Spirometry in children is one of the most frequently used tests that help in the diagnosis of asthma. The latest recommendations of the European Respiratory Society (ERS) consider the potential benefits of spirometry in suspected asthma between 5 and 16 years of age [1]. The latest Task Force of the American Thoracic Society (ATS) and ERS recommends using z-scores of -1.645 (<5th percentile) to consider abnormality in FEV₁, FVC and FEV₁/FVC ratio, and significant bronchodilator response (BDR) when the value of FVC and/or FEV₁ is >10% with respect to the predicted value calculated according to the GLI 2012 [2,3]. FEF 25-75% of forced vital capacity (FEF_25-75) is a spirometry parameter that has been related to small airway obstruction [4]. FEF_25-75 values less than 65% of predicted have also been found more frequently in rhinitis patients with onset of asthma, severe bronchial hyper reactivity, positive bronchodilator response, bronchial inflammation, dyspnea in asthma, allergic sensitization in rhinitis and uncontrolled asthma, especially that with normal FEV₁ and FEV₁/FVC [5,6]. Controversially, in 2014 Quanjer et al. published a multicenter study where they analyzed spirometry in children, adults and the elderly and concluded that FEF_25-75 correlates well with FEV₁, FVC or FEV₁/FVC, but does not contribute to clinical decision making because it is a parameter highly dependent on artifacts or FVC maneuver. In this same study, the prevalence of FEF_25-75 below the lower limit of normal (LLN) with normality in the other spirometry parameters was recognized to be higher in children than in adults [7]. Due to variability and dependence on effort, some guidelines recommend carefully reviewing the FVC maneuver and making volume adjustments when comparing FEF_25-75 before and after the bronchodilator [8]. With the advancement of precision medicine in asthma, it is becoming increasingly important to know the state of the small airway to choose the aerosol therapy that allows the best pulmonary deposition [9,10]. In pediatric asthma, there are different methods to detect Small Airway Dysfunction (SAD) such as Impulse Oscillometry (IOS), which is the most sensitive but not always available in all centers, spirometry, less sensitive but easier to access, and Multiple Breath Washout (MBW), which is generally more expensive and less accessible [11]. FEF_25-75 has been recognized as a good parameter to identify SAD in pediatric asthma, especially in centers where IOS is not available [12]. Considering the above, can we definitively rule out FEF_25-75 from spirometry in pediatric asthma?. The objective of this review was to analyze the available evidence regarding the use of FEF_25-75 in the diagnosis, monitoring and response in the treatment of asthma in children and adolescents.

FEF_25-75 in the Diagnosis of Pediatric Asthma

Around 30 years ago, a study demonstrated that FEF_25-75 can be a particularly useful spirometry parameter to demonstrate small airway dysfunction in children and adolescents with mild asthma who frequently record normal spirometry [13]. When tested in schoolchildren with asthma, the decrease in FEF_25-75 has been shown to have an inverse correlation with the level of allergic sensitization to mites measured by specific immunoglobulin E [14]. A study conducted in children and adolescents with asthma and normal FEV₁ in spirometry showed that FEF_25-75 had a good correlation with BDR in FEV₁ and Methacholine PC20. Additionally, this study showed that FEF_25-75 has a good capacity (AUC = 0.88, S = 90%, E = 67%) to predict BDR greater than 20% in FEV₁, that is, it is useful to predict reversible airflow obstruction [15]. The 10% fall in FEF_25-75 during Methacholine Challenge Test (MCT) has proven to be a useful parameter that can complement the conventional measurement of bronchial hyper responsiveness with the fall in FEV₁ below 20% [16]. Children and adolescents with allergic rhinitis and decreased FEF_25-75 may have four to nine times more severe bronchial hyper reactivity than those with normal FEF_25-75, justifying monitoring with spirometry in this group [17,18]. A study that performed Exercise Challenge Testing (ECT) in children and adolescents with asthma of varying severity demonstrated that the 26% drop in FEF25-75 after exercise may be a useful parameter to confirm exercise-induced bronchoconstriction in mild asthma when no drops in FEV₁ are observed [19]. Similar results were found in another study in asthmatic children, which found a decrease in FEF_25-75 by 28% in ECT had a slightly higher sensitivity than a 10% fall in FEV₁ and a high sensitivity for the diagnosis of asthma, especially intermittent asthma [20]. The diagnostic capacity of FEF_25-75 has also been used in pediatric asthma in combination with biomarkers such as the Fraction of Exhaled Nitric Oxide (FeNO). A study carried out in schoolchildren and adolescents with asthma vs healthy controls demonstrated by means of ROC curves that the combination of FEF_25-75 with FeNO was superior to the combination of FeNO with FEV₁ or with FEV₁/FCV. Moreover, the combination of FEF_25-75 with FeNO had greater diagnostic accuracy than both parameters separately [21]. In children and adolescents, alternative methods for diagnosis have been proposed with spirometry and FeNO. A study carried out in children and adolescents with suspected asthma demonstrated that the FEF_25-75/FeNO ratio had sensitivity, specificity and predictive values equivalent to the FEV₁/FeNO or FVC/FeNO ratios when diagnosing asthma [22]. A study to evaluate diagnostic techniques in pediatric asthma demonstrated that FEF_25-75 had a better correlation with FeNO and MCT than FEV₁. In addition, the authors point out that using the BDR of FEF_25-75 ≥ 30% would have diagnosed twice as many patients with asthma than with BDR FEV₁ ≥ 12% (23). FEF_25-75, also called Maximum Mid-Expiratory Flow (MMEF) in combination with FeNO has also shown good ability to identify Cough Variant Asthma in children [24]. Furthermore, a study in children showed that a decrease in FEF_25-75 was the spirometry parameter with the best capacity (AUC=0.79) to predict cough as a variant of asthma [25]. A study measured IOS, FeNO, spirometry and Multiple-Breath Nitrogen Washout (MBNW) testing in a group of school children with two categories of suspected mild to moderate asthma (recurrent wheezing and persistent cough) and compared them with healthy controls. Of the 4 study methods used, FEF_25-75 was the only parameter that allowed discrimination between the two categories of asthma and healthy controls [26]. FEF_25-75 has also been shown to be useful in the diagnosis of SAD in pediatric asthma. A study conducted in children and adolescents used the "prospective proof of concept (POC)" methodology to measure the performance of spirometry in the diagnosis of SAD. This study demonstrated that spirometry through the measurement of FEF_25-75 is key for the diagnosis of SAD and can be considered as a substitute for other methods with greater diagnostic sensitivity (e.g. impulse oscillometry), since it is more accessible [27]. In children and adolescents with asthma, prevalence of small airway dysfunction (SAD) has been found from 44% (FEF_25-75 z-score < 1.65) to 56% (FEF_25-75 z-score < 1.96) (28). A large study of asthmatic pre-schoolers measured SAD by spirometry using as a definition that at least two of three parameters reflecting the peripheral airway (FEF_25-75, FEF50%, and FEF75%) were below 65% and FEV₁ ≥ 80%. In this study, parameters such as FEF_25-75 had high correlations with FEV₁ (r = 0.670, p < 0.001) and FEV₁/FVC (r = 0.812, p < 0.001). This study also demonstrated by ROC curves that FEF_25-75 had a good capacity (AUC = 0.79, S = 82%, E = 68%) to predict moderate to severe bronchial hyper reactivity on methacholine [29]. In children and adolescents with asthma, a positive correlation was found between pre bronchodilator FEF_25-75 and air trapping measured by low attenuation areas in High-Resolution Computed Tomography (HRCT) [30]. Moreover, the children and adolescents with severe asthma undergoing chest Computed Tomography (CT) and who also had SAD defined by FEF_25-75 z-score < 1.645 had significantly higher bronchial wall thickening than in those without SAD (31). FEF_25-75 has also been shown to be useful for the diagnosis of SAD in asthma and obesity in children and adolescents. In children and adolescents with mild and moderate persistent asthma, it was shown that those who were classified as obese had FEF_25-75 significantly lower than those who did not have it [32,33].

BDR at FEF_25-75 is another clinical parameter that has also been studied in pediatric asthma. A study showed that the BDR of FEF_25-75 above 25% (AUC= 0.67) shows the difference between asthmatic pre-schoolers and healthy controls (34). Another study in healthy pre-schoolers found cut-off points of 35.5% in BDR FEF_25-75 of predicted and 61% of baseline [35]. In pre-schoolers, the 18.2% increase in FEF_25-75 achieves a sensitivity of 91.8% for the diagnosis of asthma when compared with healthy controls [36]. Other studies have found increases in 31% and 33% in BDR of FEF_25-75 was found to be the cut-off point that significantly differs from healthy controls [37,38]. However, the BDR at FEF_25-75 is still contradictory as a method of diagnosing pediatric asthma. A recent study showed that in the group of children with normal spirometry, the BDR > 30% in FEF_25-75 was associated with a higher bronchial hyper reactivity than those with < 30%, but the presence of false positives and negatives that this cut-off point has does not allow by itself to make the diagnosis of asthma [39]. Furthermore, a recent 3-year prospective study measuring preschool BDR with different spirometry parameters did not find BDR FEF_25-75 to be clinically relevant for predicting abnormal spirometry, BDR, or SAD at school age [40].

FEF_25-75 in the Prediction of Pediatric Asthma Severity

FEV₁ has been considered the gold standard for measuring asthma severity, but it is common for its value to be normal in mild pediatric asthma. FEF_25-75, as an index that better reflects the status of the peripheral airways, could have greater clinical utility in this group of patients [41]. A study conducted in children and adolescents showed that FEF_25-75 has a good power to predict mild asthma (AUC = 0.73), which is even superior to other parameters such as FEV₁ and FEV₁/FVC [42]. A retrospective study conducted in children and adolescents with asthma under treatment showed that the group with FEV₁ ≥ 80% and FEF_25-75 < 60% had more hospitalizations (OR = 2.4 p = 0.02) and more emergency visits (OR = 2.19, p = 0.03) than the group with FEV₁ ≥ 80% and FEF_25-75 ≥ 60% [43]. In another study conducted in children and adolescents with moderate-severe asthma with normal FEV₁, it was shown that those who registered SAD defined as FEF_25-75 z-score < 1.645, had more frequently severe asthma than moderate and more bronchodilator response than those who did not have SAD. In addition, this study showed that FEF_25-75 had a moderate correlation with difference in resistance at 5 and 20 Hertz (R5-R20) and reactance at 5 Hertz (X5), which are sensitive impulse oscillometry parameters for the diagnosis of SAD [44].

FEF_25-75 in the Prediction of Uncontrolled Pediatric Asthma

In children and schoolchildren with persistent asthma, it was shown that those with low FEF_25-75 had a higher risk of uncontrolled asthma and use of systemic corticosteroid in the last three months as well as greater use of systemic corticosteroid in the last three weeks than the group with normal FEF_25-75 [45]. A study conducted in asthmatic children showed that the group with low FEF_25-75 were more likely to present asthma symptoms in the last two weeks such as: nocturnal wheezing, decreased speed in their activities or games and school absenteeism than the group with normal FEF_25-75 [46]. A study in children with newly diagnosed asthma showed that the group with FEF_25-75 < 65% had a higher proportion of uncontrolled asthma according to GINA criteria than the group with FEF_25-75 ≥ 65% [47]. Another study conducted in children with asthma showed that the group with FEF_25-75 < 1.645 z-score had a higher proportion of uncontrolled asthma (p < 0.001) and a lower average in the children's asthma control test (C-ACT) questionnaire (p = 0.02) than the group with normal FEF_25-75 z-score [48]. A retrospective study conducted in children and adolescents under 19 years of age with asthma showed that the group with FEF_25-75 < 60% and FEV₁ ≥ 80% had a higher risk of hospitalization in the last year (OR = 2.5) than the group with FEF_25-75 ≥ 60% and FEV₁ ≥ 80% [49]. Similarly, in a study in children and adolescents with asthma showed that the group with peripheral airway obstruction (FEF_25-75 < 65% and FEV₁ ≥ 80%) had worse clinical outcomes (hospitalizations, exacerbations), lung function decline, and higher BDR (FEV₁ ≥ 12%) than the group without peripheral airway obstruction (FEF_25-75 ≥ 65% and FEV₁ ≥ 80%) [50]. In another study, it was shown that in asthmatic children with FEF_25-75 < 65% associated with uncontrolled asthma and obesity had a high risk of presenting peripheral airway impairment (PAI) measured by IOS compared to children with normal FEF_25-75, without obesity and well-controlled asthma who presented a minimal or low risk of PAI [51].

FEF_25-75 in the Persistence of Symptoms in Pediatric Asthma

A retrospective study conducted in children and adolescents showed that the persistence of respiratory symptoms in a mean follow-up of 3 years was associated with decreased FEF_25-75 (p=0.04) and allergic sensitization (p=0.03) [52]. Peripheral airway obstruction in children with asthma as measured by decreased FEF_25-75 has been shown to be associated with long-term persistence of asthma independent of major airway involvement as measured by FEV₁ [53].

FEF_25-75 in Response to Treatment in Pediatric Asthma

A study conducted in children and adolescents with controlled asthma; normal FEV₁ and no corticosteroid therapy in the last 3 months, but with high FeNO values (> 25 ppb) compared the response to inhaled corticosteroids (ICS) and placebo for 6 weeks. Unlike the placebo group, those receiving ICS had a significant increase in FEF_25-75 values, which were higher than the other spirometry parameters [54]. Another study in children and adolescents who were treated with conventional inhaled corticosteroids for 3 months enrolled patients with FEF_25-75 below 75% predicted and their treatment was switched to hydrofluoroalkane–134a beclomethoasone diproprionate (HFA-BDP), an ultrafine aerosol formulation. At follow-up (median 42 days), significant increases in FEV₁ (84.6% to 93.8% predicted, p = 0.001) and FEF_25-75 (50.75% to 68.85% predicted, p < 0.001) were shown, indicating that HFA-DBP improved large and peripheral airway function [55]. Ciclesonide is another extra-fine aerosol ICS validated for the treatment of asthma in children over 12 years of age. A review of pediatric studies with this drug demonstrated that once-daily dose of ciclesonide is able to significantly improve FEF_25-75 in children with persistent asthma compared to placebo and has a non-inferior clinical effect to other inhaled corticosteroids such as fluticasone or budesonide [56]. A three-year follow-up study of severely asthmatic children and adolescents showed that, despite treatment with high doses of corticosteroids (≥ budesonide 800 mcg or equivalent), there was a decline in the FEF_25-75 z-score, indicating that this parameter could be a marker of persistence of peripheral airway obstruction despite treatment [57]. Children with asthma who were hospitalized for exacerbation used HRCT to diagnose SAD. The sample was divided into three groups based on the treatment they received for 1 month (group A: ICS alone, group B: ICS + bronchodilator and group C: oral corticosteroid). After one month of treatment all groups significant improvement was seen in FEF_25-75 and FEF₇₅, and between groups (Group C > Group B > Group C) [58]. A recent study used Functional respiratory imaging (FRI), a dynamic computed tomography technique with 3D reconstruction, to predict the concentration of aerosols in the airway. In this study, it was shown that in children with severe asthma, the group of patients with SAD (FEF_25-75 and FEF₇₅ z-score < -1.645 and FVC z-score > -1.645) had greater central than peripheral deposition for ICS plus long-acting B2 agonists and also for salbutamol alone than the group that did not have SAD [59].

Post-hoc analysis of four studies of Tiotropium therapy (long-acting muscarinic antagonist bronchodilator) in children and adolescents with moderate/severe asthma showed that improvements in FEF_25-75 were more marked than in FEV₁, suggesting that it may be a better parameter for monitoring this therapy [60]. A "real-life" observational study conducted in children and adolescents with severe asthma under 18 years of age demonstrated that omalizumab therapy was able to significantly improve FEF_25-75 (62.9% to 76.3%, p = 0.0001) at 6 months of treatment [61]. Significant improvement in FEF_25-75 has also been shown in children with mild to moderate asthma on ICS when they have been treated with subcutaneous dust mite-specific immunotherapy for one year [62]. In addition, techniques such as asthma control programs, frequent physical activity and pulmonary rehabilitation management programs in children and adolescents have shown significant improvements in FEF_25-75 [63-66].

The evidence gathered in this review allows us to conclude that the measurement of basal FEF_25-75 is useful in the diagnosis, monitoring and response to treatment in childhood and adolescent asthma. FEF_25-75 is a parameter that correlates well with MCT, ECT, FeNO, pre- and post-bronchodilator FEV₁. Advances in precision medicine in pediatric asthma require the use of lung function parameters that reflect the state of the peripheral airway and the diagnosis of SAD. In centers that do not have other more sensitive methods for the diagnosis of SAD (e.g., IOS), the measurement of FEF_25-75 could be an adequate substitute, considering the greater access to spirometry. The main clinical utility of FEF_25-75 seems to be in mild asthma with normal values in the other spirometry parameters, however, the measurement of SAD in severe asthma and aerosol deposition has already begun to be a target for research. Heterogeneity in the cut-off points for interpreting FEF_25-75 is a limitation for the development of clinical studies, although the most recent evidence suggests that a FEF_25-75 z score below or above the lower limit of normal would be the most appropriate way to interpret its results. The BDR in FEF_25-75 remains controversial in pediatric asthma. More prospective studies are required with designs that allow eliminating the variability in the BDR in FEF_25-75, defining cut-off points with real utility in the diagnosis and follow-up of childhood asthma.

Conflicts of Interest

The author declares that they have no conflicts of interest.

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