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History of serious asthma exacerbations should be included in guidelines of asthma severity

Published:December 12, 2006DOI:https://doi.org/10.1016/j.jaci.2006.10.019

      Background

      It is unclear whether asthma severity measured with consensus guidelines is better than a history of a serious asthma exacerbation in predicting current disease activity and future clinical course.

      Objectives

      We sought to (1) compare asthma severity determined by using the Global Initiative for Asthma guidelines with a history of a serious asthma exacerbation as predictors of pulmonary function, bronchial hyperreactivity, and disease activity and (2) determine whether exacerbation history significantly adds to asthma severity in its ability to predict the same variables.

      Methods

      Forty-eight adolescents with a history of a serious asthma exacerbation were compared with 69 adolescents with asthma but without such a history. Groups were matched for age, sex, and ethnicity (age, 14.59 ± 1.74 years; 56% male; 58% white).

      Results

      Forty-two percent of subjects had severe, 28% had moderate, 15% had mild persistent, and 15% had mild intermittent asthma. Asthma severity and exacerbation history were associated with pulmonary function and markers of disease activity, whereas only exacerbation history predicted bronchial hyperreactivity (P ≤ .001). Including exacerbation history significantly augmented the ability of the severity categories to predict the asthma measures.

      Conclusion

      Although asthma severity and a history of a serious asthma exacerbation both predict pulmonary function abnormalities and current disease activity, bronchial hyperreactivity was only associated with exacerbation history. Exacerbation history improves the ability of severity to predict these key asthma measures.

      Clinical implications

      Adding a history of a serious asthma exacerbation to the consensus guidelines for asthma severity is likely to improve the ability of these clinical tools to predict current disease activity and future clinical course.

      Key words

      Abbreviations used:

      FVC (Forced vital capacity), GINA (Global Initiative for Asthma), NAEPP (National Asthma Education and Prevention Program), RV (Residual volume), SES (Socioeconomic status), TLC (Total lung capacity)
      Consensus guidelines for the management of asthma have been created to help caregivers make evidence-based treatment decisions over time. The United States' National Asthma Education and Prevention Program (NAEPP) guidelines use symptom report and lung function (FEV1) to assign asthma severity.
      National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics—2002.
      The Global Initiative for Asthma (GINA) guidelines add to the NAEPP by considering symptom control when assigning asthma severity in patients who are already taking medications.

      Global Initiative for Asthma. 2004 Update: Workshop Report, Global Strategy for Asthma Management and Prevention. Available at: http://www.ginaasthma.com/Guidelineitem.asp?11=2&12=1&intId=87. Accessed November 15, 2006.

      Studies looking at the correlation between guideline-based severity categories and objective markers of disease activity, such as pulmonary function tests and bronchial hyperreactivity, are few and contradictory. For example, the correlation of FEV1 measurement, the pulmonary function test most frequently used in consensus guidelines, with concurrent asthma symptoms is poor.
      • Spahn J.D.
      • Cherniack R.
      • Paull K.
      • Gelfand E.W.
      Is forced expiratory volume in one second the best measure of severity in childhood asthma?.
      • Colice G.L.
      • Burgt J.V.
      • Song J.
      • Stampone P.
      • Thompson P.J.
      Categorizing asthma severity.
      • Bacharier L.B.
      • Strunk R.C.
      • Mauger D.
      • White D.
      • Lemanske Jr., R.F.
      • Sorkness C.A.
      Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function.
      • Klein R.B.
      • Fritz G.K.
      • Yeung A.
      • McQuaid E.L.
      • Mansell A.
      Spirometric patterns in childhood asthma: peak flow compared with other indices.
      • Ramsey C.D.
      • Celedon J.C.
      • Sredl D.L.
      • Weiss S.T.
      • Cloutier M.M.
      Predictors of disease severity in children with asthma in Hartford, Connecticut.
      On the other hand, FEV1/forced vital capacity (FVC) ratio has been shown to correlate with asthma severity, as determined by the NAEPP guidelines.
      • Spahn J.D.
      • Cherniack R.
      • Paull K.
      • Gelfand E.W.
      Is forced expiratory volume in one second the best measure of severity in childhood asthma?.
      • Colice G.L.
      • Burgt J.V.
      • Song J.
      • Stampone P.
      • Thompson P.J.
      Categorizing asthma severity.
      • Bacharier L.B.
      • Strunk R.C.
      • Mauger D.
      • White D.
      • Lemanske Jr., R.F.
      • Sorkness C.A.
      Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function.
      • Klein R.B.
      • Fritz G.K.
      • Yeung A.
      • McQuaid E.L.
      • Mansell A.
      Spirometric patterns in childhood asthma: peak flow compared with other indices.
      • Ramsey C.D.
      • Celedon J.C.
      • Sredl D.L.
      • Weiss S.T.
      • Cloutier M.M.
      Predictors of disease severity in children with asthma in Hartford, Connecticut.
      Bronchial hyperreactivity is not considered by the NAEPP or GINA guidelines. Sont et al
      • Sont J.K.
      • Willems L.N.
      • Bel E.H.
      • van Krieken J.H.
      • Vandenbroucke J.P.
      • Sterk P.J.
      Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.
      showed that patients with asthma whose treatment was adjusted on the basis of the NAEPP guidelines and methacholine challenge results indicating bronchial hyperreactivity reported better asthma control and fewer asthma exacerbations than those managed with the NAEPP guidelines alone.
      Given the nature of the current literature regarding the correlation between severity categories determined by using consensus guidelines and objective markers of disease activity, this study took advantage of a clinically unique sample with detailed physiologic and clinical assessments to conduct a secondary analysis of how well severity levels correlated with this study's clinical asthma assessments. The study is part of a large multicenter study designed to evaluate the perception of asthma symptoms by adolescents 12 to 18 years of age. Adolescents with asthma and a history of a serious exacerbation after 5 years of age were compared with adolescents with asthma but without a history of a serious asthma exacerbation. After an asthma history was taken, each subject underwent full pulmonary function testing and a methacholine challenge to measure bronchial hyperreactivity. Because the subjects were already taking medications for the control of asthma, asthma severity categories were assigned by using the GINA guidelines.

      Global Initiative for Asthma. 2004 Update: Workshop Report, Global Strategy for Asthma Management and Prevention. Available at: http://www.ginaasthma.com/Guidelineitem.asp?11=2&12=1&intId=87. Accessed November 15, 2006.

      Our analysis compared the history of a serious asthma exacerbation with GINA-based asthma severity categories in terms of their ability to predict pulmonary function test results, bronchial hyperreactivity, and current disease activity. Additionally, we examined whether adding the clinical history of a serious exacerbation to the GINA guidelines–based asthma severity assessment would improve the ability of the severity categories to predict the variability in pulmonary function test results, bronchial hyperreactivity, and markers of current disease activity.

      Methods

      This National Heart, Lung, and Blood Institute–funded study of symptom perception in 12- to 18-year-old adolescents was conducted at Hasbro Children's Hospital in Rhode Island, the National Jewish Medical and Research Center in Colorado, and the University of Texas Health Center at Tyler. Institutional review boards at each site approved the study. Appropriate consents and assents were obtained.
      Subjects were recruited by means of referrals and advertisements and matched for age, sex, and ethnicity across 2 groups:
      • Group 1 included subjects with a physician diagnosis of asthma who were taking a daily controller medication for asthma and who had documentation of a serious asthma exacerbation after 5 years of age, as defined by intubation, seizure or loss of consciousness caused by asthma, continuous albuterol treatment for greater than 24 hours, and/or admission to the intensive care unit for asthma. These criteria are consistent with recently proposed criteria defining acute severe asthma.
        • McFadden Jr., E.R.
        Acute severe asthma.
      • Group 2 included asthma control subjects, defined as adolescents with a physician's diagnosis of asthma who were taking daily controller medications but who had never had a serious asthma exacerbation.
      Subjects were recruited and were matched across groups within each center for age, sex, and ethnicity. Subjects were excluded if they had any other chronic cardiac or respiratory illness, if their pregnancy test result was positive, or if they had sickle cell disease or trait. If a subject presented with an FEV1 value of less than 70% of predicted value on the day of the methacholine challenge, they were instructed to consult their physician and were rescheduled once their FEV1 value was confirmed to be greater than 70% of predicted value.

       Asthma severity assessment

      Asthma severity was based on the GINA guidelines for determining asthma severity in patients already taking controller medications.

      Global Initiative for Asthma. 2004 Update: Workshop Report, Global Strategy for Asthma Management and Prevention. Available at: http://www.ginaasthma.com/Guidelineitem.asp?11=2&12=1&intId=87. Accessed November 15, 2006.

      The overall severity score combined baseline percent predicted FEV1, medication taken over the last month, self-reported medication adherence data, and symptoms over the last year, as reported by parents on a standardized questionnaire, including nighttime symptoms, limitation of activity, and daytime symptoms.
      • Rosier M.J.
      • Bishop J.
      • Nolan T.
      • Robertson C.F.
      • Carlin J.B.
      • Phelan P.D.
      Measurement of functional severity of asthma in children.
      Severity categories were assigned by using an algorithm written in the SAS statistical software program (SAS, Cary, NC). A copy of this algorithm is available from the first author on request. Because treatment adherence is presumed but not formally included in the GINA guidelines, all analyses were performed with and without adherence data in the algorithm. Including self-reported adherence data did not change the results of any of the analyses.
      Baseline pulmonary function testing corrected for age, sex, height, and race was conducted according to American Thoracic Society guidelines.
      • American Thoracic Society
      Lung function testing: selection of reference values and interpretative strategies.
      The methacholine challenge was also performed according to American Thoracic Society guidelines.
      • Crapo R.O.
      • Casaburi R.
      • Coates A.L.
      • Enright P.L.
      • Hankinson J.L.
      • Irvin C.G.
      • et al.
      Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999.
      Methacholine challenge results were reported as the extrapolated dose at which FEV1 value decreased by 20% (PC20). A positive methacholine challenge result was defined as a PC20 value of less than or equal to 12.5 mg/mL, according to the protocol outlined in the Childhood Asthma Management Program study.
      • Nelson H.S.
      • Szefler S.J.
      • Jacobs J.
      • Huss K.
      • Shapiro G.
      • Sternberg A.L.
      The relationships among environmental allergen sensitization, allergen exposure, pulmonary function, and bronchial hyperresponsiveness in the Childhood Asthma Management Program.
      Markers of recent asthma disease activity, including steroid bursts, hospitalizations, emergency department visits, and days missed from school in the last year were assessed by using a standardized parent questionnaire. Socioeconomic status (SES) was assessed by using the highest of the parents' occupational and educational status.

       Statistical analysis

      JMP SAS software was used for all statistical analyses. Data analyses compared those with a history of a serious exacerbation with asthma control subjects and were performed by using t tests for continuous variables and χ2 tests for categoric variables. When asthma severity was analyzed as a binary variable to compare mild (mild intermittent and mild persistent) versus moderate/severe disease, χ2 and t-test analyses were used. When analyzing the 4 separate asthma severity levels, ANOVA techniques testing for differences between levels and for linear trends across severity levels were used, followed, when indicated, by Tukey-Kramer post-hoc tests. The data for number of steroid bursts, hospitalizations, emergency department visits, and school days missed in the past year were all transformed (ie, natural log[x+1]) because of nonnormal distributions. Stepwise hierarchic multiple regression analyses were used to ascertain whether the presence of a history of serious asthma exacerbation added to the variance explained in key clinical indicators of asthma activity over and above that caused by severity level determined by using the GINA guidelines. In these regressions severity level was forced to enter first, followed by serious exacerbation history. For each of these steps, the variance explained (R2) and statistical significance is reported. All results were reported as the mean ± SD. Statistical significance was defined as a P value of .05 or less.

      Results

       Subjects

      One hundred seventeen subjects with asthma from the 3 sites were enrolled in the study. All 117 subjects underwent spirometry and completed the questionnaires used for severity assignment; however, only 113 completed the methacholine challenge, and only 94 provided complete information about recent disease activity during the initial screening history and physical (Table I, Table II). The average age of the subjects was 14.59 ± 1.74 years, 56% were male, 58% were white, 17% were African American, and 25% described themselves as “other.” As expected, given the study design, no significant differences in age, sex, or race were found between the groups or the sites.
      Table IPulmonary function test results and markers of asthma morbidity within the 4 asthma severity levels determined by using GINA guidelines
      Pulmonary function testMild intermittent (mean ± SD)Mild persistent (mean ± SD)Moderate (mean ± SD)Severe (mean ± SD)ANOVA P value for linear trend
      Spirometry (n = 117)n = 17n = 17n = 31n = 52
      FEV1 (% predicted)102% ± 16%a100% ± 10%a85% ± 3%b89% ± 17%b.002
      FEV1/FVC (raw value)0.87 ± 0.76a0.82 ± 0.84a0.77 ± 0.11b0.79 ± 0.11b.007
      FEF25-75 (% predicted)101% ± 29%a87% ± 23%a68% ± 29%b73% ± 29%b.0003
       RV (% predicted)181.07% ± 113.89%191.51% ± 84.39%211.41% ± 124.48%209.98% ± 83.04%NS
       RV/TLC (raw value)0.22 ± 0.410.24 ± 0.540.27 ± 0.700.27 ± 0.61.007
      Methacholine challenge (n = 113)n = 17n = 17n = 29n = 50
       Positive (%)59826877NS
       PC20 (mg/mL)11.42 ± 11.835.88 ± 9.428.26 ± 10.146.20 ± 9.32NS
      Markers of asthma disease activity (n = 94)n = 12n = 15n = 20n = 47
       Age at diagnosis (y)6.68 ± 5.193.10 ± 2.264.60 ± 4.464.01 ± 3.69NS
       No. of hospitalizations in the last year0 ± 00.21 ± 0.430.17 ± 0.650.91 ± 2.28.02
       No. of emergency department visits in the last year0.08 ± 0.290.57 ± 0.850.48 ± 1.701.33 ± 2.31.009
       School days missed0 ± 03.29 ± 4.815.35 ± 9.8612.93 ± 26.33.004
       No. of steroid bursts in the last year0.17 ± 0.410.36 ± 0.500.47 ± 0.611.19 ± 1.97.006
      Differences in N values are due to differences in the ability to capture the data at the time of this publication. All values represent the mean ± SD. Superscript letters that are the same indicate no significant difference, whereas superscript letters that are different indicate a significant difference between the values at a P value of less than .05. Items in boldface are statistically significant.
      FEF25-75, Forced expiratory flow at 25% to 75% of forced vital capacity; NS, not significant.
      Table IIPulmonary function test results and markers of asthma morbidity for subjects with serious asthma exacerbations versus asthmatic control subjects
      Pulmonary function testSerious asthma exacerbation history (mean ± SD)Asthma control subjects (mean ± SD)P value
      Spirometry (n = 117)n = 48n = 69
       FEV1 (% predicted)90% ± 17%93% ± 16%NS
      FEV1/FVC (raw value)0.77 ± 0.110.81 ± 0.09.03
       FEF25-75 (% predicted)71% ± 31%82% ± 29%NS
      RV (% predicted)233% ± 108%183% ± 88%.007
       RV/TLC (raw value)0.28 ± 0.070.24 ± 0.05.0002
      Methacholine Challenge (n = 113)n = 47n = 66
      Positive (%)8261.002
      PC20 (mg/mL)4.04 ± 7.669.90 ± 10.79<.001
      Markers of asthma disease activity (n = 94)n = 40n = 54
      Age at diagnosis (y)3.35 ± 3.115.04 ± 4.39NS
       No. of hospitalizations in the last year0.74 ± 0.280.35 ± 0.22.02
       No. of emergency department visits in the last year1.00 ± 2.180.74 ± 1.66NS
      School days missed14.89 ± 28.203.24 ± 6.74.002
      No. of steroid bursts in the last year1.29 ± 2.050.39 ± 0.59.001
      Differences in N values are due to differences in the ability to capture the data at the time of this publication. Items in boldface are statistically significant.
      NS, Not significant; FEF25-75, forced expiratory flow at 25% to 75% of forced vital capacity.

       Serious exacerbation history

      Forty percent of subjects had a history of a serious asthma exacerbation after age 5 years. The average time from the most recent serious exacerbation was 3.1 ± 2.7 years. Analyses of SES variables showed that there were no significant differences in the parents' occupational categories between those with a history of a serious asthma exacerbation and those without. However, at least 1 parent was more likely to have attended some college or to have graduated from college in the group without a history of a serious asthma exacerbation (P = .03).

       Asthma severity

      By using the asthma severity algorithm, 42% of the subjects were categorized as having severe persistent asthma, 28% as having moderate persistent asthma, 15% as having mild persistent asthma, and 15% as having mild intermittent asthma. There were no significant differences in age, sex, race or SES across the 4 asthma severity groups or when severity was analyzed as 2 groups: mild (persistent and intermittent) versus moderate/severe. There were fewer subjects with mild asthma (intermittent or persistent) in the group with a history of a serious asthma exacerbation than among the asthmatic control subjects (14% vs 49%, P < .01).

       Pulmonary functions

      FEV1 was significantly associated with severity level (Table I). This is not surprising given that FEV1 is used in the GINA classification. All other variables of lung function except percent predicted residual volume (RV) showed increasing obstruction as severity increased. However, there were significant differences between individual severity categories only when the severity levels were combined to compare the mild group (mild intermittent and mild persistent) versus the moderate/severe group (FEV1/FVC: mild, 0.84 ± 0.82 vs moderate/severe, 0.77 ± 0.11 [P = .005]; RV/total lung capacity [TLC]: mild, 0.23 ± 0.48 vs moderate/severe, 0.27 ± 0.64 [P = .003]).
      The mean FEV1 value in the group with a history of a serious exacerbation was similar to that seen in those without a history of a serious exacerbation (Table II). However, the group with a history of a serious exacerbation had significantly more airflow obstruction (lower FEV1/FVC ratios) and more gas trapping corrected for lung volumes (higher RV/TLC ratios) compared with that seen in the asthma control group (Table II). When the subjects with mild asthma were excluded from the analysis of those with a history of a serious asthma exacerbation versus those without, the results were the same as the initial analysis: the FEV1/FVC ratio was still significantly lower in the serious exacerbation group (0.75 ± 0.11 for the group with a history of a serious exacerbation vs 0.80 ± 0.10, P = .03), and the percent predicted RV (244% ± 109% vs 176% ± 74%, P = .002) and RV/TLC (0.29 ± 0.07 vs 0.24 ± 0.04, P = .0007) were significantly higher in the serious exacerbation group.

       Bronchial hyperreactivity

      PC20 values were not significantly different as severity increased across the 4 individual severity groups or when asthma severity categories were combined into mild versus moderate/severe (Table I). In contrast, adolescents with a history of a serious asthma exacerbation had a significantly lower PC20 value than the asthma control group and were significantly more likely to have a positive methacholine challenge result (PC20 < 12.5 mg/mL, Table II) than adolescents without such history. When the subjects with mild asthma were excluded from the analysis of PC20 values by exacerbation history, the results remained the same. In fact, the PC20 value was even lower in the serious exacerbation group (3.13 ± 6.62 for the group with a history of a serious exacerbation versus 10.87 ± 10.67, P = .0002, Table II).
      Because some subjects had PC20 values of greater than 12.5 mg/mL, all analyses of pulmonary function and markers of disease activity were repeated, excluding such subjects. Results were unchanged for analyses comparing the severity categories. For analyses involving exacerbation history, all results remained the same, except the FEV1/FVC difference was no longer statistically significantly (P = .07).

       Markers of asthma disease activity

      Steroid bursts, hospitalizations, emergency department visits, and days missed from school all increased as GINA-based asthma severity increased, although post-hoc tests did not reveal a significant difference between any specific severity categories or across the mild versus moderate/severe grouping (Table I). In contrast, adolescents with a history of a serious exacerbation were more likely to be hospitalized, received more steroid bursts, and missed more days of school in the last year compared with the asthma control subjects (Table II). Again, when those with mild asthma were excluded from the analyses of those with and without a serious exacerbation history, the results were the same.

       Does knowledge of serious exacerbation history add to GINA severity classification?

      Table III contains the results of stepwise hierarchic multiple regression examining whether the history of a serious asthma exacerbation augments the ability of GINA-based asthma severity categories to predict lung function, bronchial hyperreactivity, and markers of disease activity. The serious exacerbation history improved on the ability of severity classification to explain variance in all of the markers of asthma activity listed in Table III, except for FEV1/FVC, forced expiratory flow at 25% to 75% of forced vital capacity (FEF25-75), and the number of emergency department visits in past year.
      Table IIIStepwise hierarchic regression analyses examining whether the presence of a history of a serious asthma exacerbation improves the prediction of asthma disease activity markers over and above GINA-based severity categories
      Percentage of variance explained (R2) and significance
      Step 1, initial R2Step 2, R2 change
      Asthma variableGINA-based severity categoriesSerious asthma exacerbation historyTotal model R2
      FEV1/FVC6.09%‡1.95%8.04%
      FEF25-75 (% predicted)10.59%§NS10.59%
      RV (% predicted)1.13%5.49%†6.62%
      RV/TLC6.44%‡7.82%‡14.26%
      PC201.94%6.80%‡8.76%
      Steroid bursts (in past year)9.50%‡10.29%‡19.79%
      Hospitalizations (in past year)6.15%†3.92%†10.07%
      Emergency department visits (in past year)7.44%‡NS7.44%
      School days missed (in past year)13.56%§6.21%†19.77%
      FEF25-75, Forced expiratory flow at 25% to 75% of forced vital capacity; NS, variable did not enter.
      Statistical significance in the hierarchic model is indicated as follows: P < .15, †P < .05, ‡P < .01, and §P < .001.

      Discussion

      In this sample of adolescents, a history of a serious asthma exacerbation after 5 years of age and increasing asthma severity were clearly associated with full pulmonary functions and markers of current symptom control, whereas only a history of a serious asthma exacerbation was able to predict bronchial hyperreactivity. Adding the history of a serious asthma exacerbation significantly improved the ability of GINA-based asthma severity to predict important markers of asthma disease activity.
      The ability of guidelines-based asthma severity to predict airway obstruction and air trapping is consistent with recent reports in the literature.
      • Spahn J.D.
      • Cherniack R.
      • Paull K.
      • Gelfand E.W.
      Is forced expiratory volume in one second the best measure of severity in childhood asthma?.
      • Bacharier L.B.
      • Strunk R.C.
      • Mauger D.
      • White D.
      • Lemanske Jr., R.F.
      • Sorkness C.A.
      Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function.
      • Ramsey C.D.
      • Celedon J.C.
      • Sredl D.L.
      • Weiss S.T.
      • Cloutier M.M.
      Predictors of disease severity in children with asthma in Hartford, Connecticut.
      However, the asthma severity categories did not predict bronchial hyperreactivity. Our data contradict previous data from the Childhood Asthma Management Study, which found that NAEPP-based asthma severity did predict increased bronchial hyperreactivity in a population of patients with less severe asthma.
      • Weiss S.T.
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      This study is the largest study showing that the history of a serious asthma exacerbation is associated with increased airway obstruction and air trapping, as well as increased bronchial hyperreactivity. Remarkably, these differences persist despite the variable length of time (0.4-5.8 years) from the serious exacerbation. Furthermore, a history of a serious asthma exacerbation improved on the ability of GINA-based severity categories to explain variance in important markers of asthma disease activity. These data help to explain why several recent studies have shown that the best predictor for being seen in the hospital or emergency department for the treatment of asthma is the history of a previous visit to the emergency department, hospital ward, or intensive care unit.
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      looking at airway inflammation in subjects with moderate persistent asthma. Although La Grutta et al found that children with moderate persistent asthma determined by using GINA guidelines had higher levels of IL-8 and exhaled nitric oxide than those with mild intermittent asthma, they also found there was significant variation in the level of inflammation within those with moderate persistent asthma. Therefore it is possible that within severity groups there are different phenotypes of asthma, some with significant bronchial hyperreactivity (and possibly airway inflammation) and some without. On the other hand, these findings contradict Delgado-Corcoran et al,
      • Delgado-Corcoran C.
      • Kissoon N.
      • Murphy S.P.
      • Duckworth L.J.
      Exhaled nitric oxide reflects asthma severity and asthma control.
      who found that exhaled nitric oxide concentrations increased across mild, moderate, and severe asthma severity categories. The lung function and bronchial hyperreactivity data in the groups with and without a serious asthma exacerbation suggest that adolescents with a history of a serious asthma exacerbation might fit into a specific asthma phenotype of children with increased bronchial hyperreactivity, airway obstruction, and, possibly, lung inflammation. However, because the relationship between bronchial hyperreactivity and airway inflammation is controversial,
      • Joseph-Bowen J.
      • de Klerk N.
      • Holt P.G.
      • Sly P.D.
      Relationship of asthma, atopy, and bronchial responsiveness to serum eosinophil cationic proteins in early childhood.
      • Silvestri M.
      • Spallarossa D.
      • Battistini E.
      • Brusasco V.
      • Rossi G.A.
      Dissociation between exhaled nitric oxide and hyperresponsiveness in children with mild intermittent asthma.
      • Franklin P.J.
      • Turner S.W.
      • Le Souef P.N.
      • Stick S.M.
      Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children.
      alternate explanations also need to be considered.
      There are several limitations of this study. First, the age range of our subjects is relatively narrow, and results might not hold for younger children or adults. Further studies need to be conducted to see whether the findings can be replicated in adolescents and generalized to individuals younger than 12 years and older than 18 years and to adults with adult-onset asthma.
      Second, asthma symptoms were assessed retrospectively and reported by the parent and therefore might be affected by recall and reporter bias. Similarly, markers of disease activity, especially days missed from school, could have been increased in those with a history of a serious asthma exacerbation because of increased parental awareness and concern. However, findings with these self-reported measures are in the same direction as those found with more objective outcomes, such as pulmonary function test and methacholine challenge results.
      Third, a potential confounder in our results is the number of subjects who had a PC20 value of greater than 12.5 mg/mL, raising the concern that these subjects did not have asthma or had only very mild asthma. However, as discussed above, excluding subjects with a PC20 value of greater than 12.5 mg/mL did not change the observed results. Additionally, although the differences in lung function seen in this study were statistically significant, they might not be considered clinically significant. The mean RV/TLC ratios are normal according to American Thoracic Society guidelines
      • American Thoracic Society
      Lung function testing: selection of reference values and interpretative strategies.
      across all of the severity groups and between the groups with a serious asthma exacerbation and those without. The FEV1/FVC ratio is only slightly less than 0.8 (indicating obstruction) in those with moderate (0.77) and severe persistent (0.79) asthma and those with the history of a severe asthma exacerbation (0.77). Similarly, the variance explained in asthma outcomes by both severity group and exacerbation history is relatively small (with a maximum of 20%), indicating that there are other important factors involved in determining such outcomes.
      In summary, this study evaluated how well the history of a serious asthma exacerbation and GINA-based asthma severity categories predict asthma disease activity. Asthma severity and the history of a serious asthma exacerbation both predicted clinically important markers of asthma activity. However, only a history of a serious asthma exacerbation was associated with bronchial hyperreactivity. In addition, the history of a serious asthma exacerbation added to the predictive power of the GINA-based asthma severity ratings for virtually all clinical variables. Hence exacerbation history shows promise as an important clinical indicator to help guide clinicians to manage patients with asthma. Further prospective studies are needed to delineate the full set of factors involved in determining asthma disease activity and future clinical course and to indicate which of those factors should be incorporated into the consensus guidelines for the treatment of asthma. For example, if future studies demonstrate that the increased bronchial hyperreactivity seen in patients with the history of a prior serious exacerbation actually places them at greater risk for recurrent asthma exacerbations, these patients might especially benefit from adjusting treatment based on repeat assessments of bronchial hyperreactivity.
      • Sont J.K.
      • Willems L.N.
      • Bel E.H.
      • van Krieken J.H.
      • Vandenbroucke J.P.
      • Sterk P.J.
      Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.
      In conclusion, the data from this study clearly indicate that adding the history of a serious asthma exacerbation to the criteria in consensus guidelines for asthma severity should improve the ability of these clinical tools to predict current disease activity and future clinical course.
      We thank Gary Larsen, MD; Stan Szefler, MD; and Hal Nelson, MD, for their consultation with this article. We would also like to thank Natalie Walders, PhD, for her contributions to the manuscript.

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