Multistep IgE Mast Cell Desensitization Is a Dose- and Time-Dependent Process Partially Regulated by SHIP-1.

Multistep mast cell desensitization blocks the release of mediators following IgE crosslinking with increasing doses of Ag. Although its in vivo application has led to the safe reintroduction of drugs and foods in IgE-sensitized patients at risk for anaphylaxis, the mechanisms of the inhibitory process have remained elusive. We sought to investigate the kinetics, membrane, and cytoskeletal changes and to identify molecular targets. IgE-sensitized wild-type murine (WT) and FcεRIα humanized (h) bone marrow mast cells were activated and desensitized with DNP, nitrophenyl, dust mites, and peanut Ags. The movements of membrane receptors, FcεRI/IgE/Ag, actin, and tubulin and the phosphorylation of Syk, Lyn, P38-MAPK, and SHIP-1 were assessed. Silencing SHIP-1 protein was used to dissect the SHIP-1 role. Multistep IgE desensitization of WT and transgenic human bone marrow mast cells blocked the release of ß-hexosaminidase in an Ag-specific fashion and prevented actin and tubulin movements. Desensitization was regulated by the initial Ag dose, number of doses, and time between doses. FcεRI, IgE, Ags, and surface receptors were not internalized during desensitization. Phosphorylation of Syk, Lyn, p38 MAPK, and SHIP-1 increased in a dose-response manner during activation; in contrast, only SHIP-1 phosphorylation increased in early desensitization. SHIP-1 phosphatase function had no impact on desensitization, but silencing SHIP-1 increased ß-hexoxaminidase release, preventing desensitization. Multistep IgE mast cell desensitization is a dose- and time-regulated process that blocks ß-hexosaminidase, impacting membrane and cytoskeletal movements. Signal transduction is uncoupled, favoring early phosphorylation of SHIP-1. Silencing SHIP-1 impairs desensitization without implicating its phosphatase function.

Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

Development, validation and application of a questionnaire to qualify the indoor environmental exposure of patients with respiratory allergy.

OBJECTIVE: Environmental control includes measures to prevent exposure to common aeroallergens in an individual's home. Questionnaires are part of the clinical practice of health assessment, and are also widely used in research. Our aim was to develop and validate a questionnaire to identify possible sources of aeroallergens present in the indoor environment. METHODS: This study describes the development, validation and application of a questionnaire. For content validation the Content Validation Index and Ordinal Cronbach's Alpha Index have been used; Polychoric Correlations for the agreement between judges; and an Exploratory Factor Analysis for the structure of the questionnaire, while for reliability assessment, Intraclass Correlation Coefficient has been applied. RESULTS: Twenty-one doctors participated as judges to validate the questionnaire, which 204 patients answered. The Content Validity Index for all the questions on the "Clarity" aspect was 0.846 ± 0.152 and on the "Relevance" aspect, 0.954 ± 0.080. Cronbach's alpha coefficient for the "Clarity" aspect was 0.88 with a 95% confidence intervals (CI) and the "Relevance" aspect, 0.94 with a 95% CI. The average Intraclass Correlation Coefficient was 0.94 and all the F tests were highly significant. CONCLUSIONS: The questionnaire developed by our group was considered valid and reliable, and is capable of portraying the home environment without the need for a personal visit to the patient's home. This questionnaire would be a good tool to use in research or during patient consultations to assess the patient's home environment, as this latter assessment is essential for the management of patients with respiratory allergies.

Acquired Angioedema due to C1-Inhibitor Deficiency: A Challenging Condition.

BACKGROUND: Acquired deficiency of C1 inhibitor (AAE-C1-INH) is a very rare cause of recurrent angioedema, with few cases reported in the literature. We aimed to describe a series of patients with AAE-C1-INH who were diagnosed and received care at angioedema reference centers in Brazil, affiliated to the Brazilian Group of Studies on Hereditary Angioedema. METHODS: Fourteen patients from 8 Brazilian Angioedema Reference Centers, diagnosed with AAE-C1-INH, were included in this study. Clinical data collected included sex, date of birth, date of onset of symptoms, date of diagnosis, plasma levels of antigenic and/or functional C1-INH, levels of C4 and C1q, location and treatment of angioedema attacks, long-term prophylaxis, associated diseases, and definitive treatment. RESULTS: Fourteen patients were identified with AAE-C1-INH. Most patients (10/14; 71.4%) were female. The median age at onset of symptoms was 56.5 years (range, 14-74 years; interquartile range [IQR], 32-64 years), and median age at diagnosis was 58.0 years (range, 20-76 years; IQR, 38-65 years), with a median time until diagnosis of 2 years (range, 0-6 years; IQR, 1-3 years). The most common manifestations were cutaneous (face, eyelids, lips, trunk, hands, feet, and genitals). Most patient had low levels of C4 (13/14; 92.8%) and of antigenic C1-INH (8/14; 57.1%). Four had decreased functional activity of C1-INH (4/7; 57.1%) and C1q levels were low in 5 patients (5/12; 41.6%). Underlying diseases were identified in all 14 patients, with lymphoma of the splenic marginal zone and monoclonal gammopathy of undetermined significance being the most frequent. Nine patients (64.2%) needed long-term prophylactic treatment for recurrent angioedema and 5 patients (46.7%) required treatment for angioedema attacks. Most of them (12/14; 85.7%) had resolution of angioedema. CONCLUSION: Therapy of AAE-C1-INH aims to control symptoms; however, diagnosis and treatment of the underlying disease, when present, should be an important target and may lead to the resolution of angioedema in patients with AAE-C1-INH.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Seroprevalence and Risk Factors Among Oligo/Asymptomatic Healthcare Workers: Estimating the Impact of Community Transmission.

We evaluated the seroprevalence of SARS-CoV-2 and risk factors among 4987 oligo/asymptomatic healthcare workers; seroprevalence was 14% and factors associated with SARS-CoV-2 infection were lower educational level (aOR, 1.93; 95% CI, 1.03-3.60), using public transport to work (aOR, 1.65; 95% CI, 1.07-2.62), and working in cleaning or security (aOR, 2.05; 95% CI, 1.04-4.03).

The Challenges in the Follow-Up and Treatment of Brazilian Children with Hereditary Angioedema.

INTRODUCTION: Hereditary angioedema (HAE) with C1 inhibitor (C1-INH) deficiency is a rare autosomal dominant disease. Although the first symptoms can appear in childhood, the diagnosis's delay has a strong impact on the patient's quality of life. We analyzed clinical and laboratory characteristics and the drug therapy of pediatric patients with HAE in Brazil. METHODS: Medical records from 18 reference centers of HAE patients under 18 years of age were evaluated after confirmed diagnosis was performed by quantitative and/or functional C1-INH. RESULTS: A total of 95 participants (51 M:44 F; mean age: 7 years old) out of 17 centers were included; 15 asymptomatic cases were identified through family history and genetic screening. Angioedema attacks affected the extremities (73.5%), gastrointestinal tract (57%), face (50%), lips (42.5%), eyelids (23.7%), genitals (23.7%), upper airways (10%), and tongue (6.3%). Family history was present in 84% of patients, and the mean delay in the diagnosis was 3.9 years. Long-term prophylaxis (51/80) was performed with tranexamic acid (39/80) and androgens (13/80); and short-term prophylaxis (9/80) was performed with tranexamic acid (6/80) and danazol (3/80). On-demand therapy (35/80) was prescribed: icatibant in 7/35, fresh frozen plasma in 16/35, C1-INH plasma-derived in 11/35, and tranexamic acid in 12/35 patients. CONCLUSIONS: This is the first study on HAE pediatric patients in Latin America. Clinical manifestations were similar to adults. Drugs such as androgens and tranexamic acid were indicated off-label, probably due to restricted access to specific drugs. Educational programs should address pediatricians to reduce late diagnosis and tailored child therapy.

Toward personalization of asthma treatment according to trigger factors.

Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma.

An expert review on breaking barriers in severe asthma in Brazil: Time to act.

Currently, Brazil lacks a national asthma management program and is burdened with nearly 200,000 hospitalizations due to the disease per year and approximately 5 deaths per day. The purpose of this article was to analyze the current issues surrounding severe asthma in Brazil, as the status of diagnosis and treatment is largely unknown, and to provide feasible recommendations to elicit imminent action. A panel of Brazilian medical experts in the field of severe asthma was provided with a series of relevant questions to address prior to a multi-day conference. Within this conference, each narrative was discussed and edited by the entire group. Through numerous rounds of discussion consensus was achieved. In order to overcome barriers to adequate asthma treatment, this panel recommends specific initiatives that can be implemented in the short-term to decrease the burden of severe asthma in Brazil. With increasing healthcare costs and limited resources globally, there is an opportunity to implement these recommendations in other countries in order to achieve adequate asthma care. Severe asthma is a heterogeneous and complex disease with various phenotypes that requires strict attention for diagnosis and management. Although this disease affects only a small proportion of the population with asthma, it poses a great burden to healthcare systems. Thus, barriers to diagnosis, treatment, and management should be overcome as quickly and efficiently as possible.

Severe atopic dermatitis: Dupilumab is not just safer, but more efficient.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsing eczema and pruritus. Until the development of Dupilumab, a new monoclonal antibody targeting IL-4 and IL-13 receptors, the current treatment of severe cases was based on immunosuppressant agents. Our main goal was to build a case series of five patients with severe atopic dermatitis, who were using immunosuppressive drugs with significant adverse effects and only partially controlled AD, and compare their symptoms, SCORAD index, treatment regimens, total and specific IgE, and blood cell count before and after the introduction of Dupilumab. SCORAD index and topical corticosteroids used on a daily basis had a significant decrease after 16 weeks of Dupilumab. Adverse effects were mild: conjunctivitis, local reaction and regional dermatosis. All patients with severe atopic dermatitis achieved better control of AD with Dupilumab than with immunosuppressive drugs. Adverse effects, secondary infections, total and specific IgE levels were greatly reduced.

BAT in the Diagnosis of Drug Allergy: a Novel Tool in Clinical Daily Practice?

PURPOSE OF REVIEW: The aim of this study is to critically review the relevant literature published on basophil activation test, presenting the current knowledge and future perspectives. RECENT FINDINGS: Basophil activation test (BAT) results varied accordingly to the class of the drug studied, and have promising results in immediate hypersensitivity reactions to pyrazolone (selective reactors), neuromuscular blockers, beta-lactams, and platinum compounds, all examples of classical IgE-mediated hypersensitivity drug reactions. Currently, BAT is applied in research settings, but based in the results of our review, the test can be considered as a diagnostic tool for daily practice for selected patients and selected drugs, when the test is available, particularly for patients who experienced severe reactions and when diagnosis cannot be stablished by serum-specific IgE and skin testing, in order to avoid unnecessary drug provocations tests.

Seasonal changes influence the improvement in asthma symptoms by exercise training in subjects with asthma*.

OBJECTIVE: To investigate whether patients with moderate-to-severe asthma who commence an exercise training program in winter or summer show differences in exercise capacity, health-related quality of life (HRQoL) and asthma symptoms. METHODS: Forty-two consecutive subjects visiting the outpatient clinic were enrolled in the 17-week rehabilitation program. One group of patients received the intervention from summer to winter (SWG, n = 21), and the other group participated from winter to summer (WSG, n = 21). Before and after the exercise training program, all patients were evaluated by cardiopulmonary exercise test, pulmonary function test, quality of life questionnaire and a daily diary that evaluated clinical asthma symptoms. RESULTS: After the training period, both groups improved similarly in health-related quality of life (HRQoL) and aerobic capacity. The WSG patients had a greater increase that those in the SWG in asthma symptom-free days (p < 0.05). CONCLUSIONS: Our results indicate that seasonal variations affect the improvement in asthma symptoms after an exercise training program but have no effect on health-related quality of life, exercise capacity or pulmonary function.

Allergic and Nonallergic Asthma Have Distinct Phenotypic and Genotypic Features.

BACKGROUND: Identification of asthma phenotypes enables a better understanding and management of this heterogeneous disease. Studies have reported associations between human leukocyte antigens (HLA) and asthma in different populations, but the results have been inconclusive and they have rarely considered the distinct disease phenotypes. Our objective was to characterize allergic and nonallergic asthma phenotypes and evaluate possible associations with the HLA system. METHODS: A total of 109 patients with asthma were prospectively followed during 2 years. They were divided into 2 groups, i.e., allergic and nonallergic asthma, according to their clinical history and skin prick test and serum-specific immunoglobulin E (IgE) results. The control group comprised 297 deceased donors of solid organs. Patients' features and HLA class I and II genotypes were assessed and compared. RESULTS: This study showed different features between asthma phenotypes. Nonallergic patients were older at the onset of asthma symptoms and had a higher rate of intolerance to nonsteroidal anti-inflammatory drugs. Allergic patients had higher total serum IgE levels, reported atopic dermatitis and rhinoconjunctivitis more frequently, and, unexpectedly, had a greater disease severity. New associations between the HLA genotypes and allergic and nonallergic asthma were identified. The HLA-B*42, HLA-C*17, HLA-DPA1*03, and HLA-DPB1*105 genotypes were associated with allergic asthma and the HLA-B*48 genotype with the nonallergic phenotype. The presence of the haplotype HLA-DPA1*03 DQA*05 was associated with allergic asthma, and the presence of HLA-DPA1*03 and the absence of HLA-DQA*05 with nonallergic asthma. CONCLUSIONS: Allergic and nonallergic asthma have distinct phenotypic and genotypic features. New associations between asthma phenotypes and HLA class I and II were identified.

Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions.

BACKGROUND: The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. OBJECTIVE: We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. METHODS: Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. RESULTS: Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. CONCLUSIONS: Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions.

Vocal cord dysfunction diagnosis may be improved by a screening check list.

BACKGROUND: Many patients with vocal cord dysfunction (VCD), with or without asthma, receive inappropriate treatment because they are misdiagnosed as having difficult-to-control asthma alone. We developed a clinical screening check list designed to aid the diagnosis of VCD. METHODS: A prospective observational study involving 80 patients aged ≥18 years, diagnosed with severe asthma. After anamnesis and physical examination, physicians completed a check list with 6 questions to identify VCD, for which the answer "yes" counted one point. Then patients underwent spirometry and laryngoscopy. On the basis of the laryngoscopic findings, we created three patient groups: VCD (vocal cord adduction during inspiration, n = 14); unconfirmed VCD (inconclusive findings, n = 29); and control (normal findings, n = 37). We attempted to determine whether any of those groups were associated with the responses to individual questions or sets of questions on the check list. RESULTS: The proportion of affirmative answers to the question "Does pulmonary auscultation reveal wheezing, predominantly in the cervical region, and/or stridor?" was significantly higher for the VCD group than for the other two groups (P = 0.006), notably in elderly patients. The variable "4 or more affirmative answers" was more common in VCD and unconfirmed VCD groups in comparison to controls (P = 0.022). CONCLUSIONS: A finding of wheezing or stridor on auscultation of the cervical region is suggestive of vocal cord dysfunction, especially in elderly patients, and such dysfunction can be confirmed through laryngoscopy. Our VCD screening check list proved to be useful in the screening of VCD among patients with severe asthma.

Aerobic training decreases bronchial hyperresponsiveness and systemic inflammation in patients with moderate or severe asthma: a randomised controlled trial.

BACKGROUND: The benefits of aerobic training for the main features of asthma, such as bronchial hyperresponsiveness (BHR) and inflammation, are poorly understood. We investigated the effects of aerobic training on BHR (primary outcome), serum inflammatory cytokines (secondary outcome), clinical control and asthma quality of life (Asthma Quality of Life Questionnaire (AQLQ)) (tertiary outcomes). METHODS: Fifty-eight patients were randomly assigned to either the control group (CG) or the aerobic training group (TG). Patients in the CG (educational programme+breathing exercises (sham)) and the TG (same as the CG+aerobic training) were followed for 3 months. BHR, serum cytokine, clinical control, AQLQ, induced sputum and fractional exhaled nitric oxide (FeNO) were evaluated before and after the intervention. RESULTS: After 12 weeks, 43 patients (21 CG/22 TG) completed the study and were analysed. The TG improved in BHR by 1 doubling dose (dd) (95% CI 0.3 to 1.7 dd), and they experienced reduced interleukin 6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1) and improved AQLQ and asthma exacerbation (p<0.05). No effects were seen for IL-5, IL-8, IL-10, sputum cellularity, FeNO or Asthma Control Questionnaire 7 (ACQ-7; p>0.05). A within-group difference was found in the ACQ-6 for patients with non-well-controlled asthma and in sputum eosinophil and FeNO in patients in the TG who had worse airway inflammation. CONCLUSIONS: Aerobic training reduced BHR and serum proinflammatory cytokines and improved quality of life and asthma exacerbation in patients with moderate or severe asthma. These results suggest that adding exercise as an adjunct therapy to pharmacological treatment could improve the main features of asthma. TRIAL REGISTRATION NUMBER: NCT02033122.

Perioperative anaphylaxis.

Perioperative anaphylaxis is a life-threatening condition with an estimated prevalence of 1:3,500 to 1:20,000 procedures and a mortality rate of up to 9 %. Clinical presentation involves signs such as skin rash, urticaria, angioedema, bronchospasm, tachycardia, bradycardia, and hypotension. Prompt recognition and treatment is of utmost importance to the patient's prognosis, since clinical deterioration can develop rapidly. Epinephrine is the main treatment drug, and its use should not be postponed, since delayed administration is associated with increased mortality. Elevated levels of serum tryptase help to confirm the diagnosis. The main agents involved in IgE-mediated perioperative anaphylaxis are neuromuscular blocking agents, latex, antibiotics, hypnotics, opioids, and colloids. Specific investigation should be conducted 4 to 6 weeks after the reaction and relies on skin tests, serum-specific IgE, and challenge procedures. This review aims to discuss the main aspects of perioperative anaphylaxis: risk factors, diagnosis, treatment, culprit agents, specific investigation, and preventive measures.

Successful treatment of severe atopic dermatitis and alopecia universalis with upadacitinib in a 29-year-old male patient.

A 29-year-old male patient had severe atopic dermatitis (AD) and alopecia universalis (AU) that could not be controlled by using classic therapy. He started taking upadacitinib and achieved an excellent response for both his AD and AU. Thus, upadacitinib represents a promising therapeutic approach for patients with severe AD and alopecia areata.