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(Chest. 2001;119:1001-1010.)
© 2001 American College of Chest Physicians

Comparisons of Peak Diurnal Expiratory Flow Variation, Postbronchodilator FEV1 Responses, and Methacholine Inhalation Challenges in the Evaluation of Suspected Asthma*

Marc F. Goldstein, MD, FCCP; Bernadette A. Veza, MBS; Eliot H. Dunsky, MD; Donald J. Dvorin, MD; George A. Belecanech, MD and Irene C. Haralabatos, MD

* From the Department of Medicine and Pediatrics (Drs. Goldstein, Dunsky, Dvorin, Belecanech, and Haralabatos), Allergy and Immunology Division, and the Interdepartmental Medical Science Program (Ms. Veza); MCP Hahnemann University, Philadelphia, PA.

Correspondence to: Marc F. Goldstein, MD, FCCP, Professional Arts Building, Suite 300, 205 N. Broad St, Philadelphia, PA 19107; e-mail: gpike35{at}aol.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: The validity of peak expiratory flow variation (PEFvar) as defined by National Heart, Lung, and Blood Institute (NHLBI) guidelines as a diagnostic tool for suspected asthma or its comparative value to methacholine inhalation challenge (MIC) or postbronchodilator (BD) FEV1 responses has not been formally assessed. We prospectively analyzed the correlation of 28 different PEFvar indexes (including 4 NHLBI-compatible indexes) with MIC and pre-BD and post-BD FEV1 responses in suspected asthmatic subjects with normal findings on lung examination, chest radiography, and baseline spirometry.

Design: Participants were asked to record peak expiratory flow four times daily for 2 to 3 weeks, followed by an MIC. During a minimum 6-month follow-up period, a clinical diagnosis of asthma was made or ruled out based on testing results and response to antiasthma therapy.

Setting: Medical school-affiliated subspecialty private practice of allergy, asthma, and immunology.

Participants: One hundred twenty-one suspected asthmatic patients with normal findings on lung examination, chest radiography, and baseline spirometry.

Measurements and results: Fifty-seven subjects completed both the peak flow diary and the MIC and were accepted for statistical analysis. There were no statistically significant correlations between any peak expiratory flow index and MIC. Among the three diagnostic tools evaluated, MIC had the highest sensitivity (85.71%). All the PEFvar indexes and post-BD responses had low sensitivity and high false-negative rates.

Conclusions: PEFvar and post-BD FEV1 responses are poor substitutes for MIC in the assessment of patients with suspected asthma with normal findings on lung examination, chest radiography, and spirometry. Our findings warrant a reconsideration of the NHLBI guidelines recommendation of the utility of PEFvar as a diagnostic tool for asthma in clinical practice.

Key Words: diurnal variation • methacholine challenge • peak expiratory flow variation • postbronchodilator FEV1 responses


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
In the absence of a "gold standard" for the diagnosis of asthma, methacholine inhalation challenge (MIC), peak expiratory flow (PEF) variation (PEFvar), and postbronchodilator (BD) FEV1 responses have been used as diagnostic tools to establish a diagnosis of asthma. Methacholine challenge is a highly reliable diagnostic test for airway hyperreactivity, with positive results in nearly all individuals with current symptomatic asthma.1 Because of concerns regarding expense and time requirements of MICs, practical alternative diagnostic tools have been proposed, specifically pre-BD and post-BD FEV1 comparisons,1 2 3 4 5 as well as ambulatory peak flow monitoring to assess for diurnal variation.1 2 3 5 6 7 8 9 10 11 Several studies have shown variable correlation of FEV1 responses to BD treatment6 8 12 13 14 15 and/or peak flow lability with methacholine or histamine inhalation challenge.6 12 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 However, most of these studies were done in patient populations with established airways obstruction. In determining PEFvar, different mathematically derived indexes have been used over the last 4 decades. However, there is no consensus as to which index is best either for epidemiologic or clinical purposes. Nevertheless, several published guidelines7 30 31 for asthma evaluation and management recommend PEFvar as a diagnostic tool in assessing patients with suspected asthma and normal spirometry findings as an alternative to bronchoprovocation challenge. The practicality and diagnostic validity of diurnal PEFvar assessment for the diagnosis of asthma have not been tested in prospective clinical trials. We therefore prospectively evaluated several PEFvar indexes in a population of patients with suspected asthma and normal spiro-metry findings. Correlation analyses of these indexes with MIC and pre-BD and post-BD FEV1 responses were performed. We also assessed the level of compliance in participants asked to perform 2 to 3 weeks of home peak flow monitoring followed by an MIC.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Subject Inclusion and Exclusion Criteria
Participants presented as self-referrals or referrals from primary-care physicians to a medical school-affiliated subspecialty private practice of allergy, asthma, and immunology. The subjects were at least 7 years of age, English speaking, and had recurrent (at least 3 months) asthma-like symptoms, including shortness of breath, coughing, wheezing, and/or chest tightness. Participants had a baseline FEV1 percent-predicted value of >= 80%, mean forced expiratory flow during the middle half of the FVC (FEF25–75%) percent-predicted value of >= 80%, and FVC percent-predicted value of >= 80%. Individuals with a history of heart failure, lung cancer, abnormal spirometry findings, abnormal chest radiography findings, abnormal lung examination findings, and/or evidence of acute respiratory tract infection were excluded from participation. Other than symptomatic cough suppressants and/or medications directed at upper respiratory tract symptoms (ie, antihistamines, decongestants, and nasal steroids), subjects were not receiving any prescriptions or over-the-counter medications or alternative remedies for respiratory symptoms. Participants had conventional wake/sleep patterns.

Pulmonary Function Tests and PEF Monitoring
A spirometer (Flowmate; Spirometrics; Auburn, ME), meeting American Thoracic Society (ATS) standards, was used and calibrated daily using a 3-L syringe.32 Recommendations made by the ATS for performing forced expiratory maneuvers were followed.32 Trained office nurses performed the pulmonary function tests (PFTs) on all participants, and a physician reviewed all calibrations and PFT results. Three forced expiratory maneuvers were performed with the subject in a standing position, with the best FEV1 result of three recorded. The PFT data were expressed in absolute terms and as a percentage of predicted normal values.11 33 Participants were instructed/trained on the proper use of a peak flowmeter (Personal Best; HealthScan Products; Cedar Grove, NJ) meeting ATS recommendations for peak flow devices.32 A baseline PEF was established from the best of three pre-BD maneuvers.7 All participants in the study used the same Personal Best peak flowmeter model and were instructed on proper technique and diary recording of the best of three maneuvers. Each participant used the same peak flowmeter to measure his/her PEF values throughout the study. Patients were instructed and evaluated on the proper use of the BD device (Maxair Autohaler; Pharmaceuticals; St. Paul, MN). Fifteen to 20 min after two puffs of the BD, triplicate PFT readings were taken and the highest of three FEV1 readings was recorded. The percentage change in FEV1 was calculated as follows:

where a >= 12% increase in post-BD FEV1 was considered indicative of significant reversibility.32

Participants were asked to measure their PEF four times each day: between 6 AM and 9 AM pre-BD, between 12 noon and 2 PM pre-BD followed by two puffs of BD, between 12:30 PM and 2:30 PM 30 min post-BD, and between 6 PM and 9 PM pre-BD for the next 2 to 3 weeks. All subjects were asked to perform three peak flow measurements for each time period and to record the highest PEF value of the three readings, consistent with ATS recommendations.32 Subjects also recorded the actual time that the readings were taken and any additional BD inhalations used. Participants were instructed to leave blank any scheduled recordings that were not performed. Participants were given a peak flowmeter, printed instructions on use and care of the peak flowmeter, and a peak flow diary for charting. Patients were requested to bring their peak flow diaries to their next visit. Additional reminders were printed on the instruction sheet and on the diary. An MIC was scheduled 3 to 4 weeks after the initial visit.

MIC
The study protocol for MIC closely followed recommendations made by the Canadian Thoracic Society,34 Rijcken et al,35 and as previously reported by our group.36 A spirometry system (model 2200; Sensormedics; Yorba Linda, CA) and a variable-pressure, constant-volume body plethysmograph (model 6200; Sensormedics) were used. Changes in FEV1, FEF25–75%, and FVC were recorded 30 s and 90 s after each inhalation dose. The same technician performed the MIC for all the participants. A positive response was defined as a >= 20% fall in FEV1 at <= 8 mg/mL of methacholine. The 8-mg/mL cutoff was chosen based on earlier observations.35 36

Informed consent was obtained from all participants. Participants were offered no honorarium.

Data Analysis
A validity check of the PEF readings obtained with the peak flowmeter at the initial visit was made by comparing the two PEF readings obtained with spirometry.7 The percentage of variation between the two readings was calculated as follows:

where PEF flowmeter readings are in liters per minute, and spirometer readings are in liters per second times 60 s/min.

Data from the most complete 14 days of the 21-day peak flow monitoring period were analyzed. Only diaries with a minimum of four complete morning and post-BD afternoon readings were used in our study, consistent with a previous study.8 The first 3 days of the PEF monitoring period were not included in the data analysis to eliminate spurious low values secondary to a "learning effect."8 The percentage of compliance of peak flow measurements/recordings was assessed by the following equation:

According to National Heart, Lung, and Blood Institute (NHLBI) guidelines7 published in 1997, ". . . a 20% difference between morning (before taking an inhaled short-acting ß2-agonist) and afternoon (after taking an inhaled short-acting ß2-agonist)" is a key indicator of asthma. The exact numerical calculation of diurnal PEFvar to establish this 20% difference, however, is not clearly defined. We therefore evaluated four daily and four mean daily (indexes 13 to 16) PEF indexes compatible with the above NHLBI definition for PEFvar using different denominators (Table 1 ). Twenty other published period indexes not compatible with NHLBI recommendations were also used (Table 1) . PEFvar calculations were made from the raw diary data for each participant. Indexes of mean daily diurnal PEFvar (indexes 1 to 5, 9 to 11, and 13 to 16) were calculated using the arithmetic mean of each daily PEF diurnal variation calculation (Table 1) . Indexes of period PEFvar (indexes 6 to 8, 12, and 17 to 28) were calculated using defined selected period measurements for both the numerator and the denominator (Table 1) . The mean daily and period PEFvar indexes were further subdivided into indexes using only pre-BD values and indexes using pre-BD and post-BD values (Table 1) .


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  		Table 1. PEF Variation Indexes Used in this Study*

 
The JMP, IN statistical package (SAS Institute; Cary, NC) and Microsoft Excel Analysis ToolPak (Gray Matter International; Cambridge, MA) were used for statistical analysis. The group range and mean (± 1 SD) were calculated for the percentage of change in post-BD FEV1, the peak flow internal validity check, the mean daily and period PEFvar indexes, and the specificity, sensitivity, and positive and negative predictive rates for period and mean daily indexes. Descriptive statistics were used to describe compliance with performing peak flow measurements and obtaining an MIC, and the compliance rates were statistically compared using a two-sided Z statistic. The r value (Pearson correlation coefficient) was determined for the correlation of the best PEFvar index, pre-BD and post-BD FEV1 responses >= 12%, and MIC responses with each other. A significance level of p = 0.050 was used.

A physician-based diagnosis of asthma was made based on asthma-like chest symptoms, physical examination findings, response to methacholine, response to treatment over time with BD and/or anti-inflammatory treatment, and serial spirometry findings.1 38 The numbers of true-positive, true-negative, false-positive, and false-negative test results were calculated for MIC, for post-BD FEV1 response, and for each mean daily and period PEFvar index. The best mean daily and period PEFvar indexes were identified as those with the best correlation coefficient with MICs. The sensitivity, specificity, and positive and negative predictive values of the best mean daily and period PEFvar, post-BD FEV1 response, and MIC were determined. The formulas used for these calculations are shown.

Sensitivity:

Specificity:

Positive predictive value:

Negative predictive value:

A false-negative MIC was defined as a negative baseline MIC in patients who, over time, developed PFT results with obstructive patterns that improved along with symptoms responding to antiasthma therapy. A false-positive MIC was defined as patients with positive MIC results, but who did not respond to BD or anti-inflammatory treatments and were found to have nonasthma causes for their initial symptoms (eg, rhinitis, postnasal drip, gastroesophageal reflux).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
One hundred twenty-one subjects met inclusion and exclusion criteria with symptoms, normal lung examination and chest radiographic findings, and normal baseline PFT results, and were asked to complete 2 to 3 weeks of peak flow monitoring, followed by an MIC. Eighty subjects (66.12%) underwent an MIC and 61 subjects (50.41%) returned an acceptable peak flow diary (a minimum of four complete morning and post-BD afternoon readings). The difference between the two compliance proportions was significant (p = 0.012) using a two-sided Z statistic. Of the 50.41% of patients completing diaries, there was a mean (± 1 SD) compliance rate of 82.16 ± 19.55%. Fifty-seven subjects (47.11%) satisfactorily completed both the peak flow diary and the MIC and were accepted for statistical analysis. There were 17 pediatric patients aged 7 to 18 years and 40 adult patients > 18 years of age. There was no difference in compliance with PEF monitoring or MIC between these two subgroups. The 28 calculated PEFvar indexes for each subject and the composite results of PEF indexes, MICs, and post-BD FEV1 response for each subject are not shown (available through e-mail correspondence). There were 41 positive MIC results (71.93%) and 16 negative MIC results (28.07%) based on the 8 mg/mL cutoff.

The range and mean (± 1 SD) of the post-BD response in FEV1 was - 10 to 18.37% and 3.41 ± 4.87%, respectively. Only 3 of the 57 subjects (5.23%) had post-BD FEV1 responses >= 12%. The calculated PEF internal validity check between baseline PEF by peak flowmeter vs PEF by baseline spirometry ranged from - 20.63 to 32.08% (mean [± 1 SD], 2.31 ± 12.51%). The range and mean (± 1 SD) of the absolute variation was - 104 to 102 L/min and 4.10 ± 49.04 L/min, respectively.

There were no statistically significant correlations between any of the PEFvar indexes with MICs. The period indexes, highest amplitude percentage low (amp%low) (index 12) and two-highest average (index 28), trended toward significance (index 12, r = 0.26, p = 0.052; index 28, r = 0.25, p = 0.056). The best mean daily index was mean amp%low (index 11), which did not have a statistically significant correlation with MIC (r = 0.17, p = 0.202).

A minimum clinical follow-up period of 6 months post-MIC (range, 6 to 9 months; mean [± 1 SD], 6.61 ± 0.90 months) was performed on all patients, which included serial assessment of symptoms, physical examination, evaluation of response to medication, and spirometry. The establishment of a physician-based diagnosis of asthma was made based on these parameters. There were no patients who acutely presented in follow-up requiring urgent BD treatment. There were seven patients who had false-negative MIC results, and there were no false-positive MIC results. The number of true-positive, true-negative, false-positive, false-negative test results for MICs, post-BD FEV1 responses, and the best (correlation with positive MIC) mean daily index (mean amp%low, index 11) and best period PEFvar index (highest amp%low, index 12) are shown in Table 2 . Regarding MICs, there were 41 true-positive, 9 true-negative, 0 false-positive, and 7 false-negative test results. Of the seven subjects with false-negative MIC results, all had significant drops of >= 25% in FEF25–75% during the MIC at <= 8 mg/mL, suggesting the presence of airways hyperactivity as previously reported by our group.36 Of the post-BD FEV1 responses, there were 3 true-positive, 9 true-negative, 0 false-positive, and 45 false-negative test results (Table 2) . Period indexes produced more true-positive test results (range, 8 to 40; mean [± 1 SD], 27.00 ± 9.47) compared to the mean daily indexes (range, 0 to 2; mean [± 1 SD], 1.17 ± 1.40). The period PEFvar index, lowest percentage mean (lowest%mean) (index 20), had the most true-positive test results, but also had the highest number of false-positive test results (data not shown). The most sensitive index was lowest%mean (index 20). The specificity of all the mean daily PEFvar indexes was 100% because there were no false-negative test results. Specificity of the period PEFvar indexes ranged from 0 to 93.33% (mean [± 1 SD], 36.83 ± 33.36%) with amp%low of means (index 8) having the best specificity. Of the three diagnostic tests, the MIC was the most sensitive test (85.71%) and had the best negative predictive value. MIC shared maximal specificity and positive predictive value with post-BD FEV1 responses and the best mean daily PEFvar index (mean amp%low, index 11; Table 2 ).


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  		Table 2. Sensitivity, Specificity, and Predictive Value of Diagnostic Tests for Asthma

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
PEF Variation
Serial PEF monitoring to calculate diurnal variation has been proposed as a marker of airway lability,8 20 and as a method of diagnosing asthma, especially in occupational settings.7 31 Asthmatic individuals are said to have greater diurnal PEFvar compared to healthy subjects. However, no clear-cut division between asthmatic and nonasthmatic individuals based on PEFvar has been universally accepted.1 2 6 8 16 39 40 In past studies, a wide variety of PEFvar has been reported in healthy nonasthmatic children (8.2 to 31%),8 healthy nonasthmatic adults (2.76 to 13.3%),2 asthmatic adults (7.56 to 50.9%),2 and children with asthma (7.1 to 22.6%).22 It is evident that some overlap in PEFvar exists between healthy and asthmatic individuals. This may be attributed to differences in methods of calculation, timing of BD administration (if used in the calculation), and/or disease stability and severity.

Despite overlaps in PEFvar in asthmatic and healthy populations and the lack of standardization of the PEFvar monitoring and its numerical expression, PEFvar has been widely advocated and used in clinical practice and asthma research.17 31 42 The NHLBI and others2 7 16 have recommended a >= 20% PEF diurnal variation as a diagnostic benchmark for asthma. The NHLBI guidelines7 also recommend that PEF monitoring for diagnostic purposes be done twice daily for 1 to 2 weeks, ie, on first morning awakening pre-BD and afternoon (between noon and 2 PM post-BD). These recommendations are based on data reported by Enright et al1 and Quackenboss et al.8 For diagnostic and epidemiologic purposes, Enright et al1 recommended 4 to 7 days of monitoring, although clinical support for this approach was not provided. Quackenboss et al8 recommended that the peak flow variation be calculated using maximum PEF values corresponding to the noon or evening readings and the minimum PEF values corresponding to the morning or bedtime readings. It was not clearly stated that these were all pre-BD values. Based on these limited data, the NHLBI recommends using pre-BD morning and post-BD afternoon recordings as the standard for PEFvar measurements. Unfortunately, the NHLBI guidelines also fail to clearly specify the numerical expression of peak flow variability. That is, it is clear that the difference between the afternoon post-BD value and the morning pre-BD value serves as the numerator of the index, but the denominator is not defined. In our study, using 4 different denominators for the PEFvar calculations consistent with NHLBI recommendations as well as 24 other PEFvar indexes, we were unable to identify a reliable index of PEFvar that could accurately correlate with a diagnosis of asthma.

In addition, there are some concerns about the NHLBI recommendation for 2 weeks of PEFvar monitoring, because the best length of monitoring to maximize variability and compliance has not been identified. It seems apparent that a longer period may provide more opportunities for exogenous exposures to trigger variability; however, compliance may wane. A shorter period may give more rapid results and improve compliance, but decreases the likelihood of adequate high-variability days being detected. Furthermore, there is no universal agreement as to whether to use both pre-BD and post-BD measurements, because BD measurements reflect two variables: diurnal variation and response to BD treatment.20

In our study, there was poor correlation of all PEFvar indexes with MIC regardless of whether pre-BD values, pre-BD and post-BD values, daily mean, or period PEFvar measurements were used. This is consistent with other studies10 22 23 29 37 41 that have failed to identify one PEFvar index that consistently discriminates between asthmatics and healthy subjects or distinguishes itself among many indexes applied to the same individual. None of the 28 indexes had statistically significant correlation with MIC.

Several other concerns have been raised concerning the usefulness of PEF measurements. The accuracy of PEFvar as recommended by the NHLBI should be checked against spirometrically determined PEFs. PEF meters have been reported to produce results that are inaccurate by up to 30%.43 In our study, the mean (± 1 SD) internal validity was 2.72 ± 12.23%, with a range from - 20.40 to 32.08% and a mean (± 1 SD) bias of 6.0 ± 47.28 L/min, higher in the peak flowmeter readings.

Subject compliance is another major concern in PEF monitoring. Many studies9 10 14 17 assume that the technique demonstrated in the office is precisely followed at home. The intensity of effort and accuracy of readings/recordings at home are serious potential sources of error in home peak flow monitoring. Over time, peak flow monitoring and record keeping may become unrewarding, time-consuming, or anxiety provoking,43 especially when participants feel well, and may have a negative impact on compliance. We found that compliance with measurements four-times daily for 2 to 3 weeks may be unachievable for most patients. There was no difference in compliance rates between children 7 to 18 years old and adults > 18 years old. In contrast, compliance with performing a requested MIC (66.12%) was higher among all age groups compared to compliance with peak flow monitoring (50.41%). There was a statistically significant difference between the number of completed MICs and the number of acceptable diary completions (p = 0.012, two-sided Z statistic). That is, there were significantly more patients who completed a one-time MIC than maintained an acceptable PEF diary over a 2- to 3-week period.

Therefore, issues regarding compliance, accuracy, and reliability of PEF readings, length of monitoring, method of calculation, timing of BD administration (if used), overlap of healthy with asthmatic PEFvar, and questions regarding invented measurements raise serious concerns about the usefulness of PEFvar as a diagnostic tool for asthma.

Comparative Analyses
Although MIC and PEFvar assess bronchial lability, they are obtained in different ways (bronchoconstriction challenge vs spontaneous variation in airways caliber because of circadian rhythms and natural exposure) and are likely to reflect different aspects of airway lability. PEF diurnal variation has the advantage of allowing more measurements of airways lability over a period of time. Several clinical and epidemiologic studies6 12 14 17 19 20 have looked at PEF diurnal variation as to whether it correlates with histamine or MIC; across these studies, there is no uniform method of calculating PEF diurnal variation, and the study populations are not comparable. Nevertheless, the correlation of diurnal PEF variation with methacholine or histamine challenge has been reported in various subgroups of patients.6 12 14 15 17 20 22 23 37 Many of these studies14 17 20 22 23 were conducted in patients with confirmed obstructive airways disease, where a correlation of PEFvar with a positive MIC may be less relevant diagnostically than in those without an established diagnosis. In our study, in patients without an established diagnosis of asthma, relying on PEFvar as the sole diagnostic test for asthma would have resulted in missing the diagnosis of asthma in as many as 42 cases (74%). This high number of false-negative PEFvar measurements is consistent with the conclusions of a recent large population study44 from Switzerland that demonstrated the unreliability of 3 weeks of PEFvar (amplitude percentage mean [amp%mean]) measurements (twice daily), as well as poor sensitivity (36%) and poor positive predictive value (16.4%) in the diagnosis of asthma. In our study, we observed no statistically significant correlation between PEFvar and positive MIC finding. A positive MIC finding had a greater sensitivity, specificity, and positive and negative predictive value than the best PEFvar index (highest amp%low; index 12).

According to the ATS, ". . . an increase in FEV1 >= 12%, with an absolute change >= 200 mL, from the baseline level, confirms that there is significant reversibility, and together with the appropriate history, the diagnosis of asthma."32 Inhalation of a selective BD in conjunction with spirometry is inexpensive, usually safe, technically easy to perform, and adds only 20 min to the evaluation. BD testing is often helpful in comparing and assessing therapeutic effectiveness. Pre-BD and post-BD FEV1 measurements have been compared to PEF diurnal variation in a limited number of studies.12 14 15 29 45 Those studies12 19 29 45 with subjects having moderate-to-severe airways obstruction showed correlation of PEFvar with post-BD FEV1 responses, whereas in a population with mild asthma, no correlation was observed.14 In a recent study comparing post-BD FEV1 response and PEF measurements, Hunter et al15 demonstrated relatively equal sensitivity (49% vs 43%, respectively) in distinguishing individuals with mild asthma from nonasthmatic individuals.

In our study, correlation statistics of post-BD FEV1 with PEFvar could not be performed because of the limited number of positive post-BD FEV1 findings. Descriptively, a higher number of participants had a >= 20% peak flow diurnal variation vs a >= 12% FEV1 post-BD response, and there was greater sensitivity (53.66%) for the best PEFvar index (highest amp%low; index 12) when compared to post-BD FEV1 changes (sensitivity, 6.12%). These findings are consistent with the expectation that individuals who at baseline are maximally bronchodilated will have minimal post-BD responses.1 3 The absence of reversibility to BD in our study population clearly did not rule out asthma, because there was a high false-negative rate (79.31%) using this parameter.

As with PEFvar and post-BD FEV1 changes, there are limited data in the literature demonstrating a correlation of pre-BD and post-BD FEV1 responses with MIC.6 13 14 Recently, Hunter et al15 reported on pre-BD and post-BD FEV1 response and MIC in a mixed group of healthy subjects, patients with mild asthma, and nonasthmatic subjects with asthma-like symptoms. The respective post-BD responses were much less sensitive (49% vs 91%) and much less specific (70% vs 90%) than MIC in diagnosing asthma.

In our study, there were only three participants who had a >= 12% improvement in post-BD FEV1. Two of these participants responded to MIC at doses < 8 mg/mL and were true-positive asthmatics. The third participant had a false-negative MIC result and eventually received a diagnosis of asthma. However, 39 participants with positive MIC results showed no significant change in the post-BD FEV1. In our study, the mean (± 1 SD) post-BD FEV1 response was 3.41 ± 4.87%, which is in the normal range for healthy individuals (- 3.5 to 8.5%).1 The false-negative rate of post-BD FEV1 responses among our subjects was 78.95%. The lack of significant FEV1 response to BD treatment was therefore not a helpful diagnostic test for asthma in our study population.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Up to this point, to our knowledge, there have been no prospective studies formally assessing the validity of PEFvar as defined by NHLBI guidelines as a screening tool for suspected asthma or its comparative value to MIC or post-BD FEV1 responses, respectively. In our prospective analysis of various mean daily and period PEF indexes, none of the NHLBI-compatible PEFvar indexes correlated well with MIC. Of the remaining 24 indexes studied, 2 indexes had marginal statistical significant correlation with MIC, and both had weak correlation coefficients with MIC. We demonstrated a 50.41% compliance rate with a 2- to 3-week period of PEF measurements vs a 66.12% compliance rate with a request for MIC. The difference in compliance was statistically significant (p = 0.012, two-sided Z statistic), indicating that patients are significantly more inclined to follow requests for a single MIC than complete 2 to 3 weeks of peak flow monitoring. We found that MIC had the highest sensitivity and highest positive and negative predictive values for the diagnosis of asthma in our study population.

PEFvar and/or pre-BD and post-BD FEV1 responses are not interchangeable with and cannot substitute for MIC in the assessment of a patient with suspected asthma with normal findings on physical examination, chest radiography, and spirometry. PEFvar and post-BD FEV1 responses may in fact measure different aspects of asthma.1 8 Paradoxically, the NHLBI recommends a PEF diurnal variation >= 20% as a diagnostic tool for asthma, while it also recognizes the limitation of PEFvar in those with intermittent disease who may have PEFvar < 20%.7 The results of our study suggest that both PEFvar and post-BD response are much less sensitive than MIC for detecting asthma. Although some epidemiologists and clinicians propose PEFvar and post-BD FEV1 responses as simpler, less expensive, objective tests for asthma diagnosis, we have found that on an individual basis, these tests have serious limitations, including low sensitivity and high false-negative rates. Furthermore, calculations of diurnal variation by a variety of indexes (including those consistent with NHLBI recommendations) failed to detect important changes in airways lability in our study population. Based on our results, relying on PEFvar as a diagnostic tool for asthma as suggested by the NHLBI may lead to underdiagnosis, undertreatment, and/or delay in early intervention. Our findings warrant a reconsideration of the NHLBI guidelines recommendation of the utility of PEFvar as an accurate diagnostic tool for asthma in clinical practice.


   Footnotes
 
Abbreviations: amp%low = amplitude percentage low; amp%mean = amplitude percentage mean; ATS = American Thoracic Society; BD = bronchodilator; FEF25–75% = mean forced expiratory flow during the middle half of the FVC; lowest%mean = lowest percentage mean; MIC = methacholine inhalation challenge; NHLBI = National Heart, Lung, and Blood Institute; PEF = peak expiratory flow; PEFvar = peak expiratory flow variation; PFT = pulmonary function test

This project was supported by the Asthma Center Education and Research Fund, a nonprofit organization dedicated to advances in asthma, and a nonrestricted research grant from Merck & Co., Inc.

Received for publication April 24, 2000. Accepted for publication October 9, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Enright, PL, Lebowitz, MD, Cockcroft, DW (1994) Physiologic measures: pulmonary function tests. Am J Respir Crit Care Med 149,S9-S18
  2. Hetzel, MR, Clark, TJH (1980) Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax 35,732-738[Abstract]
  3. . American Thoracic Society. (1993) Guidelines for the evaluation of impairment/disability in patients with asthma. Am Rev Respir Dis 147,1056-1061[ISI][Medline]
  4. Venables, KM, Burge, PS, Davison, AG, et al (1984) Peak flow rate records in surveys: reproducibility of observers’ reports. Thorax 39,828-832[Abstract]
  5. . American Thoracic Society. (1991) Lung function testing selection of reference values and interpretational strategies: a statement of the American Thoracic Society. Am Rev Respir Dis 144,1202-1218[ISI][Medline]
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