Guia prático de atualização: medicamentos biológicos no tratamento da asma, doenças alérgicas e imunodeficiências / Practical update guide: biological drugs in the treatment of asthma, allergic diseases and immunodeficiencies

O presente guia apresenta revisão extensa sobre imunobiológicos utilizados, liberados e ainda sob estudo, para o tratamento da asma, doenças alérgicas e imunodeficiências. Além das características físico-químicas de alguns desses fármacos, são revisadas as indicações e os resultados de estudos clínicos realizados para avaliar eficácia e segurança. Separados por doença específica, são apresentados os principais agentes disponíveis e aprovados para utilização segundo as normas regulatórias nacionais.

This guide presents an extensive review of immunobiological drugs used, approved and/or under investigation for the treatment of asthma, allergic diseases and immunodeficiencies. In addition to the physicochemical characteristics of some of these drugs, their indications and results of clinical studies evaluating efficacy and safety are reviewed. The main agents available and approved for use in each specific disease according to national regulatory standards are presented.

Abnormal brown adipose tissue mitochondrial structure and function in IL10 deficiency.

BACKGROUND: Inflammation is the most relevant mechanism linking obesity with insulin-resistance and metabolic disease. It impacts the structure and function of tissues and organs involved in metabolism, such as the liver, pancreatic islets and the hypothalamus. Brown adipose tissue has emerged as an important component of whole body energy homeostasis, controlling caloric expenditure through the regulation of non-shivering thermogenesis. However, little is known about the impact of systemic inflammation on the structure and function of brown adipose tissue. METHODS: The relations between IL10 and mitochondria structure/function and also with thermogenesis were evaluated by bioinformatics using human and rodent data. Real-time PCR, immunoblot, fluorescence and transmission electron microscopy were employed to determine the effect of IL10 in the brown adipose tissue of wild type and IL10 knockout mice. FINDINGS: IL10 knockout mice, a model of systemic inflammation, present severe structural abnormalities of brown adipose tissue mitochondria, which are round-shaped with loss of cristae structure and increased fragmentation. IL10 deficiency leads to newborn cold intolerance and impaired UCP1-dependent brown adipose tissue mitochondrial respiration. The reduction of systemic inflammation with an anti-TNFα monoclonal antibody partially rescued the structural but not the functional abnormalities of brown adipose tissue mitochondria. Using bioinformatics analyses we show that in both humans and mice, IL10 transcripts correlate with mitochondrial lipid metabolism and caspase gene expression. INTERPRETATION: IL10 and systemic inflammation play a central role in the regulation of brown adipose tissue by controlling mitochondrial structure and function. FUND: Sao Paulo Research Foundation grant 2013/07607-8.

Corrigendum: A Novel Homozygous JAK3 Mutation Leading to T-B+NK- SCID in Two Brazilian Patients.

[This corrects the article DOI: 10.3389/fped.2018.00230.].

A Novel Homozygous JAK3 Mutation Leading to T-B+NK- SCID in Two Brazilian Patients.

We report a novel homozygous JAK3 mutation in two female Brazilian SCID infants from two unrelated kindreds. Patient 1 was referred at 2 months of age due to a family history of immunodeficiency and the appearance of a facial rash. The infant was screened for TRECs (T-cell receptor excision circles) and KRECs (kappa-deleting recombination excision circles) for the assessment of newly formed naïve T and B cells respectively, which showed undetectable TRECs and normal numbers of KRECs. Lymphocyte immunophenotyping by flow cytometry confirmed the screening results, revealing a T-B+NK- SCID. The patient underwent successful HSCT. Patient 2 was admitted to an intensive care unit at 8 months of age with severe pneumonia, BCGosis, and oral moniliasis; she also had a positive family history for SCID but newborn screening was not performed at birth. At 10 months of age she was diagnosed as a T-B+NK- SCID and underwent successful HSCT. JAK3 sequencing revealed the same homozygous missense mutation (c.2350G>A) in both patients. This mutation affects the last nucleotide of exon 17 and it is predicted to disrupt the donor splice site. cDNA sequencing revealed skipping of exon 17 missing in both patients, confirming the predicted effect on mRNA splicing. Skipping of exon 17 leads to an out of frame deletion of 151 nucleotides, frameshift and creation of a new stop codon 60 amino acids downstream of the mutation resulting in a truncated protein which is likely nonfunctional.

Adult Food Allergy Prevalence: Reducing Questionnaire Bias.

BACKGROUND: Food allergy (FA) prevalence has increased in the last decades, but epidemiologic studies could show overestimated results. The objective of this study is to estimate the prevalence of immediate FA in adults in a region of Central Brazil, using a questionnaire to try to reduce misperceptions about FA reaction. METHODS: A cross-sectional study was conducted, enrolling an adult population aged 18-65 years comprised of families in a Central Brazilian city. In the first phase, participants answered a self-administered questionnaire for FA screening. In the second phase, the participants who reported an FA in the first questionnaire were visited to complete the second questionnaire applied by trained researchers. RESULTS: Of the 4,916 adults visited, 1,583 returned a completed questionnaire. Reported FA occurred in 171 (10.8%) subjects, and the more frequent citations were cow's milk, pork, fruits, shrimp, and vegetables. One hundred and four of these individuals completed the second questionnaire, and 15 (1.0%) were considered to have an FA diagnosis. The main foods were fruits, followed by cow's milk, shrimp, pork, and vegetables. CONCLUSION: After use of a specific questionnaire to recognize possible IgE-mediated FAs, a low frequency of FA was considered in this population. Use of a directed questionnaire administered by trained researchers could be an alternative for epidemiological IgE-mediated FA studies to achieve more accurate results.

Spirometric parameters and levels of interferon gamma and IL-5 in induced sputum from patients with allergic rhinitis or asthma.

BACKGROUND: This study was designed to analyze spirometric parameters and cytokine (interferon [IFN] gamma and IL-5) levels in induced sputum from patients with asthma or allergic rhinitis (AR) and nonatopic subjects. METHODS: Thirty-three subjects aged 18-60 years were enrolled in the present study. Eight patients had asthma without AR symptoms, 16 had AR without asthma symptoms or history, and both groups had positive skin-prick test (SPT) to aeroallergens. The nine remaining subjects were healthy nonatopic subjects with negative SPT to aeroallergens. Spirometry was performed by evaluating the forced vital capacity (FVC), forced expiratory volume in the 1st second (FEV(1)), and forced expiratory flow between 25 and 75% (FEF(25-75)) of FVC before and after bronchodilator use. Induced sputum samples were also collected for measuring cytokine (IFN-gamma and IL-5) levels by enzyme-linked immunosorbent assay. RESULTS: Significant pre- and postbronchodilator change was observed only for FEV(1) with higher variation values in asthmatic subjects compared with patients with AR (p < 0.05) and nonatopic subjects (p < 0.01). There was no significant difference in pre- and postbronchodilator spirometric parameters among the three groups, although asthmatic patients showed lower prebronchodilator FEF(25-75) values (p = 0.065). IL-5 levels were higher in induced sputum from patients with asthma and AR compared with nonatopic subjects (p = 0.020 and p = 0.032, respectively), but IFN-gamma levels showed no significant difference between the groups. CONCLUSION: Spirometric measurements were not able to show any occurrence of bronchial constriction in patients with AR, but predominant IL-5 levels in induced sputum from these patients reinforce the role of Th2-type immune response in lower respiratory airways that could contribute to the concept of "one airway, one disease."

Serum and salivary IgE, IgA, and IgG4 antibodies to Dermatophagoides pteronyssinus and its major allergens, Der p1 and Der p2, in allergic and nonallergic children.

Allergic rhinitis (AR) is a public health problem with high prevalence worldwide. We evaluated levels of specific IgE, IgA, and IgG4 antibodies to the Dermatophagoides pteronyssinus (Dpt) house dust mite and to its major allergens (Der p1 and Der p2) in serum and saliva samples from allergic and nonallergic children. A total of 86 children were analyzed, from which 72 had AR and 14 were nonallergic healthy children. Serum IgE and serum/salivary IgG4 levels to Dpt, Der p1, and Der p2 were higher in allergic children whereas serum/salivary IgA levels to all allergens were higher in nonallergic children. IgE levels positively correlated with IgG4 and IgA to all allergens in allergic children, while IgA levels negatively correlated with IgG4 to Dpt and Der p1 in nonallergic children. In conclusion, mite-specific IgA antibodies predominate in the serum and saliva of nonallergic children whereas mite-specific IgE and IgG4 are prevalent in allergic children. The presence of specific IgA appears to have a key role for the healthy immune response to mucosal allergens. Also, specific IgA measurements in serum and/or saliva may be useful for monitoring activation of tolerance-inducing mechanisms during allergen specific immunotherapeutic procedures, especially sublingual immunotherapy.

Spirometric parameters and levels of interferon gamma and IL-5 in induced sputum from patients with allergic rhinitis or asthma.

BACKGROUND: This study was designed to analyze spirometric parameters and cytokine (interferon [IFN] gamma and IL-5) levels in induced sputum from patients with asthma or allergic rhinitis (AR) and nonatopic subjects. METHODS: Thirty-three subjects aged 18-60 years were enrolled in the present study. Eight patients had asthma without AR symptoms, 16 had AR without asthma symptoms or history, and both groups had positive skin-prick test (SPT) to aeroallergens. The nine remaining subjects were healthy nonatopic subjects with negative SPT to aeroallergens. Spirometry was performed by evaluating the forced vital capacity (FVC), forced expiratory volume in the 1st second (FEV1), and forced expiratory flow between 25 and 75% (FEF25-75) of FVC before and after bronchodilator use. Induced sputum samples were also collected for measuring cytokine (IFN-gamma and IL-5) levels by enzyme-linked immunosorbent assay. RESULTS: Significant pre- and postbronchodilator change was observed only for FEV1 with higher variation values in asthmatic subjects compared with patients with AR (p < 0.05) and nonatopic subjects (p < 0.01). There was no significant difference in pre- and postbronchodilator spirometric parameters among the three groups, although asthmatic patients showed lower prebronchodilator FEF25-75 values (p = 0.065). IL-5 levels were higher in induced sputum from patients with asthma and AR compared with nonatopic subjects (p = 0.020 and p = 0.032, respectively), but IFN-gamma levels showed no significant difference between the groups. CONCLUSION: Spirometric measurements were not able to show any occurrence of bronchial constriction in patients with AR, but predominant IL-5 levels in induced sputum from these patients reinforce the role of Th2-type immune response in lower respiratory airways that could contribute to the concept of "one airway, one disease."

Deficiência de anticorpos anti-polissacarídicos: relato de casos / Impaired polysaccharide responsiveness: cases report

Introdução: A deficiência de anticorpos antipolissacaride ou deficiência parcial de anticorpos é considerada uma dasquatro imunodeficiências mais comuns da infância e sua principal manifestação são as infecções bacterianas repetitivas das vias aéreas.Descrição: São relatados casos de três pacientes com historta de infecções de repetição de diferentes evoluções cujaavaliação imunológica demonstrou uma produção alterada de anticorpos ao Streptococcus pneumoniae após imunização para os sorotipos testados, embora apresentasse níveis normais deimunoglobulinas, cuja instalação de um tratamento adequado promoveu a redução nas infecções bem como da qualidade de vida desses pacientes.Comentários: A grande maioria dos pacientes com deficiência de anticorpos antipolissacaride necessita de tratamento antibiótico agressivo nas infecções, cursos de antibióticos profiláticos, e em alguns casos, de terapia de reposição de imuneglobulinas.Alguns pacientes podem se beneficiar da vacinação heptavalente conjugada para o S.pneumoniae. É necessárioampliar a informação médica com relação ao diagnóstico apresentadonessa série, bem como, melhorar a rede laboratorial de propedêutica diagnóstica para permitir a identificação dessa patologia.

Introduction: Impaired polysaccharide responsiveness or partial antibodies defect is considered one of the four mostcommon immunodeficiencies in pediatric patients and is characterized by recurrent bacterial respiratory infectlons.Description: Three cases are related with a recurrent infections history with different evaluations, which immunological evaluations showed impaired antibodies response againstStreptococcus pneumoniae after immunization for tested serotypes,although presented normal leveis of immunoglobulin. The adequate treatment reduced the number and severity of infections and improved the patient's quality of life.Comments: The majority of patients with impaired polysaccharide responsiveness require aggressive antibiotic treatmentduring infections, serres of prophylactic antibiotics, and, rarely, IgG replacement. Some patients may clinicai benefit from írnmunization with the conjugate vaccine to S.pneumoniae. It'simportant to improve the medical information about the presenteddiagnosis, in addition to amplify the number of practiced laboratories to better identification of this disease.

Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): description of a rare non-exon 3 and a novel CIAS1 missense mutation.

We describe in this paper the phenotype-genotype analysis of a Brazilian cohort of patients with cryopyrin-associated periodic syndromes (CAPS). Patient 1 presented with an urticarial rash and recurrent fever exacerbated by cold weather, arthritis, and anterior uveitis, thus, receiving a clinical diagnosis of familial cold autoinflammatory syndrome. CIAS1 sequencing identified the T436I mutation, previously associated to a clinical phenotype of chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease. Patient 2 developed a papular exanthema with daily fever shortly after birth, frontal bossing, patellae enlargement, and cognitive and motor impairments. Sequencing identified the exceedingly rare G755R CIAS1 mutation in exon 4. Patient 3 developed skin rash and articular symptoms 6 h after birth, followed by aseptic meningitis. He was found to have the novel C148Y missense mutation in CIAS1. This report expands the spectrum of CIAS1 mutations associated to clinical disease, suggests that the same mutation can be associated with different clinical syndromes, and supports the evidence that CAPS patients should always be screened for mutations outside exon 3.

Atendimento do paciente com sibilos em Serviço de Emergência Pediátrica de Hospital Terciário / Management of wheezing patient in Pediatric Emergency Room in a Tertiary Hospital

Objetivo: Estudar a abordagem aos quadros de sibilância infantil no pronto socorro de um Hospital Terciário. Métodos: Foi realizado estudo de coorte transversal, descritivo, com análise das Guias de Atendimento de Emergência (GAE) de pacientes atendidos durante a primeira semana de julho de 2003, sendo selecionadas as guias com diagnóstico de asma, bronquite, sibilância ou broncoespasmo (BE), como marcadores de sibilância e/ou crises de asma. Resultados: Do total de 1167 atendimentos, 130 foram por diagnósticos usados como marcadores de sibilância, com idades entre dois meses e onze anos. Noventa e quatro por cento das guias permitiram avaliar dados referentes à gravidade da crise, mas apenas 30

Detection of immunoglobulin G antibodies to Neospora caninum in humans: high seropositivity rates in patients who are infected by human immunodeficiency virus or have neurological disorders.

Considering that little is known about the epidemiology of Neospora caninum infection in humans, particularly in populations with high Toxoplasma gondii infection rates, the present study aimed to investigate the presence of antibodies to N. caninum in T. gondii-seropositive and -seronegative individuals. A total of 256 serum samples divided into four groups (61 samples from human immunodeficiency virus [HIV]-positive patients, 50 samples from patients with neurological disorders, 91 samples from newborns, and 54 samples from healthy subjects) were assessed for N. caninum and T. gondii serologies by indirect fluorescent-antibody test, enzyme-linked immunosorbent assay, and immunoblotting (IB). Immunoglobulin G antibodies to N. caninum were predominantly detected in HIV-infected patients (38%) and patients with neurological disorders (18%), while newborns and healthy subjects showed lower seropositivity rates (5% and 6%, respectively). Seropositivity to N. caninum was significantly associated with seropositivity to T. gondii in both HIV-infected patients and patients with neurological disorders. Seroreactivity to N. caninum was confirmed by IB, with positive sera predominantly recognizing the 29-kDa antigen of N. caninum. The results of this study indicate the presence of N. caninum infection or exposure in humans, particularly in HIV-infected patients or patients with neurological disorders, who could have opportunistic and concurrent infections with T. gondii. These findings may bring a new concern for the unstable clinical health of HIV-infected patients and the actual role of N. caninum infection in immunocompromised patients.

Exposição alergênica em cinemas na cidade de Goiânia, GO / Allergen exposure in cinemas of Goiânia, Brazil

Objetivo: Avaliar a presença e nível dos alérgenos de Dermatophagoides pteronyssinus (Der p 1), Dermatophagoides farinae (Der f 1), Canis familiares (Can f 1), Felis domesticus (Fel d 1) e Blattella germanica (Bla g 2) em cinemas na cidade de Goiânia, GO, Brasil. Métodos: Foram coletadas amostras de poeira do chão e dos assentos da frente, do meio e do fundo de salas de cinemas, num total de 30 amostras após consentimento informado dos proprietários. A detecção dos alérgenos foi realizada pelo método ELISA.Resultados: As concentrações médias de alérgenos encontradas nos cinemas em 1g/g foram 0,35, 6,87, 0,65 e 0,07, respectivamente para Der p 1, Der f 1, Can f 1 e Fel d 1. Em nenhuma amostra foi possível a detecção de alérgenos de barata. Níveis sensibilizantes de alergénos foram observados em 76,6 per cent das amostras de Der f 1, mas também ocorreram para Der p 1 (3,33 per cent) e Can f 1 (10,0 per cent). Em 20 per cent das amostras, osníveis de Der f 1 encontrado foram superiores os considerados de risco para exacerbações das doenças alérgicas. Conclusões: As salas de cinema são ambientes fechados nas quais indivíduos susceptíveis podem entrar em contato com alérgenos e desencadearem exacerbações. Medidas para a redução dos níveis de alérgenos em locais públicos devem ser adotadas como estratégia global de controle ambiental para a melhoria da qualidade de vida em indivíduos atópicos.

Mite and pet allergen exposure in Brazilian private cars.

BACKGROUND: The role of mite and pet allergens in the development of allergic diseases has been recognized for many years. OBJECTIVE: To determine mite (Dermatophagoides pteronyssinus [Der p 1] and Dermatophagoidesfarinae [Der f 1]), cat (Felis domesticus [Fel d 1]), and dog (Canis familiaris [Can f 1]) allergen levels in Brazilian private cars. METHODS: Mite, cat, and dog allergens were measured in dust samples collected from 60 upholstered seats of private vehicles using enzyme-linked immunosorbent assays. RESULTS: Mean levels of Der p 1 (0.24 microg/g of dust; range, 0.06-2.05 microg/g of dust) and Der f 1 (0.29 microg/g of dust; range, 0.06-2.07 microg/g of dust) were extremely low in most dust samples analyzed. In contrast, sensitizing mean levels of Can f 1 (1.51 microg/g of dust; range, 0.14-30.96 microg/g of dust) and Fel d 1 (0.43 microg/g of dust; range, 0.02-5.75 microg/g of dust) were observed in 32 (53%) and 12 (20%) samples, respectively. Mean Can f 1 levels were significantly higher in cars whose owners kept dogs at home (3.27 microg/g of dust) than in those without pets (0.57 microg/g of dust; P = .008). There were no significant differences in allergen levels regarding the age of the vehicle or the number of users and whether the owners transport pets inside the vehicles. CONCLUSIONS: Private cars constitute an important pet, but not mite, allergen reservoir for continuous contamination of the indoor environment. Pet allergens may be present even in cars whose owners do not have pets. Effective measures to reduce allergen exposure in cars should be taken routinely, especially for pet-allergic patients.

Exposição alergênica em veículos privados de passeio e de transporte escolar em Uberlândia, MG / Allergen exposure in private cars and school transportation vehicles in Uberlandia, Brazil

Objetivo: Determinar o nível dos alérgenos de Dermatophagoies pteronyssinus (Der p 1), Dermatophagoies farinae (Der f 1), Canis familiaris (Can f 1) e Felis domesticus (Fe d 1) em veículos privados de passeio (VPP) e em veículos de transporte escolar (VT ) na cidade de Uberlândia, MG. Métodos: Foram coletadas amostras de poeira dos assentos de 60 VPP e 60 VT após consentimento informado dos proprietários e aplicação de questionários relativos às características dos veículos, propriedade e transporte de animais, bem como número de passageiros. A quantificação dos alérgenos foi realizada pelo método LISA de duplo anticorpo. Resultados: Baixos níveis de Der p 1 e Der f 1 foram detectados em ambos os tipos de veículos. Can f 1 foi o alérgeno predominante, com médias geométricas de 1,51 8g/g (IC 95: 0,99 menos 2,31 8g/g) em VPP e 1,03 8g/g (IC 95: 0,66 menos1,62 8g/g) em VT . Níveis sensibilizantes ³ mg/g de poeira) de Can f 1 foram encontrados em 32/60 (53,3) dos VPP e 36/60 (60) dos VT , enquanto níveis sensibilizantes de Fel d 1 foram detectados em 12/60 (20) dos VPP e 16/60 (27) os VT. Conclusões: Os veículos apresentam níveis sensibilizantes de alérgenos de animais domésticos, principamente Can f 1. A realização de medidas para redução desses alérgenos, haja visto a freqüência de uso desses veículos, é importante para uma adequada estratégia global de controle ambienta em pacientes atópicos.