oa Editorial [Hot Topic: Non-Invasive Assessment of Asthmatic Inflammation: From Bench to Bedside (Guest Editors: S. Loukides, K. Kostikas and P. Bakakos)]

Asthma is now recognized as a heterogeneous disease, based on clinical parameters, the type of inflammation, the response to treatment, the rate of exacerbations and, finally, the underlying control and/or severity. Attempts to apply the above diverse characteristics to the clinical presentation of the disease have led to the identification of different phenotypes, with significant overlapping. The field of non invasive techniques has been rapidly developed since the time that the fraction of exhaled nitric oxide (FeNO) was recognized as an easily measured mediator in the exhaled air [1]. At approximately the same time, induced sputum was recognized as a valuable technique for the identification of the inflammatory cellular population as well as for the evaluation of different mediators in sputum supernatants [2]. Exhaled breath condensate (EBC), a totally non invasive technique, gave us the opportunity to sample the airways in an even more easily applicable approach, but the several methodological pitfalls of this method prevent it from being an accurate procedure for the evaluation of airways inflammation [3]. The attempt to connect the whole asthma entity and its numerous phenotypes using those minimally invasive techniques, i.e. FeNO, induced sputum and EBC, involves two major steps: First, these techniques must become more widely accepted and applied and, second, we need data from large multicenter studies that will identify the distinct inflammatory characteristics of specific phenotypes. Every single biomarker obtained by non invasive techniques must fulfill some requirements, in order to be applicable in every day clinical practice: it must be measurable in the field, be measurable in the specific disease, have a standardized methodology, have normal values that clearly discriminate normality from disease, present reproducibility and stability within measurements, be associated with an established inflammatory process and, finally, be applicable as a tool for guided treatment strategy. According to these requirements, it is quite difficult or even impossible for a single biomarker obtained from non invasive techniques to fulfill them. The majority of the numerous studies involving non invasive techniques for the assessment of airways inflammation evaluated the discriminative power of biomarkers in respect to the presence or absence of a specific disease. This approach has certain value, but does not add useful information for clinical practice in an inflammatory disease that presents significant day-to-day variability such as asthma. A more useful approach would be to evaluate a specific biomarker using statistical tools dedicated to test the diagnostic performance of a biomarker. For example, using receiver operating characteristics (ROC) analysis we can define specific cut-off values that may characterize the potential utility of a biomarker as a predictive tool for survival or disease progression or even as a tool for the prediction of other significant outcomes related to treatment response. There is additional need for the validation of such cut-off points in prospective trials involving decisionmaking. The current literature presents only limited data in that direction at the moment. The most promising data to-date are those published for induced sputum, that have used a specific cut-off value for eosinophils as predictors of severe exacerbations in respect to treatment intervention with inhaled steroids [4]. Similar data exist for FeNO in predicting multiple outcomes in asthma, both clinical and/or inflammatory [5]. The majority of the later studies have focused on sputum cellular population, and particularly on eosinophils. In contrast to those two widely evaluated biomarkers, the literature on EBC still does not include any data for the support of the aforementioned requirements. EBC pH is nowadays considered a promising parameter, since its values may discriminate between asthmatics and normal subjects [6] and present an association with eosinophilic inflammation [7], but the absence of robust longitudinal data still limits its application in clinical practice. Recently published data in a prospective study showed that EBC pH can be used to monitor asthma exacerbations, however with no associations with alterations in lung function or FeNO [8]. In this hot topic issue, the three most widespread techniques of non invasive or minimally invasive assessment of airways inflammation are described in details, all the way from the point of technical considerations to the implementation in clinical practice. It is widely accepted that all these techniques have provided clinicians and researchers with tools for the understanding of the underlying pathophysiology of the disease. But is this the main target? Definitely not. What we really need from non invasive techniques is to be implemented in clinical practice and provide useful information for the diagnostic approach, the identification of specific phenotypes, the evaluation of asthma control and the facilitation of decision-making. FeNO represents the only exhaled asthma biomarker that has reached clinical practice today. Despite some methodological issues, FeNO represents a good surrogate biomarker of eosinophilic airways inflammation, can serve as an aid to the diagnosis of asthma, may identify loss or restoration of asthma control as well as certain clinically relevant phenotypes (including an “at risk” phenotype in severe asthma), may predict steroid response and exacerbations, and may provide a possible aid for treatment guidance, especially in patients with difficult asthma [1]. Which is the contribution of EBC in the above requirements? Although promising, EBC is currently used only as a research tool, due to the lack of appropriate standardization and the absence of reference values [9]. Some of the biomarkers obtained by EBC can identify certain phenotypes, but with significant overlapping between measurements. Last but not least, sputum induction may share with FeNO some clinically useful applications mainly related to the detection of non-adherence to corticosteroid therapy, the assessment of the adequacy of inhaled corticosteroid therapy, the long-term management of asthma and the adjustment of oral corticosteroid dose in refractory asthma. Specifically, induced sputum may be used to study the dose-response effect of inhaled corticosteroids and may be useful to establish the relative potency of different corticosteroid formulations and delivery devices. Finally, prospective studies have shown that it is better than clinical assessment in reducing the rate of exacerbations [2], especially the eosinophilic ones [10]. What do we expect from the biomarkers obtained by non invasive methods in asthma? Based on the heterogeneity of the disease, the need for identification of the different disease phenotypes within the range of these syndromes is crucial for the proper management of the individual patient. Based on current knowledge, it is not likely that a single biomarker will suffice for the identification of the underlying pathophysiology and/or the clinically useful phenotyping of asthma. What is definitely needed is the proper combination of biomarkers, even from different techniques, in order to achieve their maximal effectiveness. Clinical assessment and physiologic parameters, such as spirometry, provide highly useful information, but they can not provide objective information in relation to the inflammatory process. The quest for a non invasive inflammometer has been a target for both clinicians and researchers in the past twenty years. Considering that the term inflammation is highly heterogeneous, we should be definitely seeking ways to combine the inflammatory characteristics with clinical features in order to characterize particular phenotypes. This concept may help physicians provide individualized treatment for each patient in the future......