Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation

Abstract

This review focuses on the methods available for measuring reversible airways obstruction, bronchial hyperresponsiveness (BHR) and inflammation as hallmarks of asthma, and their role in monitoring children with asthma. Persistent bronchial obstruction may occur in asymptomatic children and is considered a risk factor for severe asthma episodes and is associated with poor asthma outcome. Annual measurement of forced expiratory volume in 1 s using office based spirometry is considered useful. Other lung function measurements including the assessment of BHR may be reserved for children with possible exercise limitations, poor symptom perception and those not responding to their current treatment or with atypical asthma symptoms, and performed on a higher specialty level. To date, for most methods of measuring lung function there are no proper randomised controlled or large longitudinal studies available to establish their role in asthma management in children.

Noninvasive biomarkers for monitoring inflammation in children are available, for example the measurement of exhaled nitric oxide fraction, and the assessment of induced sputum cytology or inflammatory mediators in the exhaled breath condensate. However, their role and usefulness in routine clinical practice to monitor and guide therapy remains unclear, and therefore, their use should be reserved for selected cases.

Short abstract

Review on the role of lung function, measurement of BHR and airway inflammation in monitoring of children with asthma http://ow.ly/KbHju

Introduction

Current guidelines recommend tailoring of asthma management according to disease control, which is generally defined by symptoms and, to a lesser extent, lung function and markers of airway inflammation. Recently, a European Respiratory Society (ERS) Task Force on Monitoring Asthma in Childhood was published [1]. As reversible airways obstruction, bronchial hyperresponsiveness (BHR) and chronic airways inflammation are hallmarks of asthma, this review focuses on available methods for and the usefulness of measuring lung function, bronchial responsiveness and inflammation when monitoring children with asthma.

Three other articles in this issue of the European Respiratory Review will address general considerations for monitoring asthma in children, monitoring symptoms, exacerbations and quality of life, and management-related issues [2–4].

Lung function

In children with asthma periodic objective assessment of pulmonary function is necessary to optimise management and ensure that therapeutic goals are being achieved. Significant bronchial obstruction may be present in asymptomatic asthmatic children and it has been shown that children with chronic airway obstruction are less likely to perceive dyspnoea compared with children with acute obstruction [5, 6]. Children with poor perception of bronchial obstruction may be at higher risk of developing severe asthma episodes and reduced lung function is associated with poor asthma outcomes [7]. Therefore, regular assessment of lung function seems logical in monitoring of children with asthma. However, only 20–40% of primary care providers use lung function measurements in asymptomatic asthmatic patients and up to 59% of paediatricians never perform lung function tests [8–11].

Maximal flow–volume curves

Maximal expiratory flow–volume curves are considered the gold standard for the assessment of lung function in children with asthma. Regular assessment of pre- and post-bronchodilator forced expiratory volume in 1 s (FEV₁) might help to identify children at risk for developing a progressive decline in airflow. Epidemiological studies have consistently shown a tracking of FEV₁ and FEV₁/forced vital capacity (FVC) ratio from childhood to adulthood [12, 13]. On a shorter timescale, FEV₁ has been shown to be an independent predictor of asthma exacerbations: asthmatic children with a baseline FEV₁ <60% predicted have a doubled risk for asthma exacerbations in the subsequent year as compared with children with an FEV₁ >80% predicted [14]. FEV₁ is considered important in defining asthma severity [15, 16]. However, many, if not most, school children have an FEV₁ >80% predicted, hence within the accepted normal range independent of their asthma severity when defined on the basis of symptoms [12, 13]. This indicates that the cut-off values may not adequately stratify asthmatic children [12]. Regular spirometry every 1–2 years has been recommended for children with asthma who are ≥5 years of age by the National Asthma Education and Prevention Program (NAEPP) guidelines [16].

In children younger than 7 years of age, FEV₁ may not be sensitive and may have a different physiological meaning as compared with older children [17]. However, there is insufficient data on the value of parameters of more peripheral airways, such as the forced expiratory flow at 50% of FVC (FEF_50%) and/or forced expiratory flow at 25–75% FVC (FEF_25–75%), in the monitoring of asthma in children. A large, retrospective cross-sectional analysis of the mean FEV₁/FVC ratios from 4–18 years of age demonstrated a steep and consistent decline with increasing age in asthmatic children suggesting the FEV₁/FVC ratios provide greater sensitivity in childhood asthma compared with FEV₁ [18].

In general, both FEV₁ and the FEV₁/FVC ratio correlate poorly with symptom-based severity in children, which may indicate that asthma management relying on reported symptoms only may be insufficient [19, 20]. To date, there is no randomised controlled trial comparing monitoring of symptoms only to monitoring of symptoms plus FEV₁ in asthmatic children.

While single FEV₁ measurements may not reflect the inherent variability of the disease, home measurements using small, electronic hand-held devices may allow day-to-day monitoring of lung function. Data on the added value of regular home lung function measurement are conflicting. FEV₁ values obtained by home spirometry over a period of 8 weeks were significantly lower on days with asthma symptoms compared with symptom free days; however, the distribution of FEV₁ values showed complete overlap between symptomatic and asymptomatic days in individual patients [21]. The clinical value of home FEV₁ measurements was reduced by a steady reduction in compliance and in the validity of the data over the study period, with wide individual differences [22]. Manoeuvre quality was influenced by age, treatment and region, and was lower in children with FEV₁ <80% predicted [23]. Brouwer et al. [21] showed very high variability of FEV₁ values over a 3-month period in asthmatic children with a poor concordance to other indices of disease activity.

In summary, in children with asthma >5 years of age the evidence indicates that it is useful to perform office based spirometry at least annually, and more frequent assessments may be indicated depending on the clinical course and the patient's asthma severity. In patients in whom symptom-guided treatment is difficult home spirometry might be useful, but should preferably be limited to a relatively short period of observation. In children with severe asthma daily telemonitoring of FEV₁ for 1 year did not reduce exacerbation rates [24].

There is a need for proper randomised controlled studies to establish the role of regular spirometry in asthma management in children. Studies should investigate the minimal or optimal frequency for the assessment of flow–volume curves. The value of the measurement of peripheral airflow obstruction, i.e. FEF_50% and/or FEF_25–75%, needs to be established as these parameters are likely to reflect the pathophysiological processes in early asthma.

Reversibility testing

The response to bronchodilators demonstrating reversibility or airway obstruction is considered a key feature of asthma and therefore consistent with the diagnosis of asthma. The American Thoracic Society (ATS)/ERS recommendations define a significant bronchodilator response (BDR) as an increase in FEV₁ ≥12% and/or ≥200 mL [25]. Children with a persistent BDR are at greater risk of developing a progressive decline in lung function, and have higher healthcare utilisation, lower asthma control and a more frequent need for oral steroid bursts. However, a persistent BDR may also be associated with poor treatment compliance or poor inhaler technique [26, 27]. The presence of a BDR in asthmatic children is correlated to measures of airway inflammation, such as the exhaled nitric oxide fraction (F_eNO), and is predictive for a positive response to inhaled corticosteroids (ICSs) [28–30]. BDR tends to decrease over time indicating airway remodelling [31].

Based on the above, assessment of BDR in asthma monitoring is useful at a high specialty level. As there are variable influences on BDR, it is pertinent that the BDR test is performed as recommended [25]. In children with asthma with reduced FEV₁ and loss of BDR (reduced post-BDR lung function) it is useful to consider further investigations and follow-up in specialist care.

A properly conducted trial using BDR to alter treatment is needed to further establish the usefulness of regular BDR measurement in clinical practice. It is still unclear which intervention should be undertaken in asthmatic children with a loss of BDR. Longitudinal or large cross-sectional studies should be carried out to assess age-specific response rates.

Measurement of peak flow

Regular monitoring of peak expiratory flow (PEF) is used widely in the management of patients with asthma as this is a simple and inexpensive method. Measurements of PEF on a day-to-day basis may allow monitoring of the variable airway obstruction, which is considered one of the key features of asthma and the variability in PEF may be predictive of exacerbations [16, 32]. The mean day-to-day variability of peak flow in healthy children is between 6.2% and 8.2%, with a 95th percentile of 12.3–31% [33, 34]. PEF has been shown to correlate with FEV₁, but this correlation worsens in asthmatic patients with airflow limitation [35]. In a study in 40 asthmatic children the percentage of correct entries in a PEF diary was only 56% during the first week and declined to <50% over the subsequent 4 weeks, with up to 50% of entries being invented or falsified [36].

Several studies have assessed the added value of daily PEF measurements to asthma management driven by symptom recognition in asthmatic children. One study found that patients who used PEF to guide therapy when symptomatic had a lower asthma severity score, fewer symptom days and less healthcare utilisation than children who either used PEF daily or evaluated subjective symptoms alone [37]. In an uncontrolled study, in 77 asthmatic children, daily PEF in combination with comprehensive asthma education resulted in a reduction in the number of asthma episodes, medical and emergency department visits, and missed school days [38]. Two randomised controlled studies did not show a benefit of PEF guided treatment compared with management based on symptoms alone, and addition of PEF did not enhance self-management even during acute exacerbations [28, 39]. Therefore, routine PEF measurements are not useful to monitor asthma in children.

Measurement of airway resistance

Interrupter resistance (R_int), impulse oscillometry (IOS) and the forced oscillation technique (FOT) assess respiratory resistance as an indirect measure of airway obstruction [40]. As these techniques can be carried out relatively independently of active collaboration they are suitable for preschool children [32, 41, 42]. While data on reference values are limited, these methods are reproducible and useful in the assessment of the BDR and bronchial responsiveness [42–48]. The cut-off values to detect significant differences between measurements are, however, variable [49, 50]. Longitudinal assessment of R_int did not improve the prediction of asthma symptoms until the age of 8 years [51]. IOS was compared with spirometry to assess the long-term effects of three controller regimens in children with persistent asthma. Whereas spirometric measures best reflected differences in controller therapy in the first 12 weeks of treatment, IOS was superior from 12 to 48 weeks [52]. By contrast to FEV₁, increased IOS indices were predictive of the loss of asthma control and the area under the curve of baseline R_5–20 Hz was 0.91 in the receiver operating characteristic analysis for the prediction of asthma control status after 8–12 weeks in a recent study in asthmatic children aged 7–17 years [53].

Despite R_int, IOS or FOT measurements having some potential as monitoring tools in preschool asthmatics, to date, there are no longitudinal studies confirming their usefulness.

Body plethysmography

While in the majority of well-controlled asthmatic children flow–volume curves are sufficient for the monitoring of the disease, body plethysmographic measurements of lung volumes (i.e. air trapping) and compression-free forced expiratory flow–volume curves by use of “chest flow” from body plethysmography may be of interest in the management of difficult and severe asthma [54]. Asthmatic children with lung hyperinflation, defined as a residual volume of >120% predicted, had more daytime asthma symptoms and lower body weight and body mass index, and 49% of children with airflow obstruction (FEV₁/FVC <80%) showed significant hyperinflation [55]. In a large study, including 2193 asthmatic children, specific airway resistance was more strongly related to FEF_50% than to FEV₁, suggesting that specific airway resistance may reflect early airway obstruction in children [56]. Specific airway resistance measured at preschool age correlated with subsequent FEF_50%; therefore, predicting subsequent mild airflow limitation. In obese asthmatic children specific airway resistance measured by body plethysmography can be helpful in differentiating lung function changes due to asthma (elevated specific airway resistance) from those due to obesity (normal specific airway resistance) [57]. To date, there are no randomised controlled studies showing that body plethysmography is useful in routine monitoring of asthma in children.

Interventional studies may establish the additional value of body plethysmographic parameters in altering asthma treatment. It is still unclear which body plethysmographic values may predict short- and long-term outcomes of asthma in children. In addition, the value of helium dilution spirometry needs to be assessed.

Multiple-breath gas washout techniques (lung clearance index)

The lung clearance index (LCI), derived from multiple-breath inert gas washout, measures overall ventilation inhomogeneity. The advantages of LCI measurements are the narrow normal range and its independence of age [58]. LCI has been shown to be a sensitive marker of early airway disease in children with asthma and, in particular, in children with cystic fibrosis [59]. S_cond (an index of conductive ventilation inhomogeneity) is based on the contribution to phase III slope from differences in ventilation distribution occurring in the conducting airway zone. A recent study in allergic asthmatic children found elevated S_cond, and a close correlation between S_cond and increased levels of F_eNO and the presence of BHR [60]. In asthmatic school children baseline LCI was significantly higher when compared with healthy age-matched controls indicating greater overall ventilation heterogeneity [61].

As appropriate studies are lacking, to date, there is no role for multiple-breath washout techniques in the routine monitoring of children with asthma. The role of LCI in measuring early airway disease in children with asthma requires further exploration. As there is now commercially available equipment for nitrogen washout and for SF₆ washout, future studies should aim to assess early asthma specific changes longitudinally in preschool and school aged children. In addition, treatment responses and predictors of the disease course should be a focus for future research.

Infant lung function

Different methods have been used to assess lung function in wheezy infants including the analysis of tidal flow–volume breathing loops, forced expirations from either normal inspiration (rapid thoracic compression technique) or from total lung capacity (raised volume rapid thoracic compression technique) or body plethysmography [62–67]. Infant lung function testing has been used to assess phenotypes in infants with wheezing and to develop prediction models for persistent asthma [68]. Reduced lung function and/or BHR in infancy were associated with persistent wheezing phenotypes, and with reduced lung function and asthma at school age [62, 67–70]. In addition, reduced lung function was predictive for wheezy symptoms in the following years [61, 71–73]. Reduced lung function in infancy was associated with respiratory morbidity and treatment needs at preschool age [65]. Some studies showed improvement of lung function, such as forced expiratory volume in 0.5 s, in infants with recurrent wheezing after ICS treatment or oral treatment with montelukast, whereas others did not show significant changes [63, 64, 74, 75].

To date, there is no role for infant lung function testing in the clinical monitoring of wheezing infants. Future research should focus on methods for infant lung function testing that allow repeated measurements in unsedated children.

Bronchial hyperresponsiveness

One major characteristic of asthma is the variability in bronchial tone in a response to a variety of different stimuli.

BHR may be assessed by bronchial provocation tests and can be used both in research and as a means of monitoring the severity of asthma. Bronchial provocation tests may be performed with different chemical substances, such as histamine or methacholine (both of which are considered nonspecific direct bronchoprovocation tests), or by inhaling allergens (specific direct bronchoprovocation tests) as well as by using variety of stimuli such as physical exercise, inhaled cold air and hyperventilation with dry air (all of which are indirect bronchial provocation tests) [76–83].

Determination the provocative concentration or dose causing a 20% reduction in FEV₁ is used for bronchoprovocation tests with methacholine, histamine and AMP, and may be used for allergen bronchoprovocation tests [77, 84]. A bronchoprovocation test with inhaled mannitol was recently developed and launched commercially in a test involving inhaling cumulative doses of mannitol through a powder inhaler. In this test a 15% reduction in FEV₁ is used as cut-off [83]. Although mannitol provocation seems safe and feasible, even in young children, the specific role of mannitol provocation in exploring BHR in asthmatic children needs further study [85]. Exercise testing is the most important measure of indirect bronchial responsiveness. A reduction in FEV₁ of at least 10% is taken as a sign of exercise-induced bronchoconstriction. A correctly performed exercise test gives information about the presence of exercise-induced bronchoconstriction as well as the motor development and fitness of the child. In all international guidelines on treating asthma in childhood mastering exercise-induced asthma is seen as a major objective in the treatment of asthma, with the exercise test as an important tool. The standardisation of the exercise test is important with regard to environmental factors such as temperature, humidity of the inhaled air and exercise load [86–88]. Running is the preferred exercise, and is most easily standardised using a treadmill for a test of 6–8 min duration, reaching and maintaining an exercise load of 90–95% of the calculated maximum for the last 4 min of the test [88–90]. The sensitivity of the exercise test can be increased by inhaling cold or dry air during exercise [91]. The exercise test can be used for the diagnosis of exercise-induced bronchoconstriction, but also to assess the protective effect of asthma drugs against exercise-induced bronchoconstriction.

With the diagnosis of asthma in mind, direct BHR is seen as the most sensitive measure of bronchial asthma, whereas indirect measures of BHR are considered to be more specific and less sensitive [77]. Compared with exercise testing, methacholine bronchoprovocation tests are more sensitive, but markedly less specific, to discriminate between asthma and other chronic lung diseases. When cold air inhalation was added to the exercise test sensitivity comparable to methacholine test was reached, while maintaining the sensitivity [91]. Indirect bronchoprovocation tests are rapidly influenced by treatment with inhaled steroids with the first effects already appearing after 1 week, whereas methacholine bronchoprovocation tests required several months of inhaled steroid treatment to show an effect [92, 93]. Treatment adjustment in children with moderate asthma, based on methacholine bronchoprovocation tests, did not result in a reduction in the percentage of symptom-free days but led to higher pre-bronchodilator FEV₁ as compared with a strategy based on symptom score only [94].

Methacholine bronchoprovocation tests may have a role in predicting later active asthma, as shown in a birth cohort study between 10 and 16 years of age [95]. In general practice moderate and severe BHR to methacholine could not be predicted by routinely available clinical and environmental information in the majority of children [96]. Similarly, several studies revealed poor correlation between reported exercise-related respiratory symptoms and the results of specific exercise testing [97].

In summary, the evidence shows that routine assessment of BHR is not useful in children with asthma; however, there may be a place for BHR assessments in children with possible exercise limitations, poor symptom perception and those not responding to their current treatment or with atypical asthma symptoms. The role of indirect provocation agents such as mannitol and AMP in asthma monitoring needs attention in longitudinal studies.

Markers of inflammation

Noninvasive biomarkers for monitoring inflammation in children are available, but their role and usefulness in routine clinical practice to monitor and guide therapy is unclear. The selection of an appropriate inflammatory marker must take several factors into consideration including safety, reproducibility, repeatability, sensitivity to treatment, and overall clinical utility.

Exhaled nitric oxide fraction

The best studied biomarker in asthma is F_eNO, which has been reported to reflect both airway and tissue eosinophilia. F_eNO can be measured noninvasively, and is an extremely attractive technique for use in children. The measurement of F_eNO has been standardised for clinical use in a joint guideline from the ATS and ERS [98]. The conventional chemiluminescence F_eNO analyser, the hand-held device and offline F_eNO measurements have been shown to produce similar results in children older than 5 years of age with a success rate of >70% and with an overall coefficient of repeatability of around 1.6–3.2 ppb [99–104]. A low F_eNO (<20 ppb) in children with asthma not treated with ICSs indicates that eosinophilic inflammation and responsiveness to corticosteroids are less likely. F_eNO values between 20 and 35 ppb are intermediate and should be interpreted cautiously, while high values above 35 ppb are indicative of eosinophilic inflammation [105, 106]. Currently, there is no international consensus on using age- and height-adjusted normal values or adjusting for atopy [105, 107]. There are many additional factors associated with minor changes in F_eNO, such as treatment compliance, diet, allergen exposure, active and passive tobacco smoke exposure, and diurnal variability. Therefore, small changes in F_eNO (i.e. <10 ppb) may be clinically irrelevant.

A F_eNO level of >49 ppb 4 weeks after stopping ICSs was found to predict asthma relapse with a sensitivity of 71% and specificity of 93% [108]. In another study, F_eNO and the percentage of sputum eosinophils were both significant predictors of failed ICS reduction in clinically stable children with mild-to-moderate asthma [109]. Two other studies failed to show any significant utility of F_eNO in predicting exacerbations in children undergoing ICS tapering [110, 111].

Most studies investigating the utility of F_eNO to guide treatment have used a combination of F_eNO with other measures of asthma control, rather than F_eNO alone. F_eNO-guided treatment in children with asthma did not show a difference between the groups in terms of the cumulative dose of ICSs (sum of doses at each visit), but there was a significant decrease in BHR in the F_eNO group [112]. In another study F_eNO-guided treatment resulted in higher expiratory flow at 50% of the predicted FVC compared with the symptom-guided group [113]. There were no significant differences in any of the other secondary outcomes: F_eNO, FEV₁, number of exacerbations, symptom control, or use of short acting β-agonists [113]. In the study by Szefler et al. [114] no differences were shown between groups looking at days with asthma symptoms, days of school missed, asthma control test score, courses of oral corticosteroids, FEV₁, or F_eNO levels. The dose of ICS was nonsignificantly higher in the F_eNO group. Daily measures of F_eNO were compared with symptoms to guide treatment changes in children [115]. Both treatment strategies resulted in a significant improvement in symptom-free days and quality of life, and a reduction in ICS dose, but neither approach was superior. Studies which have incorporated F_eNO into management algorithms have used many different protocols, not only in terms of the frequency of measurements but also the inclusion of other indices of asthma control. The results were variable with only some showing significant results, but the outcome measures were not consistent across studies.

An increasing amount of information is available relating to the utility of F_eNO assessments in younger children, and recently, normative data for F_eNO in infants has been reported [116]. In children with preschool wheeze, levels of F_eNO were higher in those with current symptoms or atopy compared with controls [117, 118]. Although anti-inflammatory therapy has been shown to reduce F_eNO in wheezy preschool children, there are no published data on its utility in monitoring control, adjusting therapy or in predicting exacerbations [63, 64, 119–121]. Some data imply that elevated F_eNO in preschool children is associated with later asthma [122–124]. Elevated F_eNO predicted decline in lung function in infants with recurrent wheezing, and the risk of future wheezing in both healthy neonates and wheezy infants [125, 126]. F_eNO does not seem to correlate well with lung function in early childhood, but it does correlate with BHR [127, 128].

Taken together, based on current evidence F_eNO is not useful for routine monitoring of children with asthma, although most task force members use F_eNO in children with difficult or uncontrolled asthma especially in specialist centres. Clinical trials that assess the utility of F_eNO in adjusting treatment or in predicting exacerbations in preschool children have not been performed. It is still unclear what represents a significant change in F_eNO in a longitudinal setting.

Sputum analysis

Analysis of induced sputum cytology is a partially noninvasive tool that allows assessment of inflammatory cells, such as eosinophils and neutrophils, as well as inflammatory mediators in supernatants.

Performance of sputum induction and sample processing have been standardised for use in children and is well described by ERS recommendations [129]. Sputum induction has been shown to be safe in asthmatic children, regardless of disease severity, and feasibility is 80–85% in children between 6 and 17 years of age [130, 131]. The methodology has not yet been standardised in preschool children.

The percentage of eosinophils is the most frequently used marker in clinical studies. In a prospective open label clinical study in 40 children with mild-to-moderate asthma reducing ICS was successful in all children who had no eosinophils in induced sputum before the reduction was undertaken. and induced sputum eosinophils ≥2% had a sensitivity of 63.6% and a specificity of 75.7% for predicting failed reduction [109]. Eosinophils in induced sputum were significantly higher in children with stable asthma who experienced exacerbations on reducing ICSs [132]. In severe asthmatic children a tailored intervention based on sputum eosinophils did not significantly reduce overall asthma exacerbations or improve asthma control when compared with conventional management based on clinical symptoms and lung function [130]. In contrast to adults, children with difficult asthma responded to high-dose corticosteroids even in the absence of sputum eosinophilia [133]. Therefore, detection of a non-eosinophilic sputum phenotype in isolation does not mean clinical ineffectiveness of corticosteroids. Longitudinal assessments of sputum eosinophils in children with severe and mild-to-moderate asthma suggest inflammatory phenotypes are not stable over time, even without any intervening changes to therapy or in the clinical disease [130].

For now, the evidence suggests that sputum induction is not useful to monitor asthma in routine clinical practice. However, for specific patients in specialised tertiary centres sputum eosinophils may be helpful when making difficult treatment decisions.

Exhaled breath condensate

Exhaled breath condensate (EBC) analysis has become an increasingly used and promising method in research, as a wide number of inflammatory mediators can be measured in EBC. It is a simple, well tolerated and safe method, even in children with severe asthma, and is feasible in 100% of children over 4 years of age [134]. Children with asthma can be discriminated from healthy controls with EBC analysis [135, 136]. However, although the method is simple, it can be influenced by a number of technical issues, which can affect the final results. Despite the publication of a joint ATS/ERS task force document on methodological considerations, many questions are not yet properly resolved [137]. EBC collection in preschool children is of particular interest as the measurement of selected exhaled markers may allow distinction between different phenotypes of wheezing [137–139]. However, the collection procedure in children younger than 4 years of age may be more difficult due to the lower level of cooperation and smaller amounts of EBC. Nevertheless, its feasibility in this age group has been demonstrated using customised devices [120, 140].

Assessment of markers of oxidative stress in the airway makes it possible to monitor otherwise neglected indicators of disease control. 8-isoprostane levels in EBC distinguished children with stable and unstable asthma, independent of treatment with ICS [141]. Hydrogen peroxide was related to asthma control in a group of asthmatics above 12 years of age [142]. In a large study, F_eNO, 8-isoprostane, interferon-γ and interleukin-4 were related to asthma control, and F_eNO, 8-isoprostane, nitrate and nitrite in EBC better indicated the degree of asthma severity [143]. More recently, Kostikas et al. [144] focused on EBC pH as a potential indicator of asthma control in a group of nearly 250 asthmatics grouped according to their level of control as defined by Global Initiative for Asthma guidelines [145]. EBC pH is known to be low during exacerbations, with normalisation after adequate treatment, and is related to disease severity [146, 147]. The measurement of EBC pH may be the most easily achievable measurement from EBC in a clinical setting since it can be performed onsite with relatively simple methods. Due to methodological issues and the lack of clinical trials of EBC in the monitoring of asthma, to date, EBC does not play a role in the monitoring of asthma in children.

Conclusions

The lack of proper randomised controlled or large longitudinal studies makes it difficult to establish the role of measuring lung function, BHR and airways inflammation in asthma management in children.

The regular measurement of FEV₁ using office based spirometry is considered useful. However, other lung function measurements including the assessment of BHR and airways inflammation may be reserved for selected children with exercise limitations, poor symptom perception or with atypical asthma symptoms and difficult or uncontrolled asthma, and performed on a higher specialty level.