Hymenoptera venom immunotherapy: Safety and efficacy of an accelerated induction regimen with depot aluminum adsorbed extracts.

Introduction: Hymenoptera venom immunotherapy (VIT) is the only therapy that protects patients with Hymenoptera venom allergy by preventing systemic reactions after a new sting. Various extracts for VIT are available and used. VIT administration consists of an induction phase and a maintenance phase. Depot preparations of Hymenoptera VIT extracts are typically used for cluster and conventional protocols, and the maintenance phase. Many patients with Hymenoptera allergy need to achieve tolerance quickly because of the high risk of re-sting and possible anaphylaxis. Objective: Our study aimed to show the safety and efficacy of an accelerated regimen with depot preparations on aluminum hydroxide by using relatively high starting doses in a heterogeneous group of patients. Methods: The research focused on a group of patients with a history of severe systemic reactions to Hymenoptera stings, with the necessity of swift immunization due to high occupational risks. Aluminum hydroxide depot extracts either of Vepula species or Apis mellifera extracts were used. Results: The induction protocol was started with the highest concentration of depot venom extract of 100,000 standard quality unit and was well tolerated by 19 of 20 patients. Onne patient presented with a mild systemic reaction during the accelerated induction schedule, which was promptly treated with intravenous steroids and intramuscular H1 antihistamine; when switched to a conventional induction protocol, he had a similar reaction but finally reached maintenance with an H1-antagonist premedication. Conclusion: If validated, the accelerated induction protocol by using depot aluminum adsorbed extracts with the highest concentration of venom from the beginning could offer a streamlined and accessible treatment modality for patients diagnosed with anaphylaxis from bee and wasp venoms in need of rapid desensitization.

An Overview on Atopic Dermatitis, Oxidative Stress, and Psychological Stress: Possible Role of Nutraceuticals as an Additional Therapeutic Strategy.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a considerable impact on patients' quality of life. Its etiology is multifactorial and, among the predisposing factors, a role is played by oxidative stress. Pollution, recurrent infections, and psychological stress contribute to oxidative stress, amplifying the production of proinflammatory cytokines and worsening barrier damage. There are various oxidative stress mechanisms involved in the pathogenesis of AD. Moreover, AD often appears to be associated with psychological disorders such as alexithymia, depression, and anxiety due to severe itching and related insomnia, as well as social distress and isolation. The increasing incidence of AD requires the evaluation of additional therapeutic approaches in order to reduce the psychological burden of this condition. Our review aims to evaluate the role of some nutraceuticals in AD treatment and its related psychological comorbidities. The combination of some natural compounds (flavonoids, alkaloids, terpenes, isothiocyanates) with traditional AD treatments might be useful in improving the effectiveness of therapy, by reducing chronic inflammation and preventing flare-ups, and in promoting corticosteroid sparing. In addition, some of these nutraceuticals also appear to have a role in the treatment of psychological disorders, although the underlying oxidative stress mechanisms are different from those already known for AD.

Highlights on the Effects of Non-Coding RNAs in the Osteonecrosis of the Jaw.

Osteonecrosis of the jaw is the progressive loss and destruction of bone affecting the maxilla or mandible in patients treated with antiresorptive and antiangiogenic agents without receiving prior radiation therapy. The pathogenesis involves the inflammatory pathway of receptor activator of nuclear factor NF-kB ligand and the macrophage colony-stimulating factor, essential for osteoclast precursors survival and proliferation and acting through its receptor c-Fms. Evidence has shown the role of non-coding RNAs in the pathogenesis of osteonecrosis of the jaw and this finding might be useful in diagnosis since these small RNAs could be considered as biomarkers of apoptotic activity in bone. Interestingly, it has been proved that miR-29 and miR-31-5p, acting on specific targets such as CALCR and RhoA, promote programmed-cell death and consequently the necrosis of bone tissue. Specific long non-coding RNAs, instead, have been detected both at reduced levels in patients with multiple myeloma and osteonecrosis, and associated with suppression of osteoblast differentiation, with consequences in the progression of mandible lesions. Among non-coding genic material, circular RNAs have the capability to modify the expression of specific mRNAs responsible for the inhibition of bisphosphonates activity on osteoclastogenesis.

MiRNAs and Microbiota in Non-Small Cell Lung Cancer (NSCLC): Implications in Pathogenesis and Potential Role in Predicting Response to ICI Treatment.

Lung cancer (LC) is one of the most prevalent cancers in both men and women and today is still characterized by high mortality and lethality. Several biomarkers have been identified for evaluating the prognosis of non-small cell lung cancer (NSCLC) patients and selecting the most effective therapeutic strategy for these patients. The introduction of innovative targeted therapies and immunotherapy with immune checkpoint inhibitors (ICIs) for the treatment of NSCLC both in advanced stages and, more recently, also in early stages, has revolutionized and significantly improved the therapeutic scenario for these patients. Promising evidence has also been shown by analyzing both micro-RNAs (miRNAs) and the lung/gut microbiota. MiRNAs belong to the large family of non-coding RNAs and play a role in the modulation of several key mechanisms in cells such as proliferation, differentiation, inflammation, and apoptosis. On the other hand, the microbiota (a group of several microorganisms found in human orgasms such as the gut and lungs and mainly composed by bacteria) plays a key role in the modulation of inflammation and, in particular, in the immune response. Some data have shown that the microbiota and the related microbiome can modulate miRNAs expression and vice versa by regulating several intracellular signaling pathways that are known to play a role in the pathogenesis of lung cancer. This evidence suggests that this axis is key to predicting the prognosis and effectiveness of ICIs in NSCLC treatment and could represent a new target in the treatment of NSCLC. In this review, we highlight the most recent evidence and data regarding the role of both miRNAs and the lung/gut microbiome in the prediction of prognosis and response to ICI treatment, focusing on the link between miRNAs and the microbiome. A new potential interaction based on the underlying modulated intracellular signaling pathways is also shown.

Allergen-specific immunotherapy and COVID-19: What happened?

BACKGROUND: The COVID-19 infection played a key role in the discontinuation of patient treatment, such as allergen-specific immunotherapy, in chronic diseases. OBJECTIVES: We conducted a retrospective observational study at Verona University Hospital, Verona, Italy, to assess the level of adherence to sublingual immunotherapy (SLIT) in patients affected by allergic rhinitis and mild asthma. MATERIALS AND METHODS: We compared and analysed data related to first prescription and collection of 5-grass-pollen 300-index of reactivity (IR) SLIT and tablet lyophilisate, containing 75,000 standardized quality tablet units (SQ-T) allergen extract of grass-pollen from Phleum pratense L, for the five-year period 2017-2021.In particular we considered the group of naïve patients from 2017 who completed pre-COVID treatment (2017-2019) and the group of naïve patients from 2019 who completed treatment during the COVID period (2019-2021). The significance test used was Student's t-test, and P ˂ 0.05 was considered as statistically significant. RESULTS: In the three-year period 2017-2019, 264 naïve patients began treatment in 2017, of these 181 continued in 2018, 135 continued in 2019. Instead, for the period 2017-2019, there were 226 naïve patients in 2019; of these 139 continued in 2020, and 102 in 2021. CONCLUSIONS: COVID-19 did not seem to influence adherence to SLIT, which declined independently even in during the pre-pandemic 3-year period.

The IL-33/IL-31 Axis in Allergic and Immune-Mediated Diseases.

Interleukin 31 (IL-31) belongs to the IL-6 superfamily [...].

The Role of Alarmins in Osteoarthritis Pathogenesis: HMGB1, S100B and IL-33.

Osteoarthritis (OA) is a multifactorial disease in which genetics, aging, obesity, and trauma are well-known risk factors. It is the most prevalent joint disease and the largest disability problem worldwide. Recent findings have described the role of damage-associated molecular patterns (DAMPs) in the course of the disease. In particular, alarmins such as HMGB1, IL-33, and S100B, appear implicated in enhancing articular inflammation and favouring a catabolic switch in OA chondrocytes. The aims of this review are to clarify the molecular signalling of these three molecules in OA pathogenesis, to identify their possible use as staging biomarkers, and, most importantly, to find out whether they could be possible therapeutic targets. Osteoarthritic cartilage expresses increased levels of all three alarmins. HMGB1, in particular, is the most studied alarmin with increased levels in cartilage, synovium, and synovial fluid of OA patients. High levels of HMGB1 in synovial fluid of OA joints are positively correlated with radiological and clinical severity. Counteracting HMGB1 strategies have revealed improving results in articular cells from OA patients and in OA animal models. Therefore, drugs against this alarmin, such as anti-HMGB1 antibodies, could be new treatment possibilities that can modify the disease course since available medications only alleviate symptoms.

Gender Differences and miRNAs Expression in Cancer: Implications on Prognosis and Susceptibility.

MicroRNAs are small, noncoding molecules of about twenty-two nucleotides with crucial roles in both healthy and pathological cells. Their expression depends not only on genetic factors, but also on epigenetic mechanisms like genomic imprinting and inactivation of X chromosome in females that influence in a sex-dependent manner onset, progression, and response to therapy of different diseases like cancer. There is evidence of a correlation between miRNAs, sex, and cancer both in solid tumors and in hematological malignancies; as an example, in lymphomas, with a prevalence rate higher in men than women, miR-142 is "silenced" because of its hypermethylation by DNA methyltransferase-1 and it is blocked in its normal activity of regulating the migration of the cell. This condition corresponds in clinical practice with a more aggressive tumor. In addition, cancer treatment can have advantages from the evaluation of miRNAs expression; in fact, therapy with estrogens in hepatocellular carcinoma determines an upregulation of the oncosuppressors miR-26a, miR-92, and miR-122 and, consequently, apoptosis. The aim of this review is to present an exhaustive collection of scientific data about the possible role of sex differences on the expression of miRNAs and the mechanisms through which miRNAs influence cancerogenesis, autophagy, and apoptosis of cells from diverse types of tumors.

Alarmins and MicroRNAs, a New Axis in the Genesis of Respiratory Diseases: Possible Therapeutic Implications.

It is well ascertained that airway inflammation has a key role in the genesis of numerous respiratory pathologies, including asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. Pulmonary tissue inflammation and anti-inflammatory responses implicate an intricate relationship between local and infiltrating immune cells and structural pulmonary cells. Alarmins are endogenic proteins discharged after cell injury in the extracellular microenvironment. The purpose of our review is to highlight the alterations in respiratory diseases involving some alarmins, such as high mobility group box 1 (HMGB1) and interleukin (IL)-33, and their inter-relationships and relationships with genetic non-coding material, such as microRNAs. The role played by these alarmins in some pathophysiological processes confirms the existence of an axis composed of HMGB1 and IL-33. These alarmins have been implicated in ferroptosis, the onset of type 2 inflammation and airway alterations. Moreover, both factors can act on non-coding genetic material capable of modifying respiratory function. Finally, we present an outline of alarmins and RNA-based therapeutics that have been proposed to treat respiratory pathologies.

Immunosenescence and Skin: A State of Art of Its Etiopathogenetic Role and Crucial Watershed for Systemic Implications.

Immunosenescence is a complex multifactorial phenomenon consisting of wide-ranging remodeling of the immune system during the life span, resulting in an age-related qualitative-quantitative decline of immune cells and cytokines. A growing body of evidence in the international literature is highlighting the etiopathogenetic role of skin immunosenescence in the onset of various dermatologic conditions. Skin immunosenescence also serves as an interesting watershed for the onset of system-wide conditions in the context of allergic inflammation. Moreover, in recent years, an increasingly emerging and fascinating etiopathogenetic parallelism has been observed between some mechanisms of immunosenescence, both at cutaneous and systemic sites. This would help to explain the occurrence of apparently unconnected comorbidities. Throughout our review, we aim to shed light on emerging immunosenescent mechanisms shared between dermatologic disorders and other organ-specific diseases in the context of a more extensive discussion on the etiopathogenetic role of skin immunosenescence. A promising future perspective would be to focus on better understanding the mutual influence between skin and host immunity, as well as the influence of high inter-individual variability on immunosenescence/inflammaging. This can lead to a more comprehensive "immunobiographic" definition of each individual.

Machine Learning Approaches in Diagnosis, Prognosis and Treatment Selection of Cardiac Amyloidosis.

Cardiac amyloidosis is an uncommon restrictive cardiomyopathy featuring an unregulated amyloid protein deposition that impairs organic function. Early cardiac amyloidosis diagnosis is generally delayed by indistinguishable clinical findings of more frequent hypertrophic diseases. Furthermore, amyloidosis is divided into various groups, according to a generally accepted taxonomy, based on the proteins that make up the amyloid deposits; a careful differentiation between the various forms of amyloidosis is necessary to undertake an adequate therapeutic treatment. Thus, cardiac amyloidosis is thought to be underdiagnosed, which delays necessary therapeutic procedures, diminishing quality of life and impairing clinical prognosis. The diagnostic work-up for cardiac amyloidosis begins with the identification of clinical features, electrocardiographic and imaging findings suggestive or compatible with cardiac amyloidosis, and often requires the histological demonstration of amyloid deposition. One approach to overcome the difficulty of an early diagnosis is the use of automated diagnostic algorithms. Machine learning enables the automatic extraction of salient information from "raw data" without the need for pre-processing methods based on the a priori knowledge of the human operator. This review attempts to assess the various diagnostic approaches and artificial intelligence computational techniques in the detection of cardiac amyloidosis.

Novel Biomarkers for Diagnosis and Monitoring of Immune Thrombocytopenia.

Lower-than-normal platelet counts are a hallmark of the acquired autoimmune illness known as immune thrombocytopenia, which can affect both adults and children. Immune thrombocytopenia patients' care has evolved significantly in recent years, but the disease's diagnosis has not, and it is still only clinically achievable with the elimination of other causes of thrombocytopenia. The lack of a valid biomarker or gold-standard diagnostic test, despite ongoing efforts to find one, adds to the high rate of disease misdiagnosis. However, in recent years, several studies have helped to elucidate a number of features of the disease's etiology, highlighting how the platelet loss is not only caused by an increase in peripheral platelet destruction but also involves a number of humoral and cellular immune system effectors. This made it possible to identify the role of immune-activating substances such cytokines and chemokines, complement, non-coding genetic material, the microbiome, and gene mutations. Furthermore, platelet and megakaryocyte immaturity indices have been emphasized as new disease markers, and prognostic signs and responses to particular types of therapy have been suggested. Our review's goal was to compile information from the literature on novel immune thrombocytopenia biomarkers, markers that will help us improve the management of these patients.

Malondialdehyde as a Potential Oxidative Stress Marker for Allergy-Oriented Diseases: An Update.

Malondialdehyde (MDA) is a compound that is derived from the peroxidation of polyunsaturated fatty acids. It has been used as a biomarker to measure oxidative stress in various biological samples in patients who are affected by a wide range of diseases. The aim of our work is to provide an updated overview of the role of MDA as a marker of oxidative stress in allergy-related diseases. We considered studies involving both paediatric and adult patients affected by rhinitis, asthma, urticaria and atopic dermatitis. The measurement of MDA was performed on different types of samples. The reported data highlight the role of serum MDA in inflammatory airway diseases. According to the literature review, the oxidative stress status in asthmatic patients, assessed via MDA determination, appears to worsen in the presence of other allergic airway diseases and in relation to the disease severity. This suggests that MDA can be a suitable marker for monitoring the disease status. However, there are several limitations in the considered studies due to the different samples used and the lack of phenotyping and description of the clinical period of patients examined. In cutaneous allergic diseases, the role of MDA is controversial because of the smallness of the studies and the heterogeneity of the samples and patients.

Antituberculosis drug-induced non-blistering systemic severe reactions: A 10-year (2012-2022) literature review.

Drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced liver injury (DILI) can hamper therapeutic strategy, contribute to multiple drug resistance and serious public health burden. Diagnosis (including allergy assessment) and management of these two severe hypersensitivity reactions in clinical practice are somewhat difficult and published scientific evidence is rather weak and limited. The first step is always represented by stopping all anti-tuberculosis (TB) drugs, treating reaction with systemic corticosteroids, and identifying the offending drug, even if it is often complicated by the patient's simultaneous intake of antibiotics. Patch tests and in vitro tests, such as lymphocyte transformation test, could bridge this diagnostic gap, but the available data are scarce and their sensitivity low. The re-challenge test is often necessary but places patients at risk for serious adverse reactions. The desensitization protocols are quite varied and not universally accepted. In this narrative review, we provide an update to the literature data on the management of DRESS and DILI with particular attention to the allergological work-up in the last decade.

Photodistributed eruptive telangiectasias: an uncommon adverse drug reaction. A retrospective case series.

Drug-induced photodistributed telangiectasia (PT) is a cutaneous adverse effect (AE) resulting from the interaction of ultraviolet radiation with pharmacotherapy. Reports of PT in the literature are scarce. We report 25 cases of drug-induced PT highlighting the potential relationship between the onset of skin lesions, drug intake and photo exposure. We alert practitioners that PT is a possible dermatological phototoxic AE of many drugs.

Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Benralizumab in the management of rare primary eosinophilic lung diseases.

Background: Eosinophils have a double-edged role in the human body, being essential in important physiologic functions but whose presence is conspicuous in a variety of diseases characterized by a T2 inflammation phenotype. Eosinophils are exquisitely sensitive to corticosteroids, and the latter have, until recently, represented the cornerstone of treatment of eosinophilic diseases. However, most patients remain dependent on oral corticosteroids, with a notable adverse effect burden and experience a chronic relapsing disease that leads to high morbidity and mortality. Treatment prospects have changed with the advent of biologic drugs that target the eosinotropic cytokine interleukin (IL) 5 or its receptor. The success of the latter drugs in severe eosinophilic asthma has paved the way for their use in other, rarer, eosinophilic lung diseases. Recently, mepolizumab, a humanized monoclonal antibody that works against IL-5, was approved for the add-on treatment of relapsing-remitting or refractory eosinophilic granulomatosis with polyangiitis (EGPA) in patients ages ≥ 6 years. Benralizumab, a humanized antibody that binds to the α portion of the IL-5 receptor, is also being tested for its efficacy in EGPA in two clinical trials, after a growing number of case reports and case series supported its use as a steroid-sparing agent in the treatment of EGPA. Methods: In this review, we summarized the scientific literature evaluating the efficacy of benralizumab treatment in patients afflicted with rare primary eosinophilic lung diseases. Results: The literature we found, largely case reports, reported that the use of benralizumab in EGPA, chronic eosinophilic pneumonia (CEP) and allergic bronchopulmonary aspergillosis (ABPA) often led to a depletion of eosinophils, less exacerbations and a decreased systemic corticosteroid burden. No adverse effects were reported. Conclusion: Benralizumab has a prospective role in the treatment of rare eosinophilic lung diseases, which needs to be further elucidated in randomized controlled trials.

IL-31: State of the Art for an Inflammation-Oriented Interleukin.

Interleukin 31 belongs to the IL-6 superfamily, and it is an itch mediator already studied in several diseases, comprising atopic dermatitis, allergic pathologies, and onco-hematological conditions. This research aims to assess the role of this cytokine in the pathogenesis of these conditions and its potential therapeutic role. The research has been conducted on articles, excluding reviews and meta-analysis, both on animals and humans. The results showed that IL-31 plays a crucial role in the pathogenesis of systemic skin manifestations, prognosis, and itch severity. Traditional therapies target this interleukin indirectly, but monoclonal antibodies (Mab) directed against it have shown efficacy and safety profiles comparable with biological drugs that are already available. Future perspectives could include the development of new antibodies against IL-31 both for humans and animals, thus adding a new approach to the therapy, which often has proven to be prolonged and specific for each patient.

MicroRNA Cross-Involvement in Acne Vulgaris and Hidradenitis Suppurativa: A Literature Review.

Acne Vulgaris (AV) and Hidradenitis suppurativa (HS) are common chronic inflammatory skin conditions that affect the follicular units that often coexist or are involved in differential diagnoses. Inflammation in both these diseases may result from shared pathways, which may partially explain their frequent coexistence. MicroRNAs (miRNAs) are a class of endogenous, short, non-protein coding, gene-silencing or promoting RNAs that may promote various inflammatory diseases. This narrative review investigates the current knowledge regarding miRNAs and their link to AV and HS. The aim is to examine the role of these molecules in the pathogenesis of AV and HS and to identify possible common miRNAs that could explain the similar characteristics of these two diseases. Five miRNA (miR-155 miR-223-, miR-21, and miRNA-146a) levels were found to be altered in both HS and AV. These miRNAs are related to pathogenetic aspects common to both pathologies, such as the regulation of the innate immune response, regulation of the Th1/Th17 axis, and fibrosis processes that induce scar formation. This review provides a starting point for further studies aimed at investigating the role of miRNAs in AV and HS for their possible use as diagnostic-therapeutic targets.

IL-33 and the Cytokine Storm in COVID-19: From a Potential Immunological Relationship towards Precision Medicine.

Coronavirus SARS-CoV-2 has represented, and still represents, a real challenge from a clinical, diagnostic and therapeutic point of view. During acute infection, the increased levels of pro-inflammatory cytokines, which are involved in the pathology of disease and the development of SARS-CoV-2-induced acute respiratory disease syndrome, the life-threatening form of this infection, are correlated with patient survival and disease severity. IL-33, a key cytokine involved in both innate and adaptive immune responses in mucosal organs, can increase airway inflammation, mucus secretion and Th2 cytokine synthesis in the lungs, following respiratory infections. Similar to cases of exposure to known respiratory virus infections, exposure to SARS-CoV-2 induces the expression of IL-33, correlating with T-cell activation and lung disease severity. In this work, we analyse current evidence regarding the immunological role of IL-33 in patients affected by COVID-19, to evaluate not only the clinical impact correlated to its production but also to identify possible future immunological therapies that can block the most expressed inflammatory molecules, preventing worsening of the disease and saving patient lives.