Dupilumab elicits a favorable response in type-2 inflammatory comorbidities of severe atopic dermatitis.

BACKGROUND: This case is the first report describing rapid, successful treatment of severe atopic dermatitis (AD) and comorbid type-2 inflammatory diseases in the same patient, with dupilumab treatment, with no side-effects. CASE PRESENTATION: We report on effects of dupilumab in a patient with severe AD, a long-standing history of a mild, perennial allergic rhino-conjunctivitis, moderate asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). CONCLUSIONS: Patients suffering from AD, asthma, allergic rhinitis and CRSwNP may be eligible for dupilumab single treatment that is possibly advantageous also from the pharmaco-economic standpoint.

Tumor Infiltrating T Cell Cytotoxicity Assay.

Cytotoxicity is the primary function of CD8+ T-cells, also called cytotoxic CD8+ T lymphocytes (or CTLs). Quantification of this capacity is of major importance in diagnostic and research tools. While phenotypic characterization of CTLs is frequent and easily performed, their function is indeed more difficult to assess. CTLs are responsible for the lysis of cells expressing foreign or modified antigen peptides on their MHC class I molecules. Here we describe the detailed protocol used for the in vitro specific lysis of target cells.

Safety of measles, mumps, and rubella vaccine in egg allergy: in vivo and in vitro management.

BACKGROUND: Egg allergy is the second most prevalent form of food allergy in childhood. In spite of the evidence accumulated, inoculating egg allergy children with attenuated vaccines grown on chick embryo cell cultures, such as the measles, mumps, and rubella (MMR) vaccine, is regarded (erroneously) as potentially dangerous or even anaphylactogenic, by many. An issue perceived as particularly conflicting also by Health Professionals. CASE PRESENTATION: A 15-year-old boy, with a history of severe egg allergy in early infancy, who was still sensitized to egg allergens, including baked egg, had never received MMR vaccination, in fear of possible anaphylaxis, in spite of the fact that this vaccination is mandatory in the first year of life, in Italy. Because of that, he was not allowed to attend school, longer, and was referred to us in order to assess the potential risk of MMR vaccination. Upon thorough allergologic workup, sensitization to MMR vaccine components was excluded by an in vivo approach, consisting in skin prick tests, intradermal tests, and subcutaneous injection test, corroborated by vaccine-specific B-lymphocyte proliferation assay, ex vivo. T-cell proliferation in response to MMR vaccine was also excluded. Eventually, the boy was inoculated with MMR vaccine and was readmitted to school. CONCLUSIONS: The diagnostic strategy adopted appears feasible and easy-to-perform and may be adopted in controversial cases (as the one reported), characterized by previous severe allergic reactions to egg. The B-lymphocyte proliferation assay we developed may represent a useful and reliable tool not only in research but also in clinical practice.

Benralizumab improves patient reported outcomes and functional parameters in difficult-to-treat patients with severe asthma: Data from a real-life cohort.

In the last decade, an increasing number of randomized controlled trials (RCTs) on biologic therapy in patients with severe asthma have included patient-reported outcomes (PROs) as secondary efficacy measures. The majority of these RCTs showed a benefit in symptoms and quality of life. However, the magnitude of this benefit remains uncertain, because it rarely exceeded the minimal important difference (MID), owing to a significant improvement in the control group (placebo effect). Real-life studies on biologic therapies assessing PRO are scarce. They may support and integrate RCT results through their different experimental design. This real-life retrospective study provides data on 15 patients with difficult-to-treat severe eosinophilic asthma treated with benralizumab up to 6 months. Asthma quality of life questionnaire (AQLQ) and asthma control test (ACT) were assessed and administered at each visit to minimize the Hawthorne effect. Changes in general accepted efficacy measures, such as forced expiratory volume in 1 s (FEV1), peak expiratory flux (PEF), exacerbation rate and blood eosinophils, from baseline were also assessed. AQLQ and ACT improved from 3.9 ± 0.4 to 5.2 ± 0.4 and from 15.6 ± 5.7 to 18.1 ± 5.6, respectively. FEV1 increased of about 250 ml (+14%). PEF increased from 288 ± 107 to 333 ± 133 l/min. The number of exacerbations requiring OCS courses decreased from 2.8 ± 2.2 to 0.5 ± 0.8. Eosinophil counts dropped to 25.6 ± 15 cells/microliter. In conclusion, most patients reported improvements in AQLQ and ACT greater than MID, suggesting that these outcome represent a sensitive tool in real-life effectiveness studies. Our approach reduced the limitations of transition questions and the Hawthorne effect, increasing findings reliability.

Desensitization in Iron Product Allergy.

Iron deficiency is the main cause of anemia in both sexes, with women being more commonly affected. Iron therapy is currently considered an effective and safe remedy to replenish the iron storages. Iron can be administrated both orally and intravenously. In particular, intravenous (IV) iron therapy is widely used when oral iron preparations are either not tolerated or ineffective. Indeed, IV iron improves iron stores more rapidly. Two main immunological responses have been described for iron hypersensitivity reactions (HSRs): IgE-mediated allergy and complement activation-related pseudo-allergy. Here, we report 3 cases of adult patients with iron allergy, who were successfully treated with two different desensitization procedures, respectively. Analysis of these cases demonstrates that, in the presence of HSRs to iron products, desensitization is an effective and safe procedure that prevents treatment discontinuation and hence allows therapeutic target achievement.

Cost-effectiveness of grass pollen allergen immunotherapy in adults.

BACKGROUND: Major scientific societies, such as the EAACI or the AAAAI, do not express any suggestion on which form of allergen immunotherapy (AIT) is to be preferred (subcutaneous immunotherapy, SCIT, vs sublingual immunotherapy, SLIT). This choice could depend on their relative pharmacoeconomic value. OBJECTIVE: To assess the cost-effectiveness of AIT for grass pollen, administered as SCIT or SLIT. METHODS: We created a Markovian Model, to evaluate, in a hypothetical cohort of adult patients suffering from moderate-to-severe rhino-conjunctivitis with or without allergic asthma, the cost-effectiveness of SLIT (tablets, Grazax® and Oralair® ) or SCIT (various currently available products, plus indirect nonmedical costs, such as travel and productivity costs) in addition to pharmacological therapy, assuming a 9-year horizon to capture AIT long-term effects. The incremental cost-effectiveness ratio (ICER) was calculated assuming pharmacological therapy as the reference comparator. RESULTS: In the base case, SCIT was slightly more expensive, but more effective than SLIT, being the most cost-effective option (ICER for SCIT, €11 418; ICER for SLIT, €15 212). ICERs greater than €120 000 for both SCIT and SLIT were demonstrated in a scenario assuming that low treatment persistence rates, which are common in real-life, lead to absence of long-term AIT clinical benefit. Considering indirect nonmedical costs SLIT resulted more cost-effective than SCIT (ICER for SCIT, €17 318; ICER for SLIT, €15 212). CONCLUSION: In daily practice, AIT for grass pollens may be a cost-effective option only in patients with low discontinuation rates. SCIT, which is less affected by this limitation than SLIT, seems the most cost-effective AIT form.

Safety and treatment compliance of subcutaneous immunotherapy: A 30-year retrospective study.

BACKGROUND: Safety and treatment compliance are still considered important shortcomings of subcutaneous immunotherapy (SCIT). OBJECTIVE: To assess the rate of side effects (SE) to SCIT and treatment compliance at a hospital medically supervised facility. METHODS: A retrospective review of patients with allergic rhino-conjunctivitis (ARC) with or without asthma, who received SCIT to mites and pollens from 1988 to 2018, was performed. The information was collected from patient's allergen immunotherapy forms that had been prospectically filled in by expert physicians. RESULTS: Two thousand two hundred patients (50.2% males; mean age 29.4 ±â€¯11.7 years) received 3037 SCIT courses. A total of 91,187 injections were given, with a mean SCIT duration of 2.5 ±â€¯1.9 years. Nine hundred fifty-seven patients (43.5%) were compliant as they completed the minimally required treatment duration of 3 years. A total of 1087 SE (1.2% of all injections; 76.8% local reactions) were reported in 513 patients (23.3%). There were 42 anaphylactic reactions (in 29 patients) during the study period; two of these were severe. Adrenalin was administered only once. No anaphylactic shock was reported. Only 39 patients (1.8%) discontinued SCIT because of SE, the majority of whom (24; 61.5%) because of systemic reactions (urticaria, asthma, anaphylaxis). Parietaria vaccines were the most frequently associated to SE. Female gender, number of vaccines administered (2 vaccine vs. 1 vaccine) and year of SCIT inception (1996-2018 vs. 1988-1995) were independently associated to SE. CONCLUSION: SCIT, although not absolutely free of risk, is safe and well tolerated. There is still room for improvement of treatment compliance.

Is immunotherapy with fungal vaccines effective?

PURPOSE OF REVIEW: Although allergen immunotherapy (AIT) for fungi has been performed for many years, evidence clearly demonstrating its clinical benefit are still lacking. Here, we reviewed the available studies assessing efficacy and safety of AIT for molds. RECENT FINDINGS: Studies on AIT for fungi were performed only for the two predominating mold species in the external environment, namely Cladosporium and Alternaria. There is no evidence for other mold species. Recent finding in the literature are lacking; the 2 most recent studies on AIT for molds were published in 2011. Overall, 13 studies were identified (the first was published in 1986), but only nine of these compared AIT to placebo. The studies are small (median study sample size, 27 patients) and of low quality, owing to several defects leading to moderate-to-high risk of bias. Symptoms improvement and medication use reduction, which are the main outcome measures of the studies, were inconsistently demonstrated. There are some concerns about safety with Cladosporium extracts, whereas vaccines with Alternaria extracts seem to be safe and well tolerated. SUMMARY: Low strength evidence suggests that mold AIT is efficacious for the treatment of respiratory allergies. High-quality studies with an adequate sample size are needed.

Immunological characterization of onion (Allium cepa) allergy.

INTRODUCTION: Onion (Allium cepa) handling can induce contact dermatitis, rhinoconjunctivitis and asthma. However, only sporadic reports exist on allergic reactions to onion consumption. AIM: We describe herein a case of a 35-year-old man who had an episode of anaphylaxis following cooked onion ingestion. We evaluated onion-specific IgE, the possible cross-reactivity between onion and peach and lymphocyte proliferation in response to onion. MATERIAL AND METHODS: Specific IgE was evaluated using two techniques: skin test and ImmunoCAP technology. Cross-reactivity between onion and peach was evaluated by IgE-ELISA inhibition test. As for lymphocyte proliferation, blood mononuclear cells were stained with CFSE dye and cultured with an in-house onion extract. Proliferation and phenotype was assessed by flow-cytometry. RESULTS: The skin test and ImmunoCAP confirmed the IgE-dependent response towards onion. The incubation of the patient serum with increasing concentrations of the peach extract reduced only scarcely (~30%) onion-specific IgE. Interestingly, B cells but not T cells showed proliferation in response to onion extract. CONCLUSIONS: In conclusion, our report shows that cooked onion can induce severe allergic reactions, suggesting the presence of thermostable components. Moreover, we applied for the first time a B-cell-based approach to the diagnosis of food allergy. This latter approach might also be applied to other allergic conditions.

Maintenance-Phase Subcutaneous Immunotherapy with House Dust Mites Induces Cyclic Immunologic Effects.

BACKGROUND: Subcutaneous immunotherapy (SCIT) is an effective treatment of respiratory allergies including house dust mite (HDM) and Hymenoptera venom allergy. During the build-up phase, the allergen is administered weekly at increasing doses, while during the maintenance phase, it is administered at a fixed high dose every 4 weeks. Upon SCIT injection, the allergen is driven to the draining lymph nodes where it most likely induces an immune response. Immunologic changes are thus supposedly induced at each injection. OBJECTIVES: It is now established that SCIT induces tolerance in the long term, but the precise underlying immunologic mechanisms remain unclear. Therefore, we wanted to analyze the immunologic changes induced in both innate and adaptive immune cells at each individual SCIT administration during the maintenance phase in HDM-allergic patients. More specifically, we wondered whether the changes in regulatory T cell (Treg) and IgE+ B cell percentages, which are observed at the end of a 3-year course of SCIT, already occurred during the maintenance phase and whether these possible changes were sustained. METHODS: We enrolled 6 patients suffering from HDM allergic rhinitis and undergoing maintenance HDM SCIT for 18-24 months. The same SCIT extract was used for all patients. We collected blood samples at 5 time points: T1 (immediately before a given SCIT injection), T2 (9 days after T1), T3 (29 days after T1 and right before the successive administration), T4 (39 days after T1), and T5 (61 days after T1 and just before the next injection). Six non-allergic age-matched healthy individuals were used as controls. Using flow cytometry, we assessed the following cell subsets in peripheral blood mononuclear cells: CD4 and CD8 T cells, Tregs, B cells, IgE+ B cells, NK and NKT cells, and total and activated basophils. RESULTS: HDM-allergic patients displayed increased percentages of CD4 and CD8 T cells and NK cells compared to healthy controls. In contrast, NKT cells, total B cells, and basophils were diminished. These differences were maintained throughout the time course and seemed to be independent of the periodical SCIT injections. On the contrary, Treg percentages were significantly reduced in all HDM-allergic patients at T1. However, they increased at T2 and T4 (9 days after each SCIT injection) but decreased again at T3 and T5, just before the next one, resulting in cyclic changes. IgE+ B cells were significantly increased at T1, even more increased after each administration (T2, T4), and went back to their initial levels at T3 and T5, also resulting in a cyclic pattern. CONCLUSIONS: Our data suggest that during the SCIT maintenance phase, cycles of expansion/contraction of Tregs and IgE+ B cells occur at each SCIT injection. Therefore, the sustained induction of immune tolerance by SCIT, through the increase of Tregs, seems to depend on the periodical exposure to the allergen, at least during the early steady state.

Mast cells and cancer.

Mast cells (MCs) are a potent proangiogenic factor in tumors, they product several pro-angiogenic factors such as fibroblast growth factor 2 (FGF-2), vascular epithelial growth factor (VEGF), tryptase and chymase. Tryptase is a serine protease classified as α-tryptase and ß-tryptase, both produced by MCs. Tryptase degrades the tissues, playing an important role in angiogenesis and in the development of metastases. Serum tryptase increases with age, with increased damage to cells and risk of developing a malignancy and it could be considered the expression of a fundamental role of MCs in tumor growth or, on the contrary, in the antitumor response. Many biomarkers have been developed in clinical practice for improving diagnosis and prognosis of some neoplasms. Elevated tryptase levels are found in subgroups of patients with haematologic and solid cancers. In the current review, we want to update the perspectives of tryptase as a potential biomarker in daily practice in different neoplasms.

Rapid desensitization for brentuximab vedotin (Adceteris®) allergy: a case report.

BACKGROUND: Brentuximab vedotin (BV) is an antibody-drug conjugate formed by an anti-CD30 chimeric IgG1 conjugated with monomethyl-auristatin-E. BV targets the CD30+ cells, which characterize Hodgkin lymphoma as well as anaplastic large cell lymphoma. Once bound to the CD30+ cells BV exerts its cytotoxic effect via the monomethyl-auristatin-E moiety. So far, accounts on immediate adverse reactions to BV remain anecdotal. Moreover, few reports exist on desensitization for BV. CASE PRESENTATION: A 20-year old male patient was diagnosed with Hodgkin lymphoma in July 2014. The first line treatment with adriblastine, bleomicine, vinblastine and dacarbazine lead to a partial remission. Thus, a treatment with BV was started. However, during the second BV infusion, he developed generalized urticaria and dyspnea. In order not to discontinue the treatment with BV, we performed a thorough allergological workup and designed a 12-step rapid desensitization protocol. Overall the desensitization procedure was well tolerated and no major adverse reactions occurred. CONCLUSION: Rapid desensitization is a suitable and safe option in the case of BV allergy and prevents the BV treatment withdrawal.