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Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure
Asthma diagnosis and treatment
Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure Signe Vahlkvist, MD, Marianne Sinding, Kirsten Skamstrup, MD, and Hans Bisgaard, MD, DMSci Copenhagen, Denmark
Background: Fractional exhaled nitric oxide (FENO) is a sensitive marker of eosinophilic airway inflammation in asthma. Available methods have restricted measurements to the clinic, giving only a snapshot of the disease, which by nature is highly variable. Objectives: We sought to investigate the feasibility, repeatability, accuracy, sensitivity, and biologic plausibility of new handheld equipment for FENO measurements. We studied day-to-day home measurements of FENO during the birch pollen season in children with allergy to birch pollen and a history of mild asthma and rhinoconjunctivitis during this season, as well as in nonatopic children. Methods: Eleven children with mild asthma and allergy to birch pollen, performed daily home measurements of FENO for 6 weeks before and during the birch pollen season by using a handheld FENO monitor (NIOX MINO). Additionally, FENO (chemiluminescence equipment [NIOX]) and spirometry were measured at the inclusion and completion visit in the clinic. Peak expiratory flow rate (PEFR) and symptoms were recorded daily. Results: Daily FENO (NIOX MINO) increased significantly (P < .001) with increasing pollen count. FENO (NIOX MINO) and FENO (NIOX) exhibited a correlation coefficient of 0.98, but FENO (NIOX MINO) was significantly higher than FENO (NIOX) (P < .01). PEFR and FEV1 remained unchanged, and few symptoms were recorded. Conclusion: Exhaled nitric oxide levels increased significantly during the pollen season, even though the patients reported only few asthmatic symptoms and no change in PEFR or spirometry. Daily measurements of FENO (NIOX MINO) might allow early detection of disease deterioration, and future studies could address such a measure for dynamic treatment strategies. Clinical implications: This simple handheld device expands the potential use of FENO to a wider group of asthma clinics and
From the Danish Pediatric Asthma Centre, Copenhagen University Hospital. Aerocrine AB provided the NIOX and NIOX MINO for the study. Disclosure of potential conflict of interest: H. Bisgaard has received honoraria for lectures and advisory boards from Aerocrine, Altana, AstraZeneca, GlaxoSmithKline, and Merck and has received grant support from Aerocrine, Merck, GlaxoSmithKline, and AstraZeneca. K. Skamstrup has received grant support from Schering-Plough, Pharmacia, and Mead Johnson; has given lectures and courses for ALK-Abello´, ScheringPlough, and Mead Johnson; and has received travel grants from AstraZeneca and Mead Johnson. The rest of the authors have declared that they have no conflict of interest. Received for publication October 9, 2005; revised March 6, 2006; accepted for publication March 13, 2006. Reprints will not be available from the authors. 0091-6749/$32.00 Ó 2006 American Academy of Allergy, Asthma and Immunology doi:10.1016/j.jaci.2006.03.018
1272
even home measurements. (J Allergy Clin Immunol 2006;117:1272-6.) Key words: Asthma, child, fractional exhaled nitric oxide, home monitoring, handheld, pollen
Fractional exhaled nitric oxide (FENO) is a well-established measure of the eosinophilic inflammation in asthma with or without simultaneous symptoms.1 It is very sensitive to disease activity2,3 and has been suggested for titrating treatment with inhaled corticosteroids (ICSs).4,5 Methods for measurements of FENO are well standardized,6 with reference values available for schoolchildren7 and commercially available equipment approved for clinical use in the United States and Europe. However, the available equipment is comparatively expensive and bulky and demands a certain technical expertise that largely restricts its use to specialist clinics. Furthermore, such snapshots of the disease at clinic visits limit the usefulness of any objective measures because the underlying inflammatory process is highly variable. This issue is in analogy with lung function measurements, in which longitudinal home measurements are recommended by guidelines.8 Home measurements of FENO would have the advantage of tracking daily changes in the disease, which might offer a more sensitive monitoring of the disease and could be of particular use for future strategies of the proposed use of FENO for dose titration of steroid treatment. We have studied the feasibility, repeatability, sensitivity, and accuracy, as well as the biologic plausibility, of daily home measurements of FENO by using a new method provided as a small, handheld, and simple to use piece of equipment allowing children to measure FENO at home. FENO was previously shown to increase in children with pollen allergy, asthma, and allergic rhinitis during their pollen season by using clinic-based measurements.9,10 We used the brief natural birch pollen exposure as an experiment by nature to illustrate the sensitivity of FENO home measurements to relevant day-to-day variability of disease activity.
METHODS The study was approved by the Copenhagen Ethics Committee (KA05012). The clinical study was of an observational nature during the 6 weeks around the birch pollen peak season. The study invited children 5 to 15 years of age with allergy to birch pollen and a history
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of seasonal asthma symptoms during the birch pollen season. The asthma diagnosis was based on the clinical history and lung function response to inhaled b2-agonists. Allergy was verified on the basis of a positive skin prick test response to birch (positive, 3 mm; ALK, Horsholm, Denmark). The enrollment visit was scheduled for the beginning of April (spring) before the expected birch pollen season, and a final visit at the clinic was scheduled 6 weeks later by the end of the pollen season. Daily peak expiratory flow rate (PEFR) was measured by using Astech peak flowmeters (Center Laboratories, Port Washington, NY), recording the best of 3 attempts in the evening after FENO measurements. Global asthma and rhinitis symptoms were recorded daily by using a score of 0 to 3, as well as use of b2-agonists. Spirometry was performed as per American Thoracic Society (ATS) standards11 by using a Jae¨ger MasterScreen (E Jaeger GmbH, Wu¨rzburg, Germany), with the children in a sitting position wearing a nose clip. Spirometry was performed after measurement of FENO. Pollen counts were performed by The Danish Meteorological Institute (www.dmi.dk) using a Burkard pollen trap located in the vicinity of the clinic’s uptake area, and data are presented as the daily average concentration of pollen grains per cubic meter of air. In addition, long-term day-to-day repeatability was studied in 3 healthy children 6 years of age by measuring FENO daily for 3 weeks.
FENO NIOX FENO was measured at the inclusion and completion visits at the clinic by using the online single-breath method with NIOX (NIOX MINO Airway Inflammation Monitor; Aerocrine AB, Solna, Sweden) chemiluminescence equipment in accordance with the ATS guidelines,6 as previously detailed7 and summarized at our Web site (www.copsac.com). Exhalation duration was 6 seconds for all children. The accuracy range of NIOX is 62.5 ppb for measured values of less than 50 ppb and 65% for measured values of 50 ppb or greater. Calibration was done every 14th day, the calibration gas and nitric oxide filter were changed every sixth month, exhalation flow was 45 to 55 mL/s, and exhalation pressure was 10 to 20 cm H2O.
FENO NIOX MINO FENO was measured every day at home during the observation period with a handheld FENO device (NIOX MINO, Aerocrine AB Fig 1).12 The initial 85-mL air sample is discharged, allowing for the relevant dead-space separation (approximately 2 mL/kg). It is based on a specially designed electrochemical sensor. The lowest detection limit is 5 ppb. The slow dynamic response of an electrochemical sensor is compensated by storing the last portion of the exhalation sample. The sample is transferred to the sensor through a pump-and-valve arrangement at the desired flow. The time for such analysis is 50 seconds, after which a zero sample is analyzed (ie, a total time of <2 minutes for a complete test). NIOX MINO is CE marked according to Medical Device Directive MDD 93/42/EEC and approved for clinical use in European Union countries. Further information is available at www.aerocrine.com. The instruction to the child entailed exhalation and then inhalation to total lung capacity through the device, which provides nitric oxide–
Asthma diagnosis and treatment
Abbreviations used ATS: American Thoracic Society FENO: Fractional exhaled nitric oxide ICS: Inhaled corticosteroid PEFR: Peak expiratory flow rate
FIG 1. FENO NIOX MINO: a handheld device for measurement of FENO. Measurement: height, 240 mm; width, 130 mm; depth, 100 mm; weight with sensor, 0.8 kg. The device is CE marked according to Medical Device Directive 93/42/EEC.
scrubbed air. Scrubbed air is also used for the zero reference comparison performed in the study instrument during every measurement cycle. Subsequent exhalation at a steady rate for 6 seconds at a flow of 50 6 5 mL/s was aided by a built-in flow control unit of the device, consisting of a mechanical pressure-flow regulator establishing a constant flow when applying an exhalation pressure of 10 to 20 cm H2O. Targeting of this exhalation flow/pressure was guided by an interactive feedback with light and sound signals. This biofeedback encouraged the child to exhale at the predetermined flow rate. The analyzer only accepted test samples if pressure stayed within 10 to 20 cm H2O (resulting in a flow rate of 45-55 mL/s) during at least 3 of 6 seconds, which is in accordance with the ATS guidelines.6 The accuracy range of NIOX MINO is 65 ppb for measured values of less than 50 ppb and 610% for FENO of 50 ppb or greater. Duplicate measurements were requested in the evening before PEFR measurement and without intake of food or medicine in the previous hour. Data were stored electronically in the device for the whole study period and printed at the clinic at the last visit. The average of 2 measurements was used for statistical analysis.
Statistical methods FENO values were analyzed after logarithmic transformation. The tracking of FENO with pollen count was analyzed by using a repeatedmeasures analysis, in which we tested for a linear trend over time for FENO (ie, the within-subject effect over time for the efficacy variables is tested). The time-series relationship was analyzed by using the Pearson correlation coefficient. The coefficient of variation was estimated from the SD of differences of repeated measurements divided by the overall mean. The t test was used for group comparisons. A P value of less than .05 was chosen as the significance level. BlandAltman plot was used for visual inspection of comparative FENO measures with NIOX MINO and NIOX.
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TABLE I. Baseline at study entrance Patient no.
Asthma diagnosis and treatment
Age (y)
Sex
Height (cm)
Weight (kg)
Medication
Allergy
FEV1 % predicted
FENO (ppb)
1 2 3 4
11 9 5 5
F F M M
139 125 114 117
30 23 23 22
terb, bud200 terb, bud200 — antihist
97 109 — 115
66 10 — —
5
6
M
111
19
terb, antihist, mont
84
—
6 7 8 9 10
8 12 10 13 11
M M M M M
131 148 144 155 140
32 36 45 44 36
terb — — — terb
88 88 117 123 95
9 19 10 8 77
7 9
F —
119 131
26 30
mont —
Birch Birch, grass Birch Birch, grass, dog, cat, dust mites Birch, grass, dog, mugworth, mold Birch, grass Birch, grass Birch Birch, grass, dog Birch, grass, dog cat, horse, mold Birch, grass —
90 96
3 10
11 Median
M, Male; F, female; terb, terbutaline dry powder inhaler as needed; bud200, budesonide dry powder inhaler, 200 mg once daily; antihist, ceterizin, 10 mg once daily as needed; mont, montelukast, 5 mg once daily.
RESULTS Fourteen children (9 boys) with seasonal allergic asthma were invited to participate in the study. Three children declined participation, and therefore 11 children were included. Baseline data are presented in Table I. All children were allergic to birch pollen and had a history of seasonal asthma symptoms during the birch pollen season. Median FEV1 was 96% of predicted value at the day of inclusion. All children used b2-agonists as needed. Two children used ICSs, and 2 other children used montelukast during the study period. Two children started ICSs (budesonide, 200-400 mg/d) 3 weeks after the study start; these were initiated by parents because of reported severe asthmatic symptoms. All children completed the study. One 5-year-old boy was unable to complete the NIOX MINO measurements. Birch pollen peaked in the first week of May (Fig 2). The birch pollen count was low (mean 6 SD, 76 6 116 U/m3) compared with that seen in the previous year (mean 6 SD, 205 6 266 U/m3). The outcome measures FENO, PEFR, and symptoms are shown together with the pollen count in Fig 2. FENO (NIOX MINO) changed significantly with time (P < .001). FENO (NIOX) also increased from enrollment (10 ppb) to study completion (34 ppb, P < .01). Correlation (Pearson) between pollen count and FENO was as follows: FENO on the same day, 0.124 (P 5 .26); FENO 1 day after, 0.169 (P 5 .12); and FENO 2 days after, 0.035 (P 5 .75). PEFR and FEV1 showed no significant change during the observation period. Symptoms were absent or low until the week after the pollen peak and increased to mild symptoms the following week. Rhinoconjunctivitis symptoms followed a similar pattern. Agreement between FENO measured by using NIOX and NIOX MINO was studied at the inclusion and completion visits (ie, 22 pairs, of which 15 provided complete
data sets). The measurements exhibited a high correlation (r 5 0.977) independent of level (Bland-Altman plot), but FENO (NIOX MINO) was significantly higher than FENO (NIOX; 30 ppb vs 26 ppb, P 5 .004). Coefficient of variation within repeats of FENO (NIOX MINO) measurements was 11% (SD/mean 5 2.9/26.3) based on the home measurements (n 5 417). A further 3 children, all 6 years of age and without atopic symptoms and reactions on standard skin tests for inhalant and food allergens, completed 21 days of daily measurements. Mean FENO was 5.17 (SD, 1.36; ie, day-to-day variation in healthy nonatopic children was 26%).
DISCUSSION The study showed feasible, repeatable, sensitive, and biologically plausible daily home measurements of FENO in asthmatic children with a new handheld device, although the accuracy seems biased when compared with that of traditional FENO measurements. The feasibility of such measurements at home was good in this group of schoolchildren. One boy of 5 years was unable to complete the FENO measurements, whereas the remaining children of 5 to 13 years (median, 9 years) reported no technical difficulties. The repeatability (coefficient of variation) was 11% within repeat measurements and 26% between day-to-day measurements. The level of birch pollen was low this year compared with that of previous years. Still, the sensitivity of the measurements was good, exceeding that of symptom reporting and lung function (PEFR and FEV1). The biologic plausibility of FENO home measurements with the NIOX MINO was demonstrated by FENO tracking the increasing natural birch pollen exposure in children
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FIG 2. Daily home measurement of FENO and PEFR compared with natural pollen counts during the birch pollen season. Shaded area, Pollen count.
with mild asthma and allergy to birch pollen. Interestingly, FENO increased in parallel with the pollen count but with a prolonged increase in the week after the pollen peak, suggesting an inflammatory process initiated by but not limited to the acute pollen exposure. Lag time was suggested from the better correlation between pollen count and FENO measured with a lag time of 1 day (rather than the same day or after 2 days). The increase in FENO was seen despite the fact that 2 children needed to start ICS treatment during the trial, 2 children were using ICSs, and 2 were using montelukast maintenance treatment. No changes were observed in PEFR or FEV1. Only mild symptoms developed after the pollen peak and during the FENO peak. This suggests FENO is a sensitive measure of asthma disease activity, more sensitive than lung function and symptom recording in children. These day-by-day findings extend previous reports of FENO measured at single time points at the clinic visits months apart during the pollen season, showing an increase in FENO during the pollen peak without a detectable change in lung function in asthmatic children.9,10 The accuracy of the NIOX MINO was biased when compared with that of the NIOX because measurements differed significantly. Still, the difference was within the accuracy range (NIOX MINO, 65 ppb; NIOX, 62.5 ppb). A negative deviation from ‘‘the true value’’ for one instrument and a positive deviation from ‘‘the true value’’ for the other instrument can result in a difference on 7.5 ppb based solely on instrumental variation. The observed difference between the devices is within this statistical spread. Currently, the NIOX MINO is precalibrated, but unlike the NIOX, it cannot be calibrated regularly. It would be desirable for future development of the NIOX MINO to
include techniques for calibration to absolute levels of FENO. However, for within evaluation, as in the current study, such calibration is less pertinent because the patient is his or her own reference (in analogy with PEFR measurements). The perspectives of FENO daily home measurements are encouraging. It can be used for more sensitive diagnoses of asthma in case of uncertain symptoms. It has been suggested to use FENO clinic measurements to guide steroid dosing.4,5 Home measurements of FENO might take such a strategy to the next level, actually titrating the steroid dose continuously at home. Of interest is also the recent proposal for symptom-driven steroid dosing,13 which might be tied in with FENO measurements to ensure the optimal disease control of such a strategy. Intermittent asthma is currently not recommended for steroid treatment. Daily home measurements of FENO might document the inflammatory process of such milder disease and reappraise the strategy for such subjects with milder asthma.14 In conclusion, we have demonstrated that daily home measurements of FENO are feasible and repeatable in school-aged children. It seems more sensitive to increased inflammatory disease activity, as seen during natural pollen exposure, than lung function and symptom recording. This promises a new simple tool to monitor the underlying inflammation in asthmatic children. REFERENCES 1. van Den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001;164:2107-13. 2. Smith AD, Cowan JO, Filsell S, McLachlan C, Monti-Sheehan G, Jackson P, et al. Diagnosing asthma: comparisons between exhaled nitric
1276 Vahlkvist et al
3.
Asthma diagnosis and treatment
4.
5.
6.
7.
oxide measurements and conventional tests. Am J Respir Crit Care Med 2004;169:473-8. Jones SL, Kittelson J, Cowan JO, Flannery EM, Hancox RJ, McLachlan CR, et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001; 164:738-43. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005;352:2163-73. Smith AD, Cowan JO, Brassett KP, Filsell S, McLachlan C, Monti-Sheehan G, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med 2005;172:453-9. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005;171: 912-30. Buchvald F, Baraldi E, Carraro S, Gaston B, de Jongste J, Pijnenburg MW, et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. J Allergy Clin Immunol 2005;115:1130-6.
J ALLERGY CLIN IMMUNOL JUNE 2006
8. Global Initiative for Asthma. Global strategy for asthma management and prevention. Bethesda (MD): National Institutes of Health National Heart, Lung, and Blood Institute; 2003. Publication no. 02-3659. 9. Baraldi E, Carra S, Dario C, Azzolin N, Ongaro R, Marcer G, et al. Effect of natural grass pollen exposure on exhaled nitric oxide in asthmatic children. Am J Respir Crit Care Med 1999;159:262-6. 10. Roberts G, Hurley C, Bush A, Lack G. Longitudinal study of grass pollen exposure, symptoms, and exhaled nitric oxide in childhood seasonal allergic asthma. Thorax 2004;59:752-6. 11. American Thoracic Society. Standardization of spirometry 1994 update. Am J Respir Crit Care Med 1995;152:1107-36. 12. Hemmingsson T, Linnarsson D, Gambert R. Novel hand-held device for exhaled nitric oxide-analysis in research and clinical applications. J Clin Monit Comput 2004;18:379-87. 13. O’Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005;171:129-36. 14. Bisgaard H, Szefler SJ. Understanding mild persistent asthma in children: the next frontier. J Allergy Clin Immunol 2005;115:708-13.
Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure Signe Vahlkvist, MD, Marianne Sinding, Kirsten Skamstrup, MD, and Hans Bisgaard, MD, DMSci Copenhagen, Denmark
Background: Fractional exhaled nitric oxide (FENO) is a sensitive marker of eosinophilic airway inflammation in asthma. Available methods have restricted measurements to the clinic, giving only a snapshot of the disease, which by nature is highly variable. Objectives: We sought to investigate the feasibility, repeatability, accuracy, sensitivity, and biologic plausibility of new handheld equipment for FENO measurements. We studied day-to-day home measurements of FENO during the birch pollen season in children with allergy to birch pollen and a history of mild asthma and rhinoconjunctivitis during this season, as well as in nonatopic children. Methods: Eleven children with mild asthma and allergy to birch pollen, performed daily home measurements of FENO for 6 weeks before and during the birch pollen season by using a handheld FENO monitor (NIOX MINO). Additionally, FENO (chemiluminescence equipment [NIOX]) and spirometry were measured at the inclusion and completion visit in the clinic. Peak expiratory flow rate (PEFR) and symptoms were recorded daily. Results: Daily FENO (NIOX MINO) increased significantly (P < .001) with increasing pollen count. FENO (NIOX MINO) and FENO (NIOX) exhibited a correlation coefficient of 0.98, but FENO (NIOX MINO) was significantly higher than FENO (NIOX) (P < .01). PEFR and FEV1 remained unchanged, and few symptoms were recorded. Conclusion: Exhaled nitric oxide levels increased significantly during the pollen season, even though the patients reported only few asthmatic symptoms and no change in PEFR or spirometry. Daily measurements of FENO (NIOX MINO) might allow early detection of disease deterioration, and future studies could address such a measure for dynamic treatment strategies. Clinical implications: This simple handheld device expands the potential use of FENO to a wider group of asthma clinics and
From the Danish Pediatric Asthma Centre, Copenhagen University Hospital. Aerocrine AB provided the NIOX and NIOX MINO for the study. Disclosure of potential conflict of interest: H. Bisgaard has received honoraria for lectures and advisory boards from Aerocrine, Altana, AstraZeneca, GlaxoSmithKline, and Merck and has received grant support from Aerocrine, Merck, GlaxoSmithKline, and AstraZeneca. K. Skamstrup has received grant support from Schering-Plough, Pharmacia, and Mead Johnson; has given lectures and courses for ALK-Abello´, ScheringPlough, and Mead Johnson; and has received travel grants from AstraZeneca and Mead Johnson. The rest of the authors have declared that they have no conflict of interest. Received for publication October 9, 2005; revised March 6, 2006; accepted for publication March 13, 2006. Reprints will not be available from the authors. 0091-6749/$32.00 Ó 2006 American Academy of Allergy, Asthma and Immunology doi:10.1016/j.jaci.2006.03.018
1272
even home measurements. (J Allergy Clin Immunol 2006;117:1272-6.) Key words: Asthma, child, fractional exhaled nitric oxide, home monitoring, handheld, pollen
Fractional exhaled nitric oxide (FENO) is a well-established measure of the eosinophilic inflammation in asthma with or without simultaneous symptoms.1 It is very sensitive to disease activity2,3 and has been suggested for titrating treatment with inhaled corticosteroids (ICSs).4,5 Methods for measurements of FENO are well standardized,6 with reference values available for schoolchildren7 and commercially available equipment approved for clinical use in the United States and Europe. However, the available equipment is comparatively expensive and bulky and demands a certain technical expertise that largely restricts its use to specialist clinics. Furthermore, such snapshots of the disease at clinic visits limit the usefulness of any objective measures because the underlying inflammatory process is highly variable. This issue is in analogy with lung function measurements, in which longitudinal home measurements are recommended by guidelines.8 Home measurements of FENO would have the advantage of tracking daily changes in the disease, which might offer a more sensitive monitoring of the disease and could be of particular use for future strategies of the proposed use of FENO for dose titration of steroid treatment. We have studied the feasibility, repeatability, sensitivity, and accuracy, as well as the biologic plausibility, of daily home measurements of FENO by using a new method provided as a small, handheld, and simple to use piece of equipment allowing children to measure FENO at home. FENO was previously shown to increase in children with pollen allergy, asthma, and allergic rhinitis during their pollen season by using clinic-based measurements.9,10 We used the brief natural birch pollen exposure as an experiment by nature to illustrate the sensitivity of FENO home measurements to relevant day-to-day variability of disease activity.
METHODS The study was approved by the Copenhagen Ethics Committee (KA05012). The clinical study was of an observational nature during the 6 weeks around the birch pollen peak season. The study invited children 5 to 15 years of age with allergy to birch pollen and a history
Vahlkvist et al 1273
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 6
of seasonal asthma symptoms during the birch pollen season. The asthma diagnosis was based on the clinical history and lung function response to inhaled b2-agonists. Allergy was verified on the basis of a positive skin prick test response to birch (positive, 3 mm; ALK, Horsholm, Denmark). The enrollment visit was scheduled for the beginning of April (spring) before the expected birch pollen season, and a final visit at the clinic was scheduled 6 weeks later by the end of the pollen season. Daily peak expiratory flow rate (PEFR) was measured by using Astech peak flowmeters (Center Laboratories, Port Washington, NY), recording the best of 3 attempts in the evening after FENO measurements. Global asthma and rhinitis symptoms were recorded daily by using a score of 0 to 3, as well as use of b2-agonists. Spirometry was performed as per American Thoracic Society (ATS) standards11 by using a Jae¨ger MasterScreen (E Jaeger GmbH, Wu¨rzburg, Germany), with the children in a sitting position wearing a nose clip. Spirometry was performed after measurement of FENO. Pollen counts were performed by The Danish Meteorological Institute (www.dmi.dk) using a Burkard pollen trap located in the vicinity of the clinic’s uptake area, and data are presented as the daily average concentration of pollen grains per cubic meter of air. In addition, long-term day-to-day repeatability was studied in 3 healthy children 6 years of age by measuring FENO daily for 3 weeks.
FENO NIOX FENO was measured at the inclusion and completion visits at the clinic by using the online single-breath method with NIOX (NIOX MINO Airway Inflammation Monitor; Aerocrine AB, Solna, Sweden) chemiluminescence equipment in accordance with the ATS guidelines,6 as previously detailed7 and summarized at our Web site (www.copsac.com). Exhalation duration was 6 seconds for all children. The accuracy range of NIOX is 62.5 ppb for measured values of less than 50 ppb and 65% for measured values of 50 ppb or greater. Calibration was done every 14th day, the calibration gas and nitric oxide filter were changed every sixth month, exhalation flow was 45 to 55 mL/s, and exhalation pressure was 10 to 20 cm H2O.
FENO NIOX MINO FENO was measured every day at home during the observation period with a handheld FENO device (NIOX MINO, Aerocrine AB Fig 1).12 The initial 85-mL air sample is discharged, allowing for the relevant dead-space separation (approximately 2 mL/kg). It is based on a specially designed electrochemical sensor. The lowest detection limit is 5 ppb. The slow dynamic response of an electrochemical sensor is compensated by storing the last portion of the exhalation sample. The sample is transferred to the sensor through a pump-and-valve arrangement at the desired flow. The time for such analysis is 50 seconds, after which a zero sample is analyzed (ie, a total time of <2 minutes for a complete test). NIOX MINO is CE marked according to Medical Device Directive MDD 93/42/EEC and approved for clinical use in European Union countries. Further information is available at www.aerocrine.com. The instruction to the child entailed exhalation and then inhalation to total lung capacity through the device, which provides nitric oxide–
Asthma diagnosis and treatment
Abbreviations used ATS: American Thoracic Society FENO: Fractional exhaled nitric oxide ICS: Inhaled corticosteroid PEFR: Peak expiratory flow rate
FIG 1. FENO NIOX MINO: a handheld device for measurement of FENO. Measurement: height, 240 mm; width, 130 mm; depth, 100 mm; weight with sensor, 0.8 kg. The device is CE marked according to Medical Device Directive 93/42/EEC.
scrubbed air. Scrubbed air is also used for the zero reference comparison performed in the study instrument during every measurement cycle. Subsequent exhalation at a steady rate for 6 seconds at a flow of 50 6 5 mL/s was aided by a built-in flow control unit of the device, consisting of a mechanical pressure-flow regulator establishing a constant flow when applying an exhalation pressure of 10 to 20 cm H2O. Targeting of this exhalation flow/pressure was guided by an interactive feedback with light and sound signals. This biofeedback encouraged the child to exhale at the predetermined flow rate. The analyzer only accepted test samples if pressure stayed within 10 to 20 cm H2O (resulting in a flow rate of 45-55 mL/s) during at least 3 of 6 seconds, which is in accordance with the ATS guidelines.6 The accuracy range of NIOX MINO is 65 ppb for measured values of less than 50 ppb and 610% for FENO of 50 ppb or greater. Duplicate measurements were requested in the evening before PEFR measurement and without intake of food or medicine in the previous hour. Data were stored electronically in the device for the whole study period and printed at the clinic at the last visit. The average of 2 measurements was used for statistical analysis.
Statistical methods FENO values were analyzed after logarithmic transformation. The tracking of FENO with pollen count was analyzed by using a repeatedmeasures analysis, in which we tested for a linear trend over time for FENO (ie, the within-subject effect over time for the efficacy variables is tested). The time-series relationship was analyzed by using the Pearson correlation coefficient. The coefficient of variation was estimated from the SD of differences of repeated measurements divided by the overall mean. The t test was used for group comparisons. A P value of less than .05 was chosen as the significance level. BlandAltman plot was used for visual inspection of comparative FENO measures with NIOX MINO and NIOX.
1274 Vahlkvist et al
J ALLERGY CLIN IMMUNOL JUNE 2006
TABLE I. Baseline at study entrance Patient no.
Asthma diagnosis and treatment
Age (y)
Sex
Height (cm)
Weight (kg)
Medication
Allergy
FEV1 % predicted
FENO (ppb)
1 2 3 4
11 9 5 5
F F M M
139 125 114 117
30 23 23 22
terb, bud200 terb, bud200 — antihist
97 109 — 115
66 10 — —
5
6
M
111
19
terb, antihist, mont
84
—
6 7 8 9 10
8 12 10 13 11
M M M M M
131 148 144 155 140
32 36 45 44 36
terb — — — terb
88 88 117 123 95
9 19 10 8 77
7 9
F —
119 131
26 30
mont —
Birch Birch, grass Birch Birch, grass, dog, cat, dust mites Birch, grass, dog, mugworth, mold Birch, grass Birch, grass Birch Birch, grass, dog Birch, grass, dog cat, horse, mold Birch, grass —
90 96
3 10
11 Median
M, Male; F, female; terb, terbutaline dry powder inhaler as needed; bud200, budesonide dry powder inhaler, 200 mg once daily; antihist, ceterizin, 10 mg once daily as needed; mont, montelukast, 5 mg once daily.
RESULTS Fourteen children (9 boys) with seasonal allergic asthma were invited to participate in the study. Three children declined participation, and therefore 11 children were included. Baseline data are presented in Table I. All children were allergic to birch pollen and had a history of seasonal asthma symptoms during the birch pollen season. Median FEV1 was 96% of predicted value at the day of inclusion. All children used b2-agonists as needed. Two children used ICSs, and 2 other children used montelukast during the study period. Two children started ICSs (budesonide, 200-400 mg/d) 3 weeks after the study start; these were initiated by parents because of reported severe asthmatic symptoms. All children completed the study. One 5-year-old boy was unable to complete the NIOX MINO measurements. Birch pollen peaked in the first week of May (Fig 2). The birch pollen count was low (mean 6 SD, 76 6 116 U/m3) compared with that seen in the previous year (mean 6 SD, 205 6 266 U/m3). The outcome measures FENO, PEFR, and symptoms are shown together with the pollen count in Fig 2. FENO (NIOX MINO) changed significantly with time (P < .001). FENO (NIOX) also increased from enrollment (10 ppb) to study completion (34 ppb, P < .01). Correlation (Pearson) between pollen count and FENO was as follows: FENO on the same day, 0.124 (P 5 .26); FENO 1 day after, 0.169 (P 5 .12); and FENO 2 days after, 0.035 (P 5 .75). PEFR and FEV1 showed no significant change during the observation period. Symptoms were absent or low until the week after the pollen peak and increased to mild symptoms the following week. Rhinoconjunctivitis symptoms followed a similar pattern. Agreement between FENO measured by using NIOX and NIOX MINO was studied at the inclusion and completion visits (ie, 22 pairs, of which 15 provided complete
data sets). The measurements exhibited a high correlation (r 5 0.977) independent of level (Bland-Altman plot), but FENO (NIOX MINO) was significantly higher than FENO (NIOX; 30 ppb vs 26 ppb, P 5 .004). Coefficient of variation within repeats of FENO (NIOX MINO) measurements was 11% (SD/mean 5 2.9/26.3) based on the home measurements (n 5 417). A further 3 children, all 6 years of age and without atopic symptoms and reactions on standard skin tests for inhalant and food allergens, completed 21 days of daily measurements. Mean FENO was 5.17 (SD, 1.36; ie, day-to-day variation in healthy nonatopic children was 26%).
DISCUSSION The study showed feasible, repeatable, sensitive, and biologically plausible daily home measurements of FENO in asthmatic children with a new handheld device, although the accuracy seems biased when compared with that of traditional FENO measurements. The feasibility of such measurements at home was good in this group of schoolchildren. One boy of 5 years was unable to complete the FENO measurements, whereas the remaining children of 5 to 13 years (median, 9 years) reported no technical difficulties. The repeatability (coefficient of variation) was 11% within repeat measurements and 26% between day-to-day measurements. The level of birch pollen was low this year compared with that of previous years. Still, the sensitivity of the measurements was good, exceeding that of symptom reporting and lung function (PEFR and FEV1). The biologic plausibility of FENO home measurements with the NIOX MINO was demonstrated by FENO tracking the increasing natural birch pollen exposure in children
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FIG 2. Daily home measurement of FENO and PEFR compared with natural pollen counts during the birch pollen season. Shaded area, Pollen count.
with mild asthma and allergy to birch pollen. Interestingly, FENO increased in parallel with the pollen count but with a prolonged increase in the week after the pollen peak, suggesting an inflammatory process initiated by but not limited to the acute pollen exposure. Lag time was suggested from the better correlation between pollen count and FENO measured with a lag time of 1 day (rather than the same day or after 2 days). The increase in FENO was seen despite the fact that 2 children needed to start ICS treatment during the trial, 2 children were using ICSs, and 2 were using montelukast maintenance treatment. No changes were observed in PEFR or FEV1. Only mild symptoms developed after the pollen peak and during the FENO peak. This suggests FENO is a sensitive measure of asthma disease activity, more sensitive than lung function and symptom recording in children. These day-by-day findings extend previous reports of FENO measured at single time points at the clinic visits months apart during the pollen season, showing an increase in FENO during the pollen peak without a detectable change in lung function in asthmatic children.9,10 The accuracy of the NIOX MINO was biased when compared with that of the NIOX because measurements differed significantly. Still, the difference was within the accuracy range (NIOX MINO, 65 ppb; NIOX, 62.5 ppb). A negative deviation from ‘‘the true value’’ for one instrument and a positive deviation from ‘‘the true value’’ for the other instrument can result in a difference on 7.5 ppb based solely on instrumental variation. The observed difference between the devices is within this statistical spread. Currently, the NIOX MINO is precalibrated, but unlike the NIOX, it cannot be calibrated regularly. It would be desirable for future development of the NIOX MINO to
include techniques for calibration to absolute levels of FENO. However, for within evaluation, as in the current study, such calibration is less pertinent because the patient is his or her own reference (in analogy with PEFR measurements). The perspectives of FENO daily home measurements are encouraging. It can be used for more sensitive diagnoses of asthma in case of uncertain symptoms. It has been suggested to use FENO clinic measurements to guide steroid dosing.4,5 Home measurements of FENO might take such a strategy to the next level, actually titrating the steroid dose continuously at home. Of interest is also the recent proposal for symptom-driven steroid dosing,13 which might be tied in with FENO measurements to ensure the optimal disease control of such a strategy. Intermittent asthma is currently not recommended for steroid treatment. Daily home measurements of FENO might document the inflammatory process of such milder disease and reappraise the strategy for such subjects with milder asthma.14 In conclusion, we have demonstrated that daily home measurements of FENO are feasible and repeatable in school-aged children. It seems more sensitive to increased inflammatory disease activity, as seen during natural pollen exposure, than lung function and symptom recording. This promises a new simple tool to monitor the underlying inflammation in asthmatic children. REFERENCES 1. van Den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001;164:2107-13. 2. Smith AD, Cowan JO, Filsell S, McLachlan C, Monti-Sheehan G, Jackson P, et al. Diagnosing asthma: comparisons between exhaled nitric
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