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The effects of electronic cigarettes (e-cigarettes) vapor on inflammation and mucin secretion on asthmatics remain insufficiently explored. This study investigated the effects of e-cigarette vapor on allergic inflammation, cytokine production, and MUC5AC/5B expression in murine asthma model. Airway hyperresponsiveness was significantly higher in the e-cigarette-exposed ovalbumin (OVA) sensitization group than in the control, e-cigarette exposure, and OVA sensitization groups. The e-cigarette-exposed OVA sensitization group showed significantly greater infiltration of inflammatory cells and Th2-mediated inflammatory cytokines (interleukin-4 and -5) compared to the control, e-cigarette exposure, and OVA sensitization groups. MUC5AC mucin levels were significantly elevated in the e-cigarette exposure, OVA sensitization, and e-cigarette-exposed OVA sensitization groups, whereas MUC5B mucin levels were significantly elevated in the OVA sensitization and e-cigarette-exposed OVA sensitization groups. The results may suggest that the exposure to e-cigarette vapor in an asthmatics promoted allergic inflammation and increased mucin secretion, ultimately leading to the exacerbation of asthma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Asthma encompasses a spectrum of phenotypes often categorized into two groups- type 2 high (T2 high) and type 2 low (T2 low). T2 high includes atopic and eosinophilic presentations whereas T2 low is non-atopic, non-eosinophilic, and oft associated with neutrophilic inflammation. Eosinophilic asthma is often driven by IgE, IL-4, IL-5, and IL-13 and TSLP. This can lead to eosinophilic inflammatory response in the airways which in turn can be used as target for treatment., Areas Covered: The article will focus on biologic therapy that is currently being used in eosinophilic asthma management in mainly the adult population including clinical trials and co-morbidities that can be treated using the same biologics. A review on asthma biologics for pediatric population has been reviewed elsewhere., Expert Opinion: Biological therapy for asthma targeting the IgE, IL-4, IL-5, IL-13, and TSLP pathways are shown to have benefit for the treatment of eosinophilic asthma, as exemplified in real-world studies. When choosing the right biological agent factors such as phenotype, comorbidities, and cost-effectiveness of the biologic agent must be taken into consideration.

Background: Nonneuronal cells, including epithelial cells, can produce acetylcholine (ACh). Muscarinic ACh receptor antagonists are used clinically to treat asthma and other medical conditions; however, knowledge regarding the roles of ACh in type 2 immunity is limited., Objective: Our aim was to investigate the roles of epithelial ACh in allergic immune responses., Methods: Human bronchial epithelial (HBE) cells were cultured with allergen extracts, and their ACh production and IL-33 secretion were studied in vitro. To investigate immune responses in vivo, naive BALB/c mice were treated intranasally with different muscarinic ACh receptor antagonists and then exposed intranasally to allergens., Results: At steady state, HBE cells expressed cellular components necessary for ACh production, including choline acetyltransferase and organic cation transporters. Exposure to allergens caused HBE cells to rapidly release ACh into the extracellular medium. Pharmacologic or small-interfering RNA-based blocking of ACh production or autocrine action through the M3 muscarinic ACh receptors in HBE cells suppressed allergen-induced ATP release, calcium mobilization, and extracellular secretion of IL-33. When naive mice were exposed to allergens, ACh was quickly released into the airway lumen. A series of clinical M3 muscarinic ACh receptor antagonists inhibited allergen-induced IL-33 secretion and innate type 2 immune response in the mouse airways. In a preclinical murine model of asthma, an ACh receptor antagonist suppressed allergen-induced airway inflammation and airway hyperreactivity., Conclusions: ACh is released quickly by airway epithelial cells on allergen exposure, and it plays an important role in type 2 immunity. The epithelial ACh system can be considered a therapeutic target in allergic airway diseases., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common β (βc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation., Objective: To determine the pathogenesis of βc receptor-mediated inflammation and remodeling in severe asthma and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease., Methods: βc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling., Results: βc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung., Conclusions: βc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anti-IL-5 monoclonal antibodies (mAbs) targeting IL-5 or IL-5 R α (including mepolizumab, benralizumab, and reslizumab) are widely used for inflammatory diseases such as asthma, eosinophilia, and polyangiitis. However, real-world data regarding its safety in a large sample population are incomplete. So, we evaluated the safety of anti-IL-5 mAbs by pharmacovigilance analyzes based on related adverse events (AEs) from the FDA Adverse Event Reporting System (FAERS)., Methods: In disproportionality analysis, four algorithms were employed to detect the signals of anti-IL-5 mAbs from the FAERS between 2016 and 2022. In addition, we also used MYSQL 8.0, Navicat Premium 15, and Microsoft EXCEL 2019 to analyze the signals of anti-IL-5 mAbs systematically., Results: There are 9,476,351 reports collected from the FAERS database, of which 22,174 reports listed anti-IL-5 mAbs as the 'primary suspected (PS)' drug. A total of 59 (20 new signals, mepolizumab) and 62 (19 new signals, benralizumab) significant disproportionality preferred terms (PTs) conforming to the four algorithms were retained synchronously. Finally, we detected that the anti-IL-5 mAbs-induced AEs occurred in 31 organ systems (mepolizumab) and 30 organ systems (benralizumab). For mepolizumab and reslizumab, unexpected and new significant PTs of AEs were found, such as asthmatic crisis, chronic obstructive pulmonary disease (COPD), pneumonia, COVID-19, pneumothorax, adrenal insufficiency and so on. Notably, the risk signal of asthmatic crisis for mepolizumab was stronger than benralizumab (ROR 108.04 [95%CI, 96.09-121.47] vs 26.83 [95%CI, 18.91-38.06]). Comparing with mepolizumab and benralizumab, we found the proportion of serious adverse events in mepolizumab was both greater than benralizumab in each age group (≤20, 20-65, and ≥ 65). The median onset time of mepolizumab was 280 days (interquartile range [IQR] 1-367 days)., Conclusion: Analysis of FAERS data identified anti-IL-5 mAbs-associated AEs, and our findings supported continuous clinical monitoring, pharmacovigilance, and further studies of anti-IL-5 mAbs. In addition, clinicians may be more aware of the limitations of use in package inserts of anti-IL-5 mAbs: Not for relief of acute bronchospasm or status asthmaticus. Because of some limitations in the FAERS such as self-reports from patients and other confounding factors, the safety of anti-IL-5 mAbs needed more studies in different dimensions, especially the risk of cancer.

Human interleukin-5 (IL-5) functions as an important pro-inflammatory factor by binding to its specific receptor, IL-5Rα, which has been implicated in the pathogenesis of asthma. Previously, a disulfide-bonded cyclic peptide AF17121 obtained from random library screening and sequence variation was found to competitively disrupt the cognate IL-5Rα/IL-5 interaction with moderate potency. In this study, the crystal complex of IL-5Rα with AF17121 was investigated at structural and energetic levels. It is revealed that the side-chain indole moiety of the AF17121 Trp5 residue is a potential site for a stem putative halogen bond (X-bond) with IL-5Rα, which is just located within the key 3 EXXR 6 motif region recognized specifically by IL-5Rα. We systematically examined four halogen substitution types at five positions of the indole moiety; QM/MM calculations theoretically unraveled that only halogenations at 5 and 6 positions can form effective X-bonds with the side-chain hydroxyl oxygen of the IL-5Rα Thr21 residue and the backbone carbonyl oxygen of Ala66 residue, respectively. Binding assays observed that I-substitution at the 5 position and Br-substitution at the 6 position can result in two potent halogenated peptides, [5I]AF17121 and [6Br]AF17121, which are improved by 1.6-fold and 3.5-fold relative to the native AF17121, respectively. 5I/6Br-double substitution, resulting in [5I/6Br]AF17121, can further enhance the peptide affinity by 7.5-fold. Structural analysis revealed that the X-bond stemming from 6Br-substitution is also involved in an orthogonal interaction system with a H-bond; they share a common backbone carbonyl oxygen acceptor of IL-5Rα Ala66 residue and exhibit a significant synergistic effect between them., (© 2023 John Wiley & Sons A/S.)

Background: Eosinophils have been divided into different subpopulations with distinct phenotypes based on CD62L expression. No data are available regarding the correlation between eosinophils subphenotypes and clinical severity of asthma, as well as the effect of anti-IL-5 therapy on these cells. The study investigates the correlation between blood CD62L low inflammatory eosinophils (iEos) and clinical severity of severe eosinophilic asthma (SEA) and evaluates the impact of mepolizumab on iEos., Methods: 112 patients were screened and were divided in two groups: biological-naive (n = 51) and biological-treated patients (n = 61). The Biological-naive patients were analyzed before treatment (Group A) and 19 out of 51 patients, were longitudinally analyzed before and after treatment with mepolizumab 100 mg s.c/4 weeks (Group B); 32 patients were excluded because they were being treated with other biological therapies. Blood eosinophils were analyzed by FACS and correlated with clinical scores. In vitro effect of IL-5 and mepolizumab on CD62L expression was assessed., Results: A significant correlation between blood CD62L low cells and clinical scores of asthma and nasal polyps, as well as the number of asthma exacerbations in the last year was shown in untreated patients. In longitudinally studied patients we observed a marked reduction of CD62L low cells paralleled by an increase in the proportion of CD62L bright cells, associated with clinical improvement of asthma control. In vitro, CD62L expression on eosinophils is modulated by IL-5 and anti-IL-5., Conclusion: A positive correlation between CD62L low iEos and the baseline clinical features of SEA with CRSwNP was shown. Furthermore mepolizumab restores the healthy balance among eosinophils sub-phenotypes in SEA patients., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Staphylococcus aureus enterotoxins (SE) may act as superantigens and induce an intense T-cell activation, causing local production of polyclonal IgE and resultant eosinophil activation., Objective: To assess whether asthma with sensitization to SE but not to common aeroallergens (AAs) displays different inflammatory characteristics., Methods: We conducted a prospective study on a series of 110 consecutive patients with asthma recruited from the University Asthma Clinic of Liège. We compared clinical, functional, and inflammatory characteristics of this general population of patients with asthma categorized into 4 groups according to sensitization to AAs and/or SE. We also compared sputum supernatant cytokines in patients sensitized to SE or not., Results: Patients with asthma sensitized only to AAs represented 30%, while 29% were sensitized to both AAs and SE. One-fifth of the population had no specific IgE. Sensitization to SE but not to AA (21%) was associated with later onset of disease, higher rate of exacerbations, nasal polyps, and more severe airway obstruction. As for airway type 2 biomarkers, patients presenting with specific IgE against SE displayed higher fractional exhaled nitric oxide, sputum IgE, and sputum IL-5 levels but not IL-4. We confirm that the presence of specific IgE against SE is associated with elevated serum IgE to levels well above those observed in patients sensitized only to AAs., Conclusions: Our study suggests that asthma specialists should measure specific IgE against SE during the phenotyping process because it may allow the identification of a subgroup of patients with more asthma exacerbations, more nasal polyposis and chronic sinusitis, lower lung function, and more intense type 2 inflammation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The unified airway hypothesis proposes that upper and lower airway diseases reflect a single pathological process manifesting in different locations within the airway. Functional, epidemiological, and pathological evidence has supported this well-established hypothesis for some time. However, literature on the pathobiologic roles/therapeutic targeting of eosinophils and IL-5 in upper and lower airway diseases (including asthma, chronic rhinosinusitis with nasal polyps [CRSwNP], and nonsteroidal anti-inflammatory drug-exacerbated respiratory disease) has recently emerged. This narrative review revisits the unified airway hypothesis by searching the scientific literature for recent learnings and clinical trial/real-world data that provide a novel perspective on its relevance for clinicians. According to the available literature, eosinophils and IL-5 have important pathophysiological roles in both the upper and lower airways, although the impact of eosinophils and IL-5 may vary in asthma and CRSwNP. Some differential effects of anti-IL-5 and anti-IL-5-receptor therapies in CRSwNP have been observed, requiring further investigation. However, pharmaceutical targeting of eosinophils and IL-5 in patients with upper, lower, and comorbid upper and lower airway inflammation has led to clinical benefit, supporting the hypothesis that these are linked conditions manifesting in different locations. Consideration of this approach may improve patient care and aid clinical decision making., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic airway diseases such as asthma are characterized by persistent type 2 immunity in the airways. We know little about the mechanisms that explain why type 2 inflammation continues in these diseases., Objective: We used mouse models to investigate the mechanisms involved in long-lasting immune memory., Methods: Naive mice were exposed intranasally to ovalbumin (OVA) antigen with Alternaria extract as an adjuvant. Type 2 memory was analyzed by parabiosis model, flow cytometry with in vivo antibody labeling, and intranasal OVA recall challenge. Gene-deficient mice were used to analyze the mechanisms., Results: In the parabiosis model, mice previously exposed intranasally to OVA with Alternaria showed more robust antigen-specific immune responses and airway inflammation than mice with circulating OVA-specific T cells. After a single airway exposure to OVA with Alternaria, CD69 + ST2 + T H 2-type T cells, which highly express type 2 cytokine messenger RNA and lack CD62L expression, appeared in lung tissue within 5 days and persisted for at least 84 days. When exposed again to OVA in vivo, these cells produced type 2 cytokines quickly without involving circulating T cells. Development of tissue-resident CD69 + ST2 + T H 2 cells and long-term memory to an inhaled antigen were abrogated in mice deficient in ST2 or IL-33, but not TSLP receptor., Conclusion: CD69 + ST2 + T H 2 memory cells develop quickly in lung tissue after initial allergen exposure and persist for a prolonged period. The ST2/IL-33 pathway may play a role in the development of immune memory in lung to certain allergens., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis characterized by asthma, systemic manifestations, and blood and tissue eosinophilia., Objective: To assess the effectiveness and safety of mepolizumab (anti-IL-5) and benralizumab (anti-IL-5Rα) in EGPA for 24 months., Methods: We conducted a multicenter observational study, including patients with EGPA treated with anti-IL-5/Rα biologics in 9 Italian specialized facilities. Systemic disease activity, remission and relapse rate were evaluated from 3 to 24 months after treatment initiation. Respiratory outcomes, hematological parameters, corticosteroid (OCS) and immunosuppressants consumption were also assessed., Results: 49 patients with relapsing-refractory EGPA were included [26 (53.1%) benralizumab 30mg, 20 (40.8%) mepolizumab 100mg, 3 (6.1%) mepolizumab 300mg]. Overall, 38.8% and 57.1% achieved remission after 12 and 24 months, respectively (69.2% benralizumab and 43.5% mepolizumab). Lower OCS intake and higher blood eosinophil count at baseline were associated with remission at 24 months. Both biologics exerted beneficial effects on severe asthma outcomes. Indeed, 61.2% (61.5% benralizumab and 60.8% mepolizumab) remained exacerbation-free during treatment. Lung function parameters showed improvements in the overall cohort (all p< 0.05), but began to decline from month 12, especially with mepolizumab. Marked reduction in blood eosinophils was registered with mepolizumab ( p< 0.0001), while benralizumab depleted both eosinophils ( p< 0.0001) and basophils ( p <0.0001). In general, 69.6% (76% benralizumab and 61.9% mepolizumab) of OCS-dependent patients lowered their daily dose by 75%, while 28.3% discontinued these drugs. Immunosuppressants were suspended in 88.2% of cases. Adverse events were reported in 8.2% of patients., Conclusions: These real-world data suggest that anti-IL-5/Rα biologics are effective and safe in the long-term as add-on treatments for patients with EGPA., Competing Interests: AP has received speaker fees from AstraZeneca, GlaxoSmithKline, Chiesi and Sanofi. AB has received speaker fees from AstraZeneca, GlaxoSmithKline, and Sanofi. MT has received speaker and consultancy fees from Novartis, AstraZeneca and GlaxoSmithKline. GSc has received speaker fees from AstraZeneca, GlaxoSmithKline, and Sanofi. AD has received speaker fees from Sanofi, AstraZeneca, GlaxoSmithKline, Novartis, Lofarma. GV has received speaker fees from GlaxoSmithKline, and Sanofi. NC has received speaker and lecturer fees from AstraZeneca, GlaxoSmithKline and Sanofi. NS has received speaker fees from AstraZeneca, GlaxoSmithKline, Chiesi and Sanofi. GP has received speaker and lecturer fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Guidotti, Menarini, Novartis and Sanofi. GC has received grants from AstraZeneca, GlaxoSmithKline, Chiesi, Sanofi and Grifols; has received speaker and lecturer fees from AstraZeneca, GlaxoSmithKline, and Sanofi; has received supports for attending meetings from AstraZeneca, Menarini and Chiesi. CC has received speaker fees from ResMed, Fisher&Paykel, Sanofi, AstraZeneca, GlaxoSmithKline and Menarini. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor EH declared a past co-authorship with the authors SN, RC, CP, AB, MT, GS, MC, AD, NC, NS, GP, GC and CC., (Copyright © 2023 Nolasco, Portacci, Campisi, Buonamico, Pelaia, Benfante, Triggiani, Spadaro, Caiaffa, Scioscia, Detoraki, Valenti, Papia, Tomasello, Crimi, Scichilone, Pelaia, Carpagnano and Crimi.)

The efficacy of benralizumab, as well as mepolizumab, to granulomatosis with polyangiitis (EGPA) involved with mononeuritis multiplex remains unclear. We experienced a case of EGPA presenting neuropathy with severe asthma. Muscle weakness due to neuropathy involved with gait disturbance was partly ameliorated by intravenous immunoglobulin therapy. Mepolizumab (100 mg/day) did not promote further improvement of neuropathy. However, the administration of benralizumab instead of mepolizumab improved neuropathy quickly and enabled walking alone. The efficacy of benralizumab for EGPA and its complication has been maintained for over four years. Benralizumab may be a possible treatment for EGPA presenting neuropathy with severe asthma.

Asthma is a chronic complex pulmonary disease characterized by airway inflammation, remodeling, and hyperresponsiveness. Vascular endothelial growth factor (VEGF) and eosinophil-derived neurotoxin (EDN) are two significant mediators involved in the pathophysiology of asthma. In asthma, VEGF and EDN levels are elevated and correlate with disease severity and airway hyperresponsiveness. Diversity in VEGF polymorphisms results in the variability of responses to glucocorticosteroids and leukotriene antagonist treatment. Targeting VEGF and eosinophils is a promising therapeutic approach for asthma. We identified lichochalcone A, bevacizumab, azithromycin (AZT), vitamin D, diosmetin, epigallocatechin gallate, IGFBP-3, Neovastat (AE-941), endostatin, PEDF, and melatonin as putative add-on drugs in asthma with anti-VEGF properties. Further studies and clinical trials are needed to evaluate the efficacy of those drugs. AZT reduces the exacerbation rate and may be considered in adults with persistent symptomatic asthma. However, the long-term effects of AZT on community microbial resistance require further investigation. Vitamin D supplementation may enhance corticosteroid responsiveness. Herein, anti-eosinophil drugs are reviewed. Among them are, e.g., anti-IL-5 (mepolizumab, reslizumab, and benralizumab), anti-IL-13 (lebrikizumab and tralokinumab), anti-IL-4 and anti-IL-13 (dupilumab), and anti-IgE (omalizumab) drugs. EDN over peripheral blood eosinophil count is recommended to monitor the asthma control status and to assess the efficacy of anti-IL-5 therapy in asthma.

Severe or refractory asthma is seen in approximately 5% of asthmatic subjects who have unsatisfactory symptom control despite adherence to high-dose inhaled glucocorticoid therapies resulting in significant morbidity, reduced quality of life with attendant implications for healthcare costs. Marked heterogeneity in symptoms and at the molecular phenotypic level are hallmarks of asthma resulting in the requirement of specifically targeted treatments to block the key pathways of the disease. Monoclonal antibody (mAb)-based biologics targeted at inhibition of the type 2 cytokines IL-4, IL-5 and IL-13 have become established as effective treatments for severe asthma, with significant clinical benefit seen in carefully selected patient populations that take asthma phenotypes and endotypes into account. The further development of reproducible and straightforward discriminatory biomarkers may aid identification of those patients most likely to benefit from treatment with these interventions., (Copyright © 2023. Published by Elsevier Inc.)

Blood eosinophils can be described as inflammatory-like (iEOS-like) and lung-resident-like (rEOS-like) eosinophils. This study is based on the hypothesis that eosinophilopoetins such as interleukin (IL)-3 and IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) alter the proliferative properties of eosinophil subtypes and may be associated with the expression of their receptors on eosinophils. We investigated 8 individuals with severe nonallergic eosinophilic asthma (SNEA), 17 nonsevere allergic asthma (AA), and 11 healthy subjects (HS). For AA patients, a bronchial allergen challenge with Dermatophagoides pteronyssinus was performed. Eosinophils were isolated from peripheral blood using high-density centrifugation and magnetic separation methods. The subtyping of eosinophils was based on magnetic bead-conjugated antibodies against L-selectin. Preactivation by eosinophilopoetins was performed by incubating eosinophil subtypes with IL-3, IL-5, and GM-CSF, and individual combined cell cultures were prepared with airway smooth muscle (ASM) cells. ASM cell proliferation was assessed using an Alamar blue assay. The gene expression of eosinophilopoetin receptors was analyzed with a qPCR. IL-5 and GM-CSF significantly enhanced the proliferative properties of iEOS-like and rEOS-like cells on ASM cells in both SNEA and AA groups compared with eosinophils not activated by cytokines (p < 0.05). Moreover, rEOS-like cells demonstrated a higher gene expression of the IL-3 and IL-5 receptors compared with iEOS-like cells in the SNEA and AA groups (p < 0.05). In conclusion: IL-5 and GM-CSF promote the proliferative properties of iEOS-like and rEOS-like eosinophils; however, the effect of only IL-5 may be related to the expression of its receptors in asthma patients.

Background: Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence., Results: We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability., Conclusions: These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma., (© 2022. The Author(s).)

Background: Mepolizumab inhibits IL-5 activity and reduces exacerbation frequency and maintenance oral corticosteroid (OCS) dosage in patients with severe eosinophilic asthma (SEA). Some patients remain dependent on OCS despite anti-IL-5 treatment, suggesting residual corticosteroid-responsive mechanisms., Objective: To determine the clinical and anti-inflammatory effects of OCS in patients with SEA on mepolizumab., Methods: We conducted a randomized, triple-blind, placebo-controlled crossover trial of prednisolone (0.5 mg/kg/d, maximum 40 mg/d, for 14 ± 2 days) in adults with SEA after 12 or more weeks of mepolizumab. We compared change in asthma symptoms, quality of life, lung function measured by spirometry and airwave oscillometry, fractional exhaled nitric oxide, and blood and sputum eosinophil cell count after prednisolone and placebo treatment., Results: A total of 27 patients completed the study. Prednisolone did not improve 5-item Asthma Control Questionnaire (mean difference in change for prednisolone vs placebo, -0.23; 95% CI, -0.58 to 0.11), mini-Asthma Quality of Life Questionnaire (0.03; 95% CI, -0.26 to 0.42), St. George's Respiratory Questionnaire (0.24; 95% CI, -3.20 to 3.69), or Visual Analogue Scale scores for overall asthma symptoms (0.11; 95% CI, -0.58 to 0.80). The mean difference for FEV 1 in favor of prednisolone was 105 mL (95% CI, -4 to 213 mL); forced expiratory flow at 25% and 75% 484 mL/s (95% CI, 151 to 816 mL/s); fractional exhaled nitric oxide reduction 41% (95% CI, 25% to 54%); blood eosinophil count reduction 49% (95% CI, 31% to 62%); and percentage of sputum eosinophil reduction 71% (95% CI, 26% to 89%)., Conclusions: OCS improved small-airway obstruction and reduced biomarkers of type 2 inflammation but had no significant effect on symptoms or quality of life in patients with SEA receiving treatment with mepolizumab., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Background: Reslizumab, a biologic targeting IL-5, has been shown to reduce asthma exacerbations and maintenance oral corticosteroid use in randomized controlled trials and pre-post studies in patients with severe eosinophilic asthma. However, real-world effectiveness data of reslizumab are scarce, and it is unknown whether reslizumab has added value after switching from another type 2 biologic., Objective: To evaluate (1) the real-world effectiveness of reslizumab on severe asthma exacerbations, maintenance oral corticosteroid use, and overall treatment response, both in biologic-naive patients who initiated reslizumab and in those who switched from another type 2 biologic; and (2) physicians' experience with reslizumab treatment., Methods: This observational real-world study evaluated data from 134 adults with severe eosinophilic asthma included in the Dutch severe asthma registry (RAPSODI), who initiated reslizumab treatment (4-weekly infusions, 0.3 mg/kg) before April 2020 and had follow-up data for 6 months and greater. Clinical asthma experts completed surveys on their experience with reslizumab treatment., Results: Overall, reslizumab reduced the exacerbation rate (odds ratio [95% CI] = 0.10 [0.05-0.21]; P < .001), oral corticosteroid use (OR [95% CI], 0.2 [0.0-0.5]; P < .001), and maintenance dose (median [CI], 5.0 [0.0-10.0] to 0.0 [0.0-5.0]; P < .001), with comparable results in biologic-naive reslizumab initiators and switchers. The overall response to reslizumab was graded good or excellent in 59.2% of patients. The additive effectiveness of reslizumab after switching from another biologic was reflected in physicians' surveys., Conclusions: Real-world data show that reslizumab reduces severe asthma exacerbations and oral corticosteroid use in patients with severe eosinophilic asthma, both in biologic-naive reslizumab initiators and in those who switched from another type 2 biologic. This additional value of reslizumab was recognized by clinical asthma experts., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described., Objective: We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease., Methods: We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain-containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet-induced obesity and asthma., Results: Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet-induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet-induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma., Conclusion: We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine-targeted biologics and inflammasome inhibitors., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: IL-5-dependent residential and IL-18-transformed pathogenic eosinophils have been reported; however, the role of IL-18-transformed CD274-expressing pathogenic eosinophils compared to IL-5-generated eosinophils in promoting airway obstruction in asthma has not yet been examined., Methods: Eosinophils are detected by tissue anti-MBP and anti-EPX immunostaining, CD274 expression by flow cytometry, and airway resistance using the Buxco FinePointe RC system., Results: We show that A. fumigatus-challenged wild-type mice, and different gene-deficient mice including naïve CC10-IL-18-transgenic mice, accumulate mostly peribronchial and perivascular CD274-expressing eosinophils except naïve CD2-IL-5-transgenic mice. Additionally, we show that CD2-IL-5 transgenic mice following rIL-18 treatment accumulate high number of CD274-expressing perivascular and peribronchial eosinophils with induced collagen, goblet cell hyperplasia and airway resistance compared to saline-challenged CD2-IL5 transgenic mice. Furthermore, we also show that even A. fumigatus-challenged IL-5 -/- mice and rIL-18 given ΔdblGATA mice accumulate CD274-expressing eosinophil-associated asthma pathogenesis including airway obstruction. Most importantly, we provide evidence that neutralization of CD274 and IL-18 in A. fumigatus-challenged mice ameliorate experimental asthma. Taken together, the data presented are clinically significant in establishing that anti-IL-18 neutralization is a novel immunotherapy to restrict asthma pathogenesis., Conclusions: We demonstrate that IL-18 is critical for inducing asthma pathogenesis, and neutralization of CD274 is a potential immunotherapeutic strategy for asthma., (© European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) affects around 60% of patients with severe eosinophilic asthma (SEA). Benralizumab was recently approved for SEA add-on treatment., Objective: To assess the real-world effectiveness of benralizumab in SEA with or without CRSwNP., Methods: We conducted a multicenter observational study, including patients with SEA treated with benralizumab for 24 weeks in 12 Italian specialized facilities. Asthma exacerbations, Asthma Control Test (ACT), lung function, oral corticosteroid (OCS) dosage, and eosinophil and basophil count in peripheral blood were recorded at baseline and after 4, 12, and 24 weeks. The 22-item Sino-Nasal Outcome Test (SNOT-22) and Lund-Mackay scores were assessed at baseline and after 24 weeks in SEA+CRSwNP., Results: A total of 137 patients with late-onset SEA were included; 57.7% (79 of 137) showed the copresence of CRSwNP. Overall, severe asthma exacerbations decreased from 4 (3-6) to 0 (0-2) (P < .0001) after 24 weeks of treatment, and significant improvements were observed as early as 4 weeks in ACT score, OCS dosage, forced expiratory volume in the 1st second (FEV 1 )%, FEV 1 (L), forced vital capacity (FVC)%, FEV 1 /FVC% (P < .0001), and forced expiratory flow between 25% and 75% of FVC (FEF 25-75 )% (P = .0022). Eosinophils and basophils in peripheral blood were rapidly depleted. In patients with SEA+CRSwNP, SNOT-22 decreased from 46 (39.5-64.5) to 32 (19-46) (P < .0001). Furthermore, in comparison with SEA, they showed enhanced responses with regard to ACT minimal clinically important difference (P = .0387), FEV 1 % (P = .017), FEV 1 (L) (P = .02), and FEF 25-75 % (P = .0362)., Conclusions: These real-world data suggest that benralizumab can represent a valid add-on therapeutic option for patients with SEA, especially with comorbid CRSwNP., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: The role of biologic treatments in severe asthma continues to expand, with five agents now approved. Selection of biologic treatment has become increasingly complex in the setting of overlapping indications and in the absence of head-to-head trials. Long-term safety data are still limited for more recently approved agents., Areas Covered: We review the evidence supporting the choice of biologic and predicting treatment response utilizing existing widely available biomarkers. In addition, we provide a digest of the long-term safety data currently available for agents approved since 2015. Data sources were identified by using PubMed in 2021., Expert Opinion: We generally favor omalizumab in the first instance for those severe asthma patients also eligible for other biologics, due to the greater long-term safety data available for this agent. Clinical characteristics predicting response, treatment priorities, and comorbidities must also be considered.

Introduction: Only little is known about COVID-19 in patients with asthma. There is no data on COVID-19 in patients with severe asthma or patients with asthma who are treated with monoclonal antibodies., Case Study: Here, we present the case of a severe eosinophilic asthmatic in whom benralizumab treatment, an anti-IL-5R monoclonal antibody, was initiated 2 years ago. Prior to benralizumab treatment, every viral infection had resulted in a prolonged course of oral corticosteroids (OCS). Since initiation of benralizumab, the patient has had good asthma control. Mid-March 2020, the patient developed high fever., Results: A SARS-CoV-2-PCR (nasopharyngeal swab) was positive. The patient's symptoms subsided after few days. No OCS was needed. The asthma control questionnaire 6-item scale worsened moderately in the week of the infection and returned to normal levels thereafter. The asthma control test, measuring longer term asthma control, showed no decline., Conclusion: The course of COVID-19 was very mild in this particular patient with severe eosinophilic asthma. So far, there is no evidence that would suggest a more severe course of COVID-19 in patients with asthma. It is worth noting, that prior to the initiation of benralizumab this patient had multiple exacerbations per year triggered by viral infections (4/year), which all required OCS. Whilst only anecdotal, this case study provides the first evidence to support the current recommendation of continuing monoclonal antibodies in patients with severe asthma during the COVID-19 pandemic.

Cicadae Periostracum (CP), derived from the slough of Cryptotympana pustulata , has been used as traditional medicine in Korea and China because of its diaphoretic, antipyretic, anti-inflammatory, antioxidant, and antianaphylactic activities. The major bioactive compounds include oleic acid (OA), palmitic acid, and linoleic acid. However, the precise therapeutic mechanisms underlying its action in asthma remain unclear. The objective of this study was to determine the antiasthmatic effects of CP in an ovalbumin (OVA)-induced asthmatic mouse model. CP and OA inhibited the inflammatory cell infiltration, airway hyperresponsiveness (AHR), and production of interleukin (IL)7 and Th2 cytokines (IL-5) in the bronchoalveolar lavage fluid and OVA-specific imunoglobin E (IgE) in the serum. The gene expression of IL-5, IL-13, CCR3, MUC5AC, and COX-2 was attenuated in lung tissues. CP and OA might inhibit the nuclear translocation of GATA-binding protein 3 (GATA-3) and retinoic acid receptor-related orphan receptor γt (RORγt) via the upregulation of forkhead box p3 (Foxp3), thereby preventing the activation of GATA-3 and RORγt. In the in vitro experiment, a similar result was observed for Th2 and GATA-3. These results suggest that CP has the potential for the treatment of asthma via the inhibition of the GATA-3/Th2 and IL-17/RORγt signaling pathways.

Background: Biological treatments directed against IgE and IL-5 have largely improved outcomes for patients with severe type 2-high asthma. However, a fraction of patients with severe asthma show insufficient treatment outcome under anti-IgE and anti-IL-5/IL-5 receptor α antibodies., Objective: To evaluate whether switching to dupilumab was of benefit in patients with insufficient outcome under previous anti-IgE or anti-IL-5/IL-5 receptor α therapy., Methods: We retrospectively analyzed 38 patients who were switched to dupilumab from a previous anti-IgE or anti-IL-5/IL-5 receptor α medication because of insufficient outcome. We defined response criteria after 3 to 6 months as an improvement in at least 1 of the following criteria without deterioration in the other criteria, comparing values under dupilumab with values under previous antibody therapy: (1) increase of 3 or more in Asthma Control Test score, (2) 50% or more reduction in oral corticosteroid dose, and (3) FEV 1 improvement greater than or equal to 150 mL, and classified patients as responders and nonresponders., Results: Switch to dupilumab led to a response in 76% of patients. In the total cohort, Asthma Control Test score increased by a mean of 2.9 (P < .0001), whereas exacerbations decreased significantly (P < .0001) and number of oral corticosteroid-dependent patients decreased from 15 to 12. Mean FEV 1 improved by 305 mL (P < .0001). Median fractional exhaled nitric oxide decreased by -30 ppb (P < .0001), whereas eosinophil counts increased by 0.17 G/L (P < .01). There were no significant differences in clinical characteristics between responders and nonresponders to dupilumab. However, patients with increased fractional exhaled nitric oxide (≥25 ppb) during previous antibody therapy were more often responders than patients with low fractional exhaled nitric oxide (<25 ppb) (P < .05)., Conclusions: Altogether, we show that a switch to dupilumab in patients with insufficient outcome under previous biological therapy was effective in most patients., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Airways are constantly exposed to antigens and various pathogens. Immune cells in the airways act as first line defense system against these pathogens, involving both innate and acquired immunity. There is accumulating evidence that innate lymphoid cells, newly identified lymphoid lineage cells, play a critical role in regulating tissue homeostasis and in the pathogenesis of inflammation. Cytokines produced by other cells activate innate lymphoid cells, which in turn produce large amount of cytokines that result in inflammation. Type 2 innate lymphoid cells (ILC2s) are recognized as key component of T helper type 2 (Th2) inflammation, and are known to be elevated in type 2 (T2) human airway diseases (asthma). Th2 cytokines produced by ILC2s amplify inflammation via activation of eosinophils, B cells, mast cell, and macrophages. "T2 high asthma" has an increased Th2 response triggered by elevation of IL-4, IL-5 and IL-13 and other inflammatory mediators, leading to increased eosinophilic inflammation. The growing evidence of ILC2 contribution in the induction and maintenance of allergic inflammation suggests that targeting upstream mediators may affect both the innate and adaptive immune responses and all disease phenotypes. Blocking ILC2 activators, activation of inhibitory pathways of ILC2, or suppression of ILC2-mediated pathways may be therapeutic strategies for the type 2 airway diseases.

Asthma is a heterogeneous respiratory disease characterized by usually reversible bronchial obstruction, which is clinically expressed by different phenotypes driven by complex pathobiological mechanisms (endotypes). Within this context, during the last years several molecular effectors and signalling pathways have emerged as suitable targets for biological therapies of severe asthma, refractory to standard treatments. Indeed, various therapeutic antibodies currently allow to intercept at different levels the chain of pathogenic events leading to type 2 (T2) airway inflammation. In addition to pro-allergic immunoglobulin E (IgE), that chronologically represents the first molecule against which an anti-asthma monoclonal antibody (omalizumab) was developed, today other targets are successfully exploited by biological treatments of severe asthma. In particular, pro-eosinophilic interleukin 5 (IL-5) can be targeted by mepolizumab or reslizumab, whereas benralizumab is a selective blocker of IL-5 receptor. Moreover, dupilumab behaves as a dual receptor antagonist of pleiotropic interleukins 4 (IL-4) and 13 (IL-13). Besides these drugs that are already available in medical practice, other biologics are under clinical development such as those targeting innate cytokines, also including the alarmin thymic stromal lymphopoietin (TSLP), which plays a key role in the pathogenesis of type 2 asthma. Therefore, ongoing and future biological therapies are significantly changing the global scenario of severe asthma management. These new therapeutic options make it possible to implement phenotype/endotype-specific treatments, that are delineating personalized approaches precisely addressing the individual traits of asthma pathobiology. Such tailored strategies are thus allowing to successfully target the immune-inflammatory responses underlying uncontrolled T2-high asthma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Pelaia, Crimi, Vatrella, Tinello, Terracciano and Pelaia.)

Interleukin (IL)-5 is a potent mediator of the inflammatory cascade in the allergic response. Its predominant role in atopic reactions makes this cytokine an ideal target for blocking the eosinophilic inflammatory hyper-responsiveness to allergens. The management of allergic diseases in childhood-such as severe asthma, atopic dermatitis, and eosinophilic esophagitis-is a challenge. In particular, there are concerns regarding the use of high-dose corticosteroids. Over the last few years, biologics targeting IL-5 or IL-5 receptor-that are mepolizumab, reslizumab, and benralizumab-represent a new, promising, and more personalized therapeutic option., (© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Asthma has been increasingly recognized as being a heterogeneous disease with multiple distinct mechanisms and pathophysiologies. Evidence continues to build regarding the existence of different cell types, environmental exposures, pathogens, and other factors that produce a similar set of symptoms known collectively as asthma. This has led to a movement from a "one size fits all" symptom-based methodology to a more patient-centered, individualized approach to asthma treatment targeting the underlying disease process. A significant contributor to this shift to more personalized asthma therapy has been the increasing availability of numerous biologic therapies in recent years, providing the opportunity for more targeted treatments. When targeted biologics began to be developed for treatment of asthma, the hope was that distinct biomarkers would become available, allowing the clinician to determine which biologic therapy was best suited for which patients. Presence of certain biomarkers, like eosinophilia or antigen-specific IgE, is important features of specific asthma phenotypes. Currently available biomarkers can help with decision making about biologics, but are generally too broad and non-specific to clearly identify an asthma phenotype or the single biologic best suited to an asthmatic. Identification of further biomarkers is the subject of intense research. Yet, identifying a patient's asthma phenotype can help in predicting disease course, response to treatment, and biologic therapies to consider. In this review, major asthma phenotypes are reviewed, and the evidence for the utility of various biologics, both those currently on the market and those in the development process, in each of these phenotypes is explored.

Introduction: Asthma exhibits marked heterogeneity in symptoms with severe or refractory asthma representing a clear area of unmet medical need. These patients require more specifically targeted treatments with monoclonal antibody-based biologics targeted at inhibition of the type 2 cytokines IL-4, IL-5 and IL-13 having considerable potential as effective treatments for severe asthma. For the most part, anti-cytokine-based biologic therapies are more likely to give significant clinical benefit in carefully selected patient populations that take asthma phenotypes and endotypes into account., Areas Covered: This review is based on recent English-language original articles in Pub Med or MedLine that reported significant clinical findings on the current status, therapeutic potential and safety of the anti-IL-5 biologics mepolizumab, reslizumab and benralizumab in the treatment of severe refractory asthma., Expert Opinion: Anti-IL-5 treatment appears effective in patients with eosinophilic asthma through exacerbation prevention with accumulating evidence of glucocorticoid-sparing effects with an acceptable safety profile for these biologics.

Asthma is a heterogeneous disease, with the immune processes behind the chronic inflammation underlying this disorder differing between the various identified asthma endotypes. In addition to heterogeneity in underlying disease pathophysiology, asthmatics fall across a broad spectrum of disease severity and can vary greatly in their response to convention asthma therapies. A small percentage of patients with severe persistent asthma will remain uncontrolled despite treatment with high-dose inhaled corticosteroids and a long-acting beta-agonist. Less than two decades ago, there were few options for these treatment-refractory asthmatics beyond chronic systemic steroids, with their myriad of treatment-limiting side effects. However, in recent years, there have been a growing number of Food and Drug Administration (FDA)-approved biologic medications with targets that include immunoglobulin E (IgE), interleukin-5 (IL-5), the IL-5 receptor and the IL-4/IL-13 receptor-alpha subunit. The current FDA-approved biologics for severe persistent asthma are omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab. These monoclonal antibodies have been shown to improve asthma control, decrease asthma exacerbations and decrease glucocorticoid dependence in certain subsets of patients with asthma. The optimal biologic for treatment of severe asthma varies from patient to patient, depending on the underlying pathophysiology of the patient's disease. For each of these medications, there are certain biomarkers that can help predict whether a patient is likely to respond favorably to the medication. This review will discuss the currently approved biologics for severe persistent asthma, including their indications, efficacy and side effects.

Background: Anti-interleukin-5 (IL-5) monoclonal antibodies can be used as add-on biological therapies in allergic and non-allergic patients with severe eosinophilic asthma. However, within such a therapeutic context real-life investigations are lacking., Objective: Therefore, the aim of the present observational study was to evaluate the effects of mepolizumab in allergic and non-allergic subjects with severe eosinophilic asthma., Methods: Relevant clinical, functional, laboratory, and pharmacotherapeutic parameters were assessed in the above patient subgroups., Results: After one year of add-on biological treatment with mepolizumab, our 88 patients experienced a remarkable improvement of their severe asthma, documented by a better symptom control, expressed by a significant improvement in asthma control test (ACT) score. Indeed, the mean value (±standard deviation) of ACT score increased from 12.55 (±3.724) to 21.08 (±3.358). Moreover, significant improvements were also detected with regard to the median values (interquartile range) of forced expiratory volume in one second (FEV 1 ), blood eosinophil numbers, annual rate of disease exacerbations, and daily intake of oral corticosteroids (OCS). In particular, FEV 1 enhanced from 1640 mL (1110-2275) to 1920 mL (1525-2615), blood eosinophil count dropped from 711.0 cells/μL (500.0-1022) to 90.00 cells/μL (50.00-117.5), the annual rate of asthma exacerbations decreased from 3.000 (2.000-6.000) to 0.000 (0.000-1.000), and the daily prednisone intake fell from 6.250 mg (0.000-25.00) to 0.000 mg (0.000-0.000). After one year of mepolizumab treatment, the improvements in clinical, functional, and haematological parameters were quite similar in patient subgroups characterized by skin prick test (SPT) negativity or positivity, respectively. A significant correlation was observed between serum IgE levels and OCS intake decrease (r = -0.2257; P < .05)., Conclusion and Clinical Relevance: Hence, our real-life data suggest that mepolizumab can represent a valid add-on therapeutic option for patients with severe eosinophilic asthma, irrespective of IgE serum concentrations, and allergic sensitization., (© 2020 John Wiley & Sons Ltd.)

We herein report a case of refractory chronic eosinophilic pneumonia (CEP) complicated with uncontrolled bronchial asthma, in which remission was successfully induced with single dose of benralizumab, a monoclonal antibody against the alpha-chain of the interleukin-5 receptor. Resolution of the patient's symptoms and consolidation on chest X-ray were observed at 2 weeks and lasted for 8 weeks after the administration of benralizumab. Benralizumab would be a novel alternative choice of treatment for CEP patients who are at risk of potential toxicity due to long-term corticosteroid therapy.

IL-5 is the most potent activator of eosinophils and is produced by Th2 cells and ILC2s. A role for IL-5 in eosinophil extracellular trap cell death, i.e., a proinflammatory cell death, has also been reported. Mepolizumab and benralizumab are humanized mAbs that target IL-5 and the IL-5 receptor α, respectively, and their therapeutic efficacy for severe asthma has been established. Although consistent differences in the efficacies of those drugs have not been proven, benralizumab extensively depleted eosinophils via Ab-dependent cell-mediated cytotoxicity. Blood eosinophil count, but not FeNO or IgE, is the best-established predictive biomarker of the efficacy of anti-IL-5 treatment. Regarding the choice of biologics, the balance between blood eosinophil count and FeNO, indication of comorbidities, longitudinal safety, and interval of injection should be considered. Mepolizumab was also effective in maintaining the remission of refractory eosinophilic granulomatous polyangiitis. Moreover, mepolizumab decreased the proportion of patients who required surgery and lowered the nasal polyp score in patients with chronic rhinosinusitis with nasal polyps; a further extensive trial is currently under way. In a phase II benralizumab study performed in Japan, no significant effect on nasal polyp score at week 12 was observed, suggesting a requirement for longer treatment. In this review, the role of IL-5 in eosinophil biology and the current status of anti-IL-5 therapy are discussed. The longitudinal safety of anti-IL-5 therapy has been increasingly established, and this strategy will be continuously indicated for eosinophilic diseases as a specific treatment for eosinophilic inflammation., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Reslizumab displays efficacy in patients with inadequately controlled eosinophilic asthma; previous reports in oral corticosteroid-dependent asthma are limited., Objective: To assess efficacy of reslizumab in oral corticosteroid-dependent patients and benefits on oral corticosteroid burden., Methods: We report post hoc analyses of pooled data from duplicate, placebo-controlled phase 3 trials. Patients aged 12 to 75 years with inadequately controlled, moderate-to-severe asthma were randomized 1:1 to receive intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 52 weeks, stratified by oral corticosteroid use at enrollment and by region. Assessments included efficacy and predictors of clinical asthma exacerbation response in oral corticosteroid-dependent patients, and systemic corticosteroids burden in the overall population., Results: Patients were randomized to reslizumab (n = 477) or placebo (n = 476); 73 (15%) patients in each group were taking oral corticosteroids at baseline. Reslizumab was favored over placebo for all efficacy end points in oral corticosteroid-dependent patients, with numerically greater improvements in oral corticosteroid-dependent patients than the overall population. Having 2 or more versus 1 clinical asthma exacerbation in the previous 12 months was the strongest positive predictor of reduced exacerbation risk with reslizumab (risk reduction, 77.5% vs 15.2%; P ≤ .02). Significantly fewer new systemic corticosteroid prescriptions were issued per patient receiving reslizumab versus placebo (mean ± SD, 0.5 ± 1.07 vs 1.0 ± 1.52; P < .0001). Total and per-patient systemic corticosteroid burdens were lower: 121,135 versus 290,977 mg and 254 versus 611 mg/patient, respectively (both P < .0001)., Conclusions: Oral corticosteroid-dependent patients benefited from reslizumab across asthma efficacy outcome measures. Reslizumab-treated patients required fewer new systemic corticosteroid prescriptions and had a lower systemic corticosteroid burden compared with placebo., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Asthma inflammatory phenotypes facilitate treatment, their clinical characteristics and biomarkers were analyzed. Materials & methods: A total of 176 asthmatics were divided into eosinophilic asthma (EA), neutrophilic asthma (NA), paucigranulocytic asthma and mixed-granulocytic asthma by induced sputum. Results: EA, NA and paucigranulocytic asthma patients were 65 (36.9%), 31 (17.6%) and 75 (42.6%). Sputum IL-5 and IL-13, blood IL-13, fractional exhaled nitric oxide (FeNO) were related to EA, the areas under the receiver operating characteristic curve were 0.790, 0.846, 0.828, 0.830, combined FeNO with blood IL-13 was 0.872. Sputum and blood IL-8, blood IL-17 were related to NA, their area under the receiver operating characteristic curve was 0.939, 0.844, 0.821, combined blood IL-8 with IL-17 was 0.882. Conclusion: Blood IL-13 and FeNO, blood IL-8 and IL-17 were alternative biomarkers of EA and NA, respectively.

Background: Mepolizumab is an anti-IL-5 antibody approved for the treatment of severe eosinophilic asthma. However, the prevalence of patients with severe asthma eligible for mepolizumab remains unknown, especially among children., Objective: To determine, in a population of patients with severe asthma from a tertiary referral center, the proportion of patients with an eosinophilic phenotype who would be eligible for mepolizumab, when stratified for the age of onset of asthma, and the prevalence of phenotypic features that favor mepolizumab therapy., Methods: An extensive database of 245 adults and children referred for severe asthma was used. The prevalence of severe asthma was estimated by using the European Respiratory Society/American Thoracic Society criteria. Patients with an eosinophilic uncontrolled phenotype qualified for mepolizumab., Results: In our cohort, 216 (88%) had severe asthma. Based on blood eosinophils of either greater than or equal to 150 cells/μL or greater than or equal to 300 cells/μL, 61%/41% had an eosinophilic phenotype, while 49%/34% were eligible for mepolizumab therapy. A greater percentage of adults (60%/47% of adults with asthma onset in adulthood [AoA] and 48%/26% adults with childhood-onset asthma [<18 years, CoA]) were eligible compared with children (33%/24%), for eosinophil counts of ≥150 and ≥300 cells/μL, respectively; P < .05. Compared with adults, children had a similar number of exacerbations while having better lung function (P < .05). Among adults, those with AoA were older, were more likely to have nasal polyps (28% vs 5%; P < .05), and had higher blood eosinophil counts (272 vs 150 cells/μL; P < .05) compared with those with CoA, with no difference in lung function noted between the 2 groups. Subjects showing greater than or equal to 500 eosinophils/μL, a strong indicator for mepolizumab therapy, had more nasal polyps, higher inhaled steroid dose, lower lung function, and AoA predominance than did those with less than 500 eosinophils/μL (P < .05)., Conclusions: A smaller percentage of children with severe asthma were eligible for mepolizumab compared with their adult peers. Severe AoA has distinct phenotypic features that favor treatment with mepolizumab, including greater eosinophilia and nasal polyposis, in contrast to CoA, which appears to have fewer features of type 2 mucosal inflammation., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Severe asthma is a disease with a heavy socio-economic burden and a relevant impact on the life of patients. Mepolizumab (MEP) was recently introduced in practice. The previous data were favourable as efficacy and safety are concerned. Nowadays, we can report the clinical data after more than one year of use of MEP in the real-life setting., Objective: To evaluate the efficacy and safety of MEP in a real life framework, mainly concerning asthma exacerbations, steroid dependence, effects on respiratory function and adverse events., Methods: This retrospective analysis was performed on 138 patients, treated with MEP for at least 12 months, and referred to eleven severe asthma clinics in Italy. All patients met the criteria for severe uncontrolled asthma according to ATS/ERS guidelines and prescribing MEP conditions according to the Italian Drug Agency (AIFA)., Results: We could observe 138 patients (78 female, age 58 ± 10 years). The average age of onset of asthma was 34 ± 16 years. The blood eosinophil count decreased from 822 ± 491/μL at baseline to 117 ± 96/μL (p < .0001) after 12 months of therapy. Exacerbations decreased from 3.8/year to 0.7/year (-81%; p < .0001). Steroid-dependent patients before MEP (80%) with a daily dose of 10.1 ± 9.4 mg prednisone decrease at 28% after 12 months with a mean of 2.0 ± 4.2 mg/day (p < .0001). The occurrence of adverse events was overall low., Conclusions & Clinical Relevance: In this real-life setting, MEP confirmed its efficacy and safety profile, already shown in clinical trials. This was apparent concerning exacerbation rate, systemic steroids intake and safety., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Asthma often coexists with chronic rhinosinusitis (CRS). Recent studies revealed that sinus inflammation in asthmatic patients was related to eosinophilic inflammation. However, the relationship between the severity of CRS and four different sputum inflammatory phenotypes as defined by the proportion of eosinophils and neutrophils is unknown. The aim of this study was to examine the impact of the severity of CRS on lower airway and systemic inflammation in asthmatic patients., Methods: We enrolled 57 adult asthmatic patients who underwent sinus computed tomography (CT). The severity of CRS was evaluated by the Lund-Mackay score (LMS). The induced sputum inflammatory phenotype was defined by eosinophils (≥/<2%) and neutrophils (≥/<60%). Peripheral blood mononuclear cells (PBMC) were collected to examine cytokine productions., Results: The median LMS of subjects was 6 (interquartile range, 0-11.5). The sputum inflammatory cell phenotype was categorized as paucicellular (n = 14), neutrophilic (n = 11), eosinophilic (n = 20), or mixed (n = 12). LMS was positively correlated with the percentage of blood eosinophils, sputum eosinophils, and mean fluorescence intensity (MFI) of IL-5 on CD4 + T cells. In the severe CRS group (LMS, 12-24), the number of mixed cellular phenotypes was higher than that in the group without CRS (LMS, 0-4) and mild-to-moderate CRS group (LMS, 5-11)., Conclusions: In asthmatic patients with severe CRS, the proportion of the mixed cellular inflammatory phenotype was increased as well as eosinophilic inflammation., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Mesenchymal stem cells (MSCs) have been investigated as a new treatment option for various diseases in recent years. However, the role of placenta-derived MSCs in children with asthma remains unclear. We assessed the effect of placenta-derived MSCs on T cell immune responses and cytokine IL-5 levels according to cultures in children with and without asthma. Study design: We enrolled children with and without asthma and recorded asthma symptom scores in the asthma group. Blood samples from children were collected to isolate peripheral blood mononuclear cells (PBMCs) and determine the total IgE level. The PBMCs were cultured in vitro with or without MSCs after stimulation with human anti-CD3 and anti-CD28 antibodies (0.5 μg/mL) to evaluate the effect of placenta-derived MSCs. Flow cytometry was performed to detect the activation and proliferation of CD4+ and CD8+ T cells. Pre- and post-culture IL-5 levels were measured in all samples. Results: The percentages of activation and proliferation among CD4+ and CD8+ T cells after coculture with MSCs were significantly lower in the asthma group ( P < 0.05). IL-5 levels differed significantly between the PBMC culture and PBMC + MSC (P+S) coculture in the asthma group ( P < 0.05). IL-5 levels differed significantly between the PBMC culture and P+S coculture in both the lower ( P < 0.05) and higher ( P < 0.0005) IgE asthma subgroups. IL-5 levels were also decreased in children with all severities of asthma ( P < 0.05). Conclusions: Placenta-derived MSCs exerted an anti-IL-5 effect and reduced the IL-5 level in culture in different subgroups of children with asthma., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Introduction : The basis of the development of the anti-interleukin-5 monoclonal antibody mepolizumab was the acknowledgment of the crucial importance of this cytokine in promoting eosinophils production, activation, and survival, which is associated with the eosinophilic asthma phenotype, as well as with other disorders characterized by high levels of eosinophils. Areas covered : All the available literature on the outcomes treatment with mepolizumab in eosinophilic disorders are reviewed, including asthma, chronic rhinosinusitis, esophagitis, granulomatosis with polyangiitis, eosinophilic chronic obstructive pulmonary disease, hypereosinophilic syndrome, and allergic bronchopulmonary aspergillosis. Expert opinion : The efficacy of mepolizumab in eosinophilic asthma is clearly demonstrated by a number of controlled trials and by meta-analyses. Among other eosinophilic disorders, controlled trials are available for chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic chronic obstructive pulmonary disease. Allergic bronchopulmonary aspergillosis, as well as other minor eosinophilic disorders, are backed only by case reports and are waiting controlled trials to verify the therapeutic role of mepolizumab.

Background: Severe non-allergic eosinophilic asthma (SNEA) is a rare asthma phenotype associated with severe clinical course, frequent exacerbations, and resistance to therapy, including high steroid doses. The key feature is type 2 inflammation with predominant airway eosinophilia. Eosinophil maturation, activation, survivability, and recruitment are mainly induced by interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) through their receptors on eosinophil surface and related with integrins activation states. The aim of the study was to estimate the expression of eosinophil β chain-signaling cytokines receptors, outer-membrane integrins, and serum-derived type 2 inflammation biomarkers in SNEA., Methods: We examined 8 stable SNEA patients with high inhaled steroid doses, 12 steroid-free patients with non-severe allergic asthma (AA), 12 healthy subjects (HS). Blood eosinophils were isolated using Ficol gradient centrifugation and magnetic separation. Eosinophils were lysed, and mRNA was isolated. Gene expressions of IL-5Rα, IL-3Rα, GM-CSFRα, and α4β1, αMβ2 integrins were analyzed using quantitative real-time reverse transcription polymerase chain reaction. Type 2 inflammation activity was evaluated measuring exhaled nitric oxide concentration (FeNO) collected with the electrochemical sensing device. Serum IL-5, IL-3, GM-CSF, periostin, chemokine ligand (CCL) 17 and eotaxin concentrations were assessed by enzyme-linked immunosorbent assay., Results: Eosinophils from SNEA patients demonstrated significantly increased gene expression of IL-3Rα, IL-5Rα and GM-CSFRα as well as α4, β1 and αM integrin subunits compared with the AA group. The highest IL-5 serum concentration was in the SNEA group; it significantly differed compared with AA and HS. GM-CSF serum levels were similar in the SNEA and AA groups and were significantly lower in the HS group. No differences in serum IL-3 concentration were found among all groups. Furthermore, serum levels of eotaxin, CCL17 and FeNO, but not periostin, differed in all groups, with the highest levels in SNEA patients., Conclusions: Eosinophil demonstrated higher expression of IL-3, IL-5, GM-CSF α-chain receptors and α4, β1, αM integrins subunits in SNEA compared with the AA group. Additionally, SNEA patients had increased serum levels of IL-5, eotaxin and CCL-17., Trial Registration: ClinicalTrials.gov Identifier NCT03388359.

Cytomegalovirus (CMV) infection has a profound impact on the host's immune system. Immunological imprinting by CMV is not restricted to immunity against CMV itself, but can affect immunity against other viral or non-viral infectious agents and also immunopathological responses. One category is heterologous immunity based on molecular mimicry, where antigen recognition receptors specific for a CMV antigen with broad avidity distribution also bind with some avidity to unrelated antigens and exert effector functions against target structures other than those linked to CMV. Another category is induction of cytokines by CMV infection that inhibit or drive immune responses to bystander antigens unrelated to CMV, and a third category is the activation of antigen-presenting cells by CMV from which unrelated antigens profit as "stowaways". A striking example of the "stowaway" category, actually one that is of medical importance, has been published recently and will be discussed here for the more general reader. Specifically, in a murine model, CMV airway infection and inhaled environmental antigen of poor intrinsic allergenic potential were found to sensitize for allergic airway disease (AAD) only when combined. As to the mechanism, viral activation of CD11b + conventional dendritic cells (CD11b + cDC) that localize to airway mucosa facilitates uptake and processing of inhaled antigen. Thus, CMV serves as a "door opener" for otherwise harmless environmental antigens that have no intrinsic property to activate DC. Antigen-laden CD11b + cDC migrate selectively to the airway draining lymph nodes, where they prime type-2 CD4 + T helper (Th-2) cells. Upon airway re-exposure to the inhaled antigen, Th-2 cells secrete interleukins (IL-4, IL-5, IL-9, and IL-25) known to induce goblet cell metaplasia, the lead histopathological manifestation of AAD that is characterized by thickening of airway epithelia and increased numbers of mucus-producing goblet cells, resulting in enhanced mucus secretion and airflow obstruction.

Objective: Asthma is a common heterogeneous disease characterized by airway inflammation and bronchoconstriction. Current treatment guidelines provide recommendations for categorizing disease severity, asthma control and management. This paper reviews asthma assessment in primary care and describes the pathophysiology, clinical characteristics and new targeted treatments available for patients with severe eosinophilic asthma. Methods: A non-systematic PubMed literature search was conducted and articles, primarily from the last 5 years, were selected based on relevance to primary care practice, asthma pathophysiology and biologic therapies. Results: Despite optimal therapy including high-dose inhaled corticosteroids (ICS), long-acting β2-agonists and tiotropium, ∼4-10% of all patients with severe asthma continue to have poor asthma control. These patients have impaired quality of life, frequent exacerbations and are exposed to the side effects of repeated courses of oral steroids. Approximately 50% of patients with severe uncontrolled asthma have eosinophilic asthma, with increased airway expression of type 2 cytokines IL-4, IL-5 and IL-13. Eosinophilic asthma is identified in primary care by having eosinophils ≥150-300 cells/μL on a complete blood count with differential. Conclusions: A new class of agents is available for patients with moderate to severe eosinophilic asthma. Four biologic therapies - mepolizumab, reslizumab, benralizumab and dupilumab - that interfere with the regulation and activity of eosinophils have been approved by the FDA for patients with moderate to severe asthma with an eosinophilic phenotype. Primary care physicians should be familiar with these medications to explain part of the rationale for referral to specialist care and manage patient expectations for treatment.

Background: Bronchial asthma (BA) is a complex disease characterised by persistent inflammation. Exhaled nitric oxide (FeNO) and blood eosinophil count (b-Eos) are biomarkers for type 2 endotype of BA., Objective: To analyse a panel of serum interleukins and total IgE in predefined by FeNO and b-Eos groups of moderate and severe BA patients., Methods: Serum levels of IL-5, IL-6, IL-8, IL-13 and IL-17A (ELISA) were measured in 30 healthy controls (HC) and 80 adult BA patients. BA patients were split into 4 groups. Group 1:Low FeNO/Low b-Eos (n = 23; 28.8%); Group 2:Low FeNO/High b-Eos (n = 17; 21.3%); Group 3:High FeNO/Low b-Eos (n = 15; 18.8%); Group 4:High FeNO/High b-Eos (n = 25; 31.3%)., Results: All interleukins and total IgE were significantly higher in patients with BA as compared with HC. IL-5 levels were highest in Group 2 (p < 0.05). IL-6, IL-13 and IL-17A levels were elevated in Groups 2, 3 and 4 as compared with HC (p < 0.05). Higher IL-8 levels were associated with a pattern of current smokers. Highest IL-17A levels were found in type 2 high groups with frequent exacerbations, mostly uncontrolled and severe BA. We have found a distinct pattern for each group based on demographic, clinical, functional, immunological and inflammatory characteristics., Conclusion: FeNO and b-Eos are useful in the identification of severe type 2 BA subgroups with frequent exacerbations. IL-5, IL-6, IL-13 and IL-17A are involved in the persistent type 2 immune response in moderate and severe BA. We have identified a pattern of refractory, severe type 2/IL-17A high BA in the real clinical practice., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

An animal (BALB/c mice) model of catalpol associated with bronchial asthma in vivo was established, and the effects of catalpol and its relationship with cytokines were investigated. A total of 30 adult BALB/c mice were randomly divided into a positive control group, a model group, and a catalpol group, with 10 mice in each group. The lung function of mice, the cell count, and the cytokine concentrations in bronchoalveolar lavage fluid (BALF) were detected. The levels of cytokines [interleukin 4 (IL-4), interleukin 5 (IL5), and interferon gamma (IFN-γ)] in BALF were measured with enzyme-linked immunosorbent assay methods. The total number of cells in the BALF of the group treated with catalpol was significantly lower than the model group. After treatment with catalpol, the eosinophils and neutrophils of the mice were remarkably reduced compared with the model group. The malondialdehyde content in the lung tissue homogenate of the mice was also decreased in the catalpol group. The cytokines IL-5 and IL-4 exhibited a similar tendency: the concentrations of IL-4 and IL-5 for the catalpol group were dramatically decreased compared with the model group. However, the IFN-γ concentration for the catalpol group was higher than the model group. The results indicated that IL-5 may involve in the pathologic process of asthma-like IL-4, and an inflammatory reaction may still exist in the airway during the remission stage of asthma. The imbalances of the cytokine network might be an important molecular basis in the asthma pathogenesis. It is suggested that catalpol may be a potential drug for the clinical treatment of asthma., (© 2018 Wiley Periodicals, Inc.)

Objective: We sought to highlight how our understanding of the pathophysiology of severe asthma has evolved over time and discuss the role of biomarkers in treatment advances and emerging new therapies., Data Sources: Nonsystematic PubMed literature search., Study Selection: Articles were selected based on areas of relevance to the classification of asthma by endotype, with an emphasis on the evolution of current treatment guidelines for severe asthma., Results: Unlike older guidelines for the treatment of severe asthma, recent updates now distinguish between asthma severity and control. Moreover, asthma classification is shifting from phenotype to endotype with the development of biomarkers used to determine the mechanism driving a patient's disease. Many cases of severe asthma are associated with type-2 inflammation with elevated eosinophil counts in the airways. In recent studies, patients with severe, uncontrolled asthma and high eosinophil counts respond to biologic therapies targeting the type-2 signaling pathway and eosinophils themselves (eg, anti-IL-5 therapy). New treatments that address the pathophysiology of asthma offer a promising alternative to control severe asthma for patients who do not respond to traditional therapies., Conclusion: Understanding and using new treatment guidelines that separate the concepts of asthma severity and control may help clinicians to identify patients with severe, uncontrolled asthma who may benefit from new treatment options, such as anti-IL-5 therapies.