Reproducibility of response to nasal lysine-aspirin challenge in patients with aspirin-induced asthma Daniel K. C. Lee, MD; Kay Haggart, BSc; and Brian J. Lipworth, MD
Background: Peak nasal inspiratory flow (PNIF) and acoustic rhinometry objectively measure the effects of nasal provocation testing. Although the latter is conventionally used in nasal lysine-aspirin challenge, use of the former in aspirin-induced asthma (AIA) has never been evaluated. Objective: To evaluate the reproducibility of PNIF and acoustic rhinometry following nasal lysine-aspirin challenge in AIA. Methods: Fourteen patients with a clear-cut history of AIA underwent nasal lysine-aspirin challenge at 2 separate visits 1 week apart. Both PNIF and minimum cross-sectional area (MCA) were measured using acoustic rhinometry for 120 minutes following standard nasal lysine-aspirin challenge (25 mg). Results: Prechallenge values were not significantly different at visit 1 vs visit 2 for mean [SEM] PNIF (128 [13] vs 127 [9] L/min) and MCA (6.89 [0.51] vs 6.94 [0.57] cm2). The mean (SEM) maximum percent PNIF change from baseline for visit 1 and visit 2 was ⫺42 (5) and ⫺42 (6), respectively, and the mean (SEM) average percent PNIF change from baseline was ⫺25 (4) and ⫺25 (6), respectively. The mean (SEM) maximum percent MCA change from baseline for visit 1 and visit 2 was ⫺49 (4) and ⫺48 (3), respectively, and the mean (SEM) average percent MCA change from baseline was ⫺25 (8) and ⫺24 (4), respectively. Coefficients of variation for maximum and average responses were 2.3% and 6.5%, respectively, for PNIF and 7.4% and 16.1% for MCA. Conclusions: Measurement of PNIF following nasal lysine-aspirin challenge is a simple and reproducible alternative to acoustic rhinometry, with maximum response being a more reproducible outcome measure than average response. Ann Allergy Asthma Immunol. 2004;93:185–188.
INTRODUCTION Ingestion of aspirin or nonsteroidal anti-inflammatory drugs can lead to a clinically distinct syndrome known as aspirininduced asthma (AIA), which is characterized by chronic rhinosinusitis, nasal polyposis, and asthma. In AIA, there is an accelerated depletion of prostaglandin E2 by aspirin, with the former already being down-regulated owing to cyclooxygenase-2 functional deficiency.1 There is currently no in vitro testing for AIA, and the diagnosis can only be established by oral or nasal provocation challenges with aspirin or nonsteroidal anti-inflammatory drugs.1 Nasal lysineaspirin challenge had been proposed as a safe test to diagnose AIA, and it is without risk of bronchospasm, which is sometimes associated with oral aspirin challenge.2 Peak nasal inspiratory flow (PNIF) and acoustic rhinometry are used to objectively measure the effects of nasal provocation testing. Although the latter is used in nasal lysine-aspirin challenge, use of the former in AIA has never been evaluated. We, therefore, undertook this study to evaluate the reproducibility of both measures following nasal provocation with lysine-aspirin in patients with AIA.
Asthma & Allergy Research Group, Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland. This study was supported by a University of Dundee departmental grant and received no support from the pharmaceutical industry. Received for publication November 11, 2003. Accepted for publication in revised form February 4, 2004.
VOLUME 93, AUGUST, 2004
PATIENTS AND METHODS Eligible patients were required to exhibit a clear-cut history of AIA, with the presence of chronic rhinosinusitis, nasal polyposis, persistent asthma, and aspirin or nonsteroidal antiinflammatory drug sensitivity leading to either acute bronchospasm or angioedema on exposure, in addition to a previous positive response to nasal lysine-aspirin challenge, as defined by a maximal decline in PNIF of at least 25% from baseline in a 120-minute period after challenge. All patients had evidence of chronic sinus inflammation on computed tomography, and the presence of grade 1 to 2 nasal polyps was determined via nasal endoscopy using a rigid 30° telescope (Hopkins; Karl Storz Endoscopy Ltd, Slough, England). Patients with occlusive grade 3 nasal polyps or nasal septal deviation of more than 50% were excluded because significant nasal obstruction would have prevented accurate measurement of PNIF. All patients received appropriate instructions and were required to demonstrate good technique, which was reassessed and reinforced before each nasal challenge at each study visit. Patients recorded their PNIF using a PNIF meter (In-Check; Clement Clarke International Ltd, Harlow, England). Nasal lysine-aspirin challenge was performed precisely as previously described.3 In brief, patients were challenged with 25 mg of lysine-aspirin (Aspisol; Bayer PLC, Newbury, England) in each inferior turbinate and underwent measurement of PNIF and the minimum cross-sectional area (MCA) using an acoustic rhinometer (A1 Executive; GM Instruments
185
Ltd, Kilwinning, Scotland), at 10-minute intervals, for 120 minutes after challenge. Patients attended 2 study visits, with each visit separated by 1 week. Patients stopped taking any concomitant leukotriene CysLT1-receptor antagonists during an initial 1-week washout period and for the duration of the study. Patients continued taking their usual asthma medication, which remained unchanged throughout the study. All patients gave informed consent, and the Tayside Committee on Medical Research Ethics approved the study. Statistical Analysis The study was powered at 80%, with ␣ error set at .05 (2-tailed) to detect a 25% difference in the maximum response between study visits, with a sample size of 12 completed patients. Analyses were performed using a statistical software package (Statgraphics; STSC Software Publishing Group, Rockville, MD). All data are given as mean (SEM). RESULTS Fourteen patients (7 men and 7 women) aged 49 (3) years were enrolled, and all completed the study per protocol. All patients were receiving therapy for AIA, including inhaled corticosteroids (beclomethasone dipropionate, n ⫽ 3; budesonide, n ⫽ 3; and fluticasone propionate, n ⫽ 5), intranasal corticosteroids (fluticasone propionate: n ⫽ 14), leukotriene CysLT1-receptor antagonists (n ⫽ 7), long-acting 2-agonists (n ⫽ 4), and short-acting 2-agonists (n ⫽ 14). The daily dose of inhaled corticosteroids was 1,145 (280) g and of intranasal corticosteroids was 657 (53) g; these values remained unchanged throughout the study. Prechallenge values were not significantly different at visit 1 vs visit 2 for PNIF (128 [13] vs 127 [9] L/min) and MCA (6.89 [0.51] vs 6.94 [0.57] cm2). The maximum percent PNIF change from baseline for visit 1 and visit 2 was ⫺42% (5%) and ⫺42% (6%), respectively, and the average percent PNIF change from baseline was ⫺25% (4%) and ⫺25% (6%), respectively. The coefficients of variation for the maximum and average PNIF responses were 2.3% and 6.5%, respectively. The maximum percent MCA change from baseline for visit 1 and visit 2 was ⫺49% (4%) and ⫺48% (3%), respectively, and the average percent MCA change from baseline was ⫺25% (8%) and ⫺24% (4%), respectively. The coefficients of variation for the maximum and average MCA responses were 7.4% and 16.1%, respectively. Individual data for the maximum response for PNIF and MCA at both visits are shown in Figure 1, with Altman Bland plots shown in Figure 2 and time-response profiles shown in Figure 3. DISCUSSION Our results show that measurement with PNIF following nasal lysine-aspirin challenge is an alternative to MCA determined by acoustic rhinometry, with maximum response being a simpler and more reproducible outcome measure than average response. PNIF is used to evaluate the response to nasal challenge testing4 and has been shown to be a more sensitive measure-
186
Figure 1. Individual data for the maximum percentage of peak nasal inspiratory flow (% PNIF) change from baseline (A) and the maximum percentage of minimum cross-sectional area (% MCA) change from baseline (B) at visit 1 and visit 2.
ment than acoustic rhinometry when used to detect the response to nasal histamine challenge.5 In addition, measurement of PNIF without nasal challenge has also been found to have a low degree of intraindividual variability (8%) for repeated measurements in patients with allergic rhinitis.6 PNIF has also been shown to correlate well with patient symptoms.7,8 Furthermore, the comparable sensitivities of PNIF and acoustic rhinometry and the good correlation with nasal symptoms have been further demonstrated in a nasal allergen challenge study in patients with allergic rhinitis.9 Acoustic rhinometry is a procedure that requires expert training in the use of the machine and the correct technique in recording measurements. It is performed at tidal breathing, whereas PNIF is performed under the dynamic stress of the maximal inspiratory flow. In addition, acoustic rhinometry is relatively time-consuming and expensive, and it requires a computer and software applications. Although acoustic
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Figure 2. Altman Bland plots for the maximum percentage of peak nasal inspiratory flow (% PNIF) change from baseline (A) and the maximum percent minimum cross-sectional area (% MCA) change from baseline (B). Solid line indicates the point of no difference between visit 1 (V1) and visit 2 (V2); and dotted lines, the 95% confidence interval.
rhinometry is commonly used to measure nasal airway patency,10 there are technical difficulties,11,12 such as the presence of artifacts arising from positioning of the probe and acoustic leakage at the nostril.13 On the other hand, PNIF is not only much cheaper but also simpler to use and portable. However, PNIF is an effort-dependent test and requires patient education and reinforcement to achieve reproducible results. Nonetheless, PNIF offers greater simplicity and practicality in terms of day-to-day clinical practice.
VOLUME 93, AUGUST, 2004
Figure 3. Time-response profiles of percentage of peak nasal inspiratory flow (% PNIF) change from baseline after nasal lysine-aspirin challenge and average % PNIF change from baseline (AV) (A) and percentage of minimum cross-sectional area (% MCA) change from baseline after nasal lysine-aspirin challenge and average % MCA change from baseline (AV) (B). Error bars represent SEM.
Examination of the Altman Bland plots in Figure 2 demonstrates close agreement between performing the 2 measurements of PNIF and MCA on separate days. Nevertheless, inspection of the individual data in Figure 1 and the timeresponse profiles in Figure 3, along with the coefficients of variation for both measurements, reveals that PNIF conferred less variability than MCA, and analysis of the response following nasal lysine-aspirin challenge shows that maximum response is a more consistent indicator than average response. In conclusion, the use of PNIF for measuring the response following nasal lysine-aspirin challenge in patients with AIA
187
offers greater reproducibility compared with the measurement of MCA by acoustic rhinometry. In addition, maximum response is a better outcome measure than average response for PNIF and MCA.
8.
REFERENCES
9.
1. Szczeklik A. Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol. 2003;111:913–921. 2. Milewski M, Mastalerz L, Nizankowska E, Szczeklik A. Nasal provocation test with lysine-aspirin for diagnosis of aspirinsensitive asthma. J Allergy Clin Immunol. 1998;101:581–586. 3. Casadevall J, Ventura PJ, Mullol J, Picado C. Intranasal challenge with aspirin in the diagnosis of aspirin intolerant asthma: evaluation of nasal response by acoustic rhinometry. Thorax. 2000;55:921–924. 4. Plavec D, Somogyi-Zalud E, Godnic-Cvar J. Modified method of nonspecific nasal provocation with histamine for routine use. Ann Allergy. 1994;72:321–328. 5. Wilson AM, Sims EJ, Robb F, Cockburn W, Lipworth BJ. Peak inspiratory flow rate is more sensitive than acoustic rhinometry or rhinomanometry in detecting corticosteroid response with nasal histamine challenge. Rhinology. 2003;41:16 –20. 6. Sims EJ, Wilson AM, White PS, Gardiner Q, Lipworth BJ. Short-term repeatability and correlates of laboratory measures of nasal function in patients with seasonal allergic rhinitis. Rhinology. 2002;40:66 – 68. 7. Fairley JW, Durham LH, Ell SR. Correlation of subjective
10. 11. 12.
13.
sensation of nasal patency with nasal inspiratory peak flow rate. Clin Otolaryngol. 1993;18:19 –22. Wilson A, Dempsey OJ, Sims EJ, Coutie WJ, Paterson MC, Lipworth BJ. Evaluation of treatment response in patients with seasonal allergic rhinitis using domiciliary nasal peak inspiratory flow. Clin Exp Allergy. 2000;30:833– 838. Ganslmayer M, Spertini F, Rahm F, Terrien MH, Mosimann B, Leimgruber A. Evaluation of acoustic rhinometry in a nasal provocation test with allergen. Allergy. 1999;54:974 –979. Fisher EW. Acoustic rhinometry. Clin Otolaryngol. 1997;22: 307–317. Dastidar P, Numminen J, Heinonen T, et al. Nasal airway volumetric measurement using segmented HRCT images and acoustic rhinometry. Am J Rhinol. 1999;13:97–103. Corey JP, Gungor A, Nelson R, Fredberg J, Lai V. A comparison of the nasal cross-sectional areas and volumes obtained with acoustic rhinometry and magnetic resonance imaging. Otolaryngol Head Neck Surg. 1997;117:349 –354. Hamilton JW, McRae RD, Jones AS. The magnitude of random errors in acoustic rhinometry and re-interpretation of the acoustic profile. Clin Otolaryngol. 1997;22:408 – 413.
Requests for reprints should be addressed to: Brian J. Lipworth, MD Asthma & Allergy Research Group Ninewells Hospital & Medical School University of Dundee Dundee DD1 9SY, Scotland E-mail:
[email protected]
.
188
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY