Mepolizumab in the management of severe eosinophilic asthma in adults: Current evidence and practical experience

Eosinophils represent approximately 1% of peripheral blood leukocytes in normal donors and their maturation and differentiation in the bone marrow are mainly regulated by interleukin (IL)-5 [Broughton et al. 2015]. IL-5, a cytokine that belongs to the \u3b2 common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils and, to some extent, of basophils. IL-5 binds to a heterodimer receptor composed of the specific subunit IL-5R\u3b1 and a common subunit \u3b2c shared with IL-3 and GM-CSF. Human eosinophils express approximately a three-fold higher level of IL-5R\u3b1 compared with basophils. Major sources of IL-5 are T-helper 2 (Th2) cells, mast cells, CD34+ progenitor cells, invariant natural killer (NK) T-cells, group 2 innate lymphoid cells (ILC2s), and eosinophils themselves. ILC2s control not only eosinophil number but also their circadian cycling through the production of IL-5

A critical appraisal on AIT in childhood asthma

Abstract: Allergen immunotherapy (AIT) is the only disease-modifying treatment approved for allergic rhinitis and allergic asthma and represents a suitable therapeutic option, especially in childhood, to modify the progression of respiratory allergic diseases. Starting from the previous \u201cgeneric class efect\u201d evaluation, as testifed by the numerous meta analyses, AIT is now considered a product-specifc pathogenic-oriented treatment. Background: AIT was empirically proposed more than one century ago in the subcutaneous form (SCIT), but the IgE-mediated mechanism of allergy was elucidated only after 50 years of clinical use of the treatment. The sublingual administration (SLIT) was developed during the 1980 ties, to achieve an improvement in safety and convenience. While SCIT is approved in the United States for the treatment of asthmatic patients with more than 12 years, so far few trials evaluated the clinical efcacy and safety of SLIT in children with allergic asthma, although the indications and some aspects remain unclear. Certainly, due to compliance problems, the age below 3 years may be reasonably considered a practical contraindication. Conclusions: Given that some specifc AIT products are efective and approved as drugs (AIFA, EMA, FDA), the use in children is still debated. Some aspects still need robust confrm: (a) the safety of AIT in asthma; (b) the optimal regimen of administration; (c) the role of AIT as preventative treatment for asthma development

Anti-Interleukin 5 (IL-5) and IL-5Ra Biological Drugs: Efficacy, Safety, and Future Perspectives in Severe Eosinophilic Asthma

The definition of asthma has changed considerably in recent years, to the extent that asthma is no longer considered a single disease but a heterogeneous disorder that includes several phenotypes and, possibly, endotypes. A more detailed analysis of the immunological mechanisms underlying the pathogenesis of asthma shows interleukin 5 (IL-5) to be a crucial cytokine in several asthma phenotypes. In fact, IL-5 exerts selective action on eosinophils, which, in turn, sustain airway inflammation and worsen asthma symptoms and control. Clinical trials have shown drugs targeting IL-5 or its receptor alpha subunit (IL-5Ra) to be a promising therapeutic approach to severe asthma, whose characteristics render standard therapy of little use: systemic corticosteroids only partially control the disease and have well-known adverse effects, and omalizumab is used for allergic subtypes. Analysis of the design process of clinical trials reveals the importance of patient selection, taking into account both clinical data (e.g., exacerbations, lung function, and quality of life) and biomarkers (e.g., eosinophils, which are predictive of therapeutic response)

Whole-exome analysis in osteosarcoma to identify a personalized therapy

Osteosarcoma is the most common pediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies of patients with conventional high grade osteosarcoma to advance our understanding of their genetic underpinnings and to correlate the genetic alteration with the clinical and pathological features of each patient to identify a personalized therapy. We identified 18,275 somatic variations in 8,247 genes and we found three mutated genes in 7/8 (87%) samples (KIF1B, NEB and KMT2C). KMT2C showed the highest number of variations; it is an important component of a histone H3 lysine 4 methyltransferase complex and it is one of the histone modifiers previously implicated in carcinogenesis, never studied in osteosarcoma. Moreover, we found a group of 15 genes that showed variations only in patients that did not respond to therapy and developed metastasis and some of these genes are involved in carcinogenesis and tumor progression in other tumors. These data could offer the opportunity to get a key molecular target to identify possible new strategies for early diagnosis and new therapeutic approaches for osteosarcoma and to provide a tailored treatment for each patient based on their genetic profile

Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification

As a relevant element of novelty, the fifth CNS WHO Classification highlights the distinctive pathobiology underlying gliomas arising primarily in children by recognizing for the first time the families of paediatric-type diffuse gliomas, both high-grade and low-grade. This review will focus on the family of paediatric-type diffuse high-grade gliomas, which includes four tumour types: 1) Diffuse midline glioma H3 K27-altered; 2) Diffuse hemispheric glioma H3 G34-mutant; 3) Diffuse paediatric-type high-grade glioma H3-wildtype and IDH-wildtype; and 4) Infant-type hemispheric glioma. The essential and desirable diagnostic criteria as well as the entities entering in the differential will be discussed for each tumour type. A special focus will be given on the issues encountered in the daily practice, especially regarding the diagnosis of the diffuse paediatric-type high-grade glioma H3-wildtype and IDH-wildtype. The advantages and the limits of the multiple molecular tests which may be utilised to define the entities of this tumour family will be evaluated in each diagnostic context

Immunostimulants in respiratory diseases: focus on Pidotimod

Usefulness of Pidotimod and its role as immunostimulant, has been discussed, we know, for several decades. Nevertheless, there is still much to know. Understanding its mechanisms and its potential usefulness in airway infections and its prevention, asthma both Th2 and non Th2 type, bronchiectasis, as adjuvant in vaccination and in allergen immunotherapy still remains to clearly unveil. The aim of this paper was to provide a useful updated review of the role of the main available immunostimulants, giving particular focus on Pidotimod use and its potentials utility in respiratory diseases. Pidotimod showed its usefulness in reducing need for antibiotics in airway infections, increasing the level of immunoglobulins (IgA, IgM, IgG) and T-lymphocyte subsets (CD3+, CD4+) endowed with immunomodulatory activity that affect both innate and adaptive immune responses. Higher expression of TLR2 and of HLA-DR molecules, induction of dendritic cell maturation and release of pro-inflammatory molecules, stimulation of T lymphocyte proliferation and differentiation toward a Th1 phenotype, as well as an increase of the phagocytosis have been demonstrated to be associated with Pidotimod in in vitro studies. All these activities are potentially useful for several respiratory conditions such as asthma, COPD, and recurrent respiratory tract infections

Real-life biomarker response to anti-IL5 and anti-IgE therapies in severe asthma patients

Funding: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. No funding was received by OPRI for its contribution.Peer reviewedPostprin

Biomarker-defined clusters by level of Type 2 inflammatory involvement in severe asthma

Peer reviewedPostprin

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come