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. Author manuscript; available in PMC: 2017 Jul 1.
Published in final edited form as: Ann Allergy Asthma Immunol. 2016 May 26;117(1):97–99. doi: 10.1016/j.anai.2016.04.029

The Association of FEF25–75 and Bronchodilator reversibility with Asthma Control and Asthma Morbidity in Inner City Children with Asthma

Watcharoot Kanchongkittiphon a,b, Jonathan M Gaffin c,d, Lianne Kopel e, Carter R Petty f, Mary E Bollinger g, Rachel Miller h,i, Matthew Perzanowski i, Elizabeth C Matsui j, Wanda Phipatanakul d,k
PMCID: PMC4930883  NIHMSID: NIHMS790466  PMID: 27236218

Spirometry is recommended by the National Asthma Education and Prevention Program guidelines as a tool for assessing asthma severity and control. The guidelines assess asthma severity and control by both clinical symptoms and forced expiratory volume in 1 second (FEV1) percent predicted. However, FEV1 is often normal in children with asthma, regardless of severity1.

Forced expiratory flow at 25% to 75% of forced vital capacity (FEF25-75) percent predicted is regarded as a more sensitive measure of small airway obstruction. It has been shown that a low FEF25-75 was associated with increased asthma severity and that low FEF25–75 may represent a risk factor for the persistence of symptoms in children with asthma2.

Previous studies have also demonstrated that an elevated bronchodilator response (BDR), defined as at least a 12% increase in FEV1 following administration of short acting beta agonist, is associated with increased airway inflammation, and poor clinical asthma outcomes3, 4.

We aimed to determine whether FEF25-75 and BDR are associated with asthma morbidity in urban children with asthma, independent of the guidelines-endorsed measure of FEV1 and FEV1/FVC.

Baseline data from subjects enrolled in 2 studies, School Inner-City Asthma Study (SICAS) during 2008–2012 and the Mouse Allergen and Asthma Intervention Trial (MAAIT) during 2010–2014, were used. Full methods including inclusion and exclusion criteria for the SICAS and MAAIT are published elsewhere5,6. Subjects with incomplete spirometry data were excluded. Pulmonary function testing was performed according to the recommendations of the American Thoracic Society guidelines and standardized to the Third National Health and Nutrition Examination Survey (NHANES) reference values for percent predicted7. Children younger than 8 years old were excluded due to limitations of NHANES reference values in this age group8. Post-bronchodilator spirometry was obtained approximately 15 minutes after nebulized albuterol. A normal FEF25-75 was defined as ≥ 75.5% predicted according to the lower limit of normal 95% confidence interval for FEF25-75 in study participants. BDR was calculated as the percent change from baseline for FEV1 by the equation: BDR = [(post-bronchodilator FEV1- pre-bronchodilator FEV1)/(pre-bronchodilator FEV1)]×100. BDR was defined as positive if there was a change in FEV1 ≥12%7.

Morbidity outcomes included the presence of any wheezing/chest tightness/cough, report of slowing down/stopping play or activities, nocturnal wheezing, and any missed school days due to asthma. We estimated unadjusted and adjusted odds ratios using logistic regression models. Statistical analyses were completed using IBM SPSS Statistics version 19.

Overall, 186 subjects from SICAS and 404 subjects from MAAIT met inclusion criteria. Regarding demographic characteristics of included subjects, mean study participants’ age was 11 years old. 59% of study participants were male. The majority of the subjects were Black and Hispanic (68%) with an annual family income of less than $25,000 per year. Minority of subjects had reported exposure to tobacco smoke (34%). Regarding spirometry indices, 24% of the study participants had FEF25-75% predicted less than 75.5%. Most subjects had persistent asthma with normal lung function in which 79% of subjects had FEV1% predicted ≥ 80%, and 63% of subjects had FEV1/FVC ≥ 80%.

Table 1 illustrates the relationship between lung function testing and clinical symptoms. SICAS subjects with a low FEF25-75 (n=54) had greater odds of asthma symptoms in the past 2 weeks compared with those with a normal FEF25-75. After adjusting for sex, age, race, income, secondhand smoke exposure, and body mass index (BMI), subjects with a low FEF25-75 had higher odds of nocturnal wheezing, odds ratio (OR) 2.1, 95% confidence interval (CI) 1.0–4.2, and higher odds of school absence due to asthma, OR 4.3, 95% CI 1.2–14.8, compared with those with a high FEF25-75. Similarly, MAAIT subjects with low FEF25-75 (n=85) had higher odds of reporting having to slow down/stop play and/or activities in the past 2 weeks compared to those with a normal FEF25-75 even adjusted for FEV1/FVC. However, in both cohorts, low FEF25-75 was not an independent predictor for poor outcomes when FEV1 % predicted was included in the model.

Table 1.

Association of FEF25-75 and BDR with asthma morbidity in last 2 weeks

Symptoms FEF25-75< 75.5%
BDR>12%
odds ratio (95% CI) adjusteda odds ratio (95% CI) adjustedb odds ratio (95% CI) adjustedc odds ratio (95% CI) odds ratio (95% CI) adjusteda odds ratio (95% CI) adjustedb odds ratio (95% CI) adjustedc odds ratio (95% CI)
SICAS cohort
Any wheezing/chest tightness/cough 1.1 (0.6–2.1) 1.1 (0.6–2.2) 1.2 (0.5–2.9) 0.9 (0.4–2.0) 1.0 (0.4–2.5) 1.2 (0.4–3.4) 1.2 (0.4–3.9) 1.0 (0.3–3.1)
Slow down/stop play/activities 1.4 (0.8–2.7) 1.6 (0.8–3.2) 1.2 (0.5–2.8) 1.6 (0.7–3.6) 1.2 (0.5–2.9) 1.1 (0.4––2.9) 0.7 (0.2–2.2) 1.1 (0.3–3.3)
Nocturnal wheezing 1.8 (0.9–3.4) 2.1 (1.0–4.2)* 1.4 (0.6–3.5) 1.8 (0.8–4.2) 2.2 (0.9–5.6) 2.4 (0.9–6.8) 1.2 (0.4–4.0) 2.4 (0.7–7.7)
Missed school day due to asthma 2.6 (0.9–8.0) 4.3 (1.2–14.8)* 1.7 (0.3–8.5) 3.7 (0.8–16.8) 7.2 (1.8–29.2)* 18.8 (2.5–138.6)* 9.6 (1.1–86.7)* 13.5 (1.5–120.2)*
MAAIT cohort
Any wheezing/chest tightness/cough 1.6 (0.9–2.8) 1.5 (0.8–2.6) 1.1 (0.6–2.2) 0.8 (0.3–1.8) 1.3 (0.8–2.2) 1.3 (0.8–2.2) 1.3 (0.8–2.2) 1.3 (0.8–2.1)
Slow down/stop play/activities 1.8 (1.1–2.9)* 1.7 (1.0–2.9)* 1.7 (0.9–3.2) 1.5 (0.7–3.2) 1.4 (0.9–2.2) 1.6 (1.0–2.5) 1.5 (0.9–2.4) 1.5 (0.9–2.3)
Nocturnal wheezing 1.7 (1.1–2.8)* 1.8 (1.1–2.9)* 1.5 (0.8–2.6) 1.1 (0.5–2.2) 1.4 (0.9–2.2) 1.5 (1.0–2.3) 1.4 (0.9–2.2) 1.3 (0.9–2.1)
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*

p<0.05

a

Adjusted for BMI, Gender, Age, Race, Income, Smoking

b

Adjusted for BMI, Gender, Age, Race, Income, Smoking, FEV1/FVC

c

Adjusted for BMI, Gender, Age, Race, Income, Smoking, FEV1

Linear regression models including 130 subjects from SICAS and 404 subjects from MAAIT with BDR testing found that subjects with positive BDR (SICAS, n=33, MAAIT, n=126) demonstrated a non-significant trend for association with greater asthma symptoms for the majority of outcomes tested, and was significantly associated with school absenteeism in SICAS. BDR in children with asthma is associated with increased airway inflammation and this may mediate the association seen in our current study.

FEF25-75 has recently received attention as a possible marker of worsened asthma control and risk for future morbidity in children2 presenting for clinical pulmonary function testing at a tertiary care center. In the cohorts included in the current study, mainly representative of children of black and Hispanic background with persistent asthma, similar trends were observed. However, the relationship between FEF25-75 and increased asthma symptoms and markers of exacerbations was not independent of the association with FEV1% predicted. This suggests that while the FEF25-75 may be an important measure of lung function that relates to important clinical outcomes, its additive value in determining loss of asthma control is limited when the FEV1 percent predicted is considered. Although FEF25-75 may be a more sensitive marker of small and medium sized airflow limitation, the hallmark of asthma, its higher coefficient of variability8 may sufficiently limit its ability to specifically identify lack of control.

A strength of this study is the large and well characterized participants from 2 inner-city children population cohort. However, we acknowledge several limitations to this analysis. Although asthma morbidity outcomes were not significantly associated with low FEF25-75 and positive BDR, most odds ratio values were consistently greater than 1, a trend that suggests the FEF25-75 relationships are not spurious. Furthermore, there is a lack of consensus of normal range for FEF25-75. While low FEF25-75 and poor clinical outcomes have been previously described in asthmatic children the absolute normal cutoff level for FEF25-75 has not been firmly established. Previous studies have cut-off values ranging from 60%–80%2, 9–10. We chose 75.5% as a cutoff based on the findings of other published studies and the distribution of data in our cohort. Similar debate over clinically significant BDR exists11, as well.

In conclusion, in urban asthmatic children, BDR might be considered in assessing asthma severity and morbidity outcomes. FEF25-75 is associated with symptoms, but its utility independent of FEV1/FVC or FEV1 is likely limited. Future studies are necessary in order to better understand the role of FEF25-75 and BDR as predictors of morbidity and markers of loss of control.

Acknowledgments

Funding: This study was supported by grants R01 AI 073964, K24 AI 106822, K24 AI 114769, K23 AI 106945, U01 AI 110397, U01 Al 083238, P30 ES009089 from the National Institutes of Health

This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102, and financial contributions from Harvard University and its affiliated academic healthcare centers.

Abbreviations

FEV1

Forced expiratory volume in 1 second

FEF25-75

Forced expiratory flow at 25% to 75% of forced vital capacity

BDR

Bronchodilator response

SICAS

School Inner-City Asthma Study

NHANES

National Health and Nutrition Examination Survey

BMI

Body mass index

OR

Odds ratio

CI

Confident interval

Footnotes

Conflict(s) of interest: All authors have no conflict of interest

Trial registration: Not applicable

The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health.

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