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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 CD62Llow 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 CD62Llow 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 CD62Llow cells paralleled by an increase in the proportion of CD62Lbright 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 CD62Llow 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. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Soporous state in acute renal failure represent an atypical presentation of parathyroid cancer. Complete prompt investigations and diagnosis have a fundamental role in the management of this disease This report describes a case of parathyroid carcinoma (PC) with an uncommon first clinical presentation: soporous state, depression, and severe cognitive decline in association with acute renal failure. After discovering extremely high serum calcium and parathyroid hormone (PTH) levels, the diagnosis of primary hyperparathyroidism (pHPT) was made and a surgical en bloc resection was performed. After the surgical intervention, the histological examination revealed the presence of a malignant parathyroid disease, thus confirming our first preoperative suspicion. [ABSTRACT FROM AUTHOR]

The discovery of the P2X7 receptor (P2X7R, originally named P2Z) in immune cells, its cloning, and the identification of its role in a multiplicity of immune-mediated diseases raised great hopes for the development of novel and more potent anti-inflammatory medicaments. Unfortunately, such hopes were partially deluded by the unsatisfactory results of most early clinical trials. This failure substantially reduced the interest of the pharmaceutical and biotech industries in the clinical development of P2X7R-targeted therapies. However, recent findings ushered in a second life for the P2X7R in diagnostic medicine. New P2X7R radioligands proved to be very reliable tools for the diagnosis of neuroinflammation in preclinical and clinical studies, and detection and measurement of free P2X7 receptor (or P2X7 subunit) in human blood suggested its potential use as a circulating marker of inflammation. Here we provide a brief review of these novel developments. [ABSTRACT FROM AUTHOR]

Background: The efficacy of benralizumab has been broadly demonstrated in severe eosinophilic asthma (SEA), but only few real-life studies evaluated its long-term effects. Here we present novel data from the ANANKE study in which a large cohort of SEA patients was treated for up to 96 weeks. Methods: ANANKE (NCT04272463) is an observational retrospective Italian study investigating the key characteristics of SEA patients (collected during the 12 months prior to benralizumab initiation) and the clinical outcomes during benralizumab treatment (annual exacerbation rate [AER], lung function, asthma control, OCS use, healthcare resource utilization). A post hoc analysis was also conducted in groups of patients based on history of previous biologic therapy (bio-experienced versus naïve patients). Analyses were descriptive only. Results: Before benralizumab initiation, evaluable SEA patients (N = 162, 61.1% females, mean age 56.0 ± 12.7) showed a median blood eosinophil count (BEC) of 600 cells/mm3 (IQR: 430–890). Patients experienced frequent exacerbations (annualized exacerbation rate [AER]: 4.10, severe AER: 0.98), with impaired lung function and poor asthma control (median ACT score: 14) despite 25.3% reported oral corticosteroid (OCS) use. Nasal polyposis was present in 53.1% patients; 47.5% patients were atopic. After 96 weeks since the start of benralizumab, nearly 90% patients were still on treatment; benralizumab dramatically decreased exacerbations (AER: − 94.9%; severe AER: − 96.9%), improved respiratory parameters (median increase in pre-bronchodilator forced expiratory volume [pre-BD FEV1]: + 400 mL) and asthma control (median ACT score: 23) while eliminating OCS in 60% patients. Importantly, benralizumab effects were either maintained or progressively improved over time, accompanied by a nearly complete depletion of BEC. Benralizumab reduced AER both in naïve (any AER: − 95.9%; severe AER: − 97.5%) and bio-experienced patients (any AER: − 92.4%; severe AER: − 94.0%). Conclusions: Profound and sustained improvements in all asthma outcomes were observed with benralizumab. The correct identification of patients' eosinophilic-driven asthma phenotype was essential to ensure the achievement of such remarkable results. Trial registration: ClinicalTrials.gov Identifier: NCT04272463. [ABSTRACT FROM AUTHOR]

Lysophosphatidylethanolamine (LPE) is a promising natural lysophospholipid which can be employed as a growth regulator for horticultural purposes. The present research was accomplished to investigate the effects of LPE (0 or 10 ppm) on the yield and quality of "Savana" strawberry plants grown during two consecutive cultivation cycles (I (2020–2021); II (2021–2022)). Plants cultivated in year I and treated with LPE revealed the highest total yield (838.3 g plant−1), marketable yield (735.4 g plant−1) and average marketable fruit weight (39.8 g plant−1). Fruits from year II plants treated with LPE had the highest total phenolics concentration (491.4 mg 100 g−1 dw). LPE significantly enhanced strawberry antioxidant activity, firmness, soluble solids content, ascorbic acid and anthocyanins by 5.2%, 7.6%, 15.3%, 13.8% and 19.7%, respectively, compared with the control. Although LPE application significantly reduced fruit dry matter, yellowness and lightness by 7.2%, 30.1% and 14.6%, respectively, it significantly increased, in year II, anthocyanins, discarded production, fruit lightness and dry matter. Overall, our findings also revealed that, even under sub-optimal growing conditions (year II), LPE application increased important productive and qualitative strawberry parameters. [ABSTRACT FROM AUTHOR]

La sindrome di Loeys-Dietz (sLD) è una malattia ereditaria caratterizzata da alterazioni del tessuto connettivo simili a quelle che si verificano nella sindrome di Ehlers-Danlos e nella sindrome di Marfan. Gli autori descrivono due nuovi casi di questa sindrome, segnalando tra i segni cutanei la presenza di idrosadenite suppurativa (IS) localizzata anche in sedi atipiche. Poiché una maggiore incidenza di IS è stata segnalata in altre malattie caratterizzate da alterazioni del collagene, come sindrome di Ehler-Danlos, sindrome di Marfan, spondiloartropatie autoimmuni, lichen sclerosus, strie diselastiche, gli autori discutono il significato di tali alterazioni nella patogenesi dell’IS. [ABSTRACT FROM AUTHOR]

Extracellular ATP (eATP) and P2 receptors are novel emerging regulators of T-lymphocyte responses. Cellular ATP is released via multiple pathways and accumulates at sites of tissue damage and inflammation. P2 receptor expression and function are affected by numerous single nucleotide polymorphisms (SNPs) associated with diverse disease conditions. Stimulation by released nucleotides (purinergic signalling) modulates several T-lymphocyte functions, among which energy metabolism. Energy metabolism, whether oxidative or glycolytic, in turn deeply affects T-cell activation, differentiation and effector responses. Specific P2R subtypes, among which the P2X7 receptor (P2X7R), are either up- or down-regulated during T-cell activation and differentiation; thus, they can be considered indexes of activation/quiescence, reporters of T-cell metabolic status and, in principle, markers of immune-mediated disease conditions. [ABSTRACT FROM AUTHOR]

Biologic agents (BA) are able to induce an adaptive immune response in a proportion of exposed patients with the onset of anti-drug antibodies (ADA), which are usually responsible for hypersensitivity reactions (HR). Drug desensitization (DD) for BA allows transient clinical tolerance to the drug in reactive patients. The paper aimed to analyse the modification of drug-specific immune responses along DD in two patients with previous ADA-mediated HR (anaphylaxis) to rituximab and tocilizumab. The in vivo and in vitro assays of humoral and cellular response to drugs were carried out in a longitudinal manner throughout the DD cycles. We observed a progressive decrease of the pre-procedure ADA titer with negativization during the DD cycles in both patients. The monitoring of the drug-specific effector cell response showed the decrease in the BA-induced proliferation, while T cell response to unrelated antigens resulted unmodified along the DD cycles. Lastly, the increase of circulating drug-specific Treg cells mainly producing IL-35 were shown during the DD treatment. This study provides evidence that DD treatment to two BA inhibits humoral and cellular anti-drug response by increasing regulatory T cells and cytokines in an antigen-restricted manner. These modifications could contribute to the safety of the procedure. [ABSTRACT FROM AUTHOR]

The outbreak of the SARS‐CoV‐2‐induced coronavirus disease 2019 (COVID‐19) pandemic re‐shaped doctor‐patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS‐CoV‐2 is not known. Severe COVID‐19 patients may experience a "cytokine storm" and associated organ damage characterized by an exaggerated release of pro‐inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti‐inflammatory cytokines and type 2 responses. This expert‐based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID‐19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self‐application. In case of an active SARS‐CoV‐2 infection, biological treatment needs to be stopped until clinical recovery and SARS‐CoV‐2 negativity is established and treatment with biologicals should be re‐initiated. Maintenance of add‐on therapy and a constant assessment of disease control, apart from acute management, are demanded. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of AI on medical images (CT, MRI, PET) has become a primary clinical and research interest. The main issues of these applications are strictly related to the reconstruction of imaging, the segmentation of tissues acquired, the selection of features, and the proper data analyses. Different approaches of AI have been proposed as the machine and deep learning, which utilize artificial neural networks inspired by neuronal architectures. Further validation of AI models for diagnosis and monitoring responses will be necessary to assess as MRI and PET/CT might provide a personalized treatment-response prediction superior to current methods. The lack of early detection and a high rate of recurrence/progression after surgery are defined as the most common causes of a very poor prognosis of Gliomas. The developments of quantification systems with special regards to artificial intelligence (AI) on medical images (CT, MRI, PET) are under evaluation in the clinical and research context in view of several applications providing different information related to the reconstruction of imaging, the segmentation of tissues acquired, the selection of features, and the proper data analyses. Different approaches of AI have been proposed as the machine and deep learning, which utilize artificial neural networks inspired by neuronal architectures. In addition, new systems have been developed using AI techniques to offer suggestions or make decisions in medical diagnosis, emulating the judgment of radiologist experts. The potential clinical role of AI focuses on the prediction of disease progression in more aggressive forms in gliomas, differential diagnosis (pseudoprogression vs. proper progression), and the follow-up of aggressive gliomas. This narrative Review will focus on the available applications of AI in brain tumor diagnosis, mainly related to malignant gliomas, with particular attention to the postoperative application of MRI and PET imaging, considering the current state of technical approach and the evaluation after treatment (including surgery, radiotherapy/chemotherapy, and prognostic stratification). [ABSTRACT FROM AUTHOR]

Background: Infliximab (IFX) carries potential risk of immunogenicity with the production of anti‐drug antibodies (ADA). ADA may belong to different isotypes and are usually measured by ELISA bridging assay. This test is not designed to detect IgG4 antibodies. The aim was to measure IgG4 anti‐IFX antibodies in a cohort of IFX‐treated patients and to evaluate their relationship with ADA and their clinical impact. Methods: Anti‐drug antibodies were detected using a bridging ELISA in the serum of 222 treated patients with different clinical outcomes to IFX. The same samples were analyzed for IgG4 anti‐IFX antibodies using an experimental ImmunoCAP assay with reduced serum IgG4 background levels. A longitudinal evaluation was performed in a subgroup of 38 patients to define the temporal evolution of IgG4 anti‐IFX. Results: IgG4 anti‐IFX was found in 26.6% of patients. Eighty of 222 patients were ADA+ (36%) and the majority (57/80, 71.3%) had IgG4 anti‐IFX. Two IgG4‐positive but ADA‐negative patients were identified. IgG4 anti‐IFX levels correlated with the serum levels of ADA. IgG4 anti‐IFX was more common in both reactive and nonresponder patients than in tolerant/responder patients. Patients who had experienced IgE‐mediated reactions displayed significantly higher IgG4 anti‐IFX than IgE‐negative reactive patients. The majority of patients tested positive for IgG4 anti‐IFX after the first seven infusions. Conclusions: IgG4 anti‐IFX is common in treated patients and a large part of ADA producing patients produce IgG4 antibodies. The IgG4 anti‐IFX response does not prevent hypersensitivity reactions to IFX and correlates with the IgE anti‐IFX response. IgG4 anti‐IFX were measured using an experimental ImmunoCAP™ assay with reduced serum IgG4 background levels based on a modified IFX ImmunoCAP for research use only. IgG4 anti‐IFX serum levels positively correlate with those of non‐isotype‐specific anti‐drug antibodies (ADA) and ADA+ patients display higher levels of IgG4 anti‐IFX than ADA− patients. IgG4 anti‐IFX are not protective against clinical outcomes since are detectable more frequently in HR and LOR than in tolerant patients. [ABSTRACT FROM AUTHOR]

Immunoglobulin G (IgG) replacement therapy is a standard treatment for patients with primary immunodeficiency diseases (PIDs). Hizentra®, a 20% human subcutaneous IgG (SCIG), is approved for biweekly administration for PIDs. The aim of the multicenter IBIS study was to prospectively investigate the efficacy of biweekly Hizentra® compared with previous IVIG or SCIG treatment regimens in patients with PIDs. The study consisted of a 12-month retrospective period followed by 12-month prospective observational period. The main endpoints included pre-infusion IgG concentrations, proportion of patients with serious bacterial infections (SBIs), other infections, hospitalizations due to PID-related illnesses, and days with antibiotics during the study periods. Of the 36 patients enrolled in the study, 35 patients continued the study (mean age 26.1 ± 14.4 years; 68.6% male). The mean pre-infusion IgG levels for prior immunoglobulin regimens during the retrospective period (7.84 ± 2.09 g/L) and the prospective period (8.55 ± 1.76 g/L) did not show any significant variations (p = 0.4964). The mean annual rate of SBIs/patient was 0.063 ± 0.246 for both prospective and retrospective periods. No hospitalizations related to PIDs were reported during the prospective period versus one in the retrospective period. All patients were either very (76.5%) or quite (23.5%) satisfied with biweekly Hizentra® at the end of the study. In conclusion, the IBIS study provided real-world evidence on the efficacy of biweekly Hizentra® in patients with PIDs, thus verifying the data generated by the pharmacometric modeling and simulation study in a normal clinical setting. [ABSTRACT FROM AUTHOR]

In Gen. ad litt. 12 Augustine discusses a model of ecstatic divination, which he calls ecstasis/extasis. It is characterized by visions instead of given words or verses received in a state of frenzy. This article focuses on Augustine's reception of earlier pagan and Christian authors who dealt with this topic, and on the contextualization in Augustine's contemporary world. [ABSTRACT FROM AUTHOR]

Nucleotides play a crucial role in extracellular signaling across species boundaries. All the three kingdoms of life (Bacteria, Archea and Eukariota) are responsive to extracellular ATP (eATP) and many release this and other nucleotides. Thus, eATP fulfills different functions, many related to danger-sensing or avoidance reactions. Basically all living organisms have evolved sensors for eATP and other nucleotides with very different affinity and selectivity, thus conferring a remarkable plasticity to this signaling system. Likewise, different intracellular transduction systems were associated during evolution to different receptors for eATP. In mammalian evolution, control of intracellular ATP (iATP) and eATP homeostasis has been closely intertwined with that of Ca2+, whether in the extracellular milieu or in the cytoplasm, establishing an inverse reciprocal relationship, i.e. high extracellular Ca2+ levels are associated to negligible eATP, while low intracellular Ca2+ levels are associated to high eATP concentrations. This inverse relationship is crucial for the messenger functions of both molecules. Extracellular ATP is sensed by specific plasma membrane receptors of widely different affinity named P2 receptors (P2Rs) of which 17 subtypes are known. This confers a remarkable plasticity to P2R signaling. The central nervous system (CNS) is a privileged site for purinergic signaling as all brain cell types express P2Rs. Accruing evidence suggests that eATP, in addition to participating in synaptic transmission, also plays a crucial homeostatic role by fine tuning microglia, astroglia and oligodendroglia responses. Drugs modulating the eATP concentration in the CNS are likely to be the new frontier in the therapy of neuroinflammation. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'. • Extracellular nucleotides are universal extracellular signaling molecules. • In the brain, ATP is a danger signal and a powerful pro-inflammatory mediator. • Multiple ATP receptors with varying affinity are expressed in the brain. • ATP signaling is increasingly involved in brain homeostasis in health and disease. • Purinergic signaling is an appealing target for the therapy of CNS diseases. [ABSTRACT FROM AUTHOR]

Background: The landscape of systemic therapies for advanced non-melanoma skin cancers has been revolutionized by the advent of immunotherapy. Cemiplimab is the only immune checkpoint inhibitor (ICI) approved by the European Medicine Agency for recurrent/metastatic cutaneous squamous cell carcinoma (cSCC). Its excellent efficacy outcomes are achieved due to its good tolerability profile. The drug-related hypersensitivity reaction (HSR) is a well-known issue in oncology, but it is rarely reported in respect to immune checkpoint inhibitors. Cemiplimab is among the agents with the best infusion tolerability profiles. Clinical practice guidelines in this field are lacking. Results: We report on the successful management of a severe infusion reaction induced by Cemiplimab in a patient with cSCC based on a desensitization protocol, which led to adequate treatment delivery and prolonged clinical benefit. A review of the available literature on HSR rates and its management with ICIs, and on drug desensitization (DD) protocols and their efficacy, was conducted to highlight the limited knowledge on this topic and its importance. Conclusion: Our experience highlights the need for a DD protocol in order to improve the treatment of HSRs, particularly when elicited by an immunotherapy agent, preventing treatment discontinuation and preserving its efficacy. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIg) is accepted as an effective and well-tolerated treatment for primary and secondary immunodeficiencies (ID) and immune thrombocytopenia (ITP). Adverse reactions of IVIg are usually mild, comprising transient flu-like symptoms, change in blood pressure and tachycardia. However IVIg therapy can be burdensome for both patients and healthcare facilities, since the infusion may take up to 4 h to administer. The objective of our multicentre, prospective, open-label phase III trial was to evaluate the tolerability and safety of human normal immunoglobulin 50 g/l (Ig VENA) at high intravenous infusion rates in adult patients with ID and ITP who had previously tolerated IVIg treatment, by progressively increasing infusion rate up to 8 ml/kg/hr. 39 ID patients received three infusions, 5 ITP patients received up to a maximum of 5 infusions for a maximum of 5 days. Overall 55 adverse events were reported in 18 patients, and all were mild and self-limiting. Two serious adverse events occurred in ID patients and 1 in an ITP patient; none was fatal or treatment-related. No clinically significant changes or abnormalities were observed in vital signs, laboratory results and HRQoL. In summary, in this study, more rapid IVIg infusions were well tolerated by ID and ITP patients, while maintaining their quality of life, helping to minimise the time spent in outpatient hospital visiting to potentially optimise adherence to treatment. [ABSTRACT FROM AUTHOR]

Antibodies recognizing infliximab (IFX) may develop in a proportion of treated patients, leading to loss of response or hypersensitivity reactions (HRs). T cell response to IFX has been poorly investigated. This paper was addressed to detect IFX-specific T cells in treated patients with inflammatory diseases developing, or not, anti-drug antibodies (ADA) and to correlate the presence of specific T cells with the clinical outcomes of the treatment. A co-culture system of IFX-loaded dendritic cells and purified autologous CD4+ T cells was used to detect memory T cells in 32 ADA+ and 39 ADA- IFX-treated patients and control groups. The cytokine profile of IFX-specific T cells was also studied in culture supernatants. IFX-specific cell proliferation was detected mainly in cells from ADA+ patients, irrespective of their different diseases. HR patients displayed higher T cell proliferation than non-responder and tolerant patients. A mixed [interferon (IFN)-γ, interleukin (IL)-13, IL-10] cytokine profile was shown in cells from ADA+ patients, while IL-10 was the most frequently detected cytokine in the supernatants of cultures from ADA- patients. Immunoglobulin (Ig)E+ADA+ patients with previous HRs exhibited a more pronounced type 2 profile than IgE-ADA+ patients. This work provides evidence that IFX-specific circulating T cells are detectable mainly in ADA+ patients with HRs, regardless of their disease. The IFX-induced cytokine pattern partially correlates with the ADA isotype. [ABSTRACT FROM AUTHOR]

Nucleotides are released from all cells through regulated pathways or as a result of plasma membrane damage or cell death. Outside the cell, nucleotides act as signalling molecules triggering multiple responses via specific plasma membrane receptors of the P2 family. In the nervous system, purinergic signalling has a key function in neurotransmission. Outside the nervous system, purinergic signalling is one of the major modulators of basal tissue homeostasis, while its dysregulation contributes to the pathogenesis of various disease, including inflammation and cancer. Pre-clinical and clinical evidence shows that selective P2 agonists or antagonists are effective treatments for many pathologies, thus highlighting the relevance of extracellular nucleotides and P2 receptors as therapeutic targets. [Display omitted] • Extracellular ATP is a main constituent of the inflammatory and tumor microenvironments. • Signals delivered by extracellular nucleotides are transduced by plasma membrane receptors belonging to the P2 receptor family. • Multiple P2 receptors with different selectivity and affinity endows signalling by extracellular nucleotides with a remarkable plasticity. • Dysregulation of this signalling system is implicated in the pathogenesis of major inflammatory diseases and cancer. • Small molecule drugs targeting P2 receptors have been successfully developed for the therapy of selected diseases. [ABSTRACT FROM AUTHOR]

Total serum IgE result from the combination of specific and non-specific pools. High specific/total IgE ratio may reflect high level of allergen-specific IgE on mast cells. No data regarding its applications to drug allergies is available. One hundred seventy-one patients with a history of immediate reactions to β-lactams, confirmed by positive skin testing, and 122 control subjects tolerant to β-lactams, were studied. CAP System was used for the detection of serum total and specific IgE antibodies. The specific/total IgE ratio was tested for diagnostic accuracy compared with conventional criteria. We finally performed a simulation study to expand our investigation of the performance of the specific/total IgE ratio index in a scenario in which the new CAP detection threshold is lowered further. Specific/total IgE ratio values ≥0.002 were observed more frequently in reactive than in controls. Seventy-four of 80 subjects with values ≥0.002 were allergic to β-lactams, yielding a positive predictive value of 92.5%. The application of specific/total IgE ratio significantly improves the positive likelihood ratio and the overall diagnostic performance. In addition, we showed the capability of this new criterion to identify true reactive patients even among subjects with high levels of total IgE (>200 kU/L). Significant increase in both receiver operator characteristic (ROC) curve and sensitivity were observed in imputed case of the simulation study. The β-lactams-specific/total IgE ratio may be an additional index compared to the common criterion of positivity to a single hapten in the allergological work-up of patients with β-lactams immediate adverse reactions. [ABSTRACT FROM AUTHOR]

Background and Objectives: Subcutaneous immunoglobulin (SCIG) therapy is becoming increasingly popular as self-administration is possible because intravenous access is unnecessary, and there is a lower frequency of systemic adverse events. The aim of this study was to evaluate the shifting from intravenous immunoglobulins (IVIGs) replacement therapy to SCIG in patients with primary immunodeficiency (PID) in a routine real-life situation. Methods: In a multicenter prospective observational study, we enrolled 50 patients suffering from PID who were monitored for 24 months; 44 patients switched from IVIG and six from different SCIG preparations. The study preparation (human IgG 16 %, Vivaglobin, CSL Behring GmbH, Germany) was subcutaneously infused weekly (maximum volume 15 mL/site; maximum infusion rate 22 mL/h). The study endpoints were: annual rate of severe bacterial infections (SBIs), local adverse reactions, quality of life, days off school/work, and days of hospitalization. Results: Thirty-three of 39 (84.6 %) patients who completed the study experienced an infection or signs thereof. Only five SBIs were observed, corresponding to an annual rate of 0.056 episodes per patient in 44 subjects [intention-to-treat (ITT) population]. A significant decrease in both days of hospitalization (1.93 ± 4.08 vs. 0.64 ± 2.94) and days off school/work (15.27 ± 23.17 vs. 2.26 ± 4.45) was recorded at 24 months. Local reactions were observed in 14/50 (28 %) patients, mainly consisting of skin manifestations at the injection site. Only three (6.8 %) patients discontinued due to infusion site reactions. In patients shifting from IVIG to SCIG, the total mean score of Life Quality Index (LQI) improved from 76.9 ± 16.8 to 90.7 ± 11.6 ( P < 0.01) at 6 months; there was an improvement also in the overall patients' evaluation. Conclusions: A total of 93.2 % patients tolerated the new route of administration and reported a significant improvement in their LQI. Our results from a routine clinical practice in a real-life population are consistent with those of phase III clinical studies. [ABSTRACT FROM AUTHOR]

Immunogenicity of biological agents leads to the development of antidrug antibodies (ADA) and it may be associated to hypersensitivity reactions. Immediate infusion reactions occur during or within 1 h after infusion, and their clinical manifestations vary considerably, ranging from mild to severe and life-threatening. Recent studies show that different mechanisms sustain hypersensitivity reactions toward biologics, and the application of novel methods for detecting ADA has demonstrated the involvement of specific IgE isotypes. Considering the severity of the reactions, it is important for clinicians to recognize their symptoms, to know their pathophysiological mechanisms, and to take risk assessment and prophylactic procedures. This review summarizes the clinical manifestations of antibody and nonantibody-mediated reactions as well as the humoral and cellular mechanisms of antidrug responses. Last, the management of patients at risk is discussed. The definition of diagnostic and prophylactic strategies represents an unavoidable need in the management of potentially reactive patients to improve the safety profile of biologics. [ABSTRACT FROM AUTHOR]

The article discusses the importance of stressors in application for college education and its decision-making process for students entering college schools in the U.S. It mentions that decision making process for students in college has undergone stress management. It notes the on the research study on the cause of stress in the college admission process. It also adds the process to reduce stress and anxiety in the admission process.

Since the late 1980s, there has been a significant increase in the number of doctoral degrees conferred upon underrepresented minority (URM) students. However, White students still account for the vast majority – approximately 80 percent – of all doctoral degrees conferred in the United States. As education stakeholders seek to diversify the professoriate, an updated examination of the baccalaureate origins of successful URM students is warranted to improve our understanding of where they are best prepared for doctoral degree programs. We used data from the Survey of Earned Doctorates (SED) and the Integrated Postsecondary Education Data System (IPEDS) to identify the baccalaureate origins of African American, Latina/o, and Asian/Pacific Islander students who received doctoral degrees between 1995 and 2005, distinguishing the top ten producing institutions for each racial/ethnic group. Using extant research, we then identified and examined institutional characteristics of those top ten producers. Findings both confirm and build upon past research showing that institutional characteristics such as sector, racial/ethnic composition, selectivity, and geographic location matter in terms of producing successful URM doctoral students. The implications of the findings are dis-cussed and suggestions for future re-search are presented for institutions that wish to recruit and retain URM students to their doctoral degree programs. [ABSTRACT FROM AUTHOR]

Background IL-17 A is associated with different asthma phenotypes as virus-associated or steroid-resistant asthma. Invariant natural killer T ( iNKT) cells play an important role in the pathogenesis of asthma. The aim of the study was to evaluate the activity of polyinosinic-polycytidylic acid [poly( I: C)] on IL-17 A production by CD1d-activated iNKT cells. Methods We analysed the in vitro effect of poly( I: C) on the release of IL-17 A by spleen and lung CD1d-activated iNKT cells with α-galactosylceramide (α- Gal Cer). Its activity was also investigated in an α- Gal Cer-induced murine models, including lung inflammation. The inhibition of IL-17 A by Toll-like receptor ( TLR) 7 agonists in the same in vitro and in vivo models has been analysed. Results Poly( I: C) upregulated the in vitro IL-17 A production by CD1d-activated NK1.1− CD4− iNKT subset, without modifying type 1 and type 2 cytokines. The two stimuli selectively upregulated IL-17A serum levels in vivo. Their intratracheal administration resulted in increased airway hyper-reactivity ( AHR), neutrophilia in bronchoalveolar lavage and airway inflammation, which were inhibited by anti- IL-17 A antibody. Poly( I: C) effects were attributable to IL1β and IL-23 release from dendritic cells, as showed by inhibition with neutralizing antibodies. TLR7 agonists inhibited the IL-17A production by poly( I: C) plus α- Gal Cer in the same models. Such effect was associated with the increased production by DC of IL-17 A-inhibiting cytokines and the dampening of IL-1β and IL-23. Conclusions Synthetic ds RNA selectively expand a CD1d-driven IL-17 A-producing iNKT cell subset, thus explaining the worsening of airway inflammation by some viral infections. TLR3- and TLR7-triggering viral sequences can exert variable and opposite effects on adaptive immune response. [ABSTRACT FROM AUTHOR]

Rituximab (RTX) is currently used in the treatment of lymphoproliferative diseases and of several rheumatologic disorders and is a frequent cause of acute infusion reactions, usually classified as cytokine release syndrome (CRS). Some infusion reactions to RTX raise concern for immediate type I hypersensitivity, even if to date RTX-specific IgE antibodies have not been reported. To improve knowledge of the mechanisms of reactions to RTX, we investigated humoral and cellular immune responses to this drug in a patient suffering from rheumatoid arthritis who displayed two immediate infusion-related reactions. RTX-exposed tolerant patients and healthy untreated subjects were used as controls. Non-isotype-specific and IgE anti-RTX antibodies were positive in the serum samples collected from the reactive patient but not in those from the control groups. Only the reactive patient also displayed skin testing positivity with RTX. More importantly, RTX-stimulated peripheral blood mononuclear cells from the reactive patient, but not from the controls, displayed a dose-dependent proliferative response associated with a Th2 cytokine production profile. Our results show the presence of RTX-specific Th2-type cells and IgE antibodies, thus suggesting that type I hypersensitivity may be an additional mechanism to CRS in the development of RTX reactions. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) disorders are the most common form of clinically significant primary immunodeficiencies found in adults. There is now clear evidence that CVID includes a group of clinically and genetically heterogenous conditions. In addition to recurrent infections, some patients are highly prone to granulomatous lesions. Rarely, CVID may be characterized by an increased number of circulating CD8+ T cells with tissue infiltration. We report a unique case of CVID associated with a sarcoidosis-like disease and polyclonal CD8+ T cell expansion with multiple tissue infiltration occurring in a subject with the chromosome translocation t(1;16). No sequence variant in TACI, APRIL, BAFF, ICOS or BTK genes was discovered. Cytometric analysis showed that the chemokine receptors expressed on peripheral and tissue CD8+ T cells are responsible for the tissue homing of the cells. Moreover, CD8+ T cells produced high amounts of IFN-γ, but not IL-4 and IL-17, with regular expression of the transcription factor Vav1. Genes coding for IL-32 and FRAP1, both involved in the regulation of memory T cell differentiation, are located in the translocation breakpoint. This suggests that a chromosomal abnormality plays a role in the clinical features of this phenotypic variant of CVID. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study evaluates the ability of a novel TLR7 ligand (9-benzyl-2-butoxy-8-hydroxy adenine, called SA-2) to affect IL-17 response. The SA-2 activity on the expression of IL-17A and IL-17-related molecules was evaluated in acute and chronic models of asthma as well as in in vivo and in vitro α-galactosyl ceramide (α-GalCer)-driven systems. SA-2 prepriming reduced neutrophils in bronchoalveolar lavage fluid and decreased methacoline-induced airway hyperresponsiveness in murine asthma models. These results were associated with the reduction of IL-17A (and type 2 cytokines) as well as of molecules favoring Th17 (and Th2) development in lung tissue. The IL-17A production in response to α-GalCer by spleen mononuclear cells was inhibited in vitro by the presence of SA-2. Reduced IL-17A (as well as IFN-γ and IL-13) serum levels in mice treated with α-GalCer plus SA-2 were also observed. The in vitro results indicated that IL-10 produced by B cells and IL-10-promoting molecules such as IFN-α and IL-27 by dendritic cells are the major player for SA-2-driven IL-17A (and also IFN-γ and IL-13) inhibition. The in vivo experiments with anti-cytokine receptor Abs provided evidence of an early IL-17A inhibition essentially due to IL-10 produced by resident peritoneal cells and of a delayed IL-17A inhibition sustained by IFN-α and IL-27, which in turn drive effector T cells to IL-10 production. These findings suggest that such TLR7 agonist downregulating Th17 (as well as Th2) response has to be considered a valid candidate for novel vaccine formulations in allergy. [ABSTRACT FROM AUTHOR]

To cite this article: Vultaggio A, Matucci A, Nencini F, Pratesi S, Parronchi P, Rossi O, Romagnani S, Maggi E. Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions. Allergy 2010; 65: 657–661. Background: Infliximab is a chimeric monoclonal antibody against TNF-α useful in the treatment of many chronic inflammatory diseases. Severe anaphylaxis has been reported during therapy, although the exact mechanism has not been fully defined. The reactions have been related to the infliximab immunogenicity and development of specific antibodies. Aims of the study: Evaluation of the development of IgE and non-IgE antibodies to infliximab and their relationship with infusion reaction. Methods: Seventy-one patients (11 reactives, 11 therapeutically nonresponders, and 49 unreactive therapeutically responders) and 20 non–infliximab-exposed control subjects (ten rheumatoid arthritis, five spondyloarthropathies, five vasculitis) were evaluated for the presence of IgE (ImmunoCAP assay), IgM, and non–isotype-specific (ELISA assays) anti-infliximab antibodies. Sera were obtained at baseline and during the course of treatment, before each infliximab infusion. Results: Eleven out of 71 patients had a hypersensitivity reaction to infliximab. Non–isotype-specific anti-infliximab antibodies were detected in eight reactive and two nonresponder patients. Three patients with severe reactions displayed anti-infliximab IgE antibodies and positive skin testing. Detectable levels of anti-infliximab IgM antibodies were shown in three additional IgE- and skin testing-negative patients. IgE and IgM antibodies to infliximab were not detectable in the two nonresponder patients. Antibodies developed before the 2nd and the 3rd infusion, and their appearance was strictly related to the timing of the reaction. Conclusions: This report indicates that in some patients with infliximab-related severe reactions, IgE or IgM antibodies against infliximab were detectable. The majority of reactions could be predicted by the appearance of anti-infliximab antibodies. [ABSTRACT FROM AUTHOR]

Background Allergic reactions to β-lactams are a frequent cause of adverse drug reactions; the diagnosis is based on history, clinical examination, skin testing (prick and intradermal) and demonstration of serum-specific IgE antibodies (Abs). Objective We compared the diagnostic performance of the Phadia CAP system for the detection of IgE to β-lactams carried out using the new test with cut-off limits of 0.10 kUA/L and the old test with cut-off limits of 0.35 kUA/L for positive results; subsequently, we analysed the effect of total serum IgE values and of atopic phenotype on the diagnostic performance of the tests. Methods The study comprised a total of 34 patients with a history of immediate adverse reactions to β-lactams, which were confirmed by positive skin testing, and 115 control subjects with tolerance to β-lactams over the last year. The Phadia CAP System was used for the determination of serum total and specific IgE Abs towards penicilloyl G (c1), penicilloyl V (c2), ampicilloyl (c5) and amoxicilloyl (c6). The overall diagnostic performance was assessed as a diagnostic odds ratio (DOR). Results The new test showed a higher sensitivity (85% vs. 44%) than the old test and a lower specificity (54% vs. 80%) but the overall diagnostic performance was poor (DOR 6.78 vs. 3.16, P=0.333) in both tests. The total IgE value influences the DOR of both tests; DOR was better for values under 200 kU/L [DOR=66; 95% confidence interval (CI): 11.3–384.1] or 500 kU/L (DOR=45.7; 95% CI: 5.3–394.4) for the new and old tests, respectively. Conclusions The reduction in the positive cut off value has not significantly improved the overall diagnostic performance of the β-lactams-specific IgE assay. Because of the influence of serum total IgE on the detection of β-lactam-specific IgE Abs, the combination of both tests is mandatory in the in vitro diagnostic approach of β-lactam allergy. [ABSTRACT FROM AUTHOR]

Abstract: Factors influencing the susceptibility to mucosal candidiasis in HIV-infected patients are not clearly understood. Since in animal models of candidiasis the T helper (Th)1- or Th2-responses are protective or non-protective, respectively, this study was aimed to evaluate the cytokine profile of T-cell response to Candida albicans in the blood and lesional tissues of human immunodeficiency virus (HIV)-infected individuals, suffering, or not, from pseudomembranous oropharyngeal candidiasis (POPC), of HIV-negative women suffering from recurrent vaginal candidiasis (RVC) and of healthy controls. Peripheral blood mononuclear cells from HIV-infected and RVC patients proliferated to C. albicans antigen more than controls. Upon antigen activation, T cells from HIV-infected patients produced low interferon (IFN)-γ, while only T cells from patients with POPC displayed high interleukin (IL)-4 and IL-5 production. POPC-positive patients also showed higher serum IgE levels than POPC-negative patients. T-cell clones generated from the oral mucosa of one HIV-infected patient with POPC produced IL-4, but not IFN-γ (Th2 phenotype), whereas clones obtained from vaginal mucosa from one RVC patient or one healthy donor showed a Th1 profile. These findings, showing a non-protective Th0/Th2 response to C. albicans antigen in the blood and lesional mucosa of HIV-infected patients with POPC, may explain the high susceptibility of candidiasis in these subjects. [Copyright &y& Elsevier]

The cytokine profile of circulating and vaginal T cells specific for immunodominant mannoprotein antigens of Candida albieans was analyzed in patients with recurrent vaginal candidiasis (RVC). Peripheral blood mononuclear cells (PBMC) from patients with RVC proliferated more than those from healthy subjects and expressed higher type 1:type 2 T helper cell cytokine ratios in response to C. albieans stimulation. A higher number of C. albieansspecific T cells was generated in PBMC from patients with RVC than in PBMC from healthy donors. C. albicans-specific T cell clones from patients with RVC produced higher levels of interferon (IFN)-γ and lower levels of interleukin (IL)-4 than clones from control women. More important, a higher proportion of C. albieans-specific T cell clones was generated from lesional mucosa of patients with RVC than from normal mucosa, all of which produced IFN- but not IL-4. These findings provide direct evidence that RVC is characterized by a highly polarized local and circulating type 1 T helper cell-like response against C. albieans antigens. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and internal organs. SSc is an immunologically mediated disease. A prominent immunological abnormality in SSc patients is the presence of circulating autoantibodies against a variety of nuclear proteins. Furthermore, SSc is characterized by the presence of increased numbers of activated T cells, with the prevalence of CD4+ cells, present in the periphery of skin lesions as well as in other organs in the early stages of the disease. We have recently shown the existence of a predominant activation of IL-4-producing Th2-like T cells in patients with SSc, which may account for the major alterations which occur in this disease. SSc has clinical and serological similarities to chronic graft versus host disease (cGVHD), although there are some important differences. T cells, which orchestrate the tissue damage, are present in great amounts in the inflammatory infiltrates in SSc- and cGVHD-affected tissues. More importantly, T cells from cGVHD tissues produce Th2-like cytokines, thus showing a pathogenetic similarity with SSc. SSc has been postulated as a type of cGVHD resulting from the transplacental transfer of cells between mother and fetus. Very recently, we have shown that in SSc, the microchimeric T cells react with the maternal MHC antigens and are able to produce Th2-type cytokines. Both features are characteristics of cGVHD, supporting the hypothesis that SSc is a disease similar to cGVHD.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

[Display omitted] It is increasingly appreciated that ion channels have a crucial role in tumors, either as promoters of cancer cell growth, or modulators of immune cell functions, or both. Among ion channels, P2X receptors have a special status because they are gated by ATP, a common and abundant component of the tumor microenvironment. Furthermore, one P2X receptor, i.e. P2X7, may also function as a conduit for ATP release, thus fuelling the increased extracellular ATP level in the tumor interstitium. These findings show that P2X receptors and extracellular ATP are indissoluble partners and key regulators of tumor growth, and suggest the exploitation of the extracellular ATP-P2X partnership to develop innovative therapeutic approaches to cancer. [ABSTRACT FROM AUTHOR]

Adenosine triphosphate (ATP) is one of the main biochemical components of the tumor microenvironment (TME), where it can promote tumor progression or tumor suppression depending on its concentration and on the specific ecto-nucleotidases and receptors expressed by immune and cancer cells. ATP can be released from cells via both specific and nonspecific pathways. A non-regulated release occurs from dying and damaged cells, whereas active release involves exocytotic granules, plasma membrane-derived microvesicles, specific ATP-binding cassette (ABC) transporters and membrane channels (connexin hemichannels, pannexin 1 (PANX1), calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs) and maxi-anion channels (MACs)). Extracellular ATP acts at P2 purinergic receptors, among which P2X7R is a key mediator of the final ATP-dependent biological effects. Over the years, P2 receptor- or ecto-nucleotidase-targeting for cancer therapy has been proposed and actively investigated, while comparatively fewer studies have explored the suitability of TME ATP as a target. In this review, we briefly summarize the available evidence suggesting that TME ATP has a central role in determining tumor fate and is, therefore, a suitable target for cancer therapy. [ABSTRACT FROM AUTHOR]

Adenosine triphosphate (ATP) is the key energy intermediate of cellular metabolic processes and a ubiquitous extracellular messenger. As an extracellular messenger, ATP acts at plasma membrane P2 receptors (P2Rs). The levels of extracellular ATP (eATP) are set by both passive and active release mechanisms and degradation processes. Under physiological conditions, eATP concentration is in the low nanomolar range but can rise to tens or even hundreds of micromoles/L at inflammatory sites. A dysregulated eATP homeostasis is a pathogenic factor in several chronic inflammatory diseases, including type 2 diabetes mellitus (T2DM). T2DM is characterized by peripheral insulin resistance and impairment of insulin production from pancreatic β-cells in a landscape of systemic inflammation. Although various hypoglycemic drugs are currently available, an effective treatment for T2DM and its complications is not available. However, counteracting systemic inflammation is anticipated to be beneficial. The postulated eATP increase in T2DM is understood to be a driver of inflammation via P2X7 receptor (P2X7R) activation and the release of inflammatory cytokines. Furthermore, P2X7R stimulation is thought to trigger apoptosis of pancreatic β-cells, thus further aggravating hyperglycemia. Targeting eATP and the P2X7R might be an appealing novel approach to T2DM therapy. [ABSTRACT FROM AUTHOR]

Abstract: Tako-Tsubo''s syndrome (apical ballooning or broken heart syndrome) is a reversible left ventricular dysfunction due to apical asynergy that occurs typically after sudden emotional stress in a subject without coronary disease. It is characterized by acute onset of chest pain or dyspnoea or both and is associated with electrocardiographic changes such as ST segment elevation and/or T wave inversion. Myocardial biomarkers may be normal or slightly elevated. Anaphylaxis is a severe, life-threatening, generalized hypersensitivity reaction, most often starting with urticaria and/or angioedema, that may involve cardiovascular and respiratory systems. Cardiovascular symptoms, including hypotension, cardiac arrhythmia and chest pain, are presumably linked to cardiac mast cell mediator release. We describe the case of a young woman who experienced a profound reversible cardiomyopathy with typical features of Tako-Tsubo''s syndrome during an anaphylactic reaction. [Copyright &y& Elsevier]

Purpose: Historically managed with intranasal corticosteroids (INCS) and endoscopic sinus surgery (ESS), type-2 Chronic RhinoSinusitis with Nasal Polyps (CRSwNP) treatment was revolutionized by the introduction of dupilumab but universally accepted guidelines are still lacking. Methods: Patients treated at our University Hospital for type-2 CRSwNP were enrolled. Demographic data were collected, as well as laboratory (eosinophils, total IgE), endoscopic [nasal polyps score (NPS), modified Lund–Kennedy score (mLKS)], radiological [Lund–Mackay score (LMS) at CT scan], SNOT-22, and olfactory [Sniffin' Sticks identification test (SSIT)] features. Patients were treated with dupilumab or ESS and re-evaluated after 3 and 12 months. Results: At 3 and 12 months, patients undergoing ESS achieved a higher reduction of NPS and mLKS, while patients receiving dupilumab experienced a higher improvement at SNOT-22 and SSIT with a greater positive variation in the prevalence of anosmia (− 57.7% vs − 42.9%) and normosmia (+ 37.8 vs + 28.5%). Mean mLKS and LMS were quite similar. Results were independent of clinical features known to contribute to CRSwNP severity, except for patients with ≥ 2 prior ESS who had a significantly lower smell improvement. Conclusion: ESS and dupilumab were effective at reducing CRSwNP inflammatory burning. CRSwNP smell impairment cannot be attributed only to olfactory cleft obstruction and other mechanisms may be involved. Dupilumab acts systemically with poor correlation with NPS. As of today, dupilumab appears to be more suitable for elderly patients with anesthesiological contraindications and/or several previous surgeries, while ESS may represent the first-line choice in surgery-naive patients. [ABSTRACT FROM AUTHOR]

Asthma is a chronic inflammatory disease that can lead to airways remodeling. Despite their well-known side-effects, oral corticosteroids (OCS) continue to be used to reduce exacerbations and control asthma symptoms in many patients. We describe two cases of uncontrolled severe asthma characterized by systemic clinical consequences of prolonged OCS use, such as diabetes, weight gain, and osteoporosis. Both patients were treated with Dupilumab. During follow-up both patients showed an improvement in asthma control and were able to gradually taper the OCS dose, thus reducing the clinical burden associated with hypercortisolism. Dupilumab was able to control both the inflammatory-induced "airway remodeling" as well as the OCS-induced "patient remodeling". [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies (mAbs) approved for use as add-on therapy in patients with severe asthma target the underlying pathogenesis of asthma.Main Body: Omalizumab binds immunoglobulin E (IgE), thereby inhibiting its interaction with the high-affinity IgE receptor and reducing the quantity of free IgE available to trigger the allergic cascade. Anti-interleukin (IL)-5 mAbs mepolizumab, benralizumab and reslizumab block the interaction between IL-5 and its receptor on eosinophils, thus targeting the eosinophilic pathway in asthma. Most mAbs are available as intravenous (IV) or subcutaneous (SC) formulations, as their high molecular weight and gastric degradation preclude oral administration. This review compares the pharmacology, efficacy, immunogenicity, injection- and infusion-related adverse drug reactions of subcutaneously administered omalizumab and mepolizumab with the intravenously administered reslizumab. In terms of pharmacokinetics, IV route of administration appears to be superior to the SC route due to quicker absorption, greater bioavailability, shorter time to maximum serum concentration and similar elimination half-life. Route of administration does not appear to translate into striking differences in efficacy and safety of mAbs used for the treatment of severe asthma, as all are generally considered to be effective and well tolerated. Hypersensitivity and administration-related reactions have been described with both IV and SC mAbs.Conclusion: mABs are effective and have low immunogenicity due to their nature as humanised antibodies. Evidence on the use of mAbs in indications other than severe asthma suggest that both the SC and the IV routes of administrations have their respective advantages and disadvantages; but their full utility remains to be elucidated. [ABSTRACT FROM AUTHOR]

Bronchial asthma (BA) is a chronic inflammatory disease with a marked heterogeneity in pathophysiology and etiology. The heterogeneity of BA may be related to the inducing mechanism(s) (allergic vs non-allergic), the histopathological background (eosinophilic vs non-eosinophilic), and the clinical manifestations, particularly in terms of severity and frequency of exacerbations. Asthma can be divided into at least two different endotypes based on the degree of Th2 inflammation (T2 'high' and T2 'low'). For patients with severe uncontrolled asthma, monoclonal antibodies (mAbs) against immunoglobulin E (IgE) or interleukin (IL)-5 are now available as add-on treatments. Treatment decisions for individual patients should consider the biological background in terms of the "driving mechanisms" of inflammation as this should predict the patients' likely responses to treatment. The question is not whether an anti-IgE or an anti-eosinophilic strategy is more effective, but rather what the mechanism is at the origin of the airway. While IgE is involved early in the inflammatory cascade and can be considered as a cause of allergic asthma, eosinophilia can be considered a consequence of the whole process. This article discusses the different roles of the IgE and IL-5/eosinophil pathways in the pathogenic mechanisms of airway inflammation occurring in allergic asthma, and the possible reasons to choose an anti-IgE mAb or anti-IL-5 treatment. [ABSTRACT FROM AUTHOR]