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(Chest. 2000;117:954-959.)
© 2000 American College of Chest Physicians

Perception of Respiratory Sensation Assessed by Means of Histamine Challenge and Threshold Loading Tests*

Ingrid D. Bijl-Hofland, MSc; Sonja G. M. Cloosterman, MSc; Constant P. van Schayck, PhD; Frank J. J. v. d. Elshout, PhD, MD; Reinier P. Akkermans, MSc and Hans Th. M. Folgering, PhD, MD

* From the Department of General Practice and Social Medicine (Drs. Bijl-Hofland, Cloosterman, Prof.dr. van Schayck, and Akkermans), University of Nijmegen; the Department of Pulmonary Diseases (Dr. van den Elshout), Rijnstate Hospital, Arnhem; and the Department of Pulmonary Diseases (Prof.dr Folgering), Dekkerswald, University of Nijmegen, The Netherlands.

Correspondence to: Ingrid. D. Bijl-Hofland, MSc, Department of General Practice and Social Medicine, CEHM 229, University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands; e-mail: I.Hofland{at}hsv.kun.nl


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Some asthmatic patients perceive the severity of their disease rather poorly. These patients may not receive optimal therapy because of underpresentation of their respiratory symptoms. It is therefore important to identify these patients. The present study evaluates a new threshold loading device for measuring the perception of respiratory sensation. This method for measuring the perception of respiratory sensation may be a viable alternative to the bronchial provocation test. The aim of the present study was to investigate whether the assessment of the perception of respiratory sensation based on a threshold loading test (inspiratory and expiratory) identifies the same subjects as poor perceivers as compared to assessment by histamine bronchial provocation test.

Method: In 36 subjects, the perception of respiratory sensation through a threshold loading device was compared to the perception of respiratory sensation during a histamine provocation test. Each test was performed with scoring of the magnitude of the respiratory sensation on a visual analog scale (VAS). The magnitude of the stimulus intensity was indicated by the percentage of decrease in FEV1 during the histamine challenge test and by the percentage of the subject’s maximum mouth pressure (percent maximal inspiratory pressure and percent maximal expiratory pressure) during the threshold loading test. The relationship between VAS values and the stimulus intensity was analyzed by determining the linear regression coefficient between the two parameters.

Results: No relationship was found between the perception of the sensation induced by the histamine challenge and that during breathing through a threshold loading device for both inspiration (Rs = 0.15; p = 0.40) and expiration (Rs = 0.13; p = 0.47). We did find a significant relation between the perception of respiratory sensation during the inspiratory and expiratory threshold loading test (Rs = 0.67; p = 0.0001). Furthermore, we defined a subgroup of patients of special interest: those with low symptoms of breathlessness and high bronchial responsiveness. Compared to the inspiratory and expiratory threshold loading test, the histamine challenge test identified more patients in the special interest group as poorest perceivers.

Conclusion: The measurement of perception by means of a threshold loading device and a histamine provocation test did not identify the same subjects as poor perceivers, probably because we did not measure the patient’s perceptiveness for exactly the same stimuli. In the population with relatively more severe asthma and very low symptoms of breathlessness, the histamine-induced bronchoconstriction test identified more patients as poorest perceivers compared to the threshold loading test.

Key Words: asthmatics • histamine challenge • perception • threshold loading


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
There are important differences between asthmatic subjects in the way they perceive airway obstruction.1 2 3 4 Some asthmatic subjects have a poor perception of respiratory sensation and may be at risk for developing severe asthma without subjective warning.1 2 3 4 Identification of patients who perceive physical signs poorly is important, especially those patients who present no symptoms at a more advanced stage of asthma. To investigate the ability of patients to perceive respiratory sensation, the bronchial provocation test has been used to induce airway obstruction as a stimulus.5 6 7 8 9 10 This test can be performed by administering increasingly higher concentrations of inhaled stimuli (such as histamine or methacholine) or cold air, distilled water, or mannitol to induce bronchoconstriction as a stimulus. However, this test does have some disadvantages. Often, only a three or less concentration can be administered in fixed sequences in hyperresponsive patients, and the stimulus range must be performed within ethical boundaries, whereas assessment on the relation between respiratory sensation and the physical change requires an adequate number of observations over a wide range of stimulus intensity.11 These problems are absent when subjects breathe through a threshold loading device in which an extensive range of stimuli can be generated through various added loads. Furthermore, the histamine provocation test takes approximately 30 to 45 min, while the threshold loading test can be performed in < 15 min.

The aim of this study was to develop a method for measuring the perception of respiratory sensation during breathing through a threshold loading device in which the mentioned drawbacks of the provocation test are absent. We have investigated whether the assessment of the perception of respiratory sensation by means of a threshold loading test produces results that are as such comparable with those of a histamine bronchial provocation test. Furthermore, we have assessed the number of poorest perceivers according to each perception measurement in the group of patients of special interest, ie, patients who do not present any symptoms in combination with a more severe degree of asthma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Patients were recruited from a research project on symptom perception in asthmatic patients 16 to 60 years of age.12 Inclusion criteria for this research project were as follows: FEV1 >= 50% of predicted value, provocative concentration of substance causing a 20% fall in FEV1 (PC20) of histamine <= 8 mg/mL, and/or reversibility of obstruction >= 15% after inhalation of salbutamol, 800 µg (compared with baseline FEV1), and lower airway complaints. Thirty-six subjects were invited for the present study. The study protocol was approved by the Medical Ethical Committee of the Department of Pulmonology Dekkerswald, University of Nijmegen, and informed consent was obtained from each patient.

Histamine Provocation Test
Each patient underwent a histamine challenge test according to European Respiratory Society standards (tidal breathing method).13 Prior to testing, no short-acting bronchodilators were used for at least 8 h and no long-acting bronchodilators and no corticosteroids for at least 12 h. Doubling concentrations of histamine starting with 0.03 up to 16 mg/mL were administered until FEV1 had dropped by at least 20% compared to baseline value, or a maximum of 16 mg/mL of histamine was given. The bronchial response to each dose of histamine was expressed as the reduction in FEV1 as a percentage of baseline value. The PC20 of inhaled histamine was obtained from the log-dose response curve by linear interpolation.

Threshold Loading Test
The breathing circuit consisted of a three-way valve in which both inspiratory and expiratory valves could be loaded by using metal disks of different weight (from 25 to 1,200 g; see Fig 1 ).14 The weight on each valve determined the threshold pressure needed for breathing. Two threshold loading tests were performed with inspiratory and expiratory loading separately and in random order. Each test consisted of seven added loads of various weight and in random order. With each added load, subjects had to take six to eight breaths through the breathing circuit. A breathing frequency of 10 breaths/min was imposed by using a metronome. Mouth pressure was recorded using a pressure transducer. Mouth pressure at each added load was expressed as the percentage of the subject’s maximum mouth pressure (percent maximal inspiratory pressure [PImax] and percent maximal expiratory pressure [PEmax]).15



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  		Figure 1.. Schematic representation of the threshold loading circuit.

 
Assessment of Respiratory Sensation
The magnitude estimation of respiratory sensation was measured with a visual analog scale (VAS) for the three different tests. The VAS has proved a sensitive tool in the assessment of breathlessness in subjects with asthma.16 The subjects rated their breathlessness on a VAS with the words minimum and maximum on the left and right ends of a 100-mm horizontal line, respectively. Subjects were told that the word minimum meant no complaints of respiratory sensation such as shortness of breath, chest tightness, and breathlessness and that maximum stood for the worst complaints of respiratory sensation imaginable. The subjects were instructed to place a vertical mark on the line, such that its position, relative to the two extremes, indicated the magnitude of respiratory sensation at the moment of measurement. VAS values were expressed as the amount of millimeters from the left side of the VAS line.

Analysis
The patients’ perception of the respiratory sensation during bronchial provocation was determined by the relationship between the VAS values and the reduction in FEV1 as a percentage of baseline value. This relationship was analyzed by means of the regression coefficient (slope a) in the linear regression analysis of VAS = y + a%{Delta}FEV1 for each patient.6 9 10 Patients’ perception of the respiratory sensation during breathing through a threshold loading device was analyzed by calculating the linear regression slope for both threshold loading tests, external loading of inspiration and expiration separately, between the VAS values and the percentage of mouth pressure from the patient’s maximum (slope b in VAS = y + b percent PImax, and slope c in VAS = y + cpercent PEmax). These slopes, representing patients’ sensitivity toward changes in stimuli, are sensitive to the range of stimuli applied during the test.

Comparison was made between the assessment of perception of respiratory sensation during bronchial provocation and during breathing through a threshold loading device by calculation of correlation coefficients between the different slopes. Furthermore, the number of poorest perceivers according to each perception measurement were assessed in the group of patients of special interest (patients with very low symptoms of breathlessness at the start of the test day [ < 5 mm VAS] in combination with a more severe degree of asthma [PC20 <= 2 mg/mL and FEV1 <= 80% predicted]). A distinction between the poorest and better perceivers has been made by labeling the patients with the lowest value of the perception score (the lowest quartile) as poor perceivers.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patients
Clinical characteristics of the study population are presented in Table 1 . The mean age of the 36 subjects was 36 years (5th to 95th percentile; range, 18 to 54 years), and 50% were men. The FEV1 expressed as percentage of the predicted value at the start of the histamine challenge was 81% (5th to 95th percentile: 64 to 107%). The airway responsiveness varied between a PC20 of 0.05 mg/mL and 6.96 mg/mL.


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  		Table 1.. Clinical Characteristics of the Study Population (n = 36)*

 
Perception of Respiratory Sensation During Bronchial Provocation
The mean VAS value at the beginning of the histamine challenge test was 11 mm (5th to 95th percentile: 0 to 35 mm). The median value of the reduction in FEV1 as a percentage of baseline value was 24% (5th to 95th percentile: 20 to 45%) and the mean maximum change in VAS value was 38 mm (5th to 95th percentile; 5 to 89 mm). The index for the perception of bronchoconstriction during bronchial provocation, quantified by the linear regression (slopes a) of the relationship between the reduction in FEV1 as a percentage of baseline value and changes in VAS value, involves 36 subjects and is represented in Figure 2 by dark bars. The median value of slope a was 0.8 mm VAS/percent fall in FEV1 (5th to 95th percentile: 4 to 85; see Table 2 ).



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  		Figure 2.. Histogram of the values of the linear regression coefficient as an index of patient’s perception of respiratory sensation during bronchial provocation (slope a), inspiratory threshold loading (slope b), and expiratory threshold loading (slope c).

 

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  		Table 2.. Perception Indexes*

 
Perception of Respiratory Sensation During a Threshold Loading Test
The mean maximum VAS value during inspiratory and expiratory threshold loading was 64 mm (5th to 95th percentile: 17 to 100 mm) and 63 mm (5th to 95th percentile: 8 to 100 mm), respectively. The perception of respiratory sensation during breathing through a threshold loading device, quantified by the linear regression coefficient describing the relationship between VAS values and the percentage of mouth pressure compared to the maximum during inspiration (slope b) and expiration (slope c) are also presented in Figure 2 as light and dark gray bars, respectively. The median value of the slopes for respiratory sensation during breathing through a threshold loading device (slopes b and c) were for inspiration and expiration 1.1 mm VAS/percent PImax (5th to 95th percentile: 0.0 to 3.9) and 0.9 mm VAS/percent PEmax (5th to 95th percentile: - 0.4 to 3.8), respectively (Table 2) .

Relationship Between the Perception of Respiratory Sensation During the Bronchial Provocation and Threshold Loading Tests
No relationship was found between the perception of sensation associated with histamine-induced bronchoconstriction and perception of sensation caused by breathing through a threshold loading device for both the inspiratory (Rs = 0.15; p = 0.40; Fig 3 ) and the expiratory (Rs = 0.13; p = 0.47; Fig 4 ) tests (Table 2) . We did find a high and significant correlation between the perception of respiratory sensation during the inspiratory and the expiratory threshold loading tests (R = 0.76; p = 0.0001; Table 2 ). There exists a strong significant relationship between the y intercepts of all regression models (Table 2) .



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  		Figure 3.. Scatter plot of the perception during the inspiratory threshold loading test (slope b) vs the perception during histamine-induced bronchoconstriction (slope a).

 


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  		Figure 4.. Scatter plot of the perception during the expiratory threshold loading test (slope c) vs the perception during histamine-induced bronchoconstriction (slope a).

 
In Table 3 , a distinction is made between patients with very low symptoms of breathlessness at the start of the test day (< 5 mm VAS) in combination with a more severe degree of asthma (PC20 <= 2 mg/mL and FEV1 <= 80% predicted) and the other subjects. Six of nine subjects with poorest perception, assessed with the histamine challenge test, had very few symptoms of breathlessness in combination with a more severe degree of asthma. Only one patient presented no symptoms in combination with a relatively severe degree of asthma in the group with the poorest perception, assessed with the expiratory threshold loading tests. In the group with poorest perceivers assessed with the inspiratory threshold loading test, none of the subjects met these conditions.


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  		Table 3.. Results in Special Interest Subjects for Each Group of Subjects With Poorest and Better Perception*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We performed this study to investigate whether the assessment of the perceptiveness of a patient with regard to respiratory sensations induced by a histamine challenge can be replaced by an inspiratory or expiratory threshold loading test. The latter test takes less time, and an extensive change in stimuli can be generated through various added loads, which can also be applied in random order. However, this study shows that the subject who is most sensitive to respiratory sensations according to the histamine challenge test is not necessarily the same subject with the highest perceptiveness with regard to respiratory sensations induced by breathing through an inspiratory or expiratory threshold loading device. The measurements of perception by means of a threshold loading device and a histamine provocation test are therefore not interchangeable.

The origin of the respiratory sensations in the three tests may be the underlying cause for this finding. The histamine challenges strongly stimulate airway irritant receptors. The threshold loading test stimulates mechanoreceptors in respiratory muscles.17 Both tests generate respiratory sensations via different pathways and cause different degrees of sensations. It could be that not the same kind of perception was identified during the threshold loading test and the bronchial challenge test. The key issue of this study remains: which measurement identified the perceptiveness of a patient for symptoms of asthma in daily life.

The slope is a continuous scale; the steeper the slope, the more sensitive a person is to signals. There is no clear distinction between poor and good perceivers. However, the observations of the present study showed that 25% of the patients with the poorest perception value (assessed by bronchial provocation) had a slope of <= 0.4. This does not mean that patients with a slope of <= 0.4 are actually absolute poor perceivers, but only that they have the lowest perception value compared to the rest of the study population.

The applied stimulus range during the threshold loading tests (60% PImax and 60% PEmax) was greater compared with the stimulus range during the bronchial challenge test (25% reduction in FEV1). Difference in stimulus range might influence the slopes. To check whether this influenced the results, we analyzed all the data with the use of an absolute perception term (perception values at 20% reduction in FEV1 and also at 20% of PImax and PEmax). However, there was no difference in the results when we used the slopes or the absolute terms in the analyses.

Another important point is that the onset of the stimulus is also different in the two tests. The bronchial challenge test increases gradually with the increasing dose of inhaled histamine, while the threshold loading test is discrete and contrasts with the unloaded breath. This difference in test conditions might be of some influence in the measurement of the slopes.

Poor perceivers who do not present any symptoms in combination with a relatively more severe degree of asthma might be most at risk, because it is likely that they will fail to seek sufficient treatment when their asthma deteriorates. The present study shows that, compared with the threshold loading tests, the histamine challenge test identified more patients as poorest perceivers in combination with these conditions (very little symptoms of breathlessness and a low lung function and a high bronchial responsiveness). Because a considerable portion of patients with very little symptoms in combination with a more severe degree of asthma could be identified by means of a histamine challenge test, we recommend the use of the bronchial challenge test for measuring the perception of respiratory sensations in asthma patients, despite the methodologic problems.

The y intercept in all three regression models indicates the perception of respiratory sensations when there is no load or stimulus applied.10 All y intercepts were strongly related. This relationship between the y intercepts is not unexpected. Most of the patients will probably perceive respiratory sensations consistently during both the start of the histamine challenge test, when bronchoconstriction was not yet induced, and at the time when no load was applied during the threshold loading tests.

The majority of the population used anti-inflammatory medication. Although patients did not take this medication prior to testing for at least 12 h, this is not long enough to return their bronchial responsiveness to their pretreatment levels. However, because all patients in the present study had a PC20 < 8 mg/mL at the test day, the provocation test induced an appropriate level of bronchoconstriction for the assessment of the perception of respiratory sensation.

Assessment of the perception of respiratory sensation during laboratory tests may help to identify poor perceivers. However, the similarity of respiratory sensation induced by histamine challenge and spontaneous sensation of asthma has not been established. Boudreau et al5 found no relationship between the ability to sense breathlessness during induced and spontaneous bronchoconstriction.

In summary, the measurement of perception by means of the threshold loading device and the histamine provocation test did not identify the same subjects as poor perceivers. Compared with the threshold loading tests, the histamine challenge test identified more patients as poorest perceivers in the group of patients of special interest (ie, patients who did not present any symptoms in combination with a more severe degree of asthma).


   Footnotes
 
Abbreviations: PC20 = provocative concentration of substance causing a 20% fall in FEV1; PEmax = maximal expiratory pressure; PImax = maximal inspiratory pressure; VAS = visual analogue scale

Received for publication May 4, 1999. Accepted for publication November 15, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Rubinfeld, AR, Pain, MCF (1976) Perception of asthma. Lancet 24,882-884
  2. Barnes, PJ (1992) Poorly perceived asthma. Thorax 47,408-409[ISI][Medline]
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  4. Kikuchi, Y, Okabe, S, Tamura, G, et al (1994) Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 330,1329-1334[Abstract/Free Full Text]
  5. Boudreau, D, Styhler, A, Gray-Donald, K, et al (1995) A comparison of breathlessness during spontaneous asthma and histamine-induced bronchoconstriction. Clin Invest Med 18,25-32[ISI][Medline]
  6. Burdon, JGW, Juniper, EF, Killian, KJ, et al (1982) The perception of breathlessness in asthma. Am Rev Respir Dis 126,825-828[ISI][Medline]
  7. Turcotte, H, Corbeil, F, Boulet, LP (1990) Perception of breathlessness during bronchoconstriction induced by antigen, exercise, and histamine challenges. Thorax 45,914-918[Abstract]
  8. Brand, PLP, Rijcken, B, Schouten, JP, et al (1992) Perception of airway obstruction in a random population sample: relationship to airway hyperresponsiveness in the absence of respiratory symptoms. Am Rev Respir Dis 146,396-401[ISI][Medline]
  9. Marks, GB, Yates, DH, Sist, M, et al (1996) Respiratory sensation during bronchial challenge testing with methacholine, sodium metabisulphite, and adenosine monophosphate. Thorax 51,793-798[Abstract]
  10. Roisman, GL, Peiffer, C, Lacronique, JG, et al (1995) Perception of bronchial obstruction in asthmatic patients: relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteroid treatment. J Clin Invest 96,12-21
  11. Bijl-Hofland, ID, Cloosterman, SGM, Folgering, HTM, et al (1999) Measuring breathlessness during histamine challenge: a simple standardised procedure in asthmatic patients. Eur Respir J 13,955-960[Abstract]
  12. Schayck, CPv, Cloosterman, SGM, Hofland, ID, et al (1995) How detrimental is chronic use of bronchodilators in asthma and chronic obstructive pulmonary disease? Am J Respir Crit Care Med 151,1317-1319[ISI][Medline]
  13. Sterk, PJ, Fabbri, LM, Quanjer, PH, et al (1993) Airway responsiveness: standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur Respir J 6,53-83[Abstract]
  14. Heijdra Y. Respiratory muscle function and nocturnal oxygenation in patients with chronic obstructive pulmonary disease. University of Nijmegen 1995:1–139
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  16. Noseda, A, Schmerber, J, Prigogine, T, et al (1992) Perceived effect on shortness of breath of an acute inhalation of saline or terbutaline: variability and sensitivity of a visual analogue scale in patients with asthma or COPD. Eur Respir J 5,1043-1053[Abstract]
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