Forced midexpiratory flow between 25% and 75% of forced vital capacity is associated with long-term persistence of asthma and poor asthma outcomes

doi:10.1016/j.jaci.2015.10.029

Journal of Allergy and Clinical Immunology

Volume 137, Issue 6, June 2016, Pages 1709-1716.e6

https://doi.org/10.1016/j.jaci.2015.10.029 Get rights and content

Background

Whether small-airway obstruction contributes to the long-term evolution of asthma remains unknown.

Objectives

Our aim was to assess whether the level of forced midexpiratory flow between 25% and 75% of forced vital capacity (FEF_25-75) was associated with the persistence of current asthma over 20 years and the subsequent risk for uncontrolled asthma independently of FEV₁.

Methods

We studied 337 participants (142 children and 225 adults) with current asthma (asthma attacks or treatment in the past 12 months) recruited to the Epidemiological Study on the Genetics and Environment of Asthma (EGEA1) and followed up at the 12- and 20-year surveys. Persistent current asthma was defined by current asthma reported at each survey. A lung function test and a methacholine challenge test were performed at EGEA1 and EGEA2. Adjusted odds ratios (ORs) were estimated for FEF_25-75 decreased by 10% of predicted value.

Results

A reduced level of FEF_25-75 at EGEA1 increased the risk of long-term asthma persistence (adjusted OR, 1.14; 95% CI, 1.00-1.29). In children the association remained significant after further adjustment for FEV₁ and in participants with FEV₁ of greater than 80% of predicted value. A reduced FEF_25-75 level at EGEA1 was significantly associated with more severe bronchial hyperresponsiveness (P < .0001) and with current asthma a decade later, with an association that tended to be stronger in those with (adjusted OR, 1.44; 95% CI, 1.14-1.81) compared with those without (adjusted OR, 1.21; 95% CI, 1.05-1.41) asthma exacerbation.

Conclusion

Our analysis is the first to suggest that small-airway obstruction, as assessed based on FEF_25-75, might contribute to the long-term persistence of asthma and the subsequent risk for poor asthma outcomes independently from effects of the large airways.

Section snippets

Population

The Epidemiological Study on the Genetics and Environment of Asthma (EGEA; https://egeanet.vjf.inserm.fr) is a French cohort including a group of asthmatic patients with their first-degree relatives and a group of control subjects recruited in the early 1990s and followed up for 20 years.¹⁷ In total, 2047 adults and children were recruited from 1991 to 1995 (EGEA1). A first follow-up of the EGEA population was conducted from 2003 to 2007 (EGEA2; 1845 subjects),¹⁸ and a second follow-up was

Population description

For more information, see Table I. The mean ages of the 142 children (39% girls) and 239 adults (56% women) with current asthma at baseline were 10.8 and 37.6 years, respectively. Among the children, 62.7% had early-onset asthma, and half of the adult population had adult-onset asthma. About half of the adults and one fourth of the children had moderate to severe persistent asthma (as previously defined²³). One third of the children and 60% of the adults have used ICSs in the past 12 months.

Discussion

Our analysis in a long-term follow-up cohort is the first to suggest that FEF_25-75 values might contribute to the long-term evolution of asthma independently from FEV₁. This study adds to the existing evidence that small-airways obstruction warrants greater attention in epidemiologic studies and in the follow-up of asthmatic patients.

One of the strengths of the EGEA relies on the phenotypic characterization of the population, including lung function measurements by trained clinical research

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The objective of this review is to provide new advances in our understanding of the clinical importance of establishing peripheral airway impairment (PAI) by impulse oscillometry (IOS) and targeted therapy, which could result in better asthma outcomes. Data sources include PubMed and Google search, limited to English language and human disease, with key words IOS and asthma. Key findings include PAI being consistently associated with uncontrolled asthma across ethnicities, using IOS reference equations factoring Hispanic and White reference algorithms. It is noted that PAI is common even in patients considered well-controlled by asthma guidelines. In a large longitudinal analysis (Assessment of Small Airways Involved in Asthma or ATLANTIS study), a composite of R5-R20, AX, and X5 ordinal scores were independently predictive of asthma control and exacerbation in a multivariate analysis, but forced expiratory volume in 1 second was not significantly predictive of morbidities. However, combining forced expiratory volume in 1 second less than 80% with PAI resulted in greater odds of identifying uncontrolled asthma and exacerbations, than either alone. Applying an external validation method in children with asthma offers the clinician the IOS reference equations best fit for their own specific population. Several clinical phenotypes can also identify PAI with high probability, useful when IOS is not available. Poor asthma outcomes for obese patients with asthma are associated with dysanapsis and PAI, not obesity alone. Extrafine inhaled corticosteroids achieve better asthma control and improve peripheral airway function with fewer exacerbations at lower dosages than nonextrafine inhaled corticosteroid aerosols. In conclusion, these data support the benefit of adding IOS to spirometry in future asthma guidelines and suggest the potential benefit from targeted therapy.
Long-Term Efficacy and Safety Among Patients With Severe Eosinophilic Asthma Treated With Mepolizumab and Its Effect on Small Airways
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The major problem at the Cleveland Allergy and Asthma Center was the need for additional therapy for severe eosinophilic asthma patients who were steroid-dependent or required frequent bursts of prednisone.
The objectives of this study were to determine the efficacy of monthly mepolizumab (MP) injections up to 6½ years using Asthma Control Quesitonnaire-7 (ACQ-7), forced expiratory volume in 1 second (FEV₁), forced expiratory flow at 25% to 75% (FEF_25%–75%) overall and among super-responders, and to understand whether FEF_25%–75% is an effective parameter to evaluate MP efficacy.
We reviewed the charts of 67 patients with severe eosinophilic asthma and compared the results between 47 super-responders and the rest of the cohort regarding ACQ-6, ACQ-7, eosinophils, FEV₁, and FEF_25%–75%. The groups of super-responders and all other patients were described with respect to initial and current values of the study end points using medians and 25th and 75th percentiles. Changes from the initial to the current values in the study end points were measured using percent changes. The Wilcoxon signed rank test was used within each group to test the null hypothesis of 0 median percent change.
After 6½ years, there were no significant changes in FEV₁. The FEF_25%–75%, had a significant median percent increase of 40% among the super-responders (P < .001), which was substantially higher (P = .026) than the median percent increase of 13.8% observed among all other patients.
The use of MP up to 6½ years was safe and effective, with significant changes to ACQ-7 and FEF_25%–75% associated with MP treatment, but not the FEV₁. A higher magnitude of changes was observed among super-responders than the rest of the cohort. Changes in FEF_25%–75% were more meaningful than changes in FEV₁ in evaluating pulmonary function responsiveness of severe eosinophilic asthma to MP.
In young children with asthma, obesity and uncontrolled disease are highly associated with peripheral airway impairment
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Despite the fact that impulse oscillometry (IOS)-determined peripheral airway impairment (PAI) phenotype is a major risk factor for uncontrolled asthma, IOS is seldom used clinically.
To identify clinical characteristics that can best identify the PAI phenotype.
Clinical characteristics and spirometry results were compared in 227 patients with asthma with the PAI phenotype determined by resistance and reactance values that exceeded IOS‑predictive normal values using Gochicoa-Rangel equations. Logistic regression analyses determined factors associated with PAI phenotype, with risk classification based on predicted probability from the final adjusted model.
Analysis for identifying PAI, present in 37% of our population, revealed statistically significant odds ratio (OR) for age (4-7 years), of 3.75 (1.47-9.55) (P = .006), obesity OR of 2.59 (1.36-4.96) (P = .004), uncontrolled asthma OR of 2.77 (1.34-5.74) (P = .006), and abnormal forced expiratory flow between 25% and 75% (FEF25%-75%) (<65%) OR of 4.22 (1.59-11.20) (P = .004). For identifying PAI in those considered well controlled, key characteristics were age (4-7 years), OR of 2.81 (1.10-7.18) (P = .03), and obesity, OR of 2.18 (1.09-4.39) (P = .03). For those 4 to 7 years old, who were obese and had uncontrolled disease, probability of PAI was greater than or equal to 80%, regardless of FEF 25%-75%. Probabilities from logistic regression analyses to identify PAI were associated with an area under the curve of 0.750, and applying standard threshold of greater than or equal to 0.50 probability for identification produced sensitivity at 49.4%, specificity at 85.3%, positive predictive value at 66.1%, negative predictive value at 74.4%, and accuracy at 72.1%.
Clinical characteristics of age at 4 to 7 years, obesity, uncontrolled asthma, and FEF 25%-75% (<65%) identify PAI with high specificity and accuracy. This approach offers the clinician a practical method for strongly considering the presence of PAI when IOS is not available.
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Environmental research on multifactorial health outcomes calls for exposome approaches able to assess the joint effect of multiple exposures.
Our aim was to identify profiles of exposure to lifestyle/environmental factors associated with lung function in adults with asthma using a cluster-based approach.
We used data from 599 adults of the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) (mean age 39.0 years, 52% men) who ever had asthma. Exposures to 53 lifestyle/environmental factors were assessed by questionnaires or geographic information systems-based models. A two-step approach was developed: 1) exposome dimension reduction by selecting factors showing association with forced expiratory volume in 1 s (FEV₁) (p < 0.20) in an exposome-wide association study (ExWAS), 2) clustering analysis using the supervised Bayesian Profile Regression (sBPR) to group individuals according to FEV₁ level and to their profile of exposure to a reduced set of uncorrelated exposures (each paired correlation<0.70) identified in step 1.
The ExWAS identified 21 factors showing suggestive association with FEV₁ (none significant when controlling for multiple tests). The sBPR conducted on 15 uncorrelated exposures identified in step 1, revealed 3 clusters composed of 30, 115 and 454 individuals with a mean ± SD FEV₁(%pred) of 79% ± 21, 90% ± 19 and 93% ± 16, respectively. Cluster 1 was composed of individuals with heavy smoking, poor diet, higher outdoor humidity and proximity to traffic, while cluster 2 and 3 included individuals with moderate/low levels of exposure to these factors.
This exposome study identified a specific profile of joint lifestyle and environmental factors, associated with a low FEV₁ in adults with asthma. None of the exposures revealed significant association when considered independently.
Mepolizumab effectiveness on small airway obstruction, corticosteroid sparing and maintenance therapy step-down in real life
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Citation Excerpt :
The forced expiratory flow at 25–75% of FVC (FEF25–75%) is the spirometric variable most commonly cited as an indicator of small airway obstruction in literature [17]. Such small airway impairment, as assessed with FEF25-75, might contribute to long-term persistent asthma and the subsequent risk for poor asthma outcomes, independently of large airway status [18]. According to recent articles, MEP can significantly improve small airways in severe eosinophilic asthma measured with multiple breath nitrogen washout [19].
Mepolizumab (MEP) has been recently introduced to treat severe eosinophilic asthma. Trials have demonstrated a significant effectiveness in this asthma phenotype. We evaluated MEP efficacy on lung function, symptoms, asthma exacerbations, biologic markers, steroid dependence and controller treatment level in real-life.
We retrospectively analyzed 134 severe asthmatics (61 males; mean age 58.3 ± 11; mean FEV₁%:72 ± 21), treated with MEP for at least 6 months (mean duration:10.9 ± 3.7 months).
FEV₁% improved significantly after MEP. Mean FEF_25-75 also increased from 37.4 ± 25.4% to 47.2 ± 27.2% (p < 0.0001). Mean baseline blood eosinophil level was 712 ± 731/μL (8.4 ± 5.2%) decreasing to 151 ± 384/μL (1.6 ± 1.6%) (p < 0.0001), FENO levels decreased likewise. MEP treatment also led to a significant ACT improvement (mean pre:14.2 ± 4.4; mean post:20.5 ± 28) and exacerbations significantly fell from 3.8 ± 1.9 to 0.8 ± 1.1 (p < 0.0001). 74% of patients were steroid-dependent before MEP. 45.4% and 46.4% of them showed a suspension and dose reduction respectively (p < 0.0001). A significant number reduced also ICS doses. Only 67% of subjects used SABA as needed before MEP, falling to 20% after MEP. About 40% of patients highlighted a maintenance therapy step-down. Subjects showing an omalizumab treatment failure before MEP had a similar positive response when compared with omalizumab untreated patients.
In real-life, MEP improved significantly all outcomes even small airway obstruction, suggesting its possible role also in distal lung region treatment. Furthermore, it demonstrated its high effectiveness in OC/ICS-sparing, in reducing SABA as needed and in stepping-down maintenance therapy. MEP is a valid alternative for patients with previous omalizumab treatment failure.
Establishment and application of reference equations for FEF<inf>50</inf> and FEF<inf>75</inf> in the Chinese population
2024, Journal of Thoracic Disease

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: Data collection and analysis funded in part by the Hospital Program of Clinical Research (PHRC)–Paris, PHRC-Grenoble, National PHRC 2012, the scientific committee “AGIR pour les Maladies Chroniques,” Merck Sharp & Dohme (MSD), and the GA²LEN project (Global Allergy and Asthma European Network).

: Disclosure of potential conflict of interest: V. Siroux receives research support from the Hospital Program for Clinical Research and AGIR “pour les Maladies Chroniques” and receives speakers' fees from Edimark Sante and Teva. S. Chanoine receives travel support from Actelion France, GlaxoSmithKline, Chiesi, and LFB. J. Bousquet serves as a consultant for Actelion, Almirall, Meda, Merck, Merck Sharp Dohme, Novartis, Sanofi-Aventis, Takeda, Teva, and Uriach. J. Just serves as a board member for Novartis and ALK-Abelló and receives speakers' fees from Novartis, ALK-Abelló, Stallergenes, and Chiesi. R. Nadif provides expert testimony for Anses and receives research support from the Hospital Program for Clinical Research. C. Pison receives consulting fees and travel support from AstraZeneca France, GlaxoSmithKline France, Novartis France, and Boehringer Ingelheim France. I. Pin receives speakers' fees from GlaxoSmithKline and Novartis and travel support from GlaxoSmithKline, Novartis, and Chiesi. The rest of the authors declare that they have no relevant conflicts of interest.

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Asthma and lower airway diseaseForced midexpiratory flow between 25% and 75% of forced vital capacity is associated with long-term persistence of asthma and poor asthma outcomes

Background

Objectives

Methods

Results

Conclusion

Section snippets

Population

Population description

Discussion

J Allergy Clin Immunol

Lancet Respir Med

Ann Allergy Asthma Immunol

Am J Med

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Heart Lung Transplant

J Heart Lung Transplant

J Allergy Clin Immunol

J Allergy Clin Immunol

The lung's “quiet zone”

N Engl J Med

Physiological measurement of the small airways

Respiration

The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity

J Asthma

Parental smoking and lung function in children: an international study

Am J Respir Crit Care Med

Occupational exposure to vapors, gases, dusts, and fumes is Associated with small airways obstruction

Am J Crit Care Med

Small airway dysfunction is associated with poorer asthma control

Eur Respir J

Asthma and lower airway disease
Forced midexpiratory flow between 25% and 75% of forced vital capacity is associated with long-term persistence of asthma and poor asthma outcomes