EDITORIALS Methacholine Challenge PD20 versus PC20 Donald W. Cockcroft Department of Medicine, Division of Respirology, Critical Care and Sleep Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Bronchoprovocation with the direct stimulus methacholine is a highly sensitive test (i.e., has a high negative predictive value) for asthma provided two important but sometimes overlooked caveats are observed. The first is the requirement for the (asthma-like) symptom to be clinically current (1) and the second is the requirement for methacholine to be inhaled without the bronchoprotecting effect of deep inhalations (2). When these caveats are observed, a normal methacholine test rules out current symptomatic asthma with reasonable certainty. There remain two significant challenges to interpretation and comparison of methacholine test results. The first is the lack of a gold standard test for asthma that is both objective and independent; this major problem is not discussed further here. The second is the multiplicity of different and often noncomparable methods. Historically, we developed the 2minute tidal breathing test with the Wright nebulizer (3) by modification of a Dutch method using 30-second inhalations and a 32-mg/ml cutoff (4) empirically assuming dose equivalence, namely that one-quarter strength (8 mg/ml) inhaled for four times as long would produce the same response. Two reasons for our modification were the difficulty of keeping histamine in solution at 32 mg/ml and the possibility that 2 minutes of tidal breathing should have a more repeatable inspiratory time than 30 seconds. Whereas early methods (5) expressed the results as a PD20 (provocation dose causing a 20% decline in FEV1) in somewhat nebulous breath units, we introduced the term PC20 (provocation concentration causing a 20% fall in FEV1)
(3) because we did not know either the amount of aerosol that passed the vocal cords or the amount that was deposited in the airways and, in addition, we recognized that a fraction of the mass loss (loosely referred to as output) was actually evaporation; this proved to be about 75% with the Wright nebulizer (6). We stressed the need to carefully standardize the nebulizer output, the concentrations, and the time interval between dose step-ups (7); this became even more important as we came to appreciate that airway responsiveness could be measured into the normal range (PC20 . 16 mg/ml) and that the measurement is inherently imprecise (repeatability about plus or minus 1–1.5 doubling concentrations) (8). The presumed dose dependence of the response has been validated by two small studies, one with histamine (9) and one with methacholine (10); both used the same nebulizer with differing inhalation times. This is confirmed in this issue of AnnalsATS (pp. 357–363) by Dell and colleagues (11) demonstrating that, with two widely different nebulizers, methacholine PD20 but not methacholine PC20 was comparable between methods. The concept of this approach arose, in part, from discussions of the current ATS/ ERS Task Force to update the 1999 bronchoprovocation guidelines (7). We suggested that expressing the methacholine challenge result as a PD20 would be a means to allow better comparison between different methods. This important paradigm shift is strongly supported in the paper by Dell and colleagues. There remain a number of important considerations regarding this approach.
One is the ideal requirement to measure the true nebulized dose by methods such as that described by Coates and colleagues (12). This avoids the overestimation of nebulizer output, which is a weakness of the traditional method of weighing before and after operation (7); for the Wright nebulizer this could be an overestimation by a factor of three- to fourfold because 75% or more of mass loss during nebulization is actually evaporation (6). Although the technology is not that complex, it will not be routinely available, particularly in clinical laboratories. Thus users will need to rely on manufacturer’s specifications or make approximations based on the previous method. We currently routinely recalibrate reusable nebulizers on a regular basis and the above method would not be routinely available. Having said that, fortunately the operating characteristics of the nebulizers we routinely use (Wright, Bennett Twin) are stable and consistent over time. A related issue concerns single-use or disposable nebulizers. This is theoretically attractive from an infection control perspective. However, it would not be practical for users to calibrate every nebulizer before a single use. Thus we will need to rely heavily on manufacturer’s specifications and assurance regarding consistency. A further concern is whether to express the PD20 cumulatively or noncumulatively. PD20 has historically been expressed as a cumulative dose (5). There is a partial cumulative effect when methacholine is inhaled in doubling dose step-ups at 5-minute intervals; the effect is closer to noncumulative than cumulative (13). By
(Received in original form January 22, 2015; accepted in final form January 23, 2015 ) Correspondence and requests for reprints should be addressed to D. W. Cockcroft, M.D., Division of Respirology, Critical Care and Sleep Medicine, Royal University Hospital, 103 Hospital Drive, Ellis Hall, Rm. 551, Saskatoon, SK, S7N 0W8 Canada. E-mail: [email protected] Ann Am Thorac Soc Vol 12, No 3, pp 291–292, Mar 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201501-049ED Internet address: www.atsjournals.org
Editorials
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EDITORIALS contrast, there is a virtually complete cumulative effect if the dose interval is reduced to 1 minute (14). This issue has caused much discussion. The most important aspect of this is not whether to report the result cumulatively or noncumulatively but rather the need to keep the time interval between dose step-up constant so that, whatever cumulative effect there is, is kept consistent. A desire to shorten the testing by reducing the time interval will increase the cumulative effect, negatively influencing both repeatability and comparability. There are validated alternative methods to shorten the test while keeping the time interval constant
(15, 16). The most important are the judicious use of a higher starting concentration/dose based on clinical features (15), and either intermittent or routine skipping (i.e., quadrupling dose step-ups) of a (doubling) dose step (7, 16). In summary, switching to routinely reporting the results of the methacholine test as a PD20 will allow comparison of methods using different nebulizers and inhalation times. There remain several important caveats for adequate interpretation. Symptoms must be clinically current (within the past few days). Methacholine must be inhaled with no deep inhalations (i.e., sub-TLC breaths). The
References 1 Cockcroft DW, Hargreave FE. Airway hyperresponsiveness: relevance of random population data to clinical usefulness. Am Rev Respir Dis 1990;142:497–500. 2 Cockcroft DW, Davis BE. The bronchoprotective effect of inhaling methacholine by using total lung capacity inspirations has a marked influence on the interpretation of the test result. J Allergy Clin Immunol 2006;117:1244–1248. 3 Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977;7:235–243. 4 van der Lende R, Visser BF, Wever-Hess J, de Vries K, Orie NG. Distribution of histamine threshold values in a random population. Rev Inst Hyg Mines (Hasselt) 1973;28:186–190. 5 Chai H, Farr RS, Froehlich LA, Mathison DA, McLean JA, Rosenthal RR, Sheffer AL II, Spector SL, Townley RG. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975;56:323–327. 6 Cockcroft DW, Hurst TS, Gore BP. Importance of evaporative water losses during standardized nebulized inhalation provocation tests. Chest 1989;96:505–508. 7 Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, et al. Guidelines for methacholine and exercise challenge testing—1999. Am J Respir Crit Care Med 2000;161:309–329.
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time interval between dose steps must be kept constant. Five minutes from the start of one to the start on the next inhalation (based on the 2-min tidal breathing method) has been suggested (3, 7); this is a 4-minute interval from the midpoint of the inhalations. The true nebulized dose, if it can be measured (rather than the mass loss after operation), should be recorded. n Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: The author thanks Jacquie Bramley for assisting in the preparation of this manuscript.
8 Dehaut P, Rachiele A, Martin RR, Malo J-L. Histamine dose–response curves in asthma: reproducibility and sensitivity of different indices to assess response. Thorax 1983;38:516–522. 9 Cockcroft DW, Berscheid BA. Standardization of inhalation provocation tests: dose vs concentration of histamine. Chest 1982; 82:572–575. 10 Drotar DE, Davis BE, Cockcroft DW. Dose versus concentration of methacholine. Ann Allergy Asthma Immunol 1999;83:229–230. 11 Dell SD, Bola SS, Foty RG, Marshall LC, Nelligan KA, Coates AL. PD20 should be used to interpret methacholine challenge tests with modern nebulizers. Ann Am Thorac Soc 2015;12:357–363. 12 Coates AL, Leung K, Dell SD. Developing alternative delivery systems for methacholine challenge tests. J Aerosol Med Pulm Drug Deliv 2014;27:66–70. 13 Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 1978;33:705–710. 14 Yan K, Salome C, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. Thorax 1983;38:760–765. 15 Juniper EF, Cockcroft DW, Hargreave FE. Histamine and methacholine inhalation tests: tidal breathing method—laboratory procedure and standardisation, 2nd ed. Lund, Sweden: AB Draco; 1994. 16 Cockcroft DW, Marciniuk DD, Hurst TS, Cotton DJ, Laframboise KF, McNab BD, Skomro RP. Methacholine challenge: test-shortening procedures. Chest 2001;120:1857–1860.
AnnalsATS Volume 12 Number 3 | March 2015
Bronchoprovocation with the direct stimulus methacholine is a highly sensitive test (i.e., has a high negative predictive value) for asthma provided two important but sometimes overlooked caveats are observed. The first is the requirement for the (asthma-like) symptom to be clinically current (1) and the second is the requirement for methacholine to be inhaled without the bronchoprotecting effect of deep inhalations (2). When these caveats are observed, a normal methacholine test rules out current symptomatic asthma with reasonable certainty. There remain two significant challenges to interpretation and comparison of methacholine test results. The first is the lack of a gold standard test for asthma that is both objective and independent; this major problem is not discussed further here. The second is the multiplicity of different and often noncomparable methods. Historically, we developed the 2minute tidal breathing test with the Wright nebulizer (3) by modification of a Dutch method using 30-second inhalations and a 32-mg/ml cutoff (4) empirically assuming dose equivalence, namely that one-quarter strength (8 mg/ml) inhaled for four times as long would produce the same response. Two reasons for our modification were the difficulty of keeping histamine in solution at 32 mg/ml and the possibility that 2 minutes of tidal breathing should have a more repeatable inspiratory time than 30 seconds. Whereas early methods (5) expressed the results as a PD20 (provocation dose causing a 20% decline in FEV1) in somewhat nebulous breath units, we introduced the term PC20 (provocation concentration causing a 20% fall in FEV1)
(3) because we did not know either the amount of aerosol that passed the vocal cords or the amount that was deposited in the airways and, in addition, we recognized that a fraction of the mass loss (loosely referred to as output) was actually evaporation; this proved to be about 75% with the Wright nebulizer (6). We stressed the need to carefully standardize the nebulizer output, the concentrations, and the time interval between dose step-ups (7); this became even more important as we came to appreciate that airway responsiveness could be measured into the normal range (PC20 . 16 mg/ml) and that the measurement is inherently imprecise (repeatability about plus or minus 1–1.5 doubling concentrations) (8). The presumed dose dependence of the response has been validated by two small studies, one with histamine (9) and one with methacholine (10); both used the same nebulizer with differing inhalation times. This is confirmed in this issue of AnnalsATS (pp. 357–363) by Dell and colleagues (11) demonstrating that, with two widely different nebulizers, methacholine PD20 but not methacholine PC20 was comparable between methods. The concept of this approach arose, in part, from discussions of the current ATS/ ERS Task Force to update the 1999 bronchoprovocation guidelines (7). We suggested that expressing the methacholine challenge result as a PD20 would be a means to allow better comparison between different methods. This important paradigm shift is strongly supported in the paper by Dell and colleagues. There remain a number of important considerations regarding this approach.
One is the ideal requirement to measure the true nebulized dose by methods such as that described by Coates and colleagues (12). This avoids the overestimation of nebulizer output, which is a weakness of the traditional method of weighing before and after operation (7); for the Wright nebulizer this could be an overestimation by a factor of three- to fourfold because 75% or more of mass loss during nebulization is actually evaporation (6). Although the technology is not that complex, it will not be routinely available, particularly in clinical laboratories. Thus users will need to rely on manufacturer’s specifications or make approximations based on the previous method. We currently routinely recalibrate reusable nebulizers on a regular basis and the above method would not be routinely available. Having said that, fortunately the operating characteristics of the nebulizers we routinely use (Wright, Bennett Twin) are stable and consistent over time. A related issue concerns single-use or disposable nebulizers. This is theoretically attractive from an infection control perspective. However, it would not be practical for users to calibrate every nebulizer before a single use. Thus we will need to rely heavily on manufacturer’s specifications and assurance regarding consistency. A further concern is whether to express the PD20 cumulatively or noncumulatively. PD20 has historically been expressed as a cumulative dose (5). There is a partial cumulative effect when methacholine is inhaled in doubling dose step-ups at 5-minute intervals; the effect is closer to noncumulative than cumulative (13). By
(Received in original form January 22, 2015; accepted in final form January 23, 2015 ) Correspondence and requests for reprints should be addressed to D. W. Cockcroft, M.D., Division of Respirology, Critical Care and Sleep Medicine, Royal University Hospital, 103 Hospital Drive, Ellis Hall, Rm. 551, Saskatoon, SK, S7N 0W8 Canada. E-mail: [email protected] Ann Am Thorac Soc Vol 12, No 3, pp 291–292, Mar 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201501-049ED Internet address: www.atsjournals.org
Editorials
291
EDITORIALS contrast, there is a virtually complete cumulative effect if the dose interval is reduced to 1 minute (14). This issue has caused much discussion. The most important aspect of this is not whether to report the result cumulatively or noncumulatively but rather the need to keep the time interval between dose step-up constant so that, whatever cumulative effect there is, is kept consistent. A desire to shorten the testing by reducing the time interval will increase the cumulative effect, negatively influencing both repeatability and comparability. There are validated alternative methods to shorten the test while keeping the time interval constant
(15, 16). The most important are the judicious use of a higher starting concentration/dose based on clinical features (15), and either intermittent or routine skipping (i.e., quadrupling dose step-ups) of a (doubling) dose step (7, 16). In summary, switching to routinely reporting the results of the methacholine test as a PD20 will allow comparison of methods using different nebulizers and inhalation times. There remain several important caveats for adequate interpretation. Symptoms must be clinically current (within the past few days). Methacholine must be inhaled with no deep inhalations (i.e., sub-TLC breaths). The
References 1 Cockcroft DW, Hargreave FE. Airway hyperresponsiveness: relevance of random population data to clinical usefulness. Am Rev Respir Dis 1990;142:497–500. 2 Cockcroft DW, Davis BE. The bronchoprotective effect of inhaling methacholine by using total lung capacity inspirations has a marked influence on the interpretation of the test result. J Allergy Clin Immunol 2006;117:1244–1248. 3 Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977;7:235–243. 4 van der Lende R, Visser BF, Wever-Hess J, de Vries K, Orie NG. Distribution of histamine threshold values in a random population. Rev Inst Hyg Mines (Hasselt) 1973;28:186–190. 5 Chai H, Farr RS, Froehlich LA, Mathison DA, McLean JA, Rosenthal RR, Sheffer AL II, Spector SL, Townley RG. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975;56:323–327. 6 Cockcroft DW, Hurst TS, Gore BP. Importance of evaporative water losses during standardized nebulized inhalation provocation tests. Chest 1989;96:505–508. 7 Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, et al. Guidelines for methacholine and exercise challenge testing—1999. Am J Respir Crit Care Med 2000;161:309–329.
292
time interval between dose steps must be kept constant. Five minutes from the start of one to the start on the next inhalation (based on the 2-min tidal breathing method) has been suggested (3, 7); this is a 4-minute interval from the midpoint of the inhalations. The true nebulized dose, if it can be measured (rather than the mass loss after operation), should be recorded. n Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: The author thanks Jacquie Bramley for assisting in the preparation of this manuscript.
8 Dehaut P, Rachiele A, Martin RR, Malo J-L. Histamine dose–response curves in asthma: reproducibility and sensitivity of different indices to assess response. Thorax 1983;38:516–522. 9 Cockcroft DW, Berscheid BA. Standardization of inhalation provocation tests: dose vs concentration of histamine. Chest 1982; 82:572–575. 10 Drotar DE, Davis BE, Cockcroft DW. Dose versus concentration of methacholine. Ann Allergy Asthma Immunol 1999;83:229–230. 11 Dell SD, Bola SS, Foty RG, Marshall LC, Nelligan KA, Coates AL. PD20 should be used to interpret methacholine challenge tests with modern nebulizers. Ann Am Thorac Soc 2015;12:357–363. 12 Coates AL, Leung K, Dell SD. Developing alternative delivery systems for methacholine challenge tests. J Aerosol Med Pulm Drug Deliv 2014;27:66–70. 13 Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 1978;33:705–710. 14 Yan K, Salome C, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. Thorax 1983;38:760–765. 15 Juniper EF, Cockcroft DW, Hargreave FE. Histamine and methacholine inhalation tests: tidal breathing method—laboratory procedure and standardisation, 2nd ed. Lund, Sweden: AB Draco; 1994. 16 Cockcroft DW, Marciniuk DD, Hurst TS, Cotton DJ, Laframboise KF, McNab BD, Skomro RP. Methacholine challenge: test-shortening procedures. Chest 2001;120:1857–1860.
AnnalsATS Volume 12 Number 3 | March 2015
