**5.3 Treatment of severe eosinophilic asthma**

Asthma guidelines are recommending the use of sputum eosinophil count in severe asthma. The international ERS/ATS guidelines on the definition, evaluation and treatment of severe asthma addressed the phenotypic management of severe asthma and evaluated the utility use of sputum eosinophilia to guide treatment. The document suggested that treatment guided by clinical criteria and sputum eosinophil counts should be performed in centers with experience in this procedure and in selected patients, allowing avoidance of inappropriate escalation of treatment and waste of resources [62]. In the global strategy for asthma management and prevention (GINA) 2019 update, this concept is reinforced by claiming that treatment guided by sputum eosinophil count has the best benefits in patients with moderate-to-severe asthma requiring secondary care [1]. Within step 5 of treatment scale, adults with persistent symptoms or exacerbations despite high-dose ICS or ICS/LABA are advised to adjust treatment based on sputum eosinophilia >3%.

When a refractory or underline type 2 inflammation is proven in severe asthma, add-on biologic type 2 target treatment must be considered for patients with exacerbations or poor symptom control [1, 59]. Actually, sputum eosinophil count also provides an effective method to identify patients who will benefit from targeted therapy with anti–IL-5 monoclonal antibodies (mAbs). In patients with refractory eosinophilic asthma that had a sputum eosinophilia >3% DCC, despite high dose of inhaled corticosteroids, and at least 2 exacerbations in the last 2 years, with the need to make a short course of systemic corticosteroids, mepolizumab therapy reduces exacerbations and improves AQLQ scores [80]. Other studies confirmed the efficacy of anti-IL-5 mAb therapy in patients with asthma who had consistently increased eosinophil counts in sputum of greater than 2.5–3% on at least two occasions [81] .

Yet, the measurement of eosinophils in sputum or airway fluids may not truly reflect the contributions of airway tissue eosinophils. Actually, a study was assessed to understand whether induced sputum has the ability to distinguish the eosinophilic and noneosinophilic phenotypes compared to bronchial biopsies in moderate and severe asthma. This study showed that among patients with severe asthma could identify a BrEos+ group with high mucosal eosinophils and a BrEos– group. Even if there was no a correlation between sputum eosinophil count and eosinophils found in the bronchial mucosa, there was a significant correlation between

**143**

precursors [91].

*Eosinophilic Phenotype: The Lesson from Research Models to Severe Asthma*

kines such as eotaxin and RANTES or epithelial activation.

the anti-IL-5 treatment compared to placebo [84].

biomarker of response to mepolizumab [86].

and IgE levels [85].

predictor marker [87].

the number of asthma exacerbations reported by the subjects with severe asthma during the year preceding the study and the percentage of sputum eosinophils [82]. This result is reflected by the fact that on one hand mepolizumab depleted <50% of bronchial tissue and bone marrow eosinophils in spite of its effect in reducing blood, BAL fluid and sputum eosinophils abolishing established airway eosinophil infiltration [83]. Among the explanation to this phenomenon, it can be supposed that eosinophils in the airway lumen may be in a different state of activation than in the bronchial mucosa or may reflect greater concentrations of intraluminal chemo-

Another possible consequence of the supposed partial effect of mepolizumab over all the aspects of eosinophilic inflammation is that FEV1, symptoms and FENO levels were not affected [80]. On one hand, this means that these therapeutic strategies may not be sufficient to reverse remodeling changes of severe asthma even if mepolizumab has been shown to decrease the deposition of tenascin, lumican and collagen III in the basal membrane of mild atopic asthmatics as well as the degree of TGF-β in the bronchoalveolar lavage fluid [43]. Accordingly, lung function was not expected to be positively modified by anti-IL-5 treatments in severe asthma and a meta-analysis of nine randomized, placebo-controlled, clinical trials including mepolizumab or reslizumab reported a mild absolute difference of FEV1 in favor of

On the other hand, the persistently high level of FENO can guess, in a proportion of eosinophilic refractory severe asthmatics, that the IL-5 pathway is not in these patients the predominant. This fact can explain why targeting the type 2 phenotype on the IL4/IL13 pathway with dupilumab, a humanized MoAb to IL4-Ra, gave partially different results. When type 2 severe asthmatics with sputum eosinophilia >3% had been enrolled to be treated with dupilumab, the endpoints consisting of improvement of control (ACQ ), symptoms and FEV1 were reached. These clinical and functional results were coupled with decreasing FENO, eotaxin 3

Another question is whether blood eosinophils are a good predictor of response to mepolizumab in patients with severe eosinophilic asthma. The DREAM study identified a blood eosinophil count of 300/mL or greater as a high predictive

In systemic corticosteroid severe asthma with persistent blood eosinophilia, at least 150 cells, the goal of reducing >75% of oral corticosteroid dose was reached in more than 40% of patients, confirming the role of persistent blood eosinophilia as

Benralizumab binds with high affinity to the alpha-chain of human IL-5R, blocking its activation and transduction and determining a neutralizing activity. Moreover, it is able to induce antibody-dependent cell-mediated cytotoxicity (ADCC) on NK cells that release cytotoxic mediators and cause eosinophil apoptosis [88]. A significant clinical efficacy in terms of reduction of annual exacerbations, improvement of FEV1 and steroid-sparing effect was demonstrated in the clinical trials [89]. A threshold of >300 cells per mcl represents a useful marker for quantifying the advantage of this treatment in patients with steroid-dependent asthma. It has been supposed that benralizumab results in a complete depletion of eosinophils in the airway lumen and this can in part explain why in the registrative studies pre-bronchodilator FEV1 improved in the treatment groups. Actually, benralizumab is highly selective on eosinophil and basophil protein and gene-related immune signaling pathways [90] and not only reaches almost complete eosinophil eliminations at plasma levels but also determines the reduction of blood eosinophil

*DOI: http://dx.doi.org/10.5772/intechopen.92123*

#### *Eosinophilic Phenotype: The Lesson from Research Models to Severe Asthma DOI: http://dx.doi.org/10.5772/intechopen.92123*

*Cells of the Immune System*

with a summary estimate of AUC of 0.78 [78]. To be noticed that among the different studies, five different definitions of airway eosinophilia had been used, but either eosinophils ≥2% or 3% was used and this did not affect the accuracy of the test. Moreover, a subanalysis of the study showed the forest plots for blood eosinophilia in detecting sputum eosinophilia in subgroup populations of asthmatics. Smoking habit, steroid-treated or untreated and asthma severity revealed a considerable variability of positive thresholds of the marker. In severe asthma, only groups with the cut-point between 275 and 315 μL gave the highest sensibility and specificity [79]. As the most robust clinical value of sputum eosinophilia is tailoring inhaled corticosteroids and reducing the frequency of asthma exacerbations, it is expected that blood eosinophilia to replace induced sputum in this context should yield a sensitivity and specificity of at least 90%, so that only a small portion of patients will be misclassified. One of the most evident limits in the role of blood eosinophilia as a biomarker comes for the cross-sectional nature of the study populations. Significant variability of blood eosinophil count in the same patient over time and

Asthma guidelines are recommending the use of sputum eosinophil count in severe asthma. The international ERS/ATS guidelines on the definition, evaluation and treatment of severe asthma addressed the phenotypic management of severe asthma and evaluated the utility use of sputum eosinophilia to guide treatment. The document suggested that treatment guided by clinical criteria and sputum eosinophil counts should be performed in centers with experience in this procedure and in selected patients, allowing avoidance of inappropriate escalation of treatment and waste of resources [62]. In the global strategy for asthma management and prevention (GINA) 2019 update, this concept is reinforced by claiming that treatment guided by sputum eosinophil count has the best benefits in patients with moderate-to-severe asthma requiring secondary care [1]. Within step 5 of treatment scale, adults with persistent symptoms or exacerbations despite high-dose ICS or ICS/LABA are advised to adjust treatment based on sputum

When a refractory or underline type 2 inflammation is proven in severe asthma,

add-on biologic type 2 target treatment must be considered for patients with exacerbations or poor symptom control [1, 59]. Actually, sputum eosinophil count also provides an effective method to identify patients who will benefit from targeted therapy with anti–IL-5 monoclonal antibodies (mAbs). In patients with refractory eosinophilic asthma that had a sputum eosinophilia >3% DCC, despite high dose of inhaled corticosteroids, and at least 2 exacerbations in the last 2 years, with the need to make a short course of systemic corticosteroids, mepolizumab therapy reduces exacerbations and improves AQLQ scores [80]. Other studies confirmed the efficacy of anti-IL-5 mAb therapy in patients with asthma who had consistently increased eosinophil counts in sputum of greater than 2.5–3% on at least two occasions [81] . Yet, the measurement of eosinophils in sputum or airway fluids may not truly reflect the contributions of airway tissue eosinophils. Actually, a study was assessed to understand whether induced sputum has the ability to distinguish the eosinophilic and noneosinophilic phenotypes compared to bronchial biopsies in moderate and severe asthma. This study showed that among patients with severe asthma could identify a BrEos+ group with high mucosal eosinophils and a BrEos– group. Even if there was no a correlation between sputum eosinophil count and eosinophils found in the bronchial mucosa, there was a significant correlation between

according to treatment status must be taken into account.

**5.3 Treatment of severe eosinophilic asthma**

**142**

eosinophilia >3%.

the number of asthma exacerbations reported by the subjects with severe asthma during the year preceding the study and the percentage of sputum eosinophils [82]. This result is reflected by the fact that on one hand mepolizumab depleted <50% of bronchial tissue and bone marrow eosinophils in spite of its effect in reducing blood, BAL fluid and sputum eosinophils abolishing established airway eosinophil infiltration [83]. Among the explanation to this phenomenon, it can be supposed that eosinophils in the airway lumen may be in a different state of activation than in the bronchial mucosa or may reflect greater concentrations of intraluminal chemokines such as eotaxin and RANTES or epithelial activation.

Another possible consequence of the supposed partial effect of mepolizumab over all the aspects of eosinophilic inflammation is that FEV1, symptoms and FENO levels were not affected [80]. On one hand, this means that these therapeutic strategies may not be sufficient to reverse remodeling changes of severe asthma even if mepolizumab has been shown to decrease the deposition of tenascin, lumican and collagen III in the basal membrane of mild atopic asthmatics as well as the degree of TGF-β in the bronchoalveolar lavage fluid [43]. Accordingly, lung function was not expected to be positively modified by anti-IL-5 treatments in severe asthma and a meta-analysis of nine randomized, placebo-controlled, clinical trials including mepolizumab or reslizumab reported a mild absolute difference of FEV1 in favor of the anti-IL-5 treatment compared to placebo [84].

On the other hand, the persistently high level of FENO can guess, in a proportion of eosinophilic refractory severe asthmatics, that the IL-5 pathway is not in these patients the predominant. This fact can explain why targeting the type 2 phenotype on the IL4/IL13 pathway with dupilumab, a humanized MoAb to IL4-Ra, gave partially different results. When type 2 severe asthmatics with sputum eosinophilia >3% had been enrolled to be treated with dupilumab, the endpoints consisting of improvement of control (ACQ ), symptoms and FEV1 were reached. These clinical and functional results were coupled with decreasing FENO, eotaxin 3 and IgE levels [85].

Another question is whether blood eosinophils are a good predictor of response to mepolizumab in patients with severe eosinophilic asthma. The DREAM study identified a blood eosinophil count of 300/mL or greater as a high predictive biomarker of response to mepolizumab [86].

In systemic corticosteroid severe asthma with persistent blood eosinophilia, at least 150 cells, the goal of reducing >75% of oral corticosteroid dose was reached in more than 40% of patients, confirming the role of persistent blood eosinophilia as predictor marker [87].

Benralizumab binds with high affinity to the alpha-chain of human IL-5R, blocking its activation and transduction and determining a neutralizing activity. Moreover, it is able to induce antibody-dependent cell-mediated cytotoxicity (ADCC) on NK cells that release cytotoxic mediators and cause eosinophil apoptosis [88]. A significant clinical efficacy in terms of reduction of annual exacerbations, improvement of FEV1 and steroid-sparing effect was demonstrated in the clinical trials [89]. A threshold of >300 cells per mcl represents a useful marker for quantifying the advantage of this treatment in patients with steroid-dependent asthma. It has been supposed that benralizumab results in a complete depletion of eosinophils in the airway lumen and this can in part explain why in the registrative studies pre-bronchodilator FEV1 improved in the treatment groups. Actually, benralizumab is highly selective on eosinophil and basophil protein and gene-related immune signaling pathways [90] and not only reaches almost complete eosinophil eliminations at plasma levels but also determines the reduction of blood eosinophil precursors [91].
