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Background and objectives Atopic dermatitis is a chronic inflammatory skin disease with a prevalence of 0.02% to 8.1% in adults. Adult patients with moderate-to-severe atopic dermatitis have frequent relapses and significant disease burden. Objectives: Characterize clinical, immunological and therapeutic features of Brazilian adults with atopic dermatitis. Methods A multicenter, observational, retrospective, descriptive registry-based study, conducted at reference hospitals, between December 2016 and October 2017. Demographics, personal and family history of atopic diseases, clinical manifestations, laboratory tests, disease severity and management were collected. Results From the 187 subjects included in the analysis, 56.1% were female and 71.7% were Caucasian, with a mean age of 24.7 years. Mean follow-up duration was 9 years. Asthma or other allergic diseases were reported by 80.2% of the patients. The main comorbidity was hypertension (10.2%) and common disease manifestations included pruritus and erythema. Lesions were generally distributed in non-flexural and flexural areas, with typical morphology. Around 83% of patients had moderate to severe disease and 8.6% reported at least one hospitalization. Most patients received topical and/or systemic pharmacological therapies, including omalizumab (5.9%); 4.3% received phototherapy. Moreover, 66.8% of patients received adjuvant therapy and 79.1% changed or discontinued treatment for atopic dermatitis due to remission (46.5%), poor effectiveness (33.7%) or lack of therapeutic adherence (12.9%). Most patients presented characteristics of type 2 inflammation, with immunoglobulin E levels above 100 IU/mL (94.4%) and peripheral blood eosinophils above 5% (55.9%). Conclusion Brazilian adult patients with severe atopic dermatitis need treatments to efficiently control the disease and improve quality of life.

Background Sensitization to house dust mites (HDM) is frequent in patients with atopic dermatitis (AD). Objective To investigate the efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides pteronyssinus(Dpt) extract in patients with AD sensitized to HDM. Methods In this randomized, double-blind, placebo-controlled trial, we enrolled 91 patients aged ≥3 years, with SCORing Atopic Dermatitis (SCORAD) ≥15 and positive skin test and/or IgE to Dpt. Patients were stratified according to age ( > 15-point decrease in SCORAD. Secondary outcomes were decreases in SCORAD and objective SCORAD (O-SCORAD), Eczema Area and Severity Index (EASI), visual analog scale (VAS) for symptoms, pruritus scale; Investigator’s Global Assessment (IGA) 0/1; and decrease ≥4 points in Dermatology Life Quality Index (DLQI). Background therapy was maintained. Results A total of 66 patients completed the study (35 HDM SLIT, 31 placebo). After 18 months, 74.2% and 58% patients in HDM SLIT and placebo groups, respectively, showed > 15-point decrease in SCORAD (relative risk[RR]1.28, 95% confidence interval[CI] 0.89-1.83). Significant SCORAD decreases from baseline of 55.6% and 34.5% in HDM SLIT and placebo groups (mean difference 20.4;95%CI 3.89-37.3); significant O-SCORAD decreases of 56.8% and 34.9% in HDM SLIT and placebo groups (mean difference 21.3;95%CI 0.66-41.81); and more patients with IGA 0/1 in HDM SLIT group as compared to placebo group (14/35 vs 5/31;RR 2.63, 95%CI 1.09-6.39), were observed at 18 months. Conclusion Our results suggest that HDM SLIT may be effective in HDM sensitized patients as an add-on treatment for AD.

Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

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.

Introduction: Patients with severe asthma may present with different phenotypes. Severe eosinophilic asthma patients require frequent use of health care resources and have impaired health-related quality of life. Objective: We sought to determine the prevalence of an eosinophilic phenotype, defined as blood eosinophil counts >300 cells/mm3, for patients with severe asthma in Brazil. Methods: This was a cross-sectional, observational study of adult patients with severe asthma (high dose inhaled corticosteroid [GINA 2018] plus second controller) in routine clinical practice in Brazil. Allergic phenotype was defined as serum IgE>100 IU/mL plus clinical features of allergy. Results: A total of 385 patients were enrolled from 10 Brazilian centers. Most were female (78.4%) and white (57.4%), with a mean age of 53±13 years old. Prevalence of patients with eosinophilic phenotype was 40.0% [95% CI: 35.1–44.9%]. Those were mainly female (76.0%), white (62.3%), with mean age 50±14 years old. Eosinophilic patients presented lower BMI, with no other relevant clinical or demographics differences compared with non-eosinophilic phenotype patients. A high prevalence of allergic phenotype of 62.6% [95% CI: 57.8%-67.4%] was also identified. There was a high overlap between phenotypes as 79.9% [95% CI: 73.5–86.2%] of eosinophilic patients were also allergic. Conclusions: The prevalence of an eosinophilic phenotype for patients with severe asthma in Brazil is high, and these patients present with clinical and demographic characteristics similar to other worldwide populations. The overlap between allergic and eosinophilic phenotypes was common.

This document summarizes the aims of GA2 LEN/HAEi Angioedema Centers of Reference and Excellence (ACAREs) and elaborates the requirements that ACAREs must fulfill to become certified. It also provides (see Appendix S1) background information on GA2LEN and HAEi, including HAEi member organizations and regional patient advocates, on why we need an Angioedema Center of Reference and Excellence (ACARE) program and network, and on the accreditation and certification process, governance and funding, and on the interaction with other GA2LEN networks of centers of reference and excellence. The protocols, aims, requirements, and provisions related to becoming a certified CARE are based on (a) the experience of the GA2LEN UCARE network and (b) input from angioedema patients, general practitioners, and angioedema specialists.

A imunoglobulina E (IgE) tem papel central na patogênese das doenças alérgicas. É parte da resposta do tipo 2, e as citocinas IL-4 e IL-13 são essenciais para que haja produção deste isotipo de imunoglobulina. Produção de IgE é também induzida por parasitas intestinais, particularmente helmintos. O objetivo do presente estudo foi avaliar a contribuição de IgE específica para ácaros, barata, gato, cachorro e para o parasita Ascaris lumbricoides sobre os níveis de IgE total entre crianças de áreas distintas no Brasil. Anticorpos IgE para ácaros Dermatophagoides pteronyssinus e Blomia tropicalis; barata Blattella germanica; gato; cachorro; e A. lumbricoides foram medidos usando o sistema ImmunoCAP, e comparados à IgE total no soro de 150 crianças de 3-6 anos de idade vivendo na cidade de Natal, endêmica para parasitoses intestinais, e de 54 crianças de 3-6 anos de idade com asma e/ou rinite, vivendo em Ribeirão Preto. Níveis de IgE total foram significantemente mais elevados em crianças de Natal quando comparados aqueles em crianças de Ribeirão Preto (média geométrica 630,9 kU/L, faixa 19,6-63.290 kU/L; e 398,1 kU/L, faixa 35,7-4.803 kU/L, respectivamente). Entre as 150 crianças de Natal, 52(34,6%) apresentaram IgE positiva para D.pteronyssinus; 70(46,6%) para B.tropicalis; 45(30%) para barata; 19(12,6%) para gato; 17(11,3%) para cachorro; e 125(83,3%) para A.lumbricoides. Entre as 54 crianças com asma e/ou rinite de Ribeirão Preto, 41(75,9%) apresentaram IgE positiva para D.pteronyssinus; 34(62,9%) para B.tropicalis; 22(40,7%) para barata; 11(20,3%) para gato; 12(22,2%) para cachorro. Embora estas crianças fossem negativas para parasitas à inclusão no estudo, 22(40,7%) tinham IgE para A.lumbricoides. Anticorpos IgE para A. lumbricoides foram mais elevados entre crianças de Natal, quando comparados a IgE para alérgenos inalantes (p

SummaryBackground Workers exposed to laboratory animals have a high risk of developing laboratory animal allergy (LAA). Atopy seems to be the main risk factor for LAA. We hypothesized that occupational sensitization is a better predictor for the development of asthma, rhinitis, and bronchial hyperresponsiveness (BHR) than common sensitization. Objective To investigate the association between occupational sensitization to laboratory animals and clinical outcomes. Methods This was a cross-sectional study performed at two universities on students and employees dealing with small rodents. The subjects were allocated in groups: non-sensitized, common sensitization, or occupational sensitization, according to the results of the skin prick test (SPT). All subjects answered a questionnaire about animal exposures, symptoms, allergic diseases, and underwent spirometry and bronchial challenge test with mannitol. Multivariate analysis was performed using Poisson regression to estimate the prevalence ratio (PR). Results Data from 453 volunteers were analysed. Non-sensitized group comprised 237 subjects; common sensitization group, 142 subjects; and occupational sensitization group, 74 subjects. Occupational sensitization was associated with greater risk for all outcomes studied. When the common sensitization group was reference, skin symptoms had PR of 1.36, 95% confidence interval (CI): 1.01-1.85; wheezing had PR of 1.75, CI 95%: 1.21-2.53; rhinitis had PR of 1.25, 95%: 1.11-1.40; nocturnal dyspnoea had PR of 2.40, 95% CI: 1.31-4.40; bronchial hyperresponsiveness (BHR) had PR of 2.47, 95% CI: 1.50-4.09; and confirmed asthma had PR of 2.65, 95% CI: 1.45-4.85. In addition, the overlap of asthma, rhinitis, and skin symptoms in a same subject was significantly more prevalent in the occupational sensitization group, 16.2% versus 4.9% in the common sensitization group. Conclusion and Clinical Relevance Occupational sensitization is associated with allergic symptoms and respiratory diseases. SPT with occupational allergens along with other parameters may contribute to detection of risk for allergic and respiratory diseases associated with exposure to laboratory animals.

Background Factors associated with recurrence of chronic rhinosinusitis (CRS) are still poorly recognized. Objective To evaluate which risk factors could influence the risk of recurrence among patients undergoing endoscopic sinus surgery in long-term follow-up. Methods Patients with CRS who underwent endoscopic sinus surgery were followed for an average period of 12 years in a nonconcurrent cohort. After surgery, patients were considered to an additional endoscopic sinus surgery if appropriate medical therapy failed during this period. The presence of nasal polyps, asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, smoking habits, peripheral blood eosinophilia, and atopy were assessed. The recurrence-free interval between groups (with or without these risk factors) was analyzed by Kaplan-Meyer curves, and the indication for a revisional surgery was considered to be the unfavorable event. Results A total of 201 patients were enrolled in this study. Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) were more likely than patients with chronic rhinosinusitis without nasal polyps (CRSsNP) to need revisional surgery (adjusted hazard ratio, 2.02). Asthma was the only factor that was significantly related to recurrence both in patients with CRSsNP (hazard ratio, 5.54) and in patients with CRSwNP (hazard ratio, 3.27). Although eosinophilia itself was not related to a higher chance of recurrence, its presence influenced the outcome of CRSwNP compared with CRSsNP and the impact of asthma among patients with CRSwNP. Conclusions Prognosis in patients with CRSwNP was inferior to that in patients with CRSsNP. Asthma was the only factor that increased the chance of recurrence in patients with either CRSsNP or CRSwNP.

SUMMARY OBJECTIVE To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.

Background Hereditary angioedema (HAE) is a rare genetic disorder mainly caused by mutations in the SERPING1 gene, determining a deficit of C1 inhibitor (C1-INH). In approximately 10% of the cases, HAE with C1-INH deficiency (C1-INH-HAE) is caused by large gene rearrangements, which are not detected by Sanger sequencing. Here we present the exon quantification technique (EQT), a molecular diagnostic test for the detection of large genetic rearrangements in SERPING1, mapping the exact size and location of the deletion caused by the recombination of Alu elements. EQT analysis was performed on total DNA extracted from blood of patients belonging to two Brazilian families with a medical history of HAE, low plasma levels of C4 and C1-INH and no pathogenic alteration in SERPING1 analyzed by Sanger sequencing. Results Two large deletions were found, one of 1356 pb and one of 1804 pb, which resulted from recombination of two Alu elements present in introns 3 and 4 of the gene. Conclusion These results showed that the EQT could be used as a simple, rapid, and efficient diagnosis test for analysis of large deletions and insertions involving SERPING1, otherwise not detected by Sanger sequencing, serving as a support technique for molecular diagnosis of HAE.

Background: Anaphylaxis is a severe and potentially fatal allergic disease or hypersensitivity reaction with variable clinical presentation. Biomarkers in anaphylaxis could be useful to improve diagnosis, to allow endotyping of patients, and to predict risk. Objective: To investigate the role of serum basal tryptase (sBT) levels in the management of patients with anaphylaxis. Methods: Patients with at least 1 episode of anaphylaxis were selected among those who attended the Allergy Clinics of the Clinical Hospital of the Ribeirão Preto Medical School, University of São Paulo, Brazil, upon evaluation by allergy/immunology specialists of our medical staff. Demographic and clinical data were obtained using a structured questionnaire. sBT levels were determined using the ImmunoCAP Tryptase immunoassay. Results: 57 patients (56.1% female) with a median age of 35 years (range 7–87 years) participated in the study. sBT levels ranged from 2.57 to 21.19 ng/mL (mean 5.17 ng/mL), with no significant differences in patients with anaphylaxis due to different triggers. Mean levels were 4.93; 5.2; 5.41, and 5.24 ng/mL for patients who had anaphylaxis due to Hymenoptera venom (n = 17), foods (n = 13), drugs (n = 13), and idiopathic disease (n = 14), respectively. Significantly higher sBT levels were observed in patients with severe anaphylaxis (grade IV) than in patients with mild-moderate disease (grades II/III) (mean levels 6.61 vs. 4.71 ng/mL, respectively). Conclusion: High sBT levels may help to identify patients at increased risk of more severe anaphylaxis, prompting physicians to initiate immediate therapy to avoid further acute episodes.

Made available in DSpace on 2018-12-11T17:22:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-09-01 Asthma is a genetically complex chronic inflammatory airway disorder, and according to disease pathogenesis, clinical manifestations may vary according to asthma severity. A gene region close to the human leukocyte antigen-G (HLA-G) gene was identified as an independent susceptibility marker for asthma. Considering that the HLA-G immune checkpoint molecule may modulate inflammation, we evaluated the diversity of the HLA-G 3′ untranslated region (3′UTR) in asthmatic patients stratified according to disease severity. We evaluate the entire HLA-G 3′UTR segment in 115 Brazilian patients stratified into mild (n=29), moderate (n=21) and severe asthmatics (n=65), and in 116 healthy individuals. HLA-G 3′UTR typing was performed using Sanger sequencing. The multiple comparisons among patients stratified according to disease severity revealed several associations; however, after Bonferroni's correction, the following results remained significant: i) the +3010C and +3142G alleles were overrepresented in mild asthma patients when compared to controls; ii) the +3010G and +3142C alleles were overrepresented in severe asthma patients in comparison to patients with mild asthma. In conclusion, the +3010C/G and +3142C/G HLA-G 3′UTR variation sites were differentially associated according to asthma severity. Department of Biochemistry and Immunology Ribeirão Preto Medical School University of São Paulo Department of Medicine Ribeirão Preto Medical School University of São Paulo São Paulo State University (UNESP) School of Medicine Molecular Genetics and Bioinformatics Laboratory São Paulo State University (UNESP) School of Medicine Department of Pathology Departamento de Química Laboratório de Pesquisas Forenses e Genômicas Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo São Paulo State University (UNESP) School of Medicine Molecular Genetics and Bioinformatics Laboratory São Paulo State University (UNESP) School of Medicine Department of Pathology

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the “Associação Brasileira de Alergia e Imunologia (ASBAI)” and the “Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)” has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Background We have shown that mycobacterial antigens and CpG oligodeoxynucleotides downmodulate airway allergic inflammation by mechanisms dependent on T-cell activation. Here, we investigated the participation of the innate response, particularly the role of MyD88 adaptor, and Fas molecules in the effectiveness of DNA-HSP65 or CpG/culture filtrated proteins (CFP) immunotherapy. Methods Mice sensitized and challenged with Der p 1 allergen were treated with DNA-HSP65, CpG/CFP, or with adoptively transferred cells from immunized mice. The treatment efficacy was assessed by evaluating eosinophil recruitment, antibody, and cytokine production. Results In addition to downregulating the Th2 response, DNA-HSP65 and CpG/CFP promoted IL-10 and IFN-γ production. Adoptive transfer of cells from mice immunized with DNA-HSP65 or CpG/CFP to allergic recipients downmodulated the allergic response. Notably, transfer of cells from DNA-HSP65- or CpG/CFP-immunized MyD88−/− mice failed to reduce allergy. Additionally, for effective reduction of allergy by cells from CpG/CFP-immunized mice, Fas molecules were required. Although DNA-HSP65 or CpG/CFP immunization stimulated antigen-specific production of IFN-γ and IL-10, the effect of DNA-HSP65 was associated with IL-10 while CpG/CFP was associated with IFN-γ. Moreover, after stimulation with mycobacterial antigens plus Der p 1 allergen, cells from mite-allergic patients with asthma exhibited similar patterns of cytokine production as those found in the lung of treated mice. Conclusions This study provides new insights on the mechanisms of allergen-free immunotherapy by showing that both DNA-HSP65 and CpG/CFP downregulated house dust mite-induced allergic airway inflammation via distinct pathways that involve not only induction of mycobacterial-specific adaptive responses but also signaling via MyD88 and Fas molecules.

The subspecialty of pediatric allergy and immunology in Brazil is in its early years and progressing steadily. This review highlights the research developed in the past years aiming to show the characteristics of allergic and immunologic diseases in this vast country. Epidemiologic studies demonstrated the high prevalence of asthma in infants, children, and adolescents. Mortality rates and average annual variation of asthma hospitalization have reduced in all pediatric age groups. Indoor aeroallergen exposure is excessively high and contributes to the high rates of allergy sensitization. Prevalence of food allergy has increased to epidemic levels. Foods (35%), insect stings (30%), and drugs (23%) are the main etiological agents of anaphylaxis in children and adolescents. Molecular diagnosis of primary immunodeficiencies (PID) showed a high incidence of fungal infections including paracoccidioidomycosis in X-linked hyper-IgM syndrome, and the occurrence of BCG adverse reactions or other mycobacterial infections in patients with chronic granulomatous disease. Education in pediatric allergy and immunology is deficient for medical students, but residency programs are effective in training internists and pediatricians for the practice of allergy. The field of PID requires further training. Last, this review is a tribute to Prof. Dr. Charles Naspitz, one of the pioneers of our specialty in Brazil.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects up to 25% of children and 10% of adults. The skin of patients with moderate to severe AD is characterized by significant barrier disruption and T helper 2 (Th2)-driven inflammation, which are thought to play a significant role in the pathogenesis of AD. Current management of AD is aimed at suppressing the inflammatory response and restoring the barrier function of the skin, reducing exacerbations, and preventing secondary skin infections. Combinations of treatment strategies are used to alleviate the symptoms of the disease; however, resolution is often temporary, and long-term usage of some of the medications for AD can be associated with significant side effects. Antibody therapies previously approved for other inflammatory diseases have been evaluated in patients with AD. Unfortunately, they have often failed to result in significant clinical improvement. Monoclonal antibodies and novel small molecules currently in development may provide more consistent benefit to patients with AD by specifically targeting the immune and molecular pathways important for the pathogenesis of AD. Here we review the state-of-the-art therapeutics targeting the Th2 axis in AD.

To cite this article: Ferraro MF, Moreno AS, Castelli EC, Donadi EA, Palma MS, Arcuri HA, Lange AP, Bork K, Sarti W, Arruda LK. A single nucleotide deletion at the C1 inhibitor gene as the cause of hereditary angioedema: insights from a Brazilian family.Allergy 2011; 66: 1384–1390. Abstract Background: Hereditary angioedema is an autosomal dominant disease characterized by episodes of subcutaneous and submucosal edema. It is caused by deficiency of the C1 inhibitor protein, leading to elevated levels of bradykinin. More than 200 mutations in C1 inhibitor gene have been reported. The aim of this study was to analyze clinical features of a large family with an index case of hereditary angioedema and to determine the disease-causing mutation in this family. Methods: Family pedigree was constructed with 275 individuals distributed in five generations. One hundred and sixty-five subjects were interviewed and investigated for mutation at the C1 inhibitor gene. Subjects reporting a history of recurrent episodes of angioedema and/or abdominal pain attacks underwent evaluation for hereditary angioedema. Results: We have identified a novel mutation at the C1 inhibitor gene, c.351delC, which is a single-nucleotide deletion of a cytosine on exon 3, resulting in frameshift with premature stop codon. Sequencing analysis of the hypothetical truncated C1 inhibitor protein allowed us to conclude that, if transcription occurs, this protein has no biological activity. Twenty-eight members of the family fulfilled diagnostic criteria for hereditary angioedema and all of them presented the c.351delC mutation. Variation in clinical presentation and severity of disease was observed among these patients. One hundred and thirty-seven subjects without hereditary angioedema did not have the c.351delC mutation. Conclusion: The present study provides definitive evidence to link a novel genetic mutation to the development of hereditary angioedema in patients from a Brazilian family.

Epidemiological and experimental evidence supports the notion that microbial infections that are known to induce Th1-type immune responses can suppress Th2 immune responses, which are characteristics of allergic disorders. However, live microbial immunization might not be feasible for human immunotherapy. Here, we evaluated whether induction of Th1 immunity by the immunostimulatory sequences of CpG-oligodeoxynucleotides (CpG-ODN), with or without culture filtrate proteins (CFP), from Mycobacterium tuberculosis would suppress ongoing allergic lung disease. Presensitized and ovalbumin (OVA)-challenged mice were treated subcutaneously with CpG, or CpG in combination with CFP (CpG/CFP). After 15 days of treatment, airway inflammation and specific T- and B-cell responses were determined. Cell transfer experiments were also performed. CpG treatment attenuated airway allergic disease; however, the combination CpG/CFP treatment was significantly more effective in decreasing airway hyperresponsiveness, eosinophilia and Th2 response. When an additional intranasal dose of CFP was given, allergy was even more attenuated. The CpG/CFP therapy also reduced allergen-specific IgG1 and IgE antibodies and increased IgG2a. Transfer of spleen cells from mice immunized with CpG/CFP also reduced allergic lung inflammation. CpG/CFP treatment induced CFP-specific production of IFN-γ and IL-10 by spleen cells and increased production of IFN-γ in response to OVA. The essential role of IFN-γ for the therapeutic effect of CpG/CFP was evidenced in IFN-γ knockout mice. These results show that CpG/CFP treatment reverses established Th2 allergic responses by an IFN-γ-dependent mechanism that seems to act both locally in the lung and systemically to decrease allergen-specific Th2 responses.

Objectives To evaluate the sensitization to aeroallergens determined by skin prick test (SPT) in Brazilian adolescents, and to correlate its positivity with the diagnosis of asthma and/or rhinitis based on the written questionnaire (WQ) of ISAAC phase III study. Patients and Methods A total of 996 adolescents (387 boys) were selected by systematic samples. A standard allergen extracts panel (positive/negative control, D pteronyssinus [Dpt], P americana [Pa], B germanica [Bg], dog, cat, fungal and grass mix) was used and its positivity compared with positive responses to asthma, rhinitis or both. Results Positive SPT to at least one allergen was observed in 466 adolescents (46.8 %), with sensitization to Dpt in 79.1 %. Positivity to more than one allergen occurred in 232 students (49.8 %). The frequency of positive SPTs was significantly higher among adolescents with asthma (OR = 2.16), rhinitis (OR = 1.69), and asthma and rhinitis (OR = 2.03). Positive SPT to four or more allergens were higher among asthmatics (OR = 2.6) and among adolescents with asthma and rhinitis (OR = 3). Conclusions A high sensitisation rate to aeroallergens was observed, significantly higher among those with asthma, rhinitis or a combination of both, especially in multiple sensitisations.

OBJECTIVES The aim of this estudy was to investigate the influence of allergen exposure levels and other risk factors for allergic sensitization, asthma, and bronchial hyperresponsiveness (BHR) in workers exposed to laboratory animals. METHODS This was a cross-sectional study performed at two universities, 123 workplaces with 737 subjects. Dust samples were collected from laboratories and animal facilities housing rats, mice, guinea pigs, rabbits, or hamsters and analyzed by enzyme-linked immunosorbent assay (ELISA) to measure allergen concentrations. We also sampled workplaces without animals. Asthma was defined by both symptoms and BHR to mannitol. The concentrations of allergens were tested for association with a skin prick test, respiratory symptoms, spirometry data, and BHR. This multivariate analysis was performed by using Poisson regression to estimate the relative risk (RR) for the exposed group. RESULTS Our sample comprised students and workers, with 336 subjects in the nonexposed group and 401 subjects in the exposed group. Sixty-nine subjects (17%) had positive results in the skin prick test for animal allergens in the exposed group; in the nonexposed group, 10 subjects had positive results (3%) (p

Background: Current guidelines on chronic spontaneous urticaria (CSU) suggest a treatment based on a 3-step approach that aims at total symptom control, starting with H1-antihistamines. However, a significant number of patients present an antihistamine-resistant urticaria that must be treated with an alternative third-line therapy such as omalizumab. Methods: Patients with a history of CSU who did not respond to treatment with high doses of modern antihistamines were treated with 150 or 300 mg of omalizumab every 4 weeks. The response to treatment was recorded as complete (CR), partial (PR) or no response. A dose adjustment was proposed according to response. Results: We treated 47 CSU patients with omalizumab (40 females), of whom 39.5% had evidence of autoimmunity. The average number of treatments was 11.4 (range 2-87). All patients had been refractory to high-dose modern antihistamines. A CR was seen in 84.6% of patients who started with 300 mg and in 60% of those who started with 150 mg. Only 1 patient had no response to both the 150- and 300-mg doses. In 6 of the PR patients with 150 mg, a higher dose of 300 mg was proposed and 4 had a CR. Four patients discontinued the treatment. No severe adverse events were reported in the patients who finished the study. Discussion: Although good results were seen in both groups, CR rates were higher in those under a high-dose initial treatment. Our data strongly suggest that the therapy should be individualized.

Summary Background Sensitization to indoor allergens, particularly to dust mites, is a strong risk factor for asthma in children and adults. Assessment of sensitization is carried out using in vivo and in vitro tests to detect specific IgE antibodies. Objective To investigate IgE antibody responses to mites in patients with asthma, wheezing and/or rhinitis, using chimeric ELISA to measure specific IgE antibodies to mite allergens Der p 1 and Der p 2. Methods Specific IgE antibodies to Der p 1 and Der p 2 were quantified by chimeric ELISA, and compared with IgE to Dermatophagoides pteronyssinus (Dpt) measured using the CAP system (Pharmacia). A panel of sera from 212 patients with asthma, wheezing and/or rhinitis and 11 controls was analysed. Results There was a significant correlation between IgE to Dpt measured by CAP and IgE to Der p 1 (r = 0.81, P

Background Urine is increasingly becoming an attractive biological fluid in clinical practice due to being an easily obtained, non-invasive sampling method, containing proteins and peptides. The aim of this study was to investigate eosinophiluria, urinary eosinophil cationic protein (uECP) and urinary IL-5 (uIL-5) in patients with Lupus Nephritis. Methods Seventy-four patients with SLE—20 with clinical and laboratory evidence of lupus nephritis (LN group) and 54 without evidence of renal involvement (non-LN group)—were analyzed regarding eosinophiluria, uECP and uIL-5. Eosinophiluria was observed by Hansel's stain, ECP by fluoroenzymeimmunoassay and uIL-5 by quantitative sandwich enzyme immunoassay. Both uECP and urinary IL-5 (uIL-5) were corrected by urinary creatinine. Eosinophiluria and uECP were compared with glomerular erythrocyturia, protein/creatinine ratio (Pr/Cr ratio), serum creatinine, estimated glomerular filtration rate (eGFR), anti-double-stranded DNA (anti-dsDNA), serum levels of complement (C3 and C4), uIL-5/Cr ratio, and SLE disease activity index. Results Patients of the LN group had higher eosinophiluria, uECP, uECP/Cr ratio levels, and uIL-5 than patients of the non-LN group (p

Written questionnaires (WQ) have been widely used in epidemiologic studies. In order to yield comparable results, they must be validated after translation to another language. The International Study of Asthma and Allergies in Childhood (ISAAC) WQ has been previously validated by a comprehensive study, but its validation in Brazil has not been performed. Our objectives were to validate the rhinitis component of the ISAAC's self-applicable WQ following its translation to Portuguese, and to determine the prevalence of rhinitis and related symptoms among Brazilian children living in the city of Sao Paulo. A group of 10 pediatricians and 10 pediatric allergists graded the questions from 0 to 2 and established a maximum score for each question. The WQ was answered by parents or guardians of children 6-7 years of age with rhinitis (R) (n = 27) and of control children of the same age without rhinitis (C) (n = 27). The WQ was also completed by adolescents 13-14 years of age with rhinitis (R) (n = 32) and without rhinitis (C) (n = 32). Half of these individuals answered the same WQ after 2-4 weeks, to ensure reproducibility. Cut-off scores of 4 and 3 were identified for the 6-7- and 13-14-year-old groups, respectively, as scores predictive of rhinitis. The prevalence of rhinitis was 28.8% in the group of 3005 children 6-7 years of age and 31.7% in the group of 3008 children 13-14 years of age, respectively. Using the global cut-off score, these prevalences were even higher, in the order of 34.7% and 40.7%, respectively. In conclusion, the rhinitis component of the ISAAC WQ was proven to be reproducible, adequate and able to discriminate children and adolescents with and without rhinitis, and revealed that the prevalence of rhinitis among Brazilian children living in the city of Sao Paulo was as high as the prevalence of rhinitis in other areas of the world.

Cockroach allergy is an important health problem associated with the development of asthma, as a consequence of chronic exposure to low levels of allergens in susceptible individuals. In the last 20 years, progress in understanding the disease has been possible, thanks to the identification and molecular cloning of cockroach allergens and their expression as recombinant proteins. Assays for assessment of environmental allergen exposure have been developed and used to measure Bla g 1 and Bla g 2, as markers of cockroach exposure. IgE antibodies to cockroach extracts and to specific purified allergens have been measured to assess sensitization and analyze association with exposure and disease. With the development of the field of structural biology and the expression of recombinant cockroach allergens, insights into allergen structure, function, epitope mapping and allergen-antibody interactions have provided further understanding of mechanisms of cockroach allergic disease at the molecular level. This information will contribute to develop new approaches to allergen avoidance and to improve diagnosis and therapy of cockroach allergy.