Blood eosinophils: In quest of a Holy Grail for personalized asthma treatment with biologicals
Authors: Milos Jesenak, Zuzana Diamant
Journal: Allergy (2020)

Treatment strategies for asthma are changing dramatically with many novel molecules entering the market, especially within the group of biologicals. Intensive investigations continue to reveal new pathogenetic aspects of the chronic airway inflammation allowing identifying a variety of asthma subendotypes and potential therapeutic targets. Better understanding of the underlying mechanisms as well as contributing factors and triggers allows personalized therapeutic approach respecting individual characteristics of distinct patients. This is a prerequisite both for long-term effective outcome as well as for safety and good tolerability of the therapy. In daily practice, physicians decide on currently available (type 2) targeted treatment options based on (non) invasive clinical and laboratory parameters, indicative of distinct asthma phenotypes or endotypes (Figure 1). Therapeutic response can thus be predicted by various biomarkers, either alone or in combination.1 Presently, the most frequently studied and commonly used biomarkers include eosinophils (from peripheral blood or sometimes from induced sputum), serum total IgE and fractional exhaled nitric oxide (FENO) levels. Biomarkers are defined as biological or physiological parameters that can be used as an indicator of either physiological or pathological processes or pharmacologic responses to therapy.1 Depending on the relationship to a certain condition or its status, positive or negative types of biomarkers can be distinguished. Currently, biomarkers can be used as an indicator of a disease, its severity, complications and/or co-morbidities. Alternatively, biomarkers are increasingly used as tools to select an appropriate therapeutic strategy, for monitoring its efficacy and sometimes also for the detection of noncompliance. In the past decades, researchers aimed to identify highly sensitive and specific point-of-care biomarkers for asthma; however, each of them comes with different limitations and level of inaccuracy.1 In the field of severe asthma management, peripheral blood eosinophils (PBE) became an important biomarker for identification of responders to (especially) anti-eosinophil biologicals (Figure 2). Although several studies showed a substantial role for PBE in different asthma phenotypes with or without IgE-mediated hypersensitivity, correct clinical application of this biomarker should take into account a variety of confounding and modifying factors. Moreover, application of outcomes from laboratory experiments or randomized controlled trials (RCT) into daily practice may carry certain risks. In this issue of Allergy journal, Bagnasco et al2 present an analysis of national data of 138 asthmatic patients treated with mepolizumab in daily practice for at least 1 year. Authors investigated if PBE counts before treatment could predict clinical, functional and/or biological outcomes following mepolizumab treatment in this patient population. All patients fulfilled the criteria for severe uncontrolled asthma according to ATS/ERS guidelines and prescribing conditions according to the Italian Drug Agency. In addition, PBE count had to be above 300 cells/μL on at least one occasion in the last 12 months pretreatment and more than 150 cells/μL before the first injection with mepolizumab. As in previous RCTs with mepolizumab,3 this real-life study also clearly confirmed the beneficial effect of these biological reducing asthma exacerbations rates, daily oral corticosteroids (OCS) doses and FENO levels, while improving asthma control scores and/or spirometric indices. However, in contrast with previous observations from RCTs (ie "the higher the baseline PBE count, the better the treatment outcome"3), in this meta-analysis no correlation was found between PBE counts before initiation of treatment and treatment outcomes, including asthma control test, OCS intake, exacerbation rate or spirometric parameters, following at least 1 year of mepolizumab treatment. Consequently, the authors concluded that in real-life situations where most patients take OCS on a regular basis, the predictive value of baseline PBE counts is limited, despite an overall good clinical effectiveness of IL5 antagonism in these patients. Although PBE counts in asthma represent an easily accessible point-of-care biomarker,1 eosinophils are primarily tissue-based cells which only pass through the circulation on their way to tissues.4 Apart from diurnal variation, PBE count can be modified by several other internal and external factors. Especially, systemic corticosteroids, even in a short course, are major eosinophil-depleters. In patients with asthma, 2 weeks of oral prednisolone dramatically reduced eosinophils (64-78%) in different body compartments and biological samples (ie, peripheral blood, sputum, bronchoalveolar lavage fluid).5 In severe asthma and in frequent exacerbators, OCS can thus limit the criteria for anti-eosinophil treatment, and hence, current guidelines (a.o. GINA2019) recommend to repeat the pretreatment PBE count several times at the lowest possible OCS dose. Interestingly, recent clinical observations showed that the risk for symptoms due to eosinophilia does not increase in a proportionate manner at higher PBE counts and that normal or even low counts do not rule out target organ infiltration by eosinophils. Thus, patients with low PBE counts and allergic/asthmatic symptoms may also present with involvement of eosinophils in their symptoms, probably due to extravasation of eosinophils and infiltration into the target organs (eg lungs, upper airways, skin).6 In conclusion, anti-eosinophil therapies are bringing new hope for many patients with severe asthma uncontrolled on standard treatment or not indicated for other targeted biologicals. Despite clearly proven effectiveness in RCTs in patients with increased PBE counts, there are probably still subgroups of patients who could also benefit from these treatment options despite PBE counts within normal or even low ranges. Therefore, more sensitive biomarkers, pathophysiological or clinical features for adequate treatment selection and indication, are highly welcome. Eosinophil activation markers such as eosinophil-derived neurotoxin (EDN), eosinophil-derived protein X (EDX), eosinophil cationic protein (ECP) and eosinophil extracellular traps (EET) may overcome certain problems and inaccuracies of PBE.7 Moreover, another possible IL5-independent mechanism of eosinophil activation, such as the activation of inflammatory response by neutrophil autophagy and neutrophil extracellular DNA traps, should be considered.8 Furthermore, predictive tools allowing the selection of patients eligible to discontinue treatment represent another still unmet need. Presently, biological therapy is considered to be long-lasting or even life-time treatment and early discontinuation usually causes loss of asthma control paralleled by an increase in eosinophil counts in a substantial part of patients.9 While none of the anti-eosinophil biologicals has shown disease-modifying effects in asthma so far, it could be speculated that starting sooner with an adequate biological therapy or combinations may have an impact on aspects of airway remodelling. Future studies should provide the answer. MJ received honoraria, consultancy and speaker fees from ALK, Stallergenes-Greer, MSD, Sanofi-Genzyme, Sanofi-Pasteur, Angelini, GSK, Novartis, Nutricia, Nestle, Mundipharma, Berlin-Chemie, CSL Behring, Hero. ZD acted as Executive and Scientific Medical Director at a phase I/II pharmacological unit (QPS-NL), which performs clinical studies for pharmaceutical companies and she received honoraria, consultancy and speaker fees from Astra-Zeneca, ALK, Aquilon, Boehringer Ingelheim, CSL, HAL Allergy, MSD, Sanofi-Genzyme. None of the authors declared any conflict of interests in relationship to this manuscript.