IR (index of reactivity)-house dust mite sublingual immunotherapy liquid formulation for allergic rhinoconjunctivitis: Systematic review and meta-analysis of randomized and nonrandomized studies.

Background: Although randomized controlled trials (RCT) are the reference standard of evidence in allergen immunotherapy (AIT), nonrandomized studies (NRS) are needed to confirm their results in more representative populations, particularly for treatment duration and persistence. However, when discrepancies are observed between RCT and NRS, NRS reliability decreases because these discrepant results are generally attributed to the methodologic flaws of NRS. Objective: We compared the benefit of sublingual AIT (SLIT) for allergic rhinoconjunctivitis in NRS versus RCT focusing on a single product/allergen to reduce heterogeneity. Methods: For meta-analysis, house dust mite (HDM) SLIT liquid formulation studies were sourced from computerized (Medline, Web of Science, and LILACS databases, to January 2023) and manual literature searches. Populations, treatments, and outcome data were combined (DerSimonian-Laird method). Noncomparative NRS were compared to RCT' SLIT arm before and after treatment. Efficacy was determined as the standardized mean difference (SMD) in symptom score (SS) and medication score (MS). Results: Data from 12 NRS (682 patients) and 8 RCT (176 patients) were analyzed. The benefit with index of reactivity (IR)-HDM SLIT liquid formulation was found significant for, first, SS in both NRS (SMD = -1.27; 95% confidence interval [CI], -1.64, -0.90) and RCT (SMD = -0.56; 95% CI, -0.90, -0.21), and second, MS with SMD equal to -1.35 (95% CI, -1.77, -0.93) and -0.46 (95% CI, -0.67, -0.25), respectively. Metaregression showed that symptom improvement was correlated with treatment duration with consistent results in NRS and RCT with 12-month SS data: -0.87 (interquartile range, -1.02, -0.77) and -0.75 (interquartile range, -0.93, -0.41), respectively. Conclusion: This meta-analysis showed comparable clinical benefit of IR-HDM SLIT liquid formulation increasing over time in both NRS and RCT, suggesting that NRS may reliably integrate RCT results and be considered for guidelines.

Latex allergy - from discovery to component-resolved diagnosis.

Latex allergy is a hypersensitivity response to natural rubber latex (NRL) proteins or rubber chemicals used in the manufacture of latex products. An accurate diagnosis is the first step in the effective management of individuals with latex allergy, especially in high-risk groups, such as healthcare workers and those affected by spina bifida. Diagnosis is based on the clinical history and an accurate allergological evaluation. In the case of type I IgE-mediated hypersensitivity re-actions, which can manifest urticaria, angioedema, rhinoconjunctivitis, asthma and anaphylaxis after latex exposure, skin prick tests or latex-specific IgE (sIgE) antibody detection using sero-logical assays can be performed to confirm sensitization. Instead, in the case of contact dermati-tis, a patch test can be applied to confirm the presence of a type IV T cell-mediated hypersensi-tivity reaction to rubber accelerators or additives. Basophils activation tests or challenge tests may be performed if there's an incongruity between the clinical history and the results of in vivo and in vitro tests. The aim of this review is to analyze the current state of the art of diagnostic techniques for latex allergy and algorithms employed in clinical practice and possible future de-velopments in this field.

An update on nonsteroidal anti-inflammatory drug-induced urticaria.

BACKGROUND: Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (HR-NSAIDs) are common adverse events related to the widespread use of over-the-counter NSAIDs for the treatment of a variety of inflammatory conditions. Urticaria is the most commonly reported immediate cutaneous clinical sign of HR-NSAIDs, but it can be a manifestation of pathophysiologically different clinical entities that require different therapeutic strategies. The aim of this study is to ease the identification of the correct phenotype of HR-NSAIDs in patients reporting urticaria associated with the intake of NSAIDs and provide updated information about their diagnosis and management. METHODS: The study is a narrative review conducted by collecting the most relevant and up-to-date data related to the classification, pathophysiology, severity, and prognosis of NSAID hypersensitivity reactions. PubMed and Embase scientific databases were used as search engines to select relevant articles. RESULTS: Patients developing HR-NSAIDs can be divided into two categories: selective responders (SR), who develop reactions after the administration of a single specific NSAID due to an underlying IgE or T-cell mediated hypersensitivity mechanism, or cross-intolerant (CI), who develop reactions to more than one chemically unrelated NSAIDs due to abnormalities in the biochemical pathways related with prostaglandin metabolism, independently from an underlying immunological mechanism. Five major different categories of HR-NSAIDs have been identified: NSAIDs-exacerbated cutaneous disease (NECD), NSAIDs-induced urticaria/angioedema with/without respiratory and systemic symptoms of anaphylaxis (NIUAA), and NSAIDs-exacerbated respiratory disease (NERD), which are developed by CI patients, and single NSAIDs-induced urticaria, angioedema and/ or anaphylaxis (SNIUAA) and single NSAIDs-induced delayed hypersensitivity reactions (SNIDHR), which are developed by CI patients. In vivo and in vitro diagnostic tests have rarely been shown to be reliable in all these entities and therefore are not routinely used in clinical practice. The management in SR patients consists of strict avoidance of the culprit drug, while for cross-intolerance reactions oral tolerance tests with safe alternative drugs (e.g. weak COX-1 inhibitors or selective COX-2 inhibitors) can be performed. CONCLUSION: HR-NSAIDs are being observed with increasing frequency, however, the pathogenesis behind some NSAIDS-associated clinical entities is still unclear. Diagnosis is mostly based on a thorough clinical history and confirmed by a drug challenge test. Clinical management is based on strict avoidance and use of alternative tolerated medications. Overall, all therapeutic decisions depend on the correct identification of the type of reaction the patient experienced.

Hypersensitivity reaction during enzyme replacement therapy in lysosomal storage disorders. A systematic review of desensitization strategies.

Lysosomal storage diseases (LSDs) are rare genetic metabolic disorders that cause the accumulation of glycosaminoglycans in lysosomes due to enzyme deficiency or reduced function. Enzyme replacement therapy (ERT) represents the gold standard treatment, but hypersensitivity reaction can occur resulting in treatment discontinuation. Thus, desensitization procedures for different culprit recombinant enzymes can be performed to restore ERT. We searched desensitization procedures performed in LSDs and focused on skin test results, protocols and premedication performed, and breakthrough reactions occurred during infusions. Fifty-two patients have been subjected to desensitization procedures successfully. Skin tests, with the culprit recombinant enzyme, deemed positive in 29 cases, doubtful in two cases, and not performed in four patients. Moreover, 29 of the 52 desensitization protocols used at the first infusion were breakthrough reaction free. Different desensitization strategies have proved safe and effective in restoring ERT in patients with previous hypersensitivity reactions. Most of these events seem to be Type I hypersensitivity reactions (IgE-mediated). Standardized in vivo and in vitro testing is necessary to better estimate the risk of the procedure and find the safest individualized desensitization protocol.

Comparison of evidence of treatment effects in randomized and nonrandomized studies on allergen immunotherapy.

Nonrandomized studies (NRS) on allergen immunotherapy (AIT) particularly lend themselves to evaluate outcomes that are insufficiently addressed in randomized controlled studies (RCTs). However, NRS are prone to several sources of bias, which limit their validity. We aimed at comparing AIT effects between RCTs and NRS and evaluate the reasons for discrepancies in study results. In this analysis, we compared NRS on AIT (including subcutaneous and sublingual immunotherapy, SCIT and SLIT, respectively) with SLIT and SCIT RCTs from published meta-analyses, assessing the Risk of Bias (RoB) for each study and the certainty of evidence from NRS and RCTs using the GRADE approach. We found: (1) very serious RoB in the 7 NRS included in the meta-analysis showing a large difference between AIT and controls (standardized mean difference [SMD] for symptom score [SS], -1.77; 95% CI, -2.30, -1.24; p < .001; I2 = 95%) with very low certainty evidence; (2) serious RoB in the 13 SCIT-RCTs reporting a moderate-to-high difference between SCIT and controls (SMD for SS, -0.81; 95% CI, -1.12, -0.49; p < .001; I2 = 88%) with moderate certainty evidence; (3) low RoB in the 13 SLIT-RCTs reporting a small benefit (SMD for SS, -0.28; 95% CI, -0.37, -0.19; p < .001; I2 = 54.2%) with high certainty evidence. Similar results were reported for medication score. Our evidence is sufficient to conclude that the magnitude of effect estimates of NRS and RCTs directly correlate with the degree of RoB and inversely with the overall evidence certainty. NRS, which are more affected than RCTs by bias resulting in low certainty evidence, showed the largest effect size. Sound NRS are needed to complement RCTs.

Allergic adverse events following immunization: Data from post-marketing surveillance in Apulia region (South of Italy).

Introduction: Among adverse events following immunization (AEFIs), allergic reactions elicit the most concern, as they are often unpredictable and can be life-threatening. Their estimates range from one in 1,000,000 to one in 50,000 vaccine doses. This report describes allergic events following immunization reported from 2020 to 2021 in Puglia, a region in the South-East of Italy with around 4 million inhabitants. Its main objective is to describe the allergic safety profile of currently employed vaccines. Materials and methods: This is a retrospective observational study. The study period spanned from January 2020 to December 2021, and the whole Apulian population was included in the study. Information regarding AEFIs reported in Puglia during the study period was gathered from the Italian Drug Authority's pharmacovigilance database (National Pharmacovigilance Network, RNF). The overall number of vaccine doses administered was extrapolated by the Apulian online immunization database (GIAVA). Reporting rates were calculated as AEFIs reported during a certain time span/number of vaccine doses administered during the same period. Results: 10,834,913 vaccine doses were administered during the study period and 95 reports of allergic AEFIs were submitted to the RNF (reporting rate 0.88/100,000 doses). 27.4% of the reported events (26/95) were classified as serious (reporting rate 0.24/100,000 doses). 68 out of 95 (71.6%) adverse events were at least partially resolved by the time of reporting and none of them resulted in the subject's death. Conclusions: Allergic reactions following vaccination were rare events, thus confirming the favourable risks/benefits ratio for currently marketed vaccines.

Systemic drug-related intertriginous and flexural exanthema-like eruption after Oxford-AstraZeneca COVID-19 vaccine.

Systemic drug-related intertriginous and flexural exanthema (SDRIFE) is an adverse drug reaction which manifests as a symmetrical erythematous rash involving the skin folds after systemic drug exposure. A vast array of possible side effects associated with administration of different anti-SARS-CoV-2 vaccines have been reported in literature since the beginning of the COVID-19 pandemic, but only few times SDRIFE-like eruptions have been described in this context. We discuss here a case of SDRIFE-like eruption following the second dose of Oxford-Astrazeneca Vaxzevria vaccine.

Dermanyssosis in the Urban Context: When the One Health Paradigm Is Put into Practice.

Poultry red mites (Dermanyssus gallinae) are primarily ectoparasites of laying hens but also parasitize synanthropic birds in urban contexts. This mite can occasionally attack mammals, including humans, and cause mild to severe dermatitis. Attacks by zoonotic Mesostigmata mites are currently an increasing but still neglected problem of urban life. The authors present two cases of dermanyssosis involving two health workers at a hospital, linked to air conditioning outdoor units colonized by pigeons. Videos that describe the environmental contamination by D. gallinae and show where the infestation originated are presented. In addition, the authors update the literature of all urban cases, which, to date, reports over 240 clinical cases, mostly in private homes but also in public buildings. Dermatitis due to these mites is often unrecognized and, therefore, misdiagnosed. This report describes how the two cases herein reported were rapidly resolved thanks to the close cooperation between veterinary parasitologists and allergologists. It is crucial to raise awareness of the problem among general practitioners and specialists. In addition, the authors suggest a reconsideration of urban architectural choices that increase the public health risk posed by dermanyssosis and other diseases related to synanthropic birds.

Distribution of KIR Genes and Their HLA Ligands in Different Viral Infectious Diseases: Frequency Study in Sicilian Population.

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR-HLA genes/groups of these three different infected populations with healthy Sicilian donors from the literature. We showed that the inhibitory KIR3DL1 gene and the KIR3DL1/HLA-B Bw4 pairing were more prevalent in individual CHB. At the same time, the frequency of HLA-C2 was increased in CHB compared to other groups. In contrast, the HLA-C1 ligand seems to have no contribution to CHB progression whereas it was significantly higher in COVID-19 and HIV-positive than healthy controls. These results suggest that specific KIR-HLA combinations can predict the outcome/susceptibility of these viral infections and allows to plan successful customized therapeutic strategies.

Novel approach to idursulfase and laronidase desensitization in type 2 and type 1 S mucopolysaccharidosis (MPS).

BACKGROUND: Idursulfase and laronidase are drugs used to treat Hunter syndrome (mucopolysaccharidosis type 2) and Scheie syndrome (mucopolysaccharidosis type 1 S), respectively. These are rare lysosomal storage disorders, leading to accumulation of glycosaminoglycans within lysosomes. Failure of early recognition of the disease and/or delay in starting the appropriate treatment result in severe clinical impairment and death. For almost 20 years, enzyme replacement therapy with recombinant proteins has represented the first line therapeutic option. However, administration of idursulfase and laronidase is associated with infusion-related hypersensitivity reactions, in approx. 20% of patients. In these patients, rapid desensitization by intravenous administration protocols has been used in order to avoid treatment discontinuation. This approach proved effective and safe. However, long-term tolerance could not be achieved. Thus, we decided to combine rapid desensitization with allergen immunotherapy-like desensitization. RESULTS: Two patients with Hunter syndrome and one patient with Scheie syndrome developed severe allergy to idursulfase and laronidase, respectively, preventing them from continuing the otherwise indispensable therapy. In all three patients, the possible IgE-mediated nature of the reactions suffered was suggested by positive skin tests with the two enzymes, respectively. By devising 12-step, 3-dilution rapid desensitization protocols, we resumed the enzyme replacement therapy. However, the prolonged time required for administration (a not negligible pitfall, since therapy should be given weekly for life) and the persistent occurrence of reactions (mild but still requiring anti-allergic medication at full dosage) led us to combine rapid desensitization with a compact 11-step, 24-day allergen immunotherapy-like desensitization protocol. Thus, idursulfase and laronidase were injected subcutaneously, with a 500-fold increase from step 1 to step 11 for idursulfase and a 222-fold increase for laronidase. This strategy led to restoration of long-term tolerance, allowing weekly intravenous therapy administration under standard conditions, according to the manufacturer instructions, in the absence of side effects and with only precautionary low-dose premedication. CONCLUSION: Rapid desensitization is a suitable and safe option in the case of idursulfase and laronidase allergy. Combination with subcutaneous allergen immunotherapy-like desensitization afforded restoration of enzyme replacement therapy given by the normal administration schedule, by inducing sustained tolerance.

Allergic contact dermatitis from vitamins: A systematic review.

Background and Aims: Vitamins are bioactive compounds naturally found in many different types of food and required by the human body for many biological functions and enzymatic activities. Due to their antioxidant properties, certain vitamin derivatives have been synthesized for inclusion in many cosmetics, thus leading to an increasing incidence of allergic contact dermatitis (ACD) cases. Therefore, the present review may be helpful to provide an insight into the sensitizing role of at least certain vitamins and may also offer possible patch test alternatives for definitive diagnosis. Methods: This study was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Literature search regarding ACD cases to vitamins was performed using the Medline, PubMed, Scopus, EMBASE, and Google Scholar databases from January 1940 up to June 2021. Results: A total of 4494 articles matched the keywords used for the researched. Records removed before screening included 15 duplicate articles and 3429 not eligible articles (e.g., not written in English, studies on animals, not relevant to the topic). A total of 1050 articles underwent the screening phase and 258 were therefore excluded as they were not primary studies. Subsequentially, 792 articles were considered eligible for the review and 688 of them were finally excluded as they did not report the outcome of interest. Therefore, 104 articles were definitely included in the present review. Conclusion: ACD to vitamins is still probably an underestimated issue in cosmetology, as many vitamins are considered "natural" and therefore "safe" ingredients. On the contrary, according to current literature, almost all vitamins contained in topical products are able to induce allergic reactions, with the exception of vitamin B2 and vitamin B9. Patch tests are not standardized, thus leading to difficulties in diagnosis.

Severe asthma and personalized approach in the choice of biologic.

PURPOSE OF REVIEW: Severe asthma requires intensive pharmacological treatment to achieve disease control. Oral corticosteroids are effective, but their use is burdened with important side effects. Biologics targeting the specific inflammatory pathways underpinning the disease have been shown to be effective but not all patients respond equally well. As we treat more patients than those who can respond, our inability to predict responders has important healthcare costs considering that biologics are expensive drugs. Thus, a more precise choice of the 'right patients' to be prescribed with the 'right biologics' would be desirable. RECENT FINDINGS: Machine learning techniques showed that it is possible to increase our ability to predict outcomes in patients treated with biologics. Recently, we identified by cluster analysis four different clusters within the T2 high phenotype with differential benralizumab response. Two of these clusters, characterized by higher levels of inflammatory markers, showed the highest response rate (80-90%). SUMMARY: Machine learning holds promise for asthma research enabling us to predict which patients will respond to which drug. These techniques can facilitate the diagnostic workflow and increase the chance of selecting the more appropriate treatment option for the individual patient, enhancing patient care and satisfaction.

Biologics in severe asthma: the role of real-world evidence from registries.

Asthma is one of the most common noncommunicable diseases; in the majority of patients it is well controlled with inhaled bronchodilators and inhaled corticosteroids, but the management of severe asthma has been a significant challenge historically. The introduction of novel biologic drugs in the past few decades has revolutionised the field, presenting physicians with a variety of biologic drugs with different mechanisms for the treatment of severe asthma.It is of crucial importance to evaluate the effectiveness of these drugs by following their "real-life" effectiveness rather than relying solely on their efficacy, established in carefully designed clinical trials, which therefore do not necessarily match the profile of the real-life patient. Understanding the actual effectiveness of the specific drugs in real-life patients is a crucial part of tailoring the right drugs to the right patients. Registries serve as an important tool in obtaining real-life evidence, since they are in effect observational studies, following the entire patient population.

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.

In Vivo and In Vitro Assessment and Proteomic Analysis of the Effectiveness of Physical Treatments in Reducing Allergenicity of Hazelnut Proteins.

Hazelnut is a widespread nut species, especially present in Europe, that can be consumed raw or roasted thanks to its pleasant taste and nutritional properties. In addition to renowned beneficial properties hazelnuts contain several proteins capable of inducing food allergy in sensitized individuals, including Cor a 2 (a profilin), Cor a 8 (a lipid transfer protein), Cor a 9 (an 11S seed storage globulin, legumin-like), and Cor a 11 (a 7S seed storage globulin, vicilin-like). In the present paper we investigated the effectiveness of autoclave-based treatments in decreasing the allergic potential of hazelnut as assessed by submitting the treated material to an in vivo skin prick test and an in vitro immunoblot analysis, with sera of allergic individuals exposed to the treated food material. This preliminary analysis showed that autoclave treatment preceded by hydration and/or followed by drying seems to be a promising approach and appears to be effective in reducing the allergenicity of hazelnuts in most patients, probably due to the denaturation of most major and minor allergenic proteins. This work opens up the opportunity to produce hypoallergenic hazelnut derivatives that can be tolerated by allergic subjects.