Vitamin C Supplementation in the Treatment of Autoimmune and Onco-Hematological Diseases: From Prophylaxis to Adjuvant Therapy.

Vitamin C is a water-soluble vitamin introduced through the diet with anti-inflammatory, immunoregulatory, and antioxidant activities. Today, this vitamin is integrated into the treatment of many inflammatory pathologies. However, there is increasing evidence of possible use in treating autoimmune and neoplastic diseases. We reviewed the literature to delve deeper into the rationale for using vitamin C in treating this type of pathology. There is much evidence in the literature regarding the beneficial effects of vitamin C supplementation for treating autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) and neoplasms, particularly hematological neoplastic diseases. Vitamin C integration regulates the cytokines microenvironment, modulates immune response to autoantigens and cancer cells, and regulates oxidative stress. Moreover, integration therapy has an enhanced effect on chemotherapies, ionizing radiation, and target therapy used in treating hematological neoplasm. In the future, integrative therapy will have an increasingly important role in preventing pathologies and as an adjuvant to standard treatments.

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.

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.

Omalizumab in middle-aged or older patients with severe allergic asthma-COPD overlap.

Introduction: Biological therapies used for severe asthma may be useful even for middle-aged or older patients who have a history of severe allergic asthma with a chronic obstructive pulmonary disease (COPD) overlap phenotype. Aim: To show omalizumab efficacy in severe allergic asthma-COPD overlap disease.Material and methods: We report our data of a retrospective study on 11 patients (mean age: 67.18 years) with a positive history of severe allergic asthma treated with omalizumab. They all presented limited reversibility of airway obstruction and signs of chronic bronchitis at radiological examinations, as in asthma-COPD overlap. Omalizumab improved conditions in terms of reduced exacerbations as well as asthma control test (ACT) and Asthma Quality of Life Questionnaire (AQLQ) scores. Results: Clinical improvement was seen already in the first year with significantly increased ACT scores (p < 0.0001) and a significantly decreased number of exacerbations (p < 0.001). Furthermore, our data showed a significant inverse correlation over time between the number of exacerbations and ACT (r = -0.83, p < 0.0001), AQLQ symptoms (r = -0.87, p < 0.0001), forced expiratory volume in 1 s (FEV1) (r = -0.71, p < 0.001) and FEV1/forced vital capacity (FVC) (r = -0.43, p = 0.04). There also was a positive correlation between ACT and FEV1 (r = 0.74, p < 0.0001), ACT and AQLQ symptoms (r = 0.93, p < 0.0001), FEV1 and AQLQ symptoms (r = 0.67, p < 0.001). All parameters continued to improve during the second year of treatment. Conclusions: Omalizumab may be relevant as a therapeutic option even in middle-aged and older patients with severe asthma.

The potential protective role of corticosteroid therapy in patients with asthma and COPD against COVID-19.

BACKGROUND: The observation of patients hospitalized for coronavirus disease (COVID-19) led us to note a lower prevalence of patients affected by chronic respiratory disease, in particular asthmatic patients, compared to the general population. Therefore, the aim of this paper is to evaluate the possible protective role of corticosteroid therapy in patients with chronic lung disease, regarding the risk of contracting severe COVID-19. MAIN BODY: SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) receptors to enter the cells. Considering the high number of these receptors in patients affected by asthma and chronic obstructive pulmonary disease (COPD), the evidence that these patients do not have a high risk of hospitalization for COVID-19 needs further study to understand what the possible protective "factors" are in these patients. In particular, the finding in some studies of reduced coronavirus replication in cell lines treated with steroids, molecules commonly used for treating chronic lung diseases, needs further attention. SHORT CONCLUSION: The hypothesis that corticosteroids, commonly used in treating airways diseases, might modify the severity of SARS-CoV-2 disease has become a key point and a possible predictive factor of a positive outcome of COVID-19 in patients treated everyday with these molecules.

Adverse reaction to local anaesthetics: Is it always allergy?

OBJECTIVE: Local anaesthetics are very commonly used drugs in dentistry, and people who undergo procedures with local anaesthetics often refer adverse reactions that are not of allergic origin. Considering that in dentistry contact with allergens is very frequent, it is essential to assess the real incidence of allergy to local anaesthetics. SUBJECTS AND METHODS: We evaluated a group of 159 patients in whom adverse reaction occurred after procedures with local anaesthetics. RESULTS: The reactions between allergy to local anaesthetic (immediate and delayed) and certain symptoms presented by patients were investigated. Allergy to latex and chlorexidine were investigated in all patients. Only one patient, who previously presented a constant erythema at the wrist after procedure with local anaesthetics, was positive to Mepivacaine patch test. Two patients were positive to latex and one to chlorexidine. CONCLUSIONS: The main finding of this study was that a reaction registered in the medical history and reported by a patient is rarely allergic but the use of vasoconstrictors or emotional factors may account for it. However, a complete allergological investigation is necessary for a correct diagnosis and future management.

The involvement of osmolarity in the safety of contrast media.

BACKGROUND: New non-ionic contrast agents, classified into low osmolar agents and iso-osmolar agents, present different biochemical characteristics that may influence the allergic reactions they cause. The aim of our study was to evaluate how osmolarity may affect safety in the use of contrast agents. CASE PRESENTATION: Six patients with a positive history for reaction to contrast agent were included in this study. Only one patient prick and intradermal skin test was positive. However, in 5 cases, patients presented an immediate reaction after administration of contrast agent that was not IgE mediated. CONCLUSIONS: In this study, we focused on iodixanol, an iso-osmolar contrast agent, finding good safety of this product in patients with previous hypersensitivity reactions to contrast agent.

A case of atopic dermatitis caused by Ascaris lumbricoides infection.

BACKGROUND: Parasite infections stimulate total and specific IgE production that, in the case of Toxocara canis infection, corresponds to chronic allergic symptoms. There may also be other infections which have similar symptoms, such as Ascaris lumbricoides infection. Ascaris lumbricoides is a large nematode that causes abdominal pain, nausea, vomiting, bloating, anorexia and intermittent diarrhoea. Patients with ascaridiasis and high IgE levels may also have allergy-like symptoms such as asthma, urticaria and atopic dermatitis. CASE PRESENTATION: We report a case of atopic dermatitis caused by Ascaris lumbricoides which shows the important role of parasitic infection in patients with long-lasting dermatitis. The patient was a 12-year old female suffering since early infancy from atopic dermatitis and asthma. She was treated for dermatitis with oral bethametasone and topical pimecrolimus with little benefit. After two cycles of mebendazole therapy, the patient showed progressive improvement of symptoms. CONCLUSIONS: In patients with dermatitis, Ascaris lumbricoides infection should be not excluded: adequate anthelmintic treatment may result in complete regression from the disease.

Drug induced Kounis syndrome: does oxidative stress play a role?

BACKGROUND: Kounis syndrome (KS) has been described as the coincidental occurrence of acute coronary syndromes during an allergic reaction with cardiac anaphylaxis. It is caused by inflammatory mediators released after exposure to drugs, food, environmental and other triggers. Oxidative stress occurring in various inflammatory disorders causes molecular damage with the production of advanced oxidation products (AOPPs) and advanced glycation end products (AGEs). CASE PRESENTATION: Markers of oxidative stress were evaluated in a patient who had experienced KS after antibiotic administration in order to investigate the possible role of these molecules in KS. No data, up to now, are available on biomarkers of oxidative stress in patients with drug-induced KS. CONCLUSIONS: AOPPs, but not AGEs, were significantly increased in the KS affected patient compared to controls as already reported in mastocytosis affected patients.

Safety of Biological Therapies for Severe Asthma: An Analysis of Suspected Adverse Reactions Reported in the WHO Pharmacovigilance Database.

BACKGROUND: The management of uncontrolled severe asthma has greatly improved since the advent of novel biologic therapies. Up to August 2022, five biologics have been approved for the type 2 asthma phenotype: anti-IgE (omalizumab), anti-IL5 (mepolizumab, reslizumab, benralizumab), and anti-IL4 (dupilumab) monoclonal antibodies. These drugs are usually well tolerated, although long-term safety information is limited, and some adverse events have not yet been fully characterized. Spontaneous reporting systems represent the cornerstone for the detection of potential signals and evaluation of the real-world safety of all marketed drugs. OBJECTIVE: The aim of this study was to provide an overview of safety data of biologics for severe asthma using VigiBase, the World Health Organization global pharmacovigilance database. METHODS: We selected all de-duplicated individual case safety reports (ICSRs) attributed to five approved biologics for severe asthma in VigiBase, up to 31st August 2022 (omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab). Descriptive frequency analyses of ICSRs were carried out both as a whole class and as individual products. Reporting odds ratios (ROR) with 95% confidence intervals (CIs) were used as the measure of disproportionality for suspected adverse drug reactions (ADRs) associated with the study drugs compared with either all other suspected drugs (Reference Group 1, RG1) or inhaled corticosteroids plus long-acting ß-agonists (ICSs/LABAs) (Reference Group 2, RG2) or with oral corticosteroids (OCSs) (Reference Group 3, RG3). RESULTS: Overall, 31,724,381 ICSRs were identified in VigiBase and 167,282 (0.5%) were related to study drugs; the remaining reports were considered as RG1. Stratifying all biologic-related ICSRs by therapeutic indication, around 29.4% (n = 48,440) concerned asthma use; omalizumab was mainly indicated as the suspected drug (n = 20,501), followed by dupilumab, mepolizumab, benralizumab and reslizumab. Most asthma ICSRs concerned adults (57%) and women (64.1%). Asthma biologics showed a higher frequency of serious suspected ADR reporting than RG1 (41.3% vs 32.3%). The most reported suspected ADRs included asthma, dyspnea, product use issue, drug ineffective, cough, headache, fatigue and wheezing. Asthma biologics were disproportionally associated with several unknown or less documented adverse events, such as malignancies, pulmonary embolism and deep vein thrombosis with omalizumab; alopecia and lichen planus with dupilumab; alopecia and herpes infections with mepolizumab; alopecia, herpes zoster and eosinophilic granulomatosis with polyangiitis related to benralizumab; and alopecia with reslizumab. CONCLUSIONS: The most frequently reported suspected ADRs of asthma biologics in VigiBase confirmed the presence of well-known adverse effects such as general disorders, injection-site reactions, nasopharyngitis, headache and hypersensitivity, while some others (e.g. asthma reactivation or therapeutic failure) could be ascribed to the indication of use. Moreover, the analysis of signals of disproportionate reporting suggests the presence of malignancies, effects on the cardiovascular system, alopecia and autoimmune conditions, requiring further assessment and investigation.

Anaphylaxis due to antiallergic and antiasthmatic biologics.

PURPOSE OF REVIEW: To provide a better understanding of the risk of anaphylaxis due to antiallergic and antiasthmatic biologics through an analysis of data reported in literature and in clinical trials, and by conducting a retrospective descriptive analysis of individual case safety reports on VigiBase, the WHO International Pharmacovigilance database. RECENT FINDINGS: Analysis of the data, as described, demonstrated safety of the antiallergic and antiasthmatic biologics with a low incidence of anaphylaxis. SUMMARY: Biologic therapies have revolutionized the treatment of many diseases, such as atopic dermatitis, nasal polyps, spontaneous chronic urticarial and severe asthma with a precise immunological action, in the sphere of precision medicine.Albeit these drugs are generally well tolerated, generating real-world evidence is crucial to re-evaluate clinically relevant adverse events, such as anaphylaxis, allowing to confirm their safety profile in particular in special populations such as paediatric patients.

Microbiota, Diet and Acute Leukaemia: Tips and Tricks on Their Possible Connections.

Acute leukaemia is probably one of the most recurrent cancers in children and younger adults, with an incidence of acute lymphoblastic leukaemia in 80% of cases and an incidence of acute myeloid leukaemia in 15% of cases. Yet, while incidence is common in children and adolescents, acute leukaemia is a rare disease whose aetiology still requires further analysis. Many studies have investigated the aetiology of acute leukaemia, reporting that the formation of gut microbiota may be modified by the start and development of many diseases. Considering that in patients affected by acute lymphoblastic leukaemia, there is an inherent disequilibrium in the gut microbiota before treatment compared with healthy patients, increasing evidence shows how dysbiosis of the gut microbiota provokes an inflammatory immune response, contributing to the development of cancer. Our analysis suggeststhe key role of gut microbiota in the modulation of the efficacy of leukaemia treatment as well as in the progress of many cancers, such as acute leukaemia. Therefore, in this paper, we present an examination of information found in literature regarding the role of dietary factors and gut microbiota alterations in the development of leukaemia and suggest possible future preventive and therapeutic strategies.

The intriguing possibility of using probiotics in allergen-specific immunotherapy.

Allergen immunotherapy (AIT) can be considered the etiological therapy for allergic rhinitis and hymenoptera venom allergy. Its role is increasingly emerging in the context of IgE mediated food allergy, where the achievement of tolerance, or the permanent resolution of an allergy, represents the optimal goal of AIT. AIT treatment, indicated in adults and children with allergic rhinitis, has a preventative effect on the development of asthma and can also be used when asthma is associated to rhinitis; however, it is not the first choice for treatment of isolated asthma. While knowledge on immunological mechanisms, efficacy, and safety of AIT is known, an intriguing line of investigation has arisen on how the action of AIT is modulated by the use of probiotics, starting from awareness that the microbiome is altered in allergic conditions: the use of probiotics in inducing the stimulation of innate immunity via toll-like receptor activation, thus acting as adjuvants in AIT, is hereby examined. Therefore, by analyzing literature on AIT and probiotics, we intend to draw attention to how the role and use of AIT are emerging as being increasingly important for both the short- and long-term management of allergic diseases and how recourse probiotics may represent an additional therapeutic strategy to modulate the effectiveness of AIT. However, further investigations are needed to better identify which probiotics to use, the dosage, and the optimal duration to obtain correct immunomodulation, and how to best customize their use, including a "AIT + probiotics" strategy in the field of precision medicine.

Air Pollution and microRNAs: The Role of Association in Airway Inflammation.

Air pollution exposure plays a key role in the alteration of gene expression profiles, which can be regulated by microRNAs, inducing the development of various diseases. Moreover, there is also evidence of sensitivity of miRNAs to environmental factors, including tobacco smoke. Various diseases are related to specific microRNA signatures, suggesting their potential role in pathophysiological processes; considering their association with environmental pollutants, they could become novel biomarkers of exposure. Therefore, the aim of the present work is to analyse data reported in the literature on the role of environmental stressors on microRNA alterations and, in particular, to identify specific alterations that might be related to the development of airway diseases so as to propose future preventive, diagnostic, and therapeutic strategies.

TSLP and HMGB1: Inflammatory Targets and Potential Biomarkers for Precision Medicine in Asthma and COPD.

The airway epithelium, through pattern recognition receptors expressed transmembrane or intracellularly, acts as a first line of defense for the lungs against many environmental triggers. It is involved in the release of alarmin cytokines, which are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Knowledge of the role of epithelial cells in orchestrating the immune response and mediating the clearance of invading pathogens and dead/damaged cells to facilitate resolution of inflammation is necessary to understand how, in many chronic lung diseases, there is a persistent inflammatory response that becomes the basis of underlying pathogenesis. This review will focus on the role of pulmonary epithelial cells and of airway epithelial cell alarmins, in particular thymic stromal lymphopoietin (TSLP) and high mobility group box 1 (HMGB1), as key mediators in driving the inflammation of chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), evaluating the similarities and differences. Moreover, emerging concepts regarding the therapeutic role of molecules that act on airway epithelial cell alarmins will be explored for a precision medicine approach in the context of pulmonary diseases, thus allowing the use of these molecules as possible predictive biomarkers of clinical and biological response.

Upsides and downsides of a telecounselling model of integrated asthma management between general practitioners and specialists.

BACKGROUND: Asthma control, one of the most important goals in the management of asthmatic patients, requires good adherence to guidelines and support at a territorial level, in particular on the part of general practitioners (GPs). A territorial hospital alliance can become a strength in asthma management, where control by GPs can also be carried out through a spirometric examination. METHODS: The realisation of a telecounselling model management of asthma between GPs and specialists was the aim of this study, to understand how to obtain good asthma control. A specific digital platform, the PneumoApp platform, was used for the insertion of clinical data and flow volume (F-V) curves, performed in asthmatic patients by GPs, and for the subsequent evaluation of these data by specialists. RESULTS: GPs have shown to be able to perform a check-up of respiratory function well using a portable spirometer, but the analysis of the collected data showed that GP assessment of the severity level of asthma is incorrect in patients with moderate-severe asthma. CONCLUSIONS: The effectiveness of a telecounselling collaboration between hospital and territory in the management of asthma patients can be improved by greater diffusion of the use of Global Initiative for Asthma (GINA) guidelines at a local level.

Relationship between hair shedding and systemic inflammation in COVID-19 pneumonia.

Background: A higher risk for COVID-19 infection and severity for men compared to women has been described since the beginning of the pandemic. The role of androgens has been recently highlighted as they control two key steps of coronavirus infection mediated through the transmembrane protease serin 2 (TMPRRS2) and the angiotensin-converting enzyme 2 (ACE2) receptor in the lung tissue. Furthermore, a high incidence of androgenic alopecia among males with COVID-19 disease have been reported.Objective: This study aims to evaluate the telogen effluvium (TE) prevalence and its relationship with clinical and immunologic parameters in a sample of patients consecutively evaluated after recovery from COVID-19 pneumonia in Northern Italy.Methods: Overall 104 patients were recruited within three months from COVID-19 pneumonia recovery; 80 (77%) had been hospitalized in a Respiratory Intensive Care Unit and the remaining ones had been treated at home. The extent of TE was assessed with a visual analogic scale for thick bundle of hairs. Demographic and clinical data and systemic inflammation biomarkers were also evaluated.Results. Thirty-two patients reported a history of TE and their mean TE-VAS score was 5.78 ± 1.72 (range 3-9). Women had about a 5-fold higher risk (odds) of complaining of TE compared to males (OR = 4.69, 95%CI: 1.91, 11.49; p = .001), and the association became stronger when adjusted for COVID-19 severity (hospital admission vs home care: OR = 6.09, 95%CI: 2.34, 15.88; p < .001). Levels of C-reactive protein >1.90 mg/l (ORadj: 2.43, 95%CI 0.85, 7.05, p = 0.096) or IL 1ß > 5 ng/l (ORadj 4.72, 95%CI: 1.31, 23.19, p = .03) were also significantly associated with TE.Conclusion: This exploratory study raises the hypothesis that hair shedding is more strictly related to the severity of COVID-19 disease and the underlying inflammation rather than to patients' hormonal status. KEY MESSAGESThe presence of Telogen effluvium (TE) was significantly more common in women.Higher severity of the Covid-19 disease seems to play a critical role, more important than the hormonal influence, in the development of TE.The severity of inflammation related to TE and Covid-19 could also play a role as suggested by the higher levels of CRP and platelets and IL1ß.

Allergic Reactions to COVID-19 Vaccines: Risk Factors, Frequency, Mechanisms and Management.

Conventional vaccines have been widely studied, along with their risk of causing allergic reactions. These generally consist of mild local reactions and only rarely severe anaphylaxis. Although all the current COVID-19 vaccines marketed in Europe have been shown to be safe overall in the general population, early post-marketing evidence has shown that mRNA-based vaccines using novel platforms (i.e., lipid nanoparticles) were associated with an increased risk of severe allergic reactions as compared to conventional vaccines. In this paper we performed an updated literature review on frequency, risk factors, and underlying mechanisms of COVID-19 vaccine-related allergies by searching MEDLINE and Google Scholar databases. We also conducted a qualitative search on VigiBase and EudraVigilance databases to identify reports of "Hypersensitivity" and "Anaphylactic reaction" potentially related to COVID-19 vaccines (Comirnaty, Spikevax, Vaxzevria and COVID-19 Janssen Vaccine), and in EudraVigilance to estimate the reporting rates of "Anaphylactic reaction" and "Anaphylactic shock" after COVID-19 vaccination in the European population. We also summarized the scientific societies' and regulatory agencies' recommendations for prevention and management of COVID-19 vaccine-related allergic reactions, especially in those with a history of allergy.