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Communications to the Editor |

Histaminne PC20 Extrapolation FREE TO VIEW

Brenton Eckert, MSc; Charles Mitchell, MBBS
Author and Funding Information

Affiliations: Princess Alexandra Hospital Brisbane, Queensland, Australia University of Queensland Brisbane, Queensland, Australia,  University of Saskatchewan Saskatoon, Saskatchewan, Canada

Correspondence to: Brenton Eckert, MSc, Department of Respiratory Medicine, Princess Alexandra Hospital, Brisbane, Queensland, Australia 4102; e-mail: eckertb@health.qld.gov.au



Chest. 2000;117(1):294-295. doi:10.1378/chest.117.1.294-a
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Published online

To the Editor:

We read with interest the article by Jokic et al (December 1998)1 because we also have investigated simple linear extrapolation for the estimation of the provocative concentration of a substance causing a 20% fall in FEV1 (PC20) in histamine and methacholine challenge tests. Our conclusions were remarkably similar to those of Jokic et al, although our method of calculation was slightly different.

In our study, we reviewed 490 consecutive histamine challenges performed according to the tidal breathing method of Cockcroft et al.2 In the 184 positive challenges (PC20, < 8 mg/mL) we compared the conventional PC20 using linear interpolation (PCint) to the PC20 calculated by linear extrapolation of the dose-response curve (PCext). The PCext was calculated in the same manner as in the study by Jokic et al, in that we assumed that the last histamine concentration (the one that induced a fall in FEV1 of > 20%) had not been administered, then we extrapolated using the last two remaining data points. The same equation was used for both calculations of PC20.

Generally, there was a poor correlation between the interpolated and extrapolated PC20 calculations (R2 = 0.25). However, if we selected only those subjects with a fall in FEV1 of > 10% to the penultimate histamine concentration (n = 123), the correlation between the PC20 calculations improved (R2 = 0.79) (Fig 1 ). When only subjects with a fall in FEV1 of> 15% to the penultimate histamine concentration were included in the analysis (n = 55), the relationship between the PC20 calculations tightened (R2 = 0.95) (Fig 2 ).

In this group, the extrapolated PC20 tended to slightly overestimate the interpolated value by approximately 15%. Correction according to the equation PC20int = 0.81*PC20ext + 0.16 accounted for this overestimation. Using this correction in calculations for the 55 subjects, there was almost no difference in the categorization of airway hyperresponsiveness between the two methods. All six subjects with severe airway responsiveness (PC20, < 0.25 mg/mL) based on interpolated PC20 remain in that category if the corrected extrapolated PC20 is substituted. The same was found in all 18 subjects categorized as having moderate airway responsiveness (PC20, 0.25 to 2 mg/mL). Only one subject in the mild category was redefined when the extrapolated PC20 was used. This subject had a borderline increase in airway responsiveness with an interpolated PC20 of 7.5 mg/mL and a corrected extrapolated PC20 of 8.1 mg/mL.

We conclude that linear extrapolation using the last two data points should be used only if the fall in FEV1 has exceeded 15%. A correction formula can be used to compensate for the overestimation of the true PC20 by the extrapolated PC20. Use of this method will negate the necessity of inducing large and potentially dangerous falls in FEV1, which sometimes are required to calculate an interpolated PC20, with negligible effect on the interpretation of the challenge test. It will also allow calculation of an accurate PC20 in research trials in those subjects who fail to meet the 20% fall in FEV1 criteria.

Figure Jump LinkFigure 1. The correlation between the PC20 calculations with an R2 of 0.79.Grahic Jump Location

Figure Jump LinkFigure 2. The correlation between the PC20 calculations with an R2 of 0.95.Grahic Jump Location

References

Jokic, R, Davis, WF, Cockcroft, DW (1998) Methacholine PC20extrapolation.Chest114,1796-1797
 
Cockcroft, DW, Killian, DN, Mellon, JT, et al Bronchial reactivity to inhaled histamine: a method and clinical survey.Clin Allergy1977;7,235-243
 
To the Editor:

We were pleased to read the commentary by Eckert and Mitchell regarding our article (December 1998)1on the extrapolation of the provocative concentration of a substance causing a 20% fall in FEV1 (PC20). The data presented in the bottom graph of Figure 1 in our article were similar to their data, ie, we used the penultimate fall in FEV1 (≥ 15%, < 20%) and the anti-penultimate fall in FEV1 to extrapolate the methacholine PC20, and we compared this to the conventional interpolated PC20. When analyzed in the same way as Eckert and Mitchell’s data, the Pearson correlation coefficient (r) was 0.91. The interclass correlation coefficient (ICC), a more appropriate test to look for equivalence as opposed to correlation,2 was 0.74. The geometric mean extrapolated PC20 was 12% larger than the interpolated value. However, our data suggest that this was not a systematic overestimation but rather was due to a large overestimation in a small number of individuals (8 of 100) who had a very shallow slope on the extrapolation line (see Fig 1 in our article,1). In fact, it was this reason that prompted us to look at a one-point extrapolation using only the penultimate fall in FEV1. This approach to extrapolation proved to be a better approach to approximating the interpolated PC20 (r = 0.995; ICC = 0.97).,1 There was a slight tendency (8%) for this approach to underestimate PC20. The accuracy of extrapolation will decrease the smaller is the fall in the FEV1. Extrapolation will be unreliable for falls in FEV1 < 10% and will be of borderline reliability with falls between 10% and 15%. Our data as well as that of Eckert and Mitchell document that extrapolation is a reliable way to estimate PC20 when the fall in FEV1 is ≥ 15%.

References
Jokic, R, Davis, EE, Cockcroft, DW Methacholine PC20extrapolation.Chest1998;114,1796-1797
 
Streiner DL, Norman GR, Reliability. In: Streiner DL, Norman GR, eds. Health measurement scales. Oxford, UK: Oxford University Press, 1989; 79–96.
 

Figures

Figure Jump LinkFigure 1. The correlation between the PC20 calculations with an R2 of 0.79.Grahic Jump Location
Figure Jump LinkFigure 2. The correlation between the PC20 calculations with an R2 of 0.95.Grahic Jump Location

Tables

References

Jokic, R, Davis, WF, Cockcroft, DW (1998) Methacholine PC20extrapolation.Chest114,1796-1797
 
Cockcroft, DW, Killian, DN, Mellon, JT, et al Bronchial reactivity to inhaled histamine: a method and clinical survey.Clin Allergy1977;7,235-243
 
Jokic, R, Davis, EE, Cockcroft, DW Methacholine PC20extrapolation.Chest1998;114,1796-1797
 
Streiner DL, Norman GR, Reliability. In: Streiner DL, Norman GR, eds. Health measurement scales. Oxford, UK: Oxford University Press, 1989; 79–96.
 
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