http://informahealthcare.com/jas ISSN: 0277-0903 (print), 1532-4303 (electronic) J Asthma, 2015; 52(1): 34–39 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/02770903.2014.947998
DIAGNOSTIC TESTING
Airways resistance in bronchial challenge testing Mark A. Baxter, MB BChir, BA (Hons), MRCP(UK), Dawn Coates, MBBS, and Andrew M. Wilson, MB ChB, MD, MRCP(UK)
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Norfolk and Norwich University Hospital, Respiratory Medicine, Colney Lane, Norwich, Norfolk, UK
Abstract
Keywords
Introduction: Measurement of airways resistance is an alternative to spirometry to assess airflow obstruction. This can be measured by the interrupter technique (RInt) using a handheld device. We wished to know how RInt compared to forced expiratory volume in 1 s (FEV1) during a histamine challenge test. Methods: Twenty-nine (13 male) patients, aged 48.9 (SD 15.3) years, referred for a histamine challenge test, were enrolled. Patients had measurement of RInt then FEV1 after administration of saline and following doubling concentrations of histamine from 0.06 to 8 mg/ml. Extrapolation of the log dose–response curve was undertaken to calculate the concentration (provocation concentration, PC) causing an increase airways resistance of 20, 40, 60, 80, 100, 120, 140 and 160% (RInt PC1.2 to RInt PC2.6) and a reduction in FEV1 by 20% (FEV1 PC20). The number of patients with a negative challenge (i.e. PC48 mg/ml histamine) was calculated for FEV1 and each change in airway resistance. Patients assessed their procedure-provoked symptoms of breathlessness, dizziness and tiredness on a visual analogue scale. Results: Geometric (SD) PC20 for FEV1 was 1.87 (0.5) mg/ml with 11 patients having a negative challenge. A RInt PC20 had the best agreement with FEV1 PC20 [Kappa 0.39 (p ¼ 0.024)]. There is a significant negative correlation between RInt and FEV1 (r ¼ 0.94). The respective mean (SD) breathlessness, dizziness and tiredness scores for RInt were 26 (4) mm, 18 (3) mm, 22 (4) mm and for spirometry were 40 (4) mm, 27 (5) mm, 31 (5) mm. There was a significant (p50.05) difference for breathlessness. Conclusion: RInt was tolerated better than spirometry. A doubling of airways resistance had the best agreement with PC20 FEV1.
Diagnostics, management/control, physiology, treatment
Introduction Airway hyper-responsiveness is a fundamental characteristic of patients with asthma and therefore bronchial challenge testing is used as an investigational test in the diagnosis of asthma [1]. Bronchial challenge testing is also used to measure treatment response [2], to assess new therapies and to compare treatment regimens [3]. It is performed by administering a stimulus or substance and measuring the response via an assessment of airway obstruction. This is usually done by assessing the forced expiratory volume in 1 s (FEV1). However, FEV1 is a patient-dependant test and requires co-operation and maximal effort from the patient. This is particularly demanding during bronchial challenge testing when multiple assessments are required during the test. Furthermore, deep inspiration modulates airway calibre in patients with asthma and in healthy individuals, and as a result, parameters derived from maximal expiratory manoeuvres may be affected [4].
Correspondence: Dr. Mark Andrew Baxter, MB BChir, Norfolk and Norwich University Hospital, Respiratory Medicine, Colney Lane, Norwich, Norwich, NR47UY United Kingdom. E-mail: [email protected]
History Received 17 May 2014 Revised 2 July 2014 Accepted 20 July 2014 Published online 19 August 2014
An alternative to FEV1 is to use airways resistance to evaluate airway calibre. This is assessed during normal tidal breathing and requires no extra effort from the patient. Most commonly, it is performed using a body plethysmograph [5] which requires the patient to sit in a large sealed chamber. Airways resistance can be measured by the interrupter technique (RInt) using a handheld portable device (MicroRint, Micromedical, Rochester, Kent). Airways resistance has been measured using the RInt extensively in children and has been shown to have a good within-occasion repeatability [6]. The MicroRint is useful in detecting changes in the airways resistance following bronchodilation with salbutamol in children aged 0.8–16 years [7] and is as sensitive as spirometry [8]. It has also been used in premature children to study airflow obstruction [9], and although feasible, the results in this group were not as good as with the body plethysmograph. However, its utility in adults has been less well evaluated. Recently, a study using MicroRint to evaluate airways resistance in older adults with intellectual disability showed that this test was feasible, repeatable and reproducible [10]. We wished to examine the change in airways resistance using the MicroRint that would provide the best agreement with a 20% fall in FEV1 (diagnostic of asthma) in adult patients suspected of having an obstructive condition.
Airways resistance in bronchial challenge testing
DOI: 10.3109/02770903.2014.947998
Methods
2 min in a 5-min cycle. The study was terminated if the spirometry fell by 20% from the diluent value or if the highest dose of histamine was administered.
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Study design This was an open observational study of patients who are identified as requiring a bronchial challenge test as a diagnostic test for asthma. All of the procedures were undertaken by one investigator (DC) at the Pulmonary Function Laboratory at Norfolk and Norwich University Hospital. After written informed consent was obtained, patients underwent a histamine challenge test with assessment of airways resistance by RInt followed by FEV1 at each time-point during the challenge. At the end of the challenge, patients were asked to complete a questionnaire to evaluate their opinions regarding the two procedures. This study had approval from York Research Ethics Committee (06/Q1108/60).
Patients Thirty consecutive patients, aged older than 18 years, referred for a bronchial challenge with a suspected diagnosis of asthma were entered into the study (Table 1). Patients were excluded from the study if they had a contra-indication for bronchial challenge testing including FEV1560% predicted or 1.5 l, myocardial infection or stroke within 3 months, uncontrolled hypertension [systolic blood pressure (BP) 4200, diastolic BP 4100], known aortic aneurysm, pregnancy or breast feeding. Short acting beta-agonists were withheld for 6 h prior to challenge, short acting anticholinergics were withheld for 8 h prior to the challenge and long acting beta-agonists and anti-cholinergics were withheld for 48 h prior to challenge. Procedures Histamine challenge Histamine challenge was conducted according to standard Norfolk and Norwich University Procedures which utilise the 2-min tidal breathing method [11]. After baseline spirometry, patients inhale placebo then doubling concentrations of histamine from 0.06 to 8 mg/ml each for Table 1. Patient demographic details, presenting symptom and treatment. Mean (SD) Age (years) Gender (Male:Female) Smoking history (Pack years) Height (cm) Weight (kg) Presenting symptom: Cough Breathlessness Wheeze Treatment: Short acting b agonist Short acting anticholinergic ICS LABA/combined ICS+LABA
35
48.93 (±15) 13:17 5.56 (±11.71) 169.09 (±9.98) 83.4 (±13.56) 23 (77%) 7 (23%) 2 (6.7%) 7 (23%) 1 (3.3%) 9 (30%) 9 (30%)
Data shown are mean(SD) or n(%) unless indicated otherwise ICS inhaled corticosteroid, LABA long-acting b agonist
Spirometry Spirometry was performed using a Jeager Pneumoscope 4.34 spirometer (Care Fusion, Basingstoke, Hampshire) according to Association for Respiratory Technology and Physiology guidelines [12]. Airways resistance Airways resistance (RInt) was measured using a MicroRint (Micromedical, Rochester, Kent) as described previously [6]. In brief, airflow was measured immediately before a shutter occluded airflow during tidal breathing. Back extrapolation of pressure–time curve using values at 30 and 70 ms was used to calculate mouth pressure (assumed to be the same as alveolar pressure) at the time of shutter closure. Resistance is calculated by dividing the flow by pressure. The procedure was performed while the patients were sitting and using a nose clip. Patients were shown the device, and the shutter closure was demonstrated so that they were not startled during the test and continued breathing tidally. Measurements were made during expiration using a mouthpiece. The median of five measurements was recorded after measurements with suboptimal traces were rejected following visual inspection [13]. This was repeated three times, and the average of these values was used in the analysis. Questionnaires At the end of the histamine challenge, test patients were asked to complete a visual analogue scale (VAS) to record their symptoms of ‘‘breathlessness’’, ‘‘dizziness’’, ‘‘chest pain’’ and ‘‘tiredness’’ for both spirometry and RInt. This was in order to record the side effects experienced by the patients in both methods. Patients were asked to draw a mark on a 10-cm line with ‘‘no symptoms’’ at the left-hand side and ‘‘very breathless’’, ‘‘very dizzy’’, ‘‘severe chest pain’’ and ‘‘very tired/exhausted’’ at the right-hand side, respectively. Patients were also asked to mark on a 10-cm line with RInt at the left-hand side and spirometry on the right-hand side to indicate which procedure was ‘‘easier to do’’, ‘‘quicker to do’’ and ‘‘a better test’’, i.e. values less than 5 cm show a preference for RInt.
Statistical analysis Data are expressed as mean and standard error of mean or geometric mean and geometric standard error of mean. The provocation concentration (PC) required to cause a fall in FEV1 of 20% (FEV1 PC20) or an increase in airways resistance of each of the cut of values: 20, 40, 60, 80, 100, 120, 140 and 160% (RInt PC1.2, RInt PC1.4, RInt PC1.6, RInt1.8, RInt2.0, RInt2.2, RInt2.4 and RInt2.6, respectively) was calculated using interpolation or extrapolation of the log dose–response curve. A value greater than 8 mg/ml was assigned a value of 8 mg/ml. We assumed an alternative diagnosis than asthma if the PC20 was greater than 8 mg/ml [1]. A comparison of the number of patients requiring 8 mg/ml
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J Asthma, 2015; 52(1): 34–39
Patients felt that RInt was easier to do [VAS 26.4 (4.4) cm], quicker to do [VAS 37.6 (5.3)] and a better test [VAS 34.6 (4.86)].
of histamine to reduce FEV1 by 20% and in increase in RINT at each of the cut of values (20–160%) was made using Kappa statistic in order to determine the agreement between the ability of FEV1 PC20 and RInt PC at each of the airways resistance values to exclude a diagnosis of asthma. We also calculated the percentage change in RInt and FEV1 from baseline at each concentration as well as the coefficient of variation for the RInt measurements. The visual analogue score data for the evaluation of the two breathing tests were compared using a paired t test.
Discussion We have shown that airways resistance as assessed by the MicroRInt was tolerated better than spirometry during histamine challenge, with nearly all patients preferring this procedure. Using a doubling in airways resistance had the best agreement with a fall in FEV1 of 20% and there was a strong negative correlation between FEV1 and airways resistance. Airways resistance was increased in those without a fall in FEV1. There is some debate as to the appropriate method of assessment and threshold value for bronchial challenge testing with airways resistance. Panagou et al. [14] evaluated the utility of airways resistance (using a doubling of airways resistance as the threshold) during methacholine challenge in 170 healthy volunteers (18% of which had bronchial hyper-responsiveness). They found that the method was reproducible and showed good correlation with PD20 FEV1 (r ¼ 0.76, p50.005), with relatively narrow limits of agreement. Madsen et al. used a threshold of 30% increase in resistance in a comparison of the interrupter method and FEV1 during histamine challenge [15]. The repeatability of this measure (after 123 min) was greater than the reproducibility (after 65 days) but both were significantly less than for FEV1, which was highly repeatable. Further to this, Dehaut et al. [16] compared an FEV1 PC20 and a 40% decrease in conductance and showed a correlation coefficient of 0.89 during a histamine challenge test in 18 patients with stable asthma. They also found that FEV1 was reproducible. These studies used the plethysmography instead of MicroRInt to assess airways resistance. Several studies have investigated the relationship between spirometry and RInt using the MicroRInt in children. Song et al. showed a fall of 15% in RInt corresponded to a fall in 10% of FEV1 during exercise challenge [17]. However, in another exercise challenge study, 15 children with a post-exercise FEV1 value of less than 85% predicted had a mean reduction in FEV1 of 15.2% and a mean increase in RInt of 37.8% [18]. Black et al. [19] compared FEV1 and RInt at baseline and following bronchodilators and showed a good correlation
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Results The FEV1 of one patient fell by more than 20% with the lowest concentration of histamine (0.06 mg/ml) and therefore the PC20 could not be calculated. This patient’s data was removed from the analysis. The demographic details of the remaining 29 individuals are shown in Table 1. The FEV1 PC20 and RInt PC1.2–RInt PC2.6 are shown in Table 2. The geometric mean FEV1 PC20 was 1.87 (0.5) mg/ ml histamine with 11 patients having a negative challenge. The agreement between FEV1 and RInt values in excluding asthma is shown (Table 2). The best agreement between a 20% fall in FEV1 was a doubling of airways resistance, i.e. a one hundred percent increase in RInt. When compared to saline, there was a significant difference in RInt at a histamine concentration of 0.06 mg/ml (p50.001) and this was also observed in FEV1 (p ¼ 0.003), suggesting that histamine produces a response in both parameters at the same concentration. Table 3 and Figure 1 show the percentage change in RInt and FEV1 from baseline in those who had a PC2058 mg/ml (i.e. negative tests excluded) at various histamine concentrations. When compared, the RInt and FEV1 showed a strong negative correlation (r ¼ 0.94). Table 4 and Figure 2 show the percentage change in those with a PC2048 mg/ml. In those in whom the FEV1 did not fall by 20%, there is still a significant increase in RInt. However, only 1 of the 8 patients in this group subsequently received a potential diagnosis of asthma. The coefficient of variation for RInt, as calculated from the three readings per histamine concentration for each patient in our study, was 0.122. The patients’ visual analogue score data are shown in Table 5. Patients found the RInt measurement easier to undertake and caused less procedure-provoked symptoms.
Table 2. Average concentrations of Histamine required to produce various changes to FEV1 and RInt values.
Measure Geom mg/ml (SEM) PC20 48 mg/ml (number of patients)* Kappa (p)
Fall in FEV1 of 20% (FEV1 0.8)
RINT increase 20% (1.2)
RINT increase 40% (1.4)
RINT increase 60% (1.6)
RINT increase 80% (1.8)
RINT increase 100% (2.0)
RINT increase 120% (2.2)
RINT increase 140% (2.4)
RINT increase 160% (2.6)
1.88 0.51 11
0.90 0.37 13
1.05 0.39 12
1.47 0.48 13
2.10 0.63 14
3.18 0.80 16
4.29 0.87 19
2.00 0.82 21
1.46 0.72 23
0.15 (0.41)
0.21 (0.26)
0.29 (0.11)
0.37 (0.039)
0.39 (0.024)
0.24 (0.149)
0.24 (0.149)
0.24 (0.149)
FEV1 Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique, Geom geometric mean, PC provocation concentration (the concentration of histamine required to produce the desired effect) *The number of patients with a PC more than 8 mg/ml i.e. deemed not to have asthma.
Airways resistance in bronchial challenge testing
DOI: 10.3109/02770903.2014.947998
Table 3. Average percentage change from baseline for RInt and FEV1 at various Histamine concentrations in those with a PC20 of 58 mg/ml.
Table 4. Average percentage change from baseline for RInt and FEV1 at various Histamine concentrations in those with a PC20 of 48 mg/ml.
Histamine concentration (mg/ml)
Histamine concentration (mg/ml)
Average change in RInt from baseline (%)
Saline 0.06 0.12 0.25 0.5 1 2 4 8
7.1 21.9 35.5 46.1 51.7 56.6 58.5 60.7 59.5
Average change in FEV1 from baseline (%) 0.33 4.0 6.0 10.3 15.5 19.5 22.7 24.3 25.1
(2.9) (4.1) (8.5) (9.0) (8.3) 11.1) (17) (13.7)
(1.0) (1.4) (1.2) (2.0) (2.4) (2.6) (2.7) (3.5)
Average change in RInt from baseline (%)
Saline 0.06 0.12 0.25 0.5 1 2 4 8
Values represented as geometric mean ± SEM. FEV1 Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique.
13.4 29.8 40.9 44.4 56.4 57.6 53.4 70.8 90.5
Average change in FEV1 from baseline (%) 2.9 3.2 4.2 4.1 6.0 7.8 9.9 12.6 14.2
(5.1) (7.3) (9.2) (12.3) (12.3) (10.0) (12.4) (24.8)
(1.0) (1.2) (1.3) (1.6) (1.9) (1.7) (1.1) (1.0)
FEV1 Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique. Values are represented as arithmetic mean ± standard error of the mean to 1 decimal place. Histamine concentrations are in mg/ml.
% Change from Baseline of RInt and FEV1 with increasing Histamine doses
% Change from Baseline of RInt and FEV1 with increasing Histamine doses 100
70 60 % Change from Baseline
80 % Change from Baseline
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60 40 20 0 0.06
0.12
0.25
0.5
1
2
4
8
−20
50 40 30 20 10 0 −10
1
2
3
4
5
6
7
8
−20 −30
Histamine Concentraon (mg/ml)
Histamine Concentraon (mg/ml)
Figure 1. Average percentage change from baseline for RInt and FEV1 at various Histamine concentrations in those with a PC20 of 58 mg/ml. FEV1: Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique. Values are represented as arithmetic mean. Histamine concentrations are in mg/ml. FEV1 is represented by the circular points. RInt is represented by the triangular points.
Figure 2. Average percentage change from baseline for RInt and FEV1 at various Histamine concentrations in those with a PC20 of 48 mg/ml. FEV1: Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique. Values are represented as arithmetic mean. Histamine concentrations are in mg/ml. FEV1 is represented by the circular points. RInt is represented by the triangular points.
(r ¼ 0.737 and r ¼ 0.64, respectively) between these two measurements in 29 children with a mean age of 7 years. Similar findings were reported by Bridge et al. [(8] in 25 asthmatic school children. However, despite a close correlation between FEV1 and RInt at baseline (in 42 children), Arets et al. [20] showed a weak and non-significant correlation between these two measurements in terms of change following bronchodilator. In adults, very few studies have assessed the use of RInt. Hsu et al. compared the values of Negative Expiratory Pressure (NEP) obtained in the assessment of the bronchodilator test (BDT) with those of spirometry and the interrupter method. They found that among 14 patients with positive BDT results, the change in FEV1 was correlated with the change in RInt (r ¼ 0.69, p50.01). In our study, we have shown that when using Micro-RInt, a doubling of RInt correlates best with a 20% fall in FEV1. We have also shown that RInt correlates strongly with FEV1 (r ¼ 0.94) and is preferred to spirometry by patients. Together, these findings suggest that Micro-RInt could potentially provide an additional diagnostic method in patients with suspected asthma.
Table 5. Patient symptoms during RInt and spirometry assessed by visual analogue scale.
Breathlessness Chest pain Dizziness Tiredness
RInt Mean (SD)
Spirometry Mean (SD)
26.1 14.7 18.2 21.6
39.6 19.9 26.7 31.3
(24.5) (14.8) (18.9) (22.5)
(23.5) (20.6) (26.9) (26.0)
p Value 0.037 0.17 0.27 0.13
Mean arithmetic mean, SD standard deviation.
This is particularly important as there is a growing body of evidence to suggest that there is a cohort of patients in whom FEV1 does not accurately rule out asthma [21]. Gartman et al. found that in their study, approximately 20% of patients referred for methacholine challenge test may have asthma inappropriately ruled out. In these patients, all had changes in airway resistance as measured by impulse oscillation system. In our cohort, of those who had a PC2048 mg/ml, only one still has a potential diagnosis of airway hyperresponsiveness, however, this may be because clinicians are using a fall in FEV1 as the gold standard diagnostic test
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for asthma. These patients unfortunately did not have any other tests performed. However, there are some technical issues that should be considered. As mentioned above, the within occasion repeatability for RInt is similar to that of spirometry but the between occasion repeatability is poor [6]. Therefore, it may be more appropriate to use RInt to assess changes during reversibility and bronchial challenge testing than to assess baseline values. This also raises the issue of using FEV1 as the ‘‘gold standard’’ to assess alternative measures, as depending on the cohort, results may be made to appear even less consistent due to occasion performance variation. The calculation of RInt assumes that the alveolar pressure equals mouth pressure and requires rapidly equilibration of these pressures. However, bronchoconstriction will reduce the speed of equilibration and therefore airways resistance by RInt will be lower than plethysmography. Furthermore, the tendency of RInt to underestimate airway obstruction increases in proportion to the severity of the airway obstruction [22]. For this reason, the utility of RInt to assess bronchodilation may be greater than that assessing bronchoconstriction during a bronchial challenge test. It is important to consider patient acceptability when evaluating different clinical procedures/assessments. Performing repeated FEV1 manoeuvres is unpleasant for patients and is user dependent. The mean visual analogue score for breathlessness with spirometry was 40/100 and tiredness was 31/100, which suggests moderate symptoms. All but eight patients felt more symptoms provoked by spirometry and there was a clear preference for RInt measurement over spirometry. Taking this into consideration, patient-independent techniques should be considered for patient preference as well as for technical reasons. There are several weaknesses of our study. Normally, the PC20 is calculated by interpolation of the last 2 points of the log dose–response curve. However, this was not possible in our study as bronchial challenge was terminated when the FEV1 fell by 20% irrespective of the change in RInt. We therefore performed extrapolation of the curve to determine the FEV1 and equivalent PC values for RInt. Another weakness is that we do not know what the expiratory reserve volume was in each patient when using RInt. This poses a problem as the volume of the lung will affect the resistance within the airways. This is not a problem when recording FEV1 as the reading is taken at end inspiration. In addition, our sample size was small and a larger study may have shown a better association between the different measurements. The measurement of RInt was made before FEV1 after each concentration of histamine, in order to reduce the effect of forced manoeuvre on RInt; however, this delayed the administration of the subsequent concentration of histamine slightly. We believe that the lengthening of the bronchial challenge test would have had a minimal impact on the measurements of airway calibre.
Conclusion In conclusion, we have shown that a 100% increase in resistance had the best agreement for diagnosing asthma as a
J Asthma, 2015; 52(1): 34–39
20% fall in FEV1. The results produced by RInt are reproducible and RInt may provide a supplementary diagnostic tool for asthma. Patients preferred the patient-independent technique when compared to spirometry and it was associated with fewer side-effects.
Declaration of interest There were no conflicts of interest for all named authors.
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19. Black J, Baxter-Jones AD, Gordon J, Findlay AL, Helms PJ. Assessment of airway function in young children with asthma: comparison of spirometry, interrupter technique, and tidal flow by inductance plethsmography. Pediatr Pulmonol 2004; 37:548–553. 20. Arets HG, Brackel HJ, van der Ent CK. Applicability of interrupter resistance measurements using the MicroRint in daily practice. Respir Med 2003;97:366–374.
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21. Gartman EJ, Dinino EK, Koo P, Roberts MB, McCool FD. Methacholine-induced airway hyper-reactivity phenotypes. J Asthma 2013;50:629–633. 22. Oswald-Mammosser M, Charloux A, Donato L, Albrech C, Speich JP, Lampert E, Lonsdorfer J. Interrupter technique versus plethysmography for measurement of respiratory resistance in children with asthma or cystic fibrosis. Pediatr Pulmonol 2000;29: 213–220.
DIAGNOSTIC TESTING
Airways resistance in bronchial challenge testing Mark A. Baxter, MB BChir, BA (Hons), MRCP(UK), Dawn Coates, MBBS, and Andrew M. Wilson, MB ChB, MD, MRCP(UK)
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Norfolk and Norwich University Hospital, Respiratory Medicine, Colney Lane, Norwich, Norfolk, UK
Abstract
Keywords
Introduction: Measurement of airways resistance is an alternative to spirometry to assess airflow obstruction. This can be measured by the interrupter technique (RInt) using a handheld device. We wished to know how RInt compared to forced expiratory volume in 1 s (FEV1) during a histamine challenge test. Methods: Twenty-nine (13 male) patients, aged 48.9 (SD 15.3) years, referred for a histamine challenge test, were enrolled. Patients had measurement of RInt then FEV1 after administration of saline and following doubling concentrations of histamine from 0.06 to 8 mg/ml. Extrapolation of the log dose–response curve was undertaken to calculate the concentration (provocation concentration, PC) causing an increase airways resistance of 20, 40, 60, 80, 100, 120, 140 and 160% (RInt PC1.2 to RInt PC2.6) and a reduction in FEV1 by 20% (FEV1 PC20). The number of patients with a negative challenge (i.e. PC48 mg/ml histamine) was calculated for FEV1 and each change in airway resistance. Patients assessed their procedure-provoked symptoms of breathlessness, dizziness and tiredness on a visual analogue scale. Results: Geometric (SD) PC20 for FEV1 was 1.87 (0.5) mg/ml with 11 patients having a negative challenge. A RInt PC20 had the best agreement with FEV1 PC20 [Kappa 0.39 (p ¼ 0.024)]. There is a significant negative correlation between RInt and FEV1 (r ¼ 0.94). The respective mean (SD) breathlessness, dizziness and tiredness scores for RInt were 26 (4) mm, 18 (3) mm, 22 (4) mm and for spirometry were 40 (4) mm, 27 (5) mm, 31 (5) mm. There was a significant (p50.05) difference for breathlessness. Conclusion: RInt was tolerated better than spirometry. A doubling of airways resistance had the best agreement with PC20 FEV1.
Diagnostics, management/control, physiology, treatment
Introduction Airway hyper-responsiveness is a fundamental characteristic of patients with asthma and therefore bronchial challenge testing is used as an investigational test in the diagnosis of asthma [1]. Bronchial challenge testing is also used to measure treatment response [2], to assess new therapies and to compare treatment regimens [3]. It is performed by administering a stimulus or substance and measuring the response via an assessment of airway obstruction. This is usually done by assessing the forced expiratory volume in 1 s (FEV1). However, FEV1 is a patient-dependant test and requires co-operation and maximal effort from the patient. This is particularly demanding during bronchial challenge testing when multiple assessments are required during the test. Furthermore, deep inspiration modulates airway calibre in patients with asthma and in healthy individuals, and as a result, parameters derived from maximal expiratory manoeuvres may be affected [4].
Correspondence: Dr. Mark Andrew Baxter, MB BChir, Norfolk and Norwich University Hospital, Respiratory Medicine, Colney Lane, Norwich, Norwich, NR47UY United Kingdom. E-mail: [email protected]
History Received 17 May 2014 Revised 2 July 2014 Accepted 20 July 2014 Published online 19 August 2014
An alternative to FEV1 is to use airways resistance to evaluate airway calibre. This is assessed during normal tidal breathing and requires no extra effort from the patient. Most commonly, it is performed using a body plethysmograph [5] which requires the patient to sit in a large sealed chamber. Airways resistance can be measured by the interrupter technique (RInt) using a handheld portable device (MicroRint, Micromedical, Rochester, Kent). Airways resistance has been measured using the RInt extensively in children and has been shown to have a good within-occasion repeatability [6]. The MicroRint is useful in detecting changes in the airways resistance following bronchodilation with salbutamol in children aged 0.8–16 years [7] and is as sensitive as spirometry [8]. It has also been used in premature children to study airflow obstruction [9], and although feasible, the results in this group were not as good as with the body plethysmograph. However, its utility in adults has been less well evaluated. Recently, a study using MicroRint to evaluate airways resistance in older adults with intellectual disability showed that this test was feasible, repeatable and reproducible [10]. We wished to examine the change in airways resistance using the MicroRint that would provide the best agreement with a 20% fall in FEV1 (diagnostic of asthma) in adult patients suspected of having an obstructive condition.
Airways resistance in bronchial challenge testing
DOI: 10.3109/02770903.2014.947998
Methods
2 min in a 5-min cycle. The study was terminated if the spirometry fell by 20% from the diluent value or if the highest dose of histamine was administered.
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Study design This was an open observational study of patients who are identified as requiring a bronchial challenge test as a diagnostic test for asthma. All of the procedures were undertaken by one investigator (DC) at the Pulmonary Function Laboratory at Norfolk and Norwich University Hospital. After written informed consent was obtained, patients underwent a histamine challenge test with assessment of airways resistance by RInt followed by FEV1 at each time-point during the challenge. At the end of the challenge, patients were asked to complete a questionnaire to evaluate their opinions regarding the two procedures. This study had approval from York Research Ethics Committee (06/Q1108/60).
Patients Thirty consecutive patients, aged older than 18 years, referred for a bronchial challenge with a suspected diagnosis of asthma were entered into the study (Table 1). Patients were excluded from the study if they had a contra-indication for bronchial challenge testing including FEV1560% predicted or 1.5 l, myocardial infection or stroke within 3 months, uncontrolled hypertension [systolic blood pressure (BP) 4200, diastolic BP 4100], known aortic aneurysm, pregnancy or breast feeding. Short acting beta-agonists were withheld for 6 h prior to challenge, short acting anticholinergics were withheld for 8 h prior to the challenge and long acting beta-agonists and anti-cholinergics were withheld for 48 h prior to challenge. Procedures Histamine challenge Histamine challenge was conducted according to standard Norfolk and Norwich University Procedures which utilise the 2-min tidal breathing method [11]. After baseline spirometry, patients inhale placebo then doubling concentrations of histamine from 0.06 to 8 mg/ml each for Table 1. Patient demographic details, presenting symptom and treatment. Mean (SD) Age (years) Gender (Male:Female) Smoking history (Pack years) Height (cm) Weight (kg) Presenting symptom: Cough Breathlessness Wheeze Treatment: Short acting b agonist Short acting anticholinergic ICS LABA/combined ICS+LABA
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48.93 (±15) 13:17 5.56 (±11.71) 169.09 (±9.98) 83.4 (±13.56) 23 (77%) 7 (23%) 2 (6.7%) 7 (23%) 1 (3.3%) 9 (30%) 9 (30%)
Data shown are mean(SD) or n(%) unless indicated otherwise ICS inhaled corticosteroid, LABA long-acting b agonist
Spirometry Spirometry was performed using a Jeager Pneumoscope 4.34 spirometer (Care Fusion, Basingstoke, Hampshire) according to Association for Respiratory Technology and Physiology guidelines [12]. Airways resistance Airways resistance (RInt) was measured using a MicroRint (Micromedical, Rochester, Kent) as described previously [6]. In brief, airflow was measured immediately before a shutter occluded airflow during tidal breathing. Back extrapolation of pressure–time curve using values at 30 and 70 ms was used to calculate mouth pressure (assumed to be the same as alveolar pressure) at the time of shutter closure. Resistance is calculated by dividing the flow by pressure. The procedure was performed while the patients were sitting and using a nose clip. Patients were shown the device, and the shutter closure was demonstrated so that they were not startled during the test and continued breathing tidally. Measurements were made during expiration using a mouthpiece. The median of five measurements was recorded after measurements with suboptimal traces were rejected following visual inspection [13]. This was repeated three times, and the average of these values was used in the analysis. Questionnaires At the end of the histamine challenge, test patients were asked to complete a visual analogue scale (VAS) to record their symptoms of ‘‘breathlessness’’, ‘‘dizziness’’, ‘‘chest pain’’ and ‘‘tiredness’’ for both spirometry and RInt. This was in order to record the side effects experienced by the patients in both methods. Patients were asked to draw a mark on a 10-cm line with ‘‘no symptoms’’ at the left-hand side and ‘‘very breathless’’, ‘‘very dizzy’’, ‘‘severe chest pain’’ and ‘‘very tired/exhausted’’ at the right-hand side, respectively. Patients were also asked to mark on a 10-cm line with RInt at the left-hand side and spirometry on the right-hand side to indicate which procedure was ‘‘easier to do’’, ‘‘quicker to do’’ and ‘‘a better test’’, i.e. values less than 5 cm show a preference for RInt.
Statistical analysis Data are expressed as mean and standard error of mean or geometric mean and geometric standard error of mean. The provocation concentration (PC) required to cause a fall in FEV1 of 20% (FEV1 PC20) or an increase in airways resistance of each of the cut of values: 20, 40, 60, 80, 100, 120, 140 and 160% (RInt PC1.2, RInt PC1.4, RInt PC1.6, RInt1.8, RInt2.0, RInt2.2, RInt2.4 and RInt2.6, respectively) was calculated using interpolation or extrapolation of the log dose–response curve. A value greater than 8 mg/ml was assigned a value of 8 mg/ml. We assumed an alternative diagnosis than asthma if the PC20 was greater than 8 mg/ml [1]. A comparison of the number of patients requiring 8 mg/ml
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J Asthma, 2015; 52(1): 34–39
Patients felt that RInt was easier to do [VAS 26.4 (4.4) cm], quicker to do [VAS 37.6 (5.3)] and a better test [VAS 34.6 (4.86)].
of histamine to reduce FEV1 by 20% and in increase in RINT at each of the cut of values (20–160%) was made using Kappa statistic in order to determine the agreement between the ability of FEV1 PC20 and RInt PC at each of the airways resistance values to exclude a diagnosis of asthma. We also calculated the percentage change in RInt and FEV1 from baseline at each concentration as well as the coefficient of variation for the RInt measurements. The visual analogue score data for the evaluation of the two breathing tests were compared using a paired t test.
Discussion We have shown that airways resistance as assessed by the MicroRInt was tolerated better than spirometry during histamine challenge, with nearly all patients preferring this procedure. Using a doubling in airways resistance had the best agreement with a fall in FEV1 of 20% and there was a strong negative correlation between FEV1 and airways resistance. Airways resistance was increased in those without a fall in FEV1. There is some debate as to the appropriate method of assessment and threshold value for bronchial challenge testing with airways resistance. Panagou et al. [14] evaluated the utility of airways resistance (using a doubling of airways resistance as the threshold) during methacholine challenge in 170 healthy volunteers (18% of which had bronchial hyper-responsiveness). They found that the method was reproducible and showed good correlation with PD20 FEV1 (r ¼ 0.76, p50.005), with relatively narrow limits of agreement. Madsen et al. used a threshold of 30% increase in resistance in a comparison of the interrupter method and FEV1 during histamine challenge [15]. The repeatability of this measure (after 123 min) was greater than the reproducibility (after 65 days) but both were significantly less than for FEV1, which was highly repeatable. Further to this, Dehaut et al. [16] compared an FEV1 PC20 and a 40% decrease in conductance and showed a correlation coefficient of 0.89 during a histamine challenge test in 18 patients with stable asthma. They also found that FEV1 was reproducible. These studies used the plethysmography instead of MicroRInt to assess airways resistance. Several studies have investigated the relationship between spirometry and RInt using the MicroRInt in children. Song et al. showed a fall of 15% in RInt corresponded to a fall in 10% of FEV1 during exercise challenge [17]. However, in another exercise challenge study, 15 children with a post-exercise FEV1 value of less than 85% predicted had a mean reduction in FEV1 of 15.2% and a mean increase in RInt of 37.8% [18]. Black et al. [19] compared FEV1 and RInt at baseline and following bronchodilators and showed a good correlation
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Results The FEV1 of one patient fell by more than 20% with the lowest concentration of histamine (0.06 mg/ml) and therefore the PC20 could not be calculated. This patient’s data was removed from the analysis. The demographic details of the remaining 29 individuals are shown in Table 1. The FEV1 PC20 and RInt PC1.2–RInt PC2.6 are shown in Table 2. The geometric mean FEV1 PC20 was 1.87 (0.5) mg/ ml histamine with 11 patients having a negative challenge. The agreement between FEV1 and RInt values in excluding asthma is shown (Table 2). The best agreement between a 20% fall in FEV1 was a doubling of airways resistance, i.e. a one hundred percent increase in RInt. When compared to saline, there was a significant difference in RInt at a histamine concentration of 0.06 mg/ml (p50.001) and this was also observed in FEV1 (p ¼ 0.003), suggesting that histamine produces a response in both parameters at the same concentration. Table 3 and Figure 1 show the percentage change in RInt and FEV1 from baseline in those who had a PC2058 mg/ml (i.e. negative tests excluded) at various histamine concentrations. When compared, the RInt and FEV1 showed a strong negative correlation (r ¼ 0.94). Table 4 and Figure 2 show the percentage change in those with a PC2048 mg/ml. In those in whom the FEV1 did not fall by 20%, there is still a significant increase in RInt. However, only 1 of the 8 patients in this group subsequently received a potential diagnosis of asthma. The coefficient of variation for RInt, as calculated from the three readings per histamine concentration for each patient in our study, was 0.122. The patients’ visual analogue score data are shown in Table 5. Patients found the RInt measurement easier to undertake and caused less procedure-provoked symptoms.
Table 2. Average concentrations of Histamine required to produce various changes to FEV1 and RInt values.
Measure Geom mg/ml (SEM) PC20 48 mg/ml (number of patients)* Kappa (p)
Fall in FEV1 of 20% (FEV1 0.8)
RINT increase 20% (1.2)
RINT increase 40% (1.4)
RINT increase 60% (1.6)
RINT increase 80% (1.8)
RINT increase 100% (2.0)
RINT increase 120% (2.2)
RINT increase 140% (2.4)
RINT increase 160% (2.6)
1.88 0.51 11
0.90 0.37 13
1.05 0.39 12
1.47 0.48 13
2.10 0.63 14
3.18 0.80 16
4.29 0.87 19
2.00 0.82 21
1.46 0.72 23
0.15 (0.41)
0.21 (0.26)
0.29 (0.11)
0.37 (0.039)
0.39 (0.024)
0.24 (0.149)
0.24 (0.149)
0.24 (0.149)
FEV1 Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique, Geom geometric mean, PC provocation concentration (the concentration of histamine required to produce the desired effect) *The number of patients with a PC more than 8 mg/ml i.e. deemed not to have asthma.
Airways resistance in bronchial challenge testing
DOI: 10.3109/02770903.2014.947998
Table 3. Average percentage change from baseline for RInt and FEV1 at various Histamine concentrations in those with a PC20 of 58 mg/ml.
Table 4. Average percentage change from baseline for RInt and FEV1 at various Histamine concentrations in those with a PC20 of 48 mg/ml.
Histamine concentration (mg/ml)
Histamine concentration (mg/ml)
Average change in RInt from baseline (%)
Saline 0.06 0.12 0.25 0.5 1 2 4 8
7.1 21.9 35.5 46.1 51.7 56.6 58.5 60.7 59.5
Average change in FEV1 from baseline (%) 0.33 4.0 6.0 10.3 15.5 19.5 22.7 24.3 25.1
(2.9) (4.1) (8.5) (9.0) (8.3) 11.1) (17) (13.7)
(1.0) (1.4) (1.2) (2.0) (2.4) (2.6) (2.7) (3.5)
Average change in RInt from baseline (%)
Saline 0.06 0.12 0.25 0.5 1 2 4 8
Values represented as geometric mean ± SEM. FEV1 Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique.
13.4 29.8 40.9 44.4 56.4 57.6 53.4 70.8 90.5
Average change in FEV1 from baseline (%) 2.9 3.2 4.2 4.1 6.0 7.8 9.9 12.6 14.2
(5.1) (7.3) (9.2) (12.3) (12.3) (10.0) (12.4) (24.8)
(1.0) (1.2) (1.3) (1.6) (1.9) (1.7) (1.1) (1.0)
FEV1 Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique. Values are represented as arithmetic mean ± standard error of the mean to 1 decimal place. Histamine concentrations are in mg/ml.
% Change from Baseline of RInt and FEV1 with increasing Histamine doses
% Change from Baseline of RInt and FEV1 with increasing Histamine doses 100
70 60 % Change from Baseline
80 % Change from Baseline
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60 40 20 0 0.06
0.12
0.25
0.5
1
2
4
8
−20
50 40 30 20 10 0 −10
1
2
3
4
5
6
7
8
−20 −30
Histamine Concentraon (mg/ml)
Histamine Concentraon (mg/ml)
Figure 1. Average percentage change from baseline for RInt and FEV1 at various Histamine concentrations in those with a PC20 of 58 mg/ml. FEV1: Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique. Values are represented as arithmetic mean. Histamine concentrations are in mg/ml. FEV1 is represented by the circular points. RInt is represented by the triangular points.
Figure 2. Average percentage change from baseline for RInt and FEV1 at various Histamine concentrations in those with a PC20 of 48 mg/ml. FEV1: Forced expiratory volume in 1 s, RInt airways resistance using the interrupter technique. Values are represented as arithmetic mean. Histamine concentrations are in mg/ml. FEV1 is represented by the circular points. RInt is represented by the triangular points.
(r ¼ 0.737 and r ¼ 0.64, respectively) between these two measurements in 29 children with a mean age of 7 years. Similar findings were reported by Bridge et al. [(8] in 25 asthmatic school children. However, despite a close correlation between FEV1 and RInt at baseline (in 42 children), Arets et al. [20] showed a weak and non-significant correlation between these two measurements in terms of change following bronchodilator. In adults, very few studies have assessed the use of RInt. Hsu et al. compared the values of Negative Expiratory Pressure (NEP) obtained in the assessment of the bronchodilator test (BDT) with those of spirometry and the interrupter method. They found that among 14 patients with positive BDT results, the change in FEV1 was correlated with the change in RInt (r ¼ 0.69, p50.01). In our study, we have shown that when using Micro-RInt, a doubling of RInt correlates best with a 20% fall in FEV1. We have also shown that RInt correlates strongly with FEV1 (r ¼ 0.94) and is preferred to spirometry by patients. Together, these findings suggest that Micro-RInt could potentially provide an additional diagnostic method in patients with suspected asthma.
Table 5. Patient symptoms during RInt and spirometry assessed by visual analogue scale.
Breathlessness Chest pain Dizziness Tiredness
RInt Mean (SD)
Spirometry Mean (SD)
26.1 14.7 18.2 21.6
39.6 19.9 26.7 31.3
(24.5) (14.8) (18.9) (22.5)
(23.5) (20.6) (26.9) (26.0)
p Value 0.037 0.17 0.27 0.13
Mean arithmetic mean, SD standard deviation.
This is particularly important as there is a growing body of evidence to suggest that there is a cohort of patients in whom FEV1 does not accurately rule out asthma [21]. Gartman et al. found that in their study, approximately 20% of patients referred for methacholine challenge test may have asthma inappropriately ruled out. In these patients, all had changes in airway resistance as measured by impulse oscillation system. In our cohort, of those who had a PC2048 mg/ml, only one still has a potential diagnosis of airway hyperresponsiveness, however, this may be because clinicians are using a fall in FEV1 as the gold standard diagnostic test
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for asthma. These patients unfortunately did not have any other tests performed. However, there are some technical issues that should be considered. As mentioned above, the within occasion repeatability for RInt is similar to that of spirometry but the between occasion repeatability is poor [6]. Therefore, it may be more appropriate to use RInt to assess changes during reversibility and bronchial challenge testing than to assess baseline values. This also raises the issue of using FEV1 as the ‘‘gold standard’’ to assess alternative measures, as depending on the cohort, results may be made to appear even less consistent due to occasion performance variation. The calculation of RInt assumes that the alveolar pressure equals mouth pressure and requires rapidly equilibration of these pressures. However, bronchoconstriction will reduce the speed of equilibration and therefore airways resistance by RInt will be lower than plethysmography. Furthermore, the tendency of RInt to underestimate airway obstruction increases in proportion to the severity of the airway obstruction [22]. For this reason, the utility of RInt to assess bronchodilation may be greater than that assessing bronchoconstriction during a bronchial challenge test. It is important to consider patient acceptability when evaluating different clinical procedures/assessments. Performing repeated FEV1 manoeuvres is unpleasant for patients and is user dependent. The mean visual analogue score for breathlessness with spirometry was 40/100 and tiredness was 31/100, which suggests moderate symptoms. All but eight patients felt more symptoms provoked by spirometry and there was a clear preference for RInt measurement over spirometry. Taking this into consideration, patient-independent techniques should be considered for patient preference as well as for technical reasons. There are several weaknesses of our study. Normally, the PC20 is calculated by interpolation of the last 2 points of the log dose–response curve. However, this was not possible in our study as bronchial challenge was terminated when the FEV1 fell by 20% irrespective of the change in RInt. We therefore performed extrapolation of the curve to determine the FEV1 and equivalent PC values for RInt. Another weakness is that we do not know what the expiratory reserve volume was in each patient when using RInt. This poses a problem as the volume of the lung will affect the resistance within the airways. This is not a problem when recording FEV1 as the reading is taken at end inspiration. In addition, our sample size was small and a larger study may have shown a better association between the different measurements. The measurement of RInt was made before FEV1 after each concentration of histamine, in order to reduce the effect of forced manoeuvre on RInt; however, this delayed the administration of the subsequent concentration of histamine slightly. We believe that the lengthening of the bronchial challenge test would have had a minimal impact on the measurements of airway calibre.
Conclusion In conclusion, we have shown that a 100% increase in resistance had the best agreement for diagnosing asthma as a
J Asthma, 2015; 52(1): 34–39
20% fall in FEV1. The results produced by RInt are reproducible and RInt may provide a supplementary diagnostic tool for asthma. Patients preferred the patient-independent technique when compared to spirometry and it was associated with fewer side-effects.
Declaration of interest There were no conflicts of interest for all named authors.
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