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(Chest. 2006;129:1492-1499.)
© 2006 American College of Chest Physicians

Role of Spirometry and Exhaled Nitric Oxide To Predict Exacerbations in Treated Asthmatics*

Arthur F. Gelb, MD, FCCP; Colleen Flynn Taylor, MA; Chris M. Shinar, PharmD; Carlos Gutierrez, MD, MSc and Noe Zamel, MD, FCCP

* From Lakewood Regional Medical Center (Drs. Gelb and Shinar, and Ms. Flynn Taylor); Lakewood, CA; and School of Medicine (Drs. Gutierrez and Zamel), University of Toronto, Toronto, ON, Canada.

Correspondence to: Arthur F. Gelb, MD, FCCP, 3650 E. South St, Suite 308, Lakewood, CA 90712; e-mail: afgelb{at}msn.com

Abstract

Objective: To evaluate the complementary roles of exhaled nitric oxide (NO) and spirometry to predict asthma exacerbations requiring one or more tapering courses of systemic corticosteroids.

Methods: We prospectively studied 44 nonsmoking asthmatics (24 women) aged 51 ± 21 years (mean ± SD) who were clinically stable for 6 weeks and receiving 250 µg of fluticasone/50 µg of salmeterol or equivalent for 3 years. Total exhaled NO (FENO), small airway/alveolar NO (CANO), large airway NO flux (J’awNO), and spirometry were measured.

Results: Baseline FEV1 was 2.1 ± 0.7 L, 70 ± 20% of predicted after 180 µg of albuterol. Twenty-two of 44 asthmatics had one or more exacerbations over 18 months, 16 of 22 asthmatics had two exacerbations, and 6 of 22 asthmatics were hospitalized, including 1 asthmatic with near-fatal asthma. When baseline FEV1 was ≤ 76% predicted, exacerbations occurred in 20 of 31 asthmatics (65%). If baseline FEV1 was > 76% of predicted, exacerbations occurred only in 2 of 13 asthmatics (15%) [p = 0.003, {chi}2]. Using a receiver operating characteristic (ROC) curve for first exacerbation, the area under the curve was 0.67 with cutoff FEV1 of 76% of predicted (sensitivity, 0.91; specificity, 0.50; positive predictive value, 0.65; negative predictive value, 0.85; positive likelihood ratio [LR(+)], 1.8; negative likelihood ratio [LR(–)], 0.18). When baseline FENO was ≥ 28 parts per billion (ppb), exacerbations occurred in 13 of 17 asthmatics (76%); if baseline FENO was < 28 ppb, exacerbations occurred in only 9 of 27 asthmatics (33%) [p = 0.005, {chi}2]. Using the ROC curve for first exacerbation, the area under the curve was 0.71 with FENO cutoff point of 28 ppb (sensitivity, 0.59; specificity, 0.82; positive predictive value, 0.77; negative predictive value, 0.87; LR(+), 3.3; LR(–), 0.5). Independent of baseline FEV1, FENO ≥ 28 ppb increased the relative risk (RR) for exacerbation by 3.4 (95% confidence interval [CI], 1.3 to 9.1; Mantel-Haenszel, p = 0.007). An abnormal increase in CANO increased RR by 3.0 (95% CI, 0.9 to 9.9; p = 0.04), and abnormal J’awNO increased RR by 2.4 (95% CI, 1.0 to 5.6; p = 0.04). Independent of baseline FENO, FEV1 ≤ 76% predicted increased RR by 1.7 (95% CI, 1.0 to 2.7; p = 0.02). Combined baseline FENO ≥ 28 ppb and FEV1 ≤ 76% of predicted identified 13 stable asthmatics with 85% probability for future exacerbation, whereas 9 asthmatics with FENO < 28 ppb and FEV1 > 76% of predicted had a 0% probability of exacerbation.

Conclusion: Combining FENO and FEV1 percentage of predicted can stratify risk for asthma exacerbation.

Key Words: asthma exacerbations • exhaled nitric oxide • spirometry

While the majority of asthmatic patients achieve symptomatic control of their illness, others for a variety of reasons remain plagued by recurrent exacerbations.1 This may result in unanticipated office and emergency department visits and hospitalizations, including infrequent episodes of near-fatal asthma, and rarely death.23456 While the majority of serious complications occur in asthmatics with moderate-to-severe persistent disease, those with mild persistent disease (FEV1 ≥ 80% of predicted) are not immune.23456 Therefore, it is crucial to develop better asthma control and intuitive testing strategies that allow the clinician to easily identify and predict which asthmatics are at high risk to for symptomatic exacerbations.

Measurement of total exhaled nitric oxide (FENO) is a relatively simple, noninvasive, sensitive, not specific, but very reproducible test for detection of endogenous inflammatory signals in childhood and adult asthmatics.78 It has been proposed as a diagnostic test for asthma.9101112 Furthermore, FENO can also be used to monitor clinical status of asthmatics, bronchial hyperresponsiveness, and response to therapy including montelukast,13 inhaled corticosteroids,1415161718192021222324 and oral corticosteroids.212526 While FENO may also be a surrogate for sputa eosinophilia in asthmatics,1214151618192022252627 it appears less so for large airway mucosal eosinophilia.2527 Presumably, the main source responsible for the increased FENO in asthma is predominantly the overexpression of inducible nitric oxide (NO) synthase in epithelial and inflammatory cells targeted by trafficking proinflammatory cytokines in both large82829 and very small airways and alveoli.212426 This study explores the complementary roles of spirometry, a marker of severity of expiratory airflow limitation, and measurement of FENO, a marker of airway and lung inflammation, to prospectively identify asthmatics over 18 months at risk for exacerbations requiring treatment with oral or parenteral corticosteroids.

Materials and Methods

Patient Selection
Normal Subjects:
We originally measured lung function and exhaled NO in 34 healthy, asymptomatic nonsmokers (13 men; mean age, 40 ± 17 years [± SD]).21

Asthmatics:
We similarly evaluated 53 nonsmoking, clinically stable asthmatic patients (24 men; mean age, 43 ± 23 years). The asthmatics were regularly followed up in a tertiary outpatient chest clinic for management of mild-to-severe persistent asthma.303132 The present cohort was subsequently identified and recruited from this group and included 44 nonsmoking, asthmatics (20 men) aged 51 ± 21 years who were clinically stable for at least 6 weeks prior to the initiation of the study. They were all receiving inhaled corticosteroids and long-acting ß2-agonists for at least 3 years. Forty-two patients were receiving 250 µg of fluticasone/50 µg of salmeterol bid, and 2 patients were receiving 200 µg of budesonide and 12 µg of formoterol bid. None were receiving systemic corticosteroids or leukotriene inhibitors within 6 weeks of the start of this study. Except for subsequent oral or parenteral corticosteroids initiated during exacerbation, the patients with asthma received the same medications for the duration of the study. Rescue medications included albuterol sulfate and/or ipratropium bromide by metered-dose inhaler (MDI) and/or home nebulizers with solutions of the aforementioned.

We modified the clinical classification of asthma to include treated asthmatics, and stratification was determined after administration of 180 µg of albuterol by MDI.303132 Mild refers to FEV1 ≥ 80% predicted, moderate as FEV1 of 79 to 61% of predicted, and severe as FEV1 < 61% of predicted.303132

All asthmatics studied had given informed consent for participation. This study was approved by the Institutional Review Board. Study design was an 18-month, prospective, nonrandomized, open-label, non-placebo-controlled trial with intent to treat all asthmatics with post hoc data analysis. All asthmatics were to be seen at least monthly in the outpatient clinic.

Measurement of Exhaled NO Gas Exchange
As previously reported21 FENO was measured at an expiratory flow rate of 100 mL/s using a chemiluminescence analyzer (Sievers NOA 280; Ionics Instruments; Boulder, CO) with varying expiratory airflow resistors (Ionics; Boulder, CO). We used guidelines as previously recommended.33343536 Exhaled NO was measured at three separate, constant expiratory flow rates: 100, 150, and 200 mL/s in triplicate; and the mean of three values obtained within 10% of each other was used to calculate bronchial NO maximal flow (large airway NO flux [J’awNO]) and small airway/alveolar NO (CANO) using the technique of Tsoukias and George.36

Lung Function Studies
When clinically stable for at least 6 weeks, asthmatic patients were instructed to continue all their medications, except to withhold inhaled long-acting ß2-agonists for 48 h and inhaled albuterol sulfate and ipratropium bromide for 6 h prior to testing. Lung function, including lung volumes, single-breath diffusing capacity, and static lung elastic recoil pressures were measured using a pressure-compensated flow plethysmograph (Model 6200 Autobox; SensorMedics, Viasys; Yorba Linda, CA) with similar techniques as previously published.213738 A panting frequency of < 1 Hz was used to avoid underestimation of alveolar pressure as measured at the mouth that could lead to spurious increase in thoracic gas volume. All asthmatics were studied at baseline. Additionally, 25 randomly chosen asthmatics who were stable for at least 3 weeks were restudied after initiation of the study to evaluate individual asthmatic long-term reproducibility of baseline spirometry and FENO.

Clinical Status
An asthmatic exacerbation was defined as clinical instability characterized by uncontrolled cough, wheezing, chest tightness, and/or shortness of breath requiring need for at least one 7- to 14-day tapering course of oral or parenteral corticosteroids. All but four of the patients were followed up. However, in the majority of cases, the decision to initiate corticosteroids was made by emergency department physicians unaware of the study protocol.

Statistical Methods
We compared values between normal control subjects and asthmatics using analysis of variance (ANOVA) on the ranks or nonparametric ANOVA, Kruskal-Wallis test. Alternatively, a Wilcoxon rank-sum test was used. Additionally, Spearman correlation coefficient, Kaplan-Meier, receiver operating characteristic (ROC) plots, {chi}2, and Mantel-Haenszel log-rank tests were used. Intraclass correlation coefficient, ANOVA, and Bland-Altman were used to evaluate reproducibility of spirometry and FENO. A positive likelihood ratio [LR(+)] was calculated as sensitivity/(1 – specificity) or true-positive rate/false-positive rate. An LR(+) reflects increased odds of having a disease, eg, asthma exacerbation after a positive test result. A negative likelihood ratio [LR(–)] is (1 – sensitivity)/specificity or false-negative rate/true-negative rate and reflects reduced odds of having asthma exacerbation after a negative test result. Likelihood ratio (LR) was also used to calculate posttest probability (LR/LR + 1). Statistical significance was p < 0.05. Statistical analysis software was used (SAS version 8.02 for Windows; SAS Institute; Cary, NC).

Previously Published Data
Baseline values for spirometry, and NO gas exchange in these 44 asthmatic patients and 34 normal control subjects were included in a larger cohort previously reported.21

Results

All asthmatics completed the 18-month study and were seen at least monthly. Results of baseline lung function studies after 180 µg of albuterol sulfate by MDI in normal control and asthmatic cohorts are described in Tables 1, 2 . Diffusing capacity was normal in all groups. Expiratory spirometry results were similarly reduced in asthmatics regardless of normal or abnormal baseline FENO. There was mild hyperinflation at total lung capacity (TLC). Asthmatics with normal FENO had TLC of 6.6 ± 1.7 L (120 ± 18% predicted), and those with elevated FENO had TLC of 7.3 ± 2.6 L (133 ± 16% predicted; p = not significant [NS]).


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  		Table 1. Comparison of Baseline Lung Function in Normal Subjects and Patients With Asthma*

 

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  		Table 2. Comparison of Results of Total Exhaled, Bronchial Flux, and Steady-State Alveolar Concentration of NO in Normal Control Subjects vs Asthmatics*

 
Results of baseline total FENO (in parts per billion [ppb]) at 100 mL/s, CANO, and J’awNO are described in Table 2. Normal value for FENO at 100 mL/s was 12 ± 5 ppb.21 Compared to normal control values, only the asthmatics with significantly abnormal FENO had elevated J’awNO and CANO.

Incidence of Asthma Exacerbations
Results are described in Figures 1234 . If the baseline FEV1 in liters was ≤ 76% of predicted, exacerbation requiring at least one course of tapering oral or parenteral corticosteroids over 18 months occurred in 20 of 31 asthmatics (65%); if FEV1 was > 76% of predicted, exacerbation occurred only in 2 of 13 asthmatics (15%) [p = 0.003, {chi}2 = 8.84]. Using ROC plots for first asthma exacerbation, with cutoff point for FEV1 at 76% predicted, the area under the curve was 0.67; sensitivity, 0.91; specificity, 0.50; positive predictive value, 0.65; negative predictive value, 0.85; LR(+), 1.8; and LR(–), 0.18. If baseline FENO was ≥ 28 ppb, exacerbation occurred in 13 of 17 asthmatics (76%); if baseline FENO was < 28 ppb, exacerbation occurred only in 9 of 27 asthmatics (33%) [p = 0.005, {chi}2 = 7.77]. Abnormal baseline FENO was present in 13 of 22 asthmatics (59%) with exacerbations. Using ROC plot for first asthma exacerbation, with cutoff point for FENO at 28 ppb, the area under the curve was 0.71; sensitivity, 0.59; specificity, 0.82; positive predictive value, 0.77; negative predictive value, 0.87; LR(+), 3.3; and LR(–), 0.5. Independent of baseline FEV1, an abnormal FENO ≥ 28 ppb increased the relative risk (RR) for exacerbation by 3.4 (95% confidence interval [CI], 1.3 to 9.1; Mantel-Haenszel, {chi}2 = 7.34, p = 0.007). Abnormal CANO increased the RR by 3.0 (95% CI, 0.9 to 9.9; Mantel-Haenszel, {chi}2 = 4.40, p = 0.04). Abnormal J’awNO increased the RR by 2.4 (95% CI, 1.0 to 5.6; Mantel-Haenszel, {chi}2 = 4.21, p = 0.04). Independent of baseline FENO, FEV1 ≤ 76% of predicted increased the RR by 1.7 (95% CI, 1.0 to 2.7; Mantel-Haenszel, {chi}2 = 4.68. p = 0.02).


Figure 1
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  		Figure 1. Distribution of clinical exacerbations in 22 of 44 asthmatics stratified by baseline FEV1 percentage of predicted (pred) and FENO of 100 mL/s. Ninety-one percent of exacerbations occurred in asthmatics with FEV1 ≤ 76% of predicted and 59% with abnormal FENO ≥ 28 ppb. Independent of baseline FEV1 percentage of predicted, FENO ≥ 28 ppb increased RR for exacerbation by 3.4 (95% CI, 1.3 to 9.1; Mantel-Haenszel, p = 0.007). Independent of baseline FENO, FEV1 ≤ 76% of predicted increased RR by 1.7 (95% CI, 1.0 to 2.7; p = 0.02).

 

Figure 2
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  		Figure 2. ROC curve for FEV1 percentage of predicted for first asthma exacerbation. AUC = area under curve; PDV = positive predictor value; NPV = negative predictor value.

 

Figure 3
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  		Figure 3. ROC curve for FENO for first asthma exacerbation. See Figure 2 for expansion of abbreviations.

 

Figure 4
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  		Figure 4. Kaplan-Meier curve for time to first asthma exacerbation, with subgroups stratified by normal or abnormal FEV1 percentage of predicted and FENO.

 
In the present study, the pretest probability for an asthma exacerbation was 0.5 (22 of 44 asthmatics over 18 months). Using a cutoff for FEV1 of ≤ 76% of predicted, the LR(+) of 1.8 yielded a probability 0.64 for future asthma exacerbation. When FEV1 cutoff was > 76% of predicted, the LR(–) of 0.18 decreased the probability of an asthma exacerbation to 15%. When FENO was ≥ 28 ppb, the LR(+) of 3.3 increased probability to 76% compared to FENO < 28 ppb, with LR(–) of 0.5 and probability of 0.33. Thirteen asthmatics with combined baseline FEV1 ≤ 76% of predicted and FENO ≥ 28 ppb had LR(+) of 5.94 and probability of an asthma exacerbation in 18 months of 85%. Alternatively, nine asthmatics with combined FEV1 > 76% and FENO < 28 ppb had LR(–) of zero and zero probability of an asthma exacerbation within 18 months. The Kaplan-Meier plot for time to first asthma exacerbation (Fig 4) demonstrated significant progressive clinical compromise when FEV1 was ≤ 76% of predicted, FENO was ≥ 28 ppb, or especially when both were abnormal.

Baseline FENO and Multiple Exacerbations
The protocol criteria for asthmatic exacerbation required one course of oral or parenteral tapering corticosteroids; however, 16 of 22 asthmatics (73%) required two separate courses and 6 of 22 asthmatics (27%) were hospitalized, including 1 with near-fatal asthma. In retrospect, baseline median (first to third interquartiles) value for FENO were 16 ppb (5 to 25 ppb) for the 22 asthmatics without exacerbation over 18 months, 22 ppb (10 to 45 ppb) for the 6 asthmatics with one exacerbation, and 28 ppb (23 to 37 ppb) for the 16 asthmatics with two or more exacerbations (Kruskall-Wallis test, p = 0.06).

Reproducibility of Spirometry and FENO
After initiation of the study and 229 ± 173 days after baseline spirometry and FENO were initially obtained, they were subsequently repeated in 25 asthmatics at random who were clinically stable for at least 3 weeks; results were not statistically different (p = NS). Fourteen of the 25 asthmatics restudied did not have an exacerbation during the 18-month study time.

In the 25 asthmatics restudied, initial FEV1 was 2.04 ± 0.74 L (74 ± 22% of predicted) and subsequently was 2.06 ± 0.74 L (75 ± 21% of predicted) [repeated-measures ANOVA F1,24 = 0.36, p = 0.55]. Intraclass correlation coefficient was 0.98 (95% CI, 0.95 to 0.99). Bland-Altman analysis indicated 92% of the differences vs mean was within ± 1.64 SD. Initial FENO was 23.5 ± 15 ppb and subsequently was 21.8 ± 15 ppb (ANOVA F1,24 = 2.75, p = 0.11); when restudied 229 ± 173 days later, the intraclass correlation coefficient was 0.94 (95% CI, 0.88 to 0.97). The Bland-Altman analysis indicated 88% of the differences vs mean were within ± 1.64 SD. Furthermore, no asthmatic patient went from a normal to abnormal FENO value or vice versa.

Lung Mechanics
Baseline static lung elastic recoil pressure at 100% predicted TLC was abnormally reduced. In the group with elevated FENO, values were 14 ± 8 cm H2O, 63 ± 23% of predicted vs 10 ± 5 cm H2O, 48 ± 24% of predicted in the group with normal FENO (p = NS).

Discussion

Results of this prospective study with post hoc data analysis demonstrated that exacerbations requiring at least one course of oral or parenteral corticosteroids over 18 months occurred in 22 of 44 nonsmoking, treated asthmatics with mild-to-severe expiratory airflow limitation who were clinically stable for at least 6 weeks at baseline. Ninety-one percent of all exacerbations (20 of 22 cases) occurred in asthmatics whose baseline FEV1 was ≤ 76% predicted; 59% of all exacerbations (13 of 22 cases) occurred when FENO was elevated ≥ 28 ppb.

Asthmatics with baseline combined FEV1 ≤ 76% predicted and FENO ≥ 28 ppb had LR(+) of 5.94 and probability of an asthma exacerbation in 18 months of 85%. Alternatively, asthmatics with combined FEV1 > 76% and FENO < 28 ppb had LR(–) of zero and zero probability of an asthma exacerbation within 18 months.

Kharitonov et al7 demonstrated excellent within-day and > 5-day reproducibility of measured FENO in healthy control subjects and in mild asthmatic adults and children. The present study extends these observations to 229 ± 173 days in clinically stable adult patients with mild-to-severe asthma.

The current results extend our previous retrospective observations in asthmatics categorized as clinically difficult to manage because they required two or more hospitalizations over 2 years, or three or more 7- to 14-day tapering courses of oral or parenteral corticosteroids over 1 year.21 We noted a greater proportion of asthmatics categorized as clinically difficult to manage had abnormally elevated FENO: 79% vs 41% ({chi}2, p = 0.06), when compared to asthmatics categorized as not difficult to manage.21

Green et al19 used monthly concurrent monitoring of spirometry and FENO in conjunction with measuring sputa eosinophilia as part of a management strategy to reduce asthma exacerbations. Smith et al23 used serial measurements of FENO to complement clinical management to significantly reduce maintenance dose of inhaled corticosteroids in mild chronic asthmatics not receiving long-acting ß2-agonists. Jones et al,14 Jatakanon et al,16 and Leuppi et al15 prospectively studied adult asthmatics during stepwise dose reduction of inhaled corticosteroids and noted good1416 to poor15 ability for FENO to predict exacerbations. Pijnenberg et al17 prospectively noted FENO was a good predictor of exacerbations in asthmatic children in remission after inhaled corticosteroids were discontinued. Harkins et al39 studied 20 clinically stable, treated patients with moderate-to-severe persistent asthma and FEV1 < 80% of predicted and noted increased exhaled NO at baseline could predict asthma exacerbations in 11 patients within 2-week follow-up from baseline.

Results in the present study also demonstrated asthma exacerbations are associated with increased NO flux that originates both in large airways as well as from the most distal small airways and/or alveoli. However, only the large airways can be more easily targeted with inhaled corticosteroids to reduce the smoldering inflammatory component.24 Previous studies4041 in cohorts of persistent asthmatics noted improved FEV1 percentage of predicted to increasing doses of inhaled corticosteroids, with variable improvement in clinical parameters compared to moderate doses. This is consistent with a previous physiologic study42 using heliox curves that suggested the predominant site of expiratory airflow limitation in nonsmoking chronic asthmatics resided in the large airways and in smokers in the small airways.

In the study by Szefler et al,40 post hoc data analysis revealed asthmatics with the greatest FEV1 response had high FENO, sputa eosinophils > 2%, FEV1 response to albuterol > 15%, and history of asthma < 10 years. In the absence of these factors, asthmatics failed to show improvement with inhaled corticosteroids.

Our current observation of increased CANO as a source of endogenous inflammation is consistent with our previous study21 in refractory moderate-to-severe asthma, the report by Berry et al,26 and the results of Lehtimaki et al24 in mild asthmatics. Moreover, independent of baseline FEV1 percentage of predicted, increased CANO did predict increased asthma exacerbations in the present study. Furthermore, we have previously shown that 5 days of 30 mg of prednisone is capable of suppressing increased CANO.21 Berry et al26 noted similar results after 30 of mg prednisone for 14 days. We believe the increased CANO reflects smoldering inflammation in the most distal airways and/or alveoli and is not due to small airway axial contamination.35 Supporting this concept are studies reporting inflammatory cells in BAL fluid43 and in transbronchial lung biopsies in asthmatics.44 Furthermore, Berry et al26 reported good concordance between increased CANO and eosinophil count in BAL fluid.26 Observations by Mauad and colleagues45 demonstrated decreased and fragmented elastic fibers in subepithelial layers in large airways in fatal asthma. Mauad et al46 also noted fragmentation and decreased elastic fibers that anchor the small membranous bronchiole into the lung parenchyma but not in the distal alveoli. These structural alterations might contribute to the loss of lung elasticity currently and previously reported by us,213738 as well as disruption of the normal airway-parenchymal interdependence.

In conclusion, baseline combined measurements of both postbronchodilator FEV1 percentage of predicted and FENO in clinically stable, treated, nonsmoking patients with asthma may help risk stratify for subsequent exacerbations. Future studies are needed to validate and corroborate our threshold values for FEV1 percentage of predicted and FENO. Additionally, it is important to determine the therapeutic role of increased doses of inhaled corticosteroids and/or other antiinflammatory agents to reduce FENO and improve expiratory airflow limitation and reduce asthma exacerbations.

Acknowledgements

We thank Christy Kirkendall and Michelle Curry for patient scheduling and coordination, and Aia White-Podue and Donna Robinson for manuscript preparation.

Footnotes

Abbreviations: ANOVA = analysis of variance; CANO = small airway/alveolar nitric oxide; CI = confidence interval; FENO = total exhaled nitric oxide; J’awNO = large airway nitric oxide flux; MDI = metered-dose inhaler; NO = nitric oxide; NS = not significant; LR = likelihood ratio; LR(+) = positive likelihood ratio; LR(–) = negative likelihood ratio; ppb = parts per billion; ROC = receiver operative characteristic; RR = relative risk; TLC = total lung capacity

Received for publication May 18, 2005. Accepted for publication December 16, 2005.

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K. G. Lim and C. Mottram
The Use of Fraction of Exhaled Nitric Oxide in Pulmonary Practice
Chest, May 1, 2008; 133(5): 1232 - 1242.
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