to organic dust did not influence bronchial responsiveness to eucapnic hyperventilation. Dry air induced a median FEV1 change of - 4.3% (25th to 75th percentiles, - 7.2 to - 1.8%) and - 4.8% (- 6.7 to - 1.6%) between 1 min and 15 min after exposure, respectively (p = 0.72; Fig 2 ). In one subject, FEV1 fell 15% following hyperventilation prior to exposure and 20% after exposure to dust in a swine confinement building. In another subject, FEV1 was reduced by 14% before and 5% after exposure.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we demonstrated an increase in the bronchial response to methacholine but not to eucapnic hyperventilation of dry air after exposure to organic dust in a swine confinement building. Seven hours after the beginning of exposure, bronchial responsiveness to methacholine increased approximately three doubling concentration steps in all subjects. We also confirmed that 3 h of exposure to swine dust causes increase in body temperature and symptoms such as shivering, headache, and malaise in healthy nonatopic subjects, in accordance with a number of previous studies.9 10 11 1 3 In the present study, bronchial responsiveness to methacholine was normalized, ie, back to pre-exposure values, 1 week after exposure; however, in a previous study,9 we found bronchial responsiveness to methacholine to be increased still 1 week after exposure. The most plausible explanation to this discrepancy is differences in exposure levels in the two studies, which took place in different swine confinement buildings. There is also a possibility that differences in the dust content of agents causing increased bronchial responsiveness may explain the different outcomes.16 The number of pigs in the confinement buildings was different, 700 pigs in the study by Malmberg and Larsson9 and 300 in the present study, as was the exposure time, 2 to 5 h and 3 h, respectively. In contrast to the previous study, the swine confinement building in the present investigation was equipped with sprinklers to bind the dust and prevent excessive dust flow within the swine house. Another factor that may have influenced the comparison is that the previous study9 was based on only six subjects. There are other studies17 that show a longer duration of the increase in hyperresponsiveness than we reported here. Cormier et al17 showed that all subjects who had a drop in their PC20 after exposure in a swine confinement building had returned to pre-exposure values after 2 to 3 weeks.

We found no increased bronchial responsiveness to eucapnic hyperventilation following dust exposure. It seems clear that the airways inflammation in asthma is associated with a bronchoconstrictor response to hyperventilation,18 whereas the present results demonstrate that the airways inflammation following organic dust exposure is not. Thus, hyperventilation-induced bronchoconstriction seems to be feature exclusive for asthma. Increased airway responsiveness to methacholine seems to be a less-specific reaction, associated with several different types of airway inflammation.

We hypothesized that, as in asthma, cysteinyl leukotrienes and other mast cell mediators contribute to the development of increased bronchial responsiveness following exposure to organic dust in healthy subjects. A proposed mechanism of hyperventilation-induced bronchospasm in asthma is evaporative water loss from airway mucosa, leading to hyperosmolality of the airway lining fluid that triggers mast cells to release mediators.19 20 It has been shown that urinary excretion of 9{alpha},11ß-PGF2, a prostaglandin D2 metabolite that is almost exclusively produced by activated human mast cells, increases in asthmatic subjects in connection with exercised-induced bronchoconstriction.21 Levels of a neutrophilic chemotactic factor and histamine in blood have also been shown to increase following exercise in asthmatic patients with exercised-induced bronchoconstriction.22 23 These studies thus indicate that inflammatory mechanisms are involved in hyperventilation-induced bronchospasm in patients with asthma.

We have previously demonstrated that urinary excretion of 9{alpha},11ß-PGF2 and leukotriene E4 increases following exposure to swine dust in healthy subjects,3 indicating that the reaction to dust involves mast cells and cysteinyl leukotrienes. If mast cell activation following dust exposure resembles the situation found in asthma, it seemed reasonable to anticipate that the response to eucapnic hyperventilation of dry air would increase following dust exposure. However, exposure to dust in a swine confinement building did not yield increased bronchial responsiveness to dry air like that seen in asthmatic subjects. Thus, airway inflammation of different "profiles" is related to airway hyperresponsiveness with different features.

The chronic inflammatory reaction after exposure to organic dust, manifested as an increased number of neutrophils, macrophages, and activated lymphocytes, is similar to the inflammation observed in patients with chronic bronchitis.24 25 Ramsdale et al26 found in a previous study that all subjects with asthma but only 3 of 27 subjects with chronic bronchitis had bronchoconstriction develop in response to an indirect stimulus (hyperventilation of cold air).

At a cutoff limit of 10% decrease in FEV1, the eucapnic hyperventilation test has a sensitivity of approximately 55% and a specificity of approximately 95% for asthmatics.18 27 28 29 In the present study, FEV1 was reduced > 15% following hyperventilation of dry air in two subjects (in one subject before and after exposure and in one subject only before exposure). These two subjects did not have a history of asthma. The finding may be explained by an ongoing viral infection,30 although all participants denied current respiratory infection. Another possible explanation could be that these subjects have an occult asthma, although it is less likely concerning the subject with a significant drop in FEV1 before and not after exposure. The positive findings in these subjects are thus not clear.

For practical reasons, lung function tests and bronchial provocations were performed 7 h after exposure to dust. From previous studies,1 3 9 it is clear that bronchial responsiveness to methacholine is increased by approximately three doubling concentration steps at this time point. However, there are no data to show that the maximal response is obtained at this time point, and it is not clear whether the timing is optimal to demonstrate bronchial responsiveness to dry-air hyperventilation. We did not find even a tendency toward a postexposure increase in response to hyperventilation, which supports the interpretation that the airway reaction to isocapnic hyperventilation is unaltered after organic dust exposure in healthy subjects.

It could be argued that a crossover design would be preferable to a parallel-group design in a study like this. There are, however, major problems with a crossover design. First, it is not clear how long the airway inflammatory reaction influences the airways following dust exposure. Thus, we do not know how long a washout period would be needed between the two exposures to ensure that the first exposure does not influence the second exposure. In the present study, methacholine responsiveness was back to baseline 1 week after exposure but VC was not. This implies that the airways may be affected for several weeks after exposure. Thus, the time interval between two exposures to dust should be 4 weeks or even more to preclude overlap effects. Second, if the time interval between the two exposures has to be increased, other factors, such as airway infections, may influence the outcome.

In conclusion, the bronchial response to methacholine but not to eucapnic hyperventilation of dry air increases after exposure to organic dust in a swine confinement house. These results show that the features of the increased bronchial responsiveness after exposure to organic dust are different from the features of bronchial hyperreponsiveness in asthma.


   Acknowledgements
 
The authors thank Siw Siljerud, Fernado Acevedo, and Alexandra Ek for technical assistance.


   Footnotes
 
Abbreviations: CI = confidence interval; DRS = dose-response slope; PC20 = provocative concentration of methacholine causing a 20% decline in FEV1; PD20 = provocative dose of methacholine causing a 20% decline in FEV1; RV = residual volume; TLC = total lung capacity; VC = vital capacity

This study was supported by The Swedish Heart-Lung Foundation.

Received for publication May 24, 2001. Accepted for publication November 19, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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