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Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a relapsing disease with frequent glucocorticoid dependence. Mepolizumab has been demonstrated to reduce flares and spare glucocorticoids (GC). However, EGPA is a heterogeneous condition and the effects of mepolizumab on specific disease manifestations has not been completely delimitated. Objectives To analyse the impact of mepolizumab on manifestations derived from small-vessel vasculitis, ENT (ear, nose and throat) symptoms, asthma, eosinophilic tissue infiltration and anti-neutrophil cytoplasmic antibody (ANCA) status in a single-centre cohort of EGPA patients. Methods Medical charts of EGPA patients treated with mepolizumab were retrospectively reviewed by the authors to describe demographics, clinical characteristics, steroid dose at the initiation of mepolizumab and during follow-up, flares, disease activity, damage accrual and laboratory results. Results and conclusions Among 56 patients with EGPA regularly controlled at our department, 11 patients were treated with mepolizumab because of corticodependence and unsatisfactory disease control. The mean time of treatment was 38 months (range: 3-66 months). Patients with persistent symptoms improved their asthma control, but 3 of them persisted with recurrent ENT symptoms in spite of treatment with mepolizumab. None of the patients developed vasculitic manifestations (cutaneous, neurological, gastrointestinal, renal) during treatment. All patients achieved a Birmingham Vasculitis Activity Score (BVAS) of 0 points at 12 months or earlier. In general, patients reduced the number of flares, which tended to be milder, and all related to asthma or ENT manifestations. The improvement in disease activity allowed notable glucocorticoid tapering.

Recent therapeutic advances in the management of asthma have underscored the importance of eosinophilia and the role of pro-eosinophilic mediators such as IL-5 in asthma. Given that a subset of patients with COPD may display peripheral eosinophilia similar to what is observed in asthma, a number of recent studies have implied that eosinophilic COPD is a distinct entity. This review will seek to contrast the mechanisms of eosinophilia in asthma and COPD, the implications of eosinophilia for disease outcome, and review current data regarding the utility of peripheral blood eosinophilia in the management of COPD patients.

Background: Neuregulin 4 (Nrg4) is a novel adipocytokine which has been proposed to play a role in modulating energy metabolism and pathogeneses of atherosclerosis. However, no published research is available about the mechanisms underlying the anti-atherosclerotic effect of Nrg4. Regarding the close link between adipocytokines and immune system, we wonder whether there is a relation between Nrg4 and athero-protective cytokines. The aim of this study was to investigate the relationship between serum Nrg4 levels and type 2 cytokines in Iranian patients with coronary artery disease (CAD). Methods: In this case-control study, 125 CAD patients were compared to 55 healthy controls. Serum concentration of Nrg4, IL-5, IL-9 and IL-13 were measured using ELISA. The associations of circulating Nrg4 and IL-5, IL-9, IL-13 were assessed using linear regression analyses. Results: Serum concentration of IL-9 was significantly higher in patients compared to the healthy controls (317.9±139 versus 228.3±99.1, P= ˂0.0001). IL-13 and Nrg4 were significantly lower in patients compared to the healthy controls (4.3±3.7 versus 6.1±3.9, P=0.01 and 0.5 versus 1.3, P=0.001 respectively). Multiple linear regression analyses revealed that IL-9 was negatively correlated with Nrg4 (β= -0.3, P=0.009). Conclusion: Our study ،for the first-time, provides the clinical evidence revealing that circulating Nrg4 concentrations are inversely correlated with IL-9 in Iranian patients with CAD, suggesting that the protective role of Nrg4 on atherosclerosis may be, in part, mediated by the proatherogenic cytokine, IL-9.

Актуальність. Огляд вітчизняної та зарубіжної науково-дослідної літератури свідчить, що на сьогодні системні наукові дослідження щодо взаємозв’язку між рівнем нейропептиду VIP (вазоактивний інтестинальний пептид — vasoactive intestinal peptide) та інтерлейкіну-5 у сироватці крові та станом мозкової гемодинаміки у хворих на бронхіальну астму дітей відсутні. Метою дослідження було встановити можливі впливи нейропептиду VIP та інтерлейкіну-5 на показники екстракраніальної гемодинаміки у хворих на бронхіальну астму дітей, проаналізувати гендерні особливості цих показників. Матеріали та методи. Проведено імунологічне дослідження сироватки крові для визначення рівня нейропептиду VIP та інтерлейкіну-5 у 54 хворих на бронхіальну астму дітей, серед яких були 21 дівчинка та 33 хлопчики віком 10–17 років. Контрольну групу становили 20 здорових дітей, які були ідентичні хворим за гендерним та віковим складом. Діти були обстежені двічі — при неконтрольованому та контрольованому перебігу хвороби. Також усім дітям проведено ультразвукове допплерографічне дослідження магістральних судин голови та шиї. Результати. Аналіз рівнів нейропептиду VIP та інтерлейкіну-5 установив гендерну залежність їх коливань: рівень нейропептиду VIP був статистично нижчим, а інтерлейкіну-5 — вищим у хворих хлопчиків із неконтрольованим перебігом бронхіальної астми порівняно із здоровими хлопчиками. У хворих із контрольованим перебігом бронхіальної астми негативний вплив на показники екстракраніальної гемодинаміки є мінімальним як у дівчаток, так й у хлопчиків. Висновки. Для здійснення дієвого контролю над перебігом захворювання потрібно враховувати зміни показників екстракраніальної гемодинаміки у хворих на бронхіальну астму дітей залежно від їх статі, що дозволить уникнути цереброваскулярних ускладнень у даного контингенту хворих.

Aims Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms. Method and results MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and type 2 innate lymphoid cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation. Conclusion IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis. Translational perspective Accumulating evidence suggests that modulation of innate and adaptive immune responses is a promising therapeutic strategy for myocardial infarction. In this study, we demonstrate that IL-5 exerts cardioprotective effects on infarcted myocardium by promoting eosinophil accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis. Hence, regulation of cardiac IL-5 level or eosinophil count may become a therapeutic approach for post-myocardial infarction cardiac repair in humans.

Aim. The aim of the study was to differentiate the endotypes in allergic rhinitis by key allergy markers in a mixed group of patients.Material and Methods. The study comprised a total of 48 patients, men and women, aged 18-60 years suffering from three endotypes of allergic rhinitis including the classic, local, and dual allergic rhinitis. The standard diagnostics of allergic rhinitis included taking a history of allergies, family history of allergic disease, video rhinoscopy, serum total IgE level assessment, allergy skin tests to house dust mite and pollen allergens, and study of eosinophilic inflammation parameters (eosinophil cationic protein, interleukin-5 (IL5), and eosinophil counts in blood and nasal secretion).Results. Based on total IgE level, the general group of patients was divided to two subgroups: subgroup 1 comprised patients with high IgE level (n = 22); subgroup 2 comprised patients with low IgE level (n = 26). Most of patients in these groups had contradictory results of allergy skin tests i.e. positive allergy skin test results in case of high IgE level (group 1) and vice versa. Cluster analysis-based exminations of general group allowed to categorize three subgroups of patients: patients with classic allergic rhinitis (n = 22), local allergic rhinitis (n = 22), and dual allergic rhinitis (n = 4). Besides, an increased rate of anxiety disorder was found in patients with local allergic rhinitis (p < 0.001).Conclusion. The obtained data showed promise for a new research trend in studying allergic rhinitis endotypes, namely: investigation of neuroimmune relationships in allergic tolerance disruption in the presence of this pathology.

Background Asthma and chronic obstructive pulmonary disease (COPD) are the most common respiratory diseases, presenting overlapping prevalence with age. Mepolizumab is a humanized monoclonal antibody targeting interleukin-5. In major randomized clinical trials, this antibody reportedly reduced the circulating eosinophil count, exacerbation rate, and oral corticosteroid (OCS) dosage in patients with severe eosinophilic asthma. However, data regarding the efficacy of mepolizumab in elderly patients with asthma and overlapping COPD are limited. Methods This was a single-center, retrospective, observational study. Elderly patients (age ≥65 years) administered mepolizumab between August 2016 and March 2019 were enrolled and the effects of mepolizumab on the eosinophil level, exacerbation numbers, OCS dosage, and lung functions were assessed. We compared treatment responses in patients with asthma and COPD overlap (ACO) with responses observed in patients with severe asthma alone. Adverse events were also evaluated. Results Twenty patients (10 men and 10 women), with a mean age of 77.5 ± 1.3 years, were included. Mepolizumab significantly reduced the blood eosinophil count, as well as significantly decreased clinically significant exacerbation, in both populations. The OCS dosage was significantly reduced in patients treated receiving maintenance OCS therapy. However, mepolizumab did not improve lung function in either population, and no significant difference was observed in treatment responses between patients with asthma alone and ACO. Conclusions Mepolizumab may be effective in elderly patients with eosinophilic asthma and ACO.

Add-on therapy with monoclonal antibodies is the recommended therapy for severe asthmatic patients refractory to maintenance treatment. In randomized control trials, mepolizumab reduced the number of exacerbations, the need of oral corticosteroids (OCS), increased asthma control, and lung function in a population of uncontrolled severe eosinophilic asthmatic patients. In this piece of work, we aimed to assess mepolizumab efficacy and safety in a cohort of patients with severe eosinophilic asthma in real-life conditions.A retrospective study was carried out at eight hospitals from Asturias (Spain). The sample included patients treated with mepolizumab from 1 January 2016 to 31 March 2019. Demographic and clinical variables were collected, including OCS use, asthma control, lung function, and exacerbation rate.Sixty-nine patients (72% women) with mean age 56 ± 13 years were included. Annual exacerbation rate decreased from 4.7 (SD 3.7) to 1.3 (SD 2.5) (Overall, this study demonstrates mepolizumab efficacy and safety in a cohort of patients with uncontrolled severe eosinophilic asthma in routine clinical practice.

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti‐IL‐5 and anti‐IL‐13 treatment have shown some therapeutic promise. Herein, we present evidence that pre‐ and post‐intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec‐F(+) eosinophils in Aspergillus‐challenged asthma and EoE, CD2‐IL‐5 induced global eosinophilia, and DOX regulated IL‐13‐induced asthma. We used flow cytometry and anti‐major basic protein (MBP) immunostaining to examine eosinophils in the spleen, bone marrow, BALF, lung, oesophagus and intestine. Additionally, we also performed ELISA and Western blot analyses to show that tacrolimus treatment also reduces the levels of eosinophil‐specific cytokines IL‐4, IL‐5, IL‐13 and TGF‐β, eosinophil‐specific chemokines Eotaxin‐1 and Eotaxin‐2, and progenitors of target RCAN1 mRNA and protein levels. Additionally, the current investigations also show that the TGF‐β‐mediated oesophageal and lung fibrosis is also reduced in Aspergillus‐challenged, CD2‐IL‐5 transgenic and DOX‐responsive IL‐13 mice. Mechanistically, we show that tacrolimus in vitro treatment inhibited bone marrow‐derived eosinophil proliferation and viability by promoting eosinophil apoptosis that may be associated with downregulation of RCAN1. Taken together, we provide in vivo and in vitro evidence that tacrolimus ameliorates eosinophil levels and associated pathogenesis in allergen‐, IL‐5‐ and IL‐13‐induced EoE, EG and asthma pathogenesis. Considering tacrolimus side‐effects and reactivity to several other drugs, we propose the topical use of tacrolimus for paediatric and low‐dose oral for adult patients as a novel therapeutic strategy for the clinical trial to reduce mucosal eosinophilia first in steroid‐refractory or elemental diet non‐responsive adult EoE, EG and asthma patients.

Background There is no trial to make a diagnostic tool of allergic rhinitis (AR) utilizing biomarkers from nasal fluid. Base on previous studies, we selected following five biomarkers in nasal fluids that represent the characteristics of allergic reactions: tryptase, eosinophil cationic protein (ECP), interleukin 5 (IL-5), Clara cell protein 16 (CC16) and CC16-to-albumin ratio. Objective This study aimed to identify biomarkers in nasal discharge that may be used in biosensors to diagnose AR as an additional diagnostic tool. Methods Patients showed rhinorrhea and tested positive on allergic skin and specific immunoglobulin E (IgE) tests were included in the AR group. The non-AR group included individuals no dominant nasal symptoms and tested negative on allergy tests. Nasal lavage fluid samples were collected from all participants. Biomarkers in the samples were quantified using enzyme-linked immunosorbent assay. Results Forty-five patients with AR and 28 non-AR subjects were enrolled in this study. Comparing the concentrations of biomarkers, the concentrations of tryptase and IL-5 were significantly higher in the AR group than in the NAR group. And CC16 level and CC16-to-albumin ratio were significantly lower in the AR group. In the combination of tryptase or CC16-to-albumin ratio, the sensitivity was 90.7% and the specificity was 64.3% ( p = 0.013). Conclusion The combination of “tryptase or CC16-to-albumin” could be used as a screening tool for AR. Although this diagnostic method could not replace conventional diagnostic tools, we could consider the method we proposed as an additional screening tool for patients who could not undergo allergy tests.

Despite a common CD4+ T-cell precursor, helper T (Th) 1 and 2 lymphocytes affect different immunologic responses, including cellular and humoral pathways, respectively. Th1 cells stimulate the activation of type 1 macrophages, IgG/immunoglobulin M production, and cytokine release (eg, interferon gamma [IFN-γ], interleukin 2) to respond to intracellular pathogens. In contrast, Th2 cells target extracellular pathogens, leading to increases in immunoglobulin E and proliferation of eosinophils, basophils, B lymphocytes, type 2 macrophages, and mast cells through the actions of interleukin 4 (IL-4), interleukin 5, interleukin 13 (IL-13), and interleukin 31.1 Th17 cells are important for host defense against extracellular bacteria and fungi, as well as injury, and are thought to be key drivers of autoimmune diseases. Th17 cells produce interleukin 17A, interleukin 17F, interleukin 22, and C-C motif chemokine ligand 20 and are characterized by neutrophil and macrophage recruitment. The Th2 cytokine, IL-4, has been shown to inhibit Th17 development.2 Dupilumab (Dupixent, Regeneron Pharmaceuticals and Sanofi Genzyme), a fully human monoclonal (IgG4) antibody, inhibits the signaling of IL-4/13 by blocking the shared receptor subunit, IL-4 receptor α. Dupilumab is an effective treatment for a number of Th2-driven conditions, including atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyposis. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, which is characterized by multifocal demyelination and neuroaxonal degeneration, where the immune system is skewed toward Th1/Th17 axes.3 Interestingly, epidemiologic studies have suggested that a history of allergic diseases may confer some protection from MS.4 We report a temporal association of relapsing-remitting MS flareup and dupilumab treatment for AD. We provide a potential mechanism by which dupilumab leads to Th2 suppression with secondary Th1/17 dysregulation.

Background: ARF nucleotide-binding site opener (ARNO) is a guanine nucleotide-exchange factor for ADP-ribosylation factor proteins. ARF nucleotide-binding site opener also binds MyD88, and small-molecule inhibition of ARNO reduces inflammation in animal models of inflammatory arthritis and acute inflammation. However, whether genetic deletion of Arno in mice reduces pathologic inflammation has not yet been reported. Furthermore, its role in the nasal cavity has yet to be investigated. Objective: To generate Arno knockout mice and to determine whether genetic loss of ARNO reduces eosinophilic inflammation in the ovalbumin (OVA) murine model of rhinitis. Methods: Arno knockout mice were generated and wild type and knockout littermates were subjected to the OVA-induced mouse model of rhinosinutitis. Eosinophilic inflammation was assessed through immunofluorescent quantification of EMBP+ eosinophils in the septal mucosa and cytokine expression was assessed by quantitative polymerase chain reaction. Results: Arno knockout mice are viable and fertile without any noted deficits. Arno wild type and knockout mice subjected to the OVA-induced model of rhinitis demonstrated an average of 314.5 and 153.8 EMBP+ cells per mm2 septal tissue, respectively ( P < .05). Goblet cells per mm of basal lamina were assessed via Alcian blue and there was no statistically significant difference between Arno wild type and knockout mice. Ovalbumin-induced expression of interleukin-5 (IL-5) was significantly reduced in Arno knockout mice ( P < .05). There was no statistically significant reduction in IL-4, IL-13, or eotaxin-1 expression. Conclusions: These data demonstrate that deletion of Arno reduces eosinophilic inflammation and IL-5 expression in an OVA-induced model of rhinitis.

Not fully maturated immune system in preterm neonates may contribute to the increased susceptibility to infection. The levels of some cytokines can be useful in the prediction and diagnosis of sepsis in premature neonates. In the present study, we evaluated the potential predictive role of IFN-γ and IL-5 in cord and venous blood, together with the determination of C-reactive protein and procalcitonin (PCT) for sepsis development in premature neonates. A total of 80 participants were included. The laboratory results and clinical histories showed that 21 participants had sepsis. Early onset sepsis was detected in 3 patients while late onset sepsis was observed in 18 participants. The venous plasma levels of IFN-γ and PCT was markedly increased in sepsis groups when compared to the participants without sepsis. On the other hand, levels of IL-5 did not significantly change in the evaluated groups of sepsis and in the control group of participants. Simultaneously, plasma venous levels were not altered in any of the evaluated groups. Obtained findings suggest that venous plasma levels of IFN-γ, rather than levels of IFN-γ in cord blood plasma, and PCT may have predictive potential for sepsis development in preterm neonates. Further studies are necessary to get more comprehension of the complex function of cytokines for sepsis development in preterm neonates.

Introduction/Objective. Acute pancreatitis (AP) is a relatively common disease which in most patients has favorable course. However, in approximately 20% patients, the course of the disease is more severe with high mortality (40?50%). The evaluation of disease severity is now primarily based on protocols that includes clinical, laboratory, and radiographic diagnostic procedures, APACHE II score, Ranson score, CT index, and CT necrosis score. Key cells in the immunopathogenesis of AP are T-lymphocytes, and recent studies indicate the role of Th2 and their effector cytokines: interleukin (IL) -4 and interleukin (IL) -5. The purpose of our study was to determine the potential clinical value of IL-4 and IL-5 as biochemical markers for predicting development of severe, necrotizing form of acute pancreatitis with systemic complication such as systemic inflammatory response syndrome (SIRS). Methods. This prospective study included 240 patients hospitalized at The Clinic for Emergency Surgery of Clinical Center of Serbia as AP. Levels of IL-4 and IL-5 in serum were detected using commercial Bender Med Systems (BMS716FF) kits. Results. IL-4 and IL-5 were statistically significant increased on the second day of hospitalization with maximum values on the third day. In patients with severe AP complicated with necrosis and/or sepsis values were rising all through the seventh day. Conclusion. Levels of IL-4 and IL-5 in peripheral blood correlate with SIRS, Ranson score and clinical outcome in AP patients, therefore these cytokines are potential early biomarkers of disease progression and related complications.

Introduction: Few studies assess biologicals such as, omalizumab, mepolizumab, benralizumab, and dupilumab in patients suffering from chronic rhinosinusitis with nasal polyposis (CRSwNP). The reported success rate in these studies differ, and it remains uncertain if there are any biomarkers to predict successful therapy. Our aim was to analyze the therapeutic outcome in a real life setting and to identify predictive biomarkers for successful treatment. Methods: Data from patients with CRSwNP treated with a monoclonal antibody between November 2014 and January 2020 were analyzed retrospectively. Improvement in the polyp score and clinical symptoms like nasal obstruction, sense of smell, nasal discharge, and facial pain were evaluated. Other characteristics, including use of nasal or systemic steroids, comorbidities, previous history of sinus surgery, eosinophilia tissue, blood values (eosinophils, total immunoglobulin E, eosinophilic cationic protein, and interleukin 5), and allergic sensitization in serum were also investigated to identify possible predictive biomarkers. Results: Forty-eight treatments in 29 patients (m/f = 15/14) aged 27–70 years were reviewed. Treatments with mepolizumab showed the best success rates (78.9%), followed by omalizumab (50%) and benralizumab treatments (50%). However, a correlation between biomarkers and treatment success could not be found. Discussion/Conclusion: Treatment of CRSwNP with biologicals is a promising option for severe cases not responding to conventional therapy, including difficult-to-treat patients. Predictive biomarkers for a successful treatment could not be identified, but the reduction of eosinophilic cationic protein was linked with the response.

To study the effect of IL-5 on the immune response and lung injury in rats with sepsis. We constructed a rat model of sepsis by cecal ligation and puncture (CLP). The rats were randomly divided into the control group, the sham group, the CLP group and the IL-5 group, with 6 rats in each group. With the induction of CLP, the lung tissue of rats was severely injured, and the water content of lung tissue was significantly increased. Moreover, the ratio of CD4+/CD8+ was significantly decreased and Th1/Th2 was significantly increased in the peripheral blood. The content of IL-6, TNF-α, and HMGB1 was found to be increased in the CLP group. However, with the injection of IL-5, the degree of lung tissue injury in CLP rats was alleviated and the water content of lung tissue was significantly reduced. The ratio of CD4+/CD8+ was increased and Th1/Th2 was significantly down-regulated in the peripheral blood and the levels of IL-6, TNF-α, and HMGB1 in serum were significantly decreased. In conclusion, IL-5 can alleviate lung injury by regulating the immune response and inhibiting the systemic inflammatory response induced by sepsis., Graphical abstract

Fructooligosaccharides (FOS), a prebiotic supplement, can enhance immunological responses, probably through regulation of gastrointestinal microflora. On the other hand, some environmental pollutants have adjuvanticity against allergic reactions/diseases. The purpose of this study was to evaluate the effects of dietary supplementation with FOS on a murine model of enhanced ovalbumin (OVA)-related allergic peritonitis induced by di-(2-ethylhexyl) phthalate (DEHP). C3H/HeN mice were intraperitoneally administered OVA and DEHP, and fed a diet containing 2.5% FOS. Thereafter, several parameters were evaluated. Supplementation with FOS alleviated OVA plus DEHP-related peritoneal inflammation characterized by infiltration of polymorphonuclear leukocytes including neutrophils in the peritoneal cavity. Also, FOS administration declined the number of mast cells of OVA + DEHP treated mice. FOS suppressed the elevated protein level of interleukin-5, eotaxin, and keratinocyte-derived chemoattractant, in the peritoneal lavage fluids. Our results suggest that dietary supplementation with FOS can prevent or ameliorate enhanced allergic peritoneal inflammation induced by DEHP.

Background Anti-IL-5 antibodies represent an established therapy for severe eosinophilic asthma (SEA), but some patients show inadequate response. The objective of this study was to assess the effects of a switch to anti-IL-5Rα therapy in patients with inadequate response to anti-IL-5 therapy. Methods In this retrospective multi-centre, real-life study, we analysed all SEA patients switched from anti-IL-5 to anti-IL-5Rα therapy due to inadequate response or intolerability. Pulmonary function tests, blood gas analyses, asthma control tests (ACT) and oral corticosteroid (OCS) usage were analysed and compared at three timepoints: baseline (BL, before anti-IL-5 therapy), timepoint 1 (T1, under anti-IL-5 therapy) and timepoint 2 (T2, under anti-IL-5Rα therapy). Results Of 665 patients treated with anti-IL-5 antibodies, 70 were switched to anti-IL-5Rα and 60 were included in the analysis. Median treatment duration was 8 months [IQR 5; 15] for anti-IL-5 and 5 months [IQR 4; 6] for anti-IL-5Rα therapy. FEV1 was 61% of predicted at BL [IQR 41; 74], 61% [IQR 43; 79] at T1 and 68% [IQR 49; 87] at T2 (pT1-T2=0.011). ACT score was 10 [IQR 8; 13], 16 [IQR 10; 19] and 19 [IQR 14; 22], respectively (both p

Eosinophilic granulomatosis with polyangiitis (EGPA) is one of the principal causes of vasculitic neuropathy.1 Recently, clinicopathologic differences among patients with EGPA based on their antineutrophil cytoplasmic antibody (ANCA) status have been reported.1–3 Furthermore, the efficacy of mepolizumab (an anti-interleukin-5 [IL-5] antibody drug) for the treatment of patients with EGPA has been demonstrated.4 IL-5 is a cytokine that is essential for eosinophil proliferation, maturation, differentiation,4–6 and survival.3 Although IL-5 is considered to be closely related to the pathogenesis of EGPA, the relationship between serum IL-5 and the clinicopathologic features of EGPA has not been determined.

Malignant tumors are often associated with eosinophilic pleural effusion. Here, we encountered a case of interleukin‐5 (IL‐5)‐producing malignant pleural mesothelioma with eosinophilic pleural effusion. The patient was a 50‐year‐old male. He had a history of a cough for several weeks and had visited a local doctor. Left pleural effusion was noted, and the patient was referred to our hospital. He was diagnosed with malignant pleural mesothelioma by pleural biopsy, with eosinophilic pleural effusion. IL‐5 in the pleural effusion increased, and tumor cells were IL‐5‐positive by immunostaining. There have been few reports of IL‐5‐producing tumors, and this is the first report of IL‐5‐producing malignant pleural mesothelioma. Host‐tumor cell interactions cause eosinophilic pleural effusion. In patients with eosinophilic pleural effusion, malignant pleural effusion should be considered. It is necessary to clarify the pathophysiology of malignant tumors and eosinophils., This is the first report of IL‐5‐producing malignant pleural mesothelioma with eosinophilic pleural effusion.

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.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.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.

Introduction and objectives Interleukin (IL)-5 is an anti-inflammatory cytokine that has been demonstrated to be involved in cardiovascular diseases, including aortic aneurysm and heart failure. This study aimed to investigate the involvement of IL-5 in coronary artery disease (CAD) and the possible mechanisms. Methods We analyzed IL-5 expression in human coronary artery specimens collected from CAD patients and deceased donors. Plasma IL-5, IL-17, and interferon-γ levels in CAD patients were detected using ELISA kits, with samples from chest pain patients (non-CAD) as controls. Mouse CD4+T helper (Th) cells were separated, and the effect of IL-5 on Th1, regulatory T cell and Th17 differentiation and mRNA levels of their characteristic cytokines were detected using flow cytometry and reverse transcription-quantitative polymerase chain reaction, respectively. Results IL-5 was significantly decreased in the coronary plaque of CAD patients compared with the deceased donors group, and IL-5 was mainly derived from macrophages in the coronary artery plaque. Compared with the non-CAD group, plasma IL-5 levels in the CAD groups were significantly lower, and the sequence from high to low was stable angina pectoris, unstable angina pectoris, and acute myocardial infarction. Binary linear regression analysis showed that IL-5 was independently correlated with the occurrence of CAD. Recombinant mouse IL-5 treatment decreased Th1 and Th17 levels and mRNA expression of their characteristic cytokines in oxidized low-density lipoprotein-treated CD4+Th cells. Conclusion IL-5 levels were decreased in CAD patients and inhibited oxidized low-density lipoprotein Th1 and Th17 differentiation in vitro.

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. Keywords: Benralizumab, Chronic rhinosinusitis with nasal polyps, Eosinophils, IL-5, Mepolizumab

CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25-T cells’ activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressedfoxp3, irf4, gata3andil5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p+CD25+cells expressed moreIl5raand responded to specific donor Lewis but not self. Enriched CD4+CD25+cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3andIl5.These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.

New therapeutic monoclonal antibodies targeting the IL-5/IL-5 receptor pathway are extremely efficient in depleting blood eosinophils from subjects with asthma [...]

Objective: In recent years concept of precision medicine for phenotyping disease has come up which is important to offer the personalised treatment. This study was based on assessing serum IL-5 levels in subgroups of allergic and non-allergic asthma based on total serum Immunoglobulin E(IgE) Methods: The study was conducted from Jan-Apr 2020 at KGMU, India.25 patients with diagnosis of bronchial asthma were enrolled with age >12years and then patients were subjected to total serum IgE levels. Based on history of atopy and Serum IgE levels the patients were further divided in allergic and non-allergic subgroups. Serum IL-5 levels were measured in both groups as an attempt to segregate the endotypes. Results: On the basis of history of atopy and serum IgE levels the patients were divided in allergic and non-allergic subgroups with 15 and 10 patients respectively. The allergic subgroup had a mean IgE level of 2273IU/ml with maximum and minimum values of 4600 and 1713 and non-allergic one had a mean value of 81 IU/ml with maximum and minimum values of 66 and 99.The IL-5 levels were elevated in 5 patients of the allergic subgroup with average value of 57.7 pg/ml(values more than 15.6 were considered positive).However no correlation was found between the IgE and IL-5 levels. IL-5 levels were not elevated in the non-allergic subgroup. No statistical gender or phenotypic association could be established. Conclusion: Understanding of asthma phenotypes and endotypes is important because the diverseness of this disease results into varying response to therapies. IL-5 along with IL-4 and 13 plays a pivotal role in the Th-2 eosinophilic inflammation with most of the existing and emerging biologicals targeted towards Th2 cytokines.

Background: Interleukin 5, an archetypal type 2 cytokine, is fundamental to eosinophilic airways disease, considered to signal the bone marrow to promote eosinophil progenitor maturation and increase levels of eosinophils in the circulation. Aim: To investigate the relationship between airway IL-5 concentrations and inflammatory phenotypes of severe asthma. Methods: Healthy volunteers and biologic naive severe asthma patients were clinically characterised and had blood and induced sputum samples collected. Sputum was analysed for differential cell count and supernatant (PBS processed) proteins, measured by single plex ELISA. Eosinophilic asthma was defined as sputum eosinophils >2%. Between group comparisons were assessed by Kruskal Wallis and relationships between variables by spearman rank correlations. Results: 17 healthy controls, 53 non-eosinophilic and 26 eosinophilic patients with severe asthma participated in the study. In severe asthma, there were modest correlations between sputum IL-5 and sputum eosinophils (r = 0.519, p Discussion: Despite high levels of steroid treatment, there is persistent IL-5 generation within the airways of severe asthma.

Cardiovascular disease is the most prevalent cause of morbidity and mortality in diabetes. Epicardial adipose tissue (EAT) lies in direct contact with the myocardium and coronary arteries and can influence cardiac (patho) physiology through paracrine signaling pathways. This study hypothesized that the proteins released from EAT represent a critical molecular link between the diabetic state and coronary artery endothelial cell dysfunction. To simulate type 2 diabetes-associated metabolic and inflammatory status in an ex vivo tissue culture model, human EAT samples were treated with a cocktail composed of high glucose, high palmitate, and lipopolysaccharide (gplEAT) and were compared with control EAT (conEAT). Compared to conEAT, gplEAT showed a markedly increased gene expression profile of proinflammatory cytokines, corroborating EAT inflammation, a hallmark feature observed in patients with type 2 diabetes. Luminex assay of EAT-secretome identified increased release of various proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interferon-alpha 2 (IFNA2), interleukin 1 beta (IL1B), interleukin 5 (IL5), interleukin 13 (IL13), and CCL5, among others, in response to high glucose, high palmitate, and lipopolysaccharide. Conditioned culture media was used to collect the concentrated proteins (CPs). In response to gplEAT-CPs, human coronary artery endothelial cells (HCAECs) exhibited an inflammatory endothelial cell phenotype, featuring a significantly increased gene expression of proinflammatory cytokines and cell surface expression of VCAM-1. Moreover, gplEAT-CPs severely decreased Akt-eNOS signaling, nitric oxide production, and angiogenic potential of HCAECs, when compared with conEAT-CPs. These findings indicate that EAT inflammation may play a key role in coronary artery endothelial cell dysfunction in type 2 diabetes.

Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)‐4, IL‐5 and IL‐13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL‐5R and IL‐5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late‐onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non‐response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL‐5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non‐response.

Introduction A recent study from our laboratory demonstrated a number of neurobehavioral abnormalities in mice colony injected with a mouse-weight equivalent dose of all vaccines that are administered to infants in their first 18 months of life according to the U. S. pediatric vaccination schedule. Cytokines have been studied extensively as blood immune and inflammatory biomarkers, and their association with neurodevelopmental disorders. Given the importance of cytokines in early neurodevelopment, we aimed to investigate the potential post-administration effects of the U. S. pediatric vaccines on circulatory cytokines in a mouse model. In the current study, cytokines have been assayed at early and late time points in mice vaccinated early in postnatal life and compared with placebo controls. Materials and methods Newborn mouse pups were divided into three groups: i) vaccine (V1), ii) vaccine ​× ​3 (V3) and iii) placebo control. V1 group was injected with mouse weight-equivalent of the current U. S. pediatric vaccine schedule. V3 group was injected with same vaccines but at triple the dose and the placebo control was injected with saline. Pups were also divided according to the sampling age into two main groups: acute- and chronic-phase group. Blood samples were collected at postnatal day (PND) 23, two days following vaccine schedule for the acute-phase group or at 67 weeks post-vaccination for the chronic-phase groups. Fifteen cytokines were analyzed: GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, MCP-1, TNF-α, and VEGF-A. Wilcoxon Rank Sum test or unpaired Student's t-test was performed where applicable. Results IL-5 levels in plasma were significantly elevated in the V1 and V3 group compared with the control only in the acute-phase group. The elevation of IL-5 levels in the two vaccine groups were significant irrespective of whether the sexes were combined or analyzed separately. Other cytokines (VEGF-A, TNF-α, IL-10, MCP-1, GM-CSF, IL-6, and IL-13) were also impacted, although to a lesser extent and in a sex-dependent manner. In the acute-phase group, females showed a significant increase in IL-10 and MCP-1 levels and a decrease in VEGF-A levels in both V1 and V3 group compared to controls. In the acute-phase, a significant increase in MCP-1 levels in V3 group and CM-CSF levels in V1 and V3 group and decrease in TNF-α levels in V1 group were observed in treated males as compared with controls. In chronic-phase females, levels of VEGF-A in V1 and V3 group, TNF-α in V3 group, and IL-13 in V1 group were significantly decreased in contrast with controls. In chronic-phase males, TNF-α levels were significantly increased in V1 group and IL-6 levels decreased in V3 group in comparison to controls. The changes in levels of most tested cytokines were altered between the early and the late postnatal assays. Conclusions IL-5 levels significantly increased in the acute-phase of the treatment in the plasma of both sexes that were subjected to V1 and V3 injections. These increases had diminished by the second test assayed at week 67. These results suggest that a profound, albeit transient, effect on cytokine levels may be induced by the whole vaccine administration supporting our recently published observations regarding the behavioral abnormalities in the same mice. These observations support the view that the administration of whole pediatric vaccines in a neonatal period may impact at least short-term CNS functions in mice.

Hypereosinophilic syndrome (HES) is a group of a rare diseases characterized by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a humanized, monoclonal antibody against interleukin 5 (IL-5) receptor α, which is expressed on human eosinophils. Here, we present the case of a patient with severe HES in whom treatment with benralizumab, an anti-IL-5 receptor monoclonal antibody, was initiated 6 months ago. Prior to benralizumab administration, the patient was treated with glucocorticoids (GS) and mepolizumab. However, instead of the applied treatment and normal level of peripheral eosinophils the patient presented with fluctuating lower respiratory tract symptoms and recurrent exacerbations of HES. Treatment with benralizumab (30 mg s.c. every 4-6 weeks) was started, resulting in significant improvement of respiratory signs and symptoms, normalization of eosinophil count and significant reduction of the methylprednisolone dose (after 5 doses of benralizumab administration). No substantial side effects have been noted during treatment and 6-month follow-up. We argue that in the severe and relapsing course of HES, rescue treatment with benralizumab should be taken into account, particularly in cases of relative inefficacy of GS and mepolizumab.

A 61‐year‐old woman with hypereosinophilia and elevated interleukin (IL)‐5 level was admitted to our hospital after detection of multiple liver tumors. Liver biopsy demonstrated that the tumor consisted of scar tissue with remnants of eosinophilic infiltration, suggesting that it had formed by massive eosinophilic infiltration. The hypereosinophilia was treated mainly by prednisolone, and thereafter, the liver tumors disappeared. However, 10 months postadmission, CD4+ T‐cell lymphoma, which can produce IL‐5, was detected in the nasopharynx and oropharynx. Therefore, we believe that this is a rare case of hypereosinophilia‐related liver pseudotumor induced by presumed by IL‐5 elevation., Multiple liver tumors due to hypereosinophilia caused by interleukin (IL)‐5 disappeared mainly on steroid therapy. IL‐5 elevation that induced hypereosinophilia was due to the potent hidden T‐cell malignant lymphoma.

Backgrounds: Asthma is a chronic airway inflammation which is a manifestation of complex interactions between cells and moleculer mediators. The aims asthma management is to reach asthma in controlled state. Providing an additional therapy in these circumstances is necessary to control asthma. Quercetin as an adjunctive therapy in asthma therapy may improve clinical symptoms and lung function. Methods: Experimental clinical trials of pretest of and postest design were conducted on 34 patient’s asthma at Dr. Moewardi Hospital Surakarta in 6 October–10 December 2018. Subject of treatment group (n= 17) was given quercetin 500 mg per day within 28 days, the control group (n=17) received only standar therapy asthma. Decreased airway inflammation was assessed based on the percentage of blood eosinophil and IL-5. Clinical improvement was assessed by ACT score while lung function used FEV1. Results: Quercetin decreased the inflammatory airways in patients with asthma evidenced by significant decrease in plasma IL-5 of treatment groups but no significant differences between treatment and control group, the mean decrease of blood eosinophil in the treatment group was significant. Querectin improved lung function with decrease FEV1 of treatment groups but no significant differences between treatment and control group and there was a clinical improvement with significant ACT score enhancement in the treatment group. Conclusion: The administration of quercetin significantly reduced inflammation based on decreased levels of eosinophils. There are improvement of lung function and clinical symptoms after quercetin. (J Respir Indo. 2020; 40(1): 16-23)

Subclinical inflammatory reaction is associated with non-insulin dependent diabetes. Therefore, the aim of the present study is to describe the effect of the three cytokines: interferon γ (IFN-γ), interleukin (IL)-4 and IL-5 on the development of type 2 diabetes (T2D). Forty-five volunteers (after their permission) were participated in this work; according to their clinical examination and laboratory investigations (fasting blood sugar, 2 hours postprandial, HbA1c and lipid profile), they were divided into thirteen control (non-diabetic) (five females and eight males) and thirty-two diabetic patients (twenty-one females and eleven males). Thereafter, their sera were evaluated for C-reactive protein (CRP), IFN-γ, IL-4 and IL-5. The results revealed an increasing trend of CRP and a significant increase of IFN-γ in diabetic patients with no sex difference. A positive correlation between IFN-γ and both IL-4 and IL-5 in control, and a positive correlation between IL-4 and IL-5 in diabetic patients had been visualized. These results denoted that there may be an association of the pro-inflammatory cytokines in the etiology of diabetes mellitus type 2.

Background: Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. A number of studies have identified the association between interleukin (IL)-5 C-746T and C-703T polymorphisms and asthma risk, however, the results still remain inconclusive. The objective of the present study was to identify the effect of IL-5 polymorphisms in asthma susceptibility. Methods: PubMed and Google Scholar databases were searched. The odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the effect and strength of association in the random-effects model or fixed-effects model. Results: A total of 4 case–control and 2 cross-sectional studies were screened out, including 1499 asthma patients and 3766 controls. Two single-nucleotide polymorphisms of the IL-5 gene were identified. Our results detected a no significant association between IL-5 C-746T polymorphisms and asthma risk in the total population (CC genotype showed OR = 0.82, 95% CI = 0.67–1.00, P = 0.05, I2 = 0%; CT genotype showed OR = 0.94, 95% CI = 0.78–1.13, P = 0.50, I2 = 24%; and TT genotype showed OR = 0.85, 95% CI = 0.64–1.13, P = 0.27, I2 = 0%) while a significant association between IL-5 C-703T polymorphisms and asthma in children according to review results. Conclusion: The meta-analysis findings suggest a lack of direct association between the IL-5 C-746T polymorphism and asthma and found that C-703T polymorphisms of the IL-5 gene might contribute to asthma risk. Future well-designed case–control studies with a large population and more ethnicities are still needed to estimate the association.

Physicians may encounter blood or tissue eosinophilia through a routine complete blood count with differential or a tissue pathology report. In this article, the basic biology of eosinophils is reviewed and definitions of blood eosinophilia, as well as the challenges of defining tissue eosinophilia, are discussed. Conditions associated with eosinophilia are briefly discussed as well as a general approach to evaluating eosinophilia. Future challenges include determining which eosinophil-associated diseases benefit from eosinophil-targeted therapy and identifying biomarkers for disease activity and diagnosis.

Introduction Allergic rhinosinusitis (AR) is a clinical manifestation of a type 1 hypersensitive reaction. A complex of reactions involving components of the immune system - cells, mediators, cytokines, neuropeptides, adhesion molecules etc., are involved in the manifestation of the disease symptoms. Aim To evaluate the role of some serum and local cytokines and IgE molecules in the pathogenesis of AR comparing results in patients and healthy controls. Material and methods The study was conducted at the Prof. Dr. St. Kirkovich University Hospital and Medical University, Stara Zagora, Bulgaria. Results A trend towards higher serum levels in patients with AR compared to controls was found for IL-4, but with no significant difference. In the group of AR patients, those with the intermittent form had higher, although with no significance, interleukin 4 (IL-4) levels in the lavage compared to those with the persistent form. In nasal lavage fluids a tendency towards higher IL-5 levels was found in intermittent AR patients compared to those with persistent AR. A slight trend towards significantly higher serum levels of IL-13 in overweight patients compared to those with normal weight was found. Conclusions Regardless of the obvious differences of the concentrations of the cytokines studied in our groups, oftentimes no significant difference is observed. More studies should be conducted in order to show the role of IL-4, -5, -13, and IgE in the pathogenesis and severity of the disease.

Drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), is a severe reaction to medications that presents with rash, fever, and lymphadenopathy. Patients typically have eosinophilia and end-organ damage, most commonly to the kidneys or liver. If the heart is involved, either hypersensitivity myocarditis or acute necrotizing eosinophilic myocarditis (ANEM) can occur; the former is often reversible, and the latter is usually fatal.1 DIHS can persist for months after drug withdrawal, and different organ systems can be affected at different times. Symptoms can persist for a year or more.1 DIHS is treated with high doses of corticosteroids, which may be administered for months. DIHS is a type IV hypersensitivity reaction resulting in a T helper cell 2 (Th2)–predominant immune response with recruitment and activation of eosinophils. Interleukin 5 (IL-5), an eosinophil activator, and eosinophil chemokines, C-C motif chemokine ligand (CCL)17 and CCL22, are involved in DIHS and other eosinophilic disorders.2, 3, 4, 5, 6 In DIHS, other cytokines including IL-6, IL-10, and IL-13 are also thought to play a role in pathogenesis.7, 8 IL-5 blockers can be used to treat some eosinophilic disorders but these agents do not block these other pathogenic cytokines. However, all of these cytokines rely on the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway and can be simultaneously targeted using JAK inhibitors. It is not known whether molecularly targeted small molecule inhibitors are effective or work rapidly enough to treat severe drug reactions such as DIHS. Here we report 2 consecutive patients with severe DIHS with myocardial involvement treated with the JAK inhibitor tofacitinib.

Visual Abstract, Highlights • There is strong experimental evidence that IL-5 has a protective role in atherosclerosis but the clinical importance of this remains poorly studied. • In a prospective study involving 696 subjects with a follow-up of close to 17 years we show that baseline plasma levels of IL-5 do not predict risk for coronary events and stroke. • However, subjects with high levels of IL-5 were less likely to have a carotid plaque at the baseline investigation. • Experimental studies using a shear stress-modifying cast to the carotid artery of Apoe−/− mice deficient for IL-5 showed that lack of IL-5 was associated with increased plaque formation at sites of oscillatory blood flow. • The findings are in line with previous experimental observations of an atheroprotective role of IL-5 but do not support the use of IL-5 measurement in cardiovascular risk prediction., Summary Experimental studies have suggested an atheroprotective role of interleukin (IL)-5 through the stimulation of natural immunoglobulin M antibody expression. In the present study we show that there are no associations between baseline levels of IL-5 and risk for development of coronary events or stroke during a 15.7 ± 6.3 years follow-up of 696 subjects randomly sampled from the Malmö Diet and Cancer study. However, presence of a plaque at the carotid bifurcation was associated with lower IL-5 and IL-5 deficiency resulted in increased plaque development at sites of oscillatory blood flow in Apoe−/− mice suggesting a protective role for IL-5 in plaque development.

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 (≥/

Background: childhood atopic dermatitis (AD) most commonly presentswith sensitization to environmental allergens. Presence of food allergenspecificIgE is common in childhood and does not always correlate withclinical symptoms, which in children usually affect the skin and mayexacerbate the course of AD. Exposure to an allergen in the gastrointestinaltract activates Th2 immune reactions. Objective: with this study we wantedto compare blood and stool Th2 cytokine concentrations and fecalcalprotectin (FC) value in pediatric AD with (eAD) and without (iAD)sensitization to food. Methods: 51 children with AD were enrolled in thestudy. 57% (n=29) had food allergen specific IgE and comprised eADgroup, 43% (n=22) – iAD group. Blood and stool were tested for IL-4, IL-5,IL-13 concentrations using an enzyme linked immunosorbent assay. Stoolsamples were tested for FC concentrations. Results: iAD had significantlyhigher blood and stool IL-4 values than eAD: 2.82 pg/ml vs. 0, p=0.005;2.98 pg/ml vs. 0, p=0.007, respectively. There was no difference in IL-5 andIL-13 blood and stool concentrations between the groups. Children with ADhad significantly higher FC values, compared to healthy controls: 36.5mg/kg vs. 6.45 mg/kg, p=0.018. FC was slightly higher in eAD group thaniAD, but the difference was not significant: 38.5 mg/kg vs. 25.0 mg/kg,p=0.861 . Conclusions: sensitization to food is not significantly associatedwith Th2 cytokines in pediatric AD patients. Increase in FC values ischaracteristic to AD, but not sensitization to food.

BACKGROUND: Adiposity is associated with high serum levels of adipokines and chemokines which are possibly implicated in a co-existence of obesity and asthma. OBJECTIVES: Elucidate the possible roles of leptin, interleukin (IL)-4, IL-5 and IL-21 in linking obesity with childhood asthma. DESIGN: Cross-sectional, analytical. SETTING: Population of schoolchildren in a small Saudi city. SUBJECTS AND METHODS: The study included a representative sample of Saudi schoolchildren grouped as obese asthmatics, non-obese asthmatics, or obese nonasthmatics, with nonobese nonasthmatics as a control group. An asthma control test was done for the asthmatic groups. MAIN OUTCOME MEASURES: Serum levels of leptin, IL-4, IL-5, and IL-21. SAMPLE SIZE: 345 male schoolchildren with a mean (SD) age of 13.0 (2.3) years. RESULTS: Median serum leptin concentrations in obese asthmatics were significantly higher than in nonobese asthmatics (P

IL-5 is an important role cytokine on the RA. IL-5 has an important role on eosinophils. ARIA-WHO made classification of RA based on how long the clinical symptoms and the impact on quality of life. The aim of this study was to know the classification of RA with IL-5 on RA study. This study used a cross-sectional method with 39 samples. The examination of IL-5 used ELISA. The highest classification of RA was medium-severe persistent of 43.58% with the mean value IL-5 was 56.25 pg/ml. Based on the test of Kruskal Wallis, it was obtained p-value = 0.664. Conclusion: There was no significant relation between classification RA and IL-5.

The interleukin 5 (IL-5) pathway is an important component in the pathophysiology of severe eosinophilic asthma. Mepolizumab is a monoclonal antibody that targets the IL-5 pathway. Clinical trials showed efficacy of Mepolizumab in patients with severe eosinophilic asthma. However, reports on experience with treatment in a real-world cohort are limited.Evaluation of the efficacy and safety of Mepolizumab for treatment of severe eosinophilic asthma in a real-world cohort of patients.A clinical prospective observational trial included all patients18 years treated with Mepolizumab between March 2016 to March 2019 at Rabin Medical Center. The composite primary outcome measures evaluated: increase in FEV1 by≥ 200 ml and/or decrease in exacerbation rate of ≥50% and/or cessation of oral corticosteroids (OCS) treatment or ≥50% decrease in dosage. Also evaluated: blood eosinophil count, adverse events and quality of life.Of 61 patients, 50 (82.0%) achieved the primary outcome. The number of patients who suffered from frequent exacerbations decreased from 52 (85.2%) to 8 (13.1%) (Treatment with mepolizumab was well tolerated and significantly lowered the exacerbation rate and OCS dependence in a real-world cohort of severe eosinophilic asthma patients. Response to therapy was within six months and treatment effect was sustained over time.