Gut microbiome signature and nasal lavage inflammatory markers in young people with asthma.

Background: Asthma is a complex disease and a severe global public health problem resulting from interactions between genetic background and environmental exposures. It has been suggested that gut microbiota may be related to asthma development; however, such relationships needs further investigation. Objective: This study aimed to characterize the gut microbiota as well as the nasal lavage cytokine profile of asthmatic and nonasthmatic individuals. Methods: Stool and nasal lavage samples were collected from 29 children and adolescents with type 2 asthma and 28 children without asthma in Brazil. Amplicon sequencing of the stool bacterial V4 region of the 16S rRNA gene was performed using Illumina MiSeq. Microbiota analysis was performed by QIIME 2 and PICRUSt2. Type 2 asthma phenotype was characterized by high sputum eosinophil counts and positive skin prick tests for house dust mite, cockroach, and/or cat or dog dander. The nasal immune marker profile was assessed using a customized multiplex panel. Results: Stool microbiota differed significantly between asthmatic and nonasthmatic participants (P = .001). Bacteroides was more abundant in participants with asthma (P < .05), while Prevotella was more abundant in nonasthmatic individuals (P < .05). In people with asthma, the relative abundance of Bacteroides correlated with IL-4 concentration in nasal lavage samples. Inference of microbiota functional capacity identified differential fatty acid biosynthesis in asthmatic compared to nonasthmatic subjects. Conclusion: The stool microbiota differed between asthmatic and nonasthmatic young people in Brazil. Asthma was associated with higher Bacteroides levels, which correlated with nasal IL-4 concentration.

A network meta-analysis of the association between patient traits and response to regular dosing with ICS plus short-acting ß2-agonist reliever or ICS/formoterol reliever only in mild asthma.

INTRODUCTION/BACKGROUND: Mild asthma treatment recommendations include intermittent inhaled corticosteroid (ICS)/formoterol dosing or regular ICS dosing with short-acting ß2-agonist reliever. Due to the heterogeneity of asthma, identification of traits associated with improved outcomes to specific treatments would be clinically beneficial. AIMS/OBJECTIVES: To assess the impact of patient traits on treatment outcomes of regular ICS dosing compared with intermittent ICS/formoterol dosing, a systematic literature review (SLR) and network meta-analysis (NMA) was conducted. Searches identified randomised controlled trials (RCTs) of patients with asthma aged ≥12 years, containing ≥1 regular ICS dosing or intermittent ICS/formoterol dosing treatment arm, reporting traits and outcomes of interest. RESULTS: The SLR identified 11 RCTs of mild asthma, of 14,516 patients. A total of 11 traits and 11 outcomes of interest were identified. Of these, a feasibility assessment indicated possible assessment of three traits (age, baseline lung function, smoking history) and two outcomes (exacerbation rate, change in lung function). The NMA found no significant association of any trait with any outcome with regular ICS dosing relative to intermittent ICS/formoterol dosing. Inconsistent reporting of traits and outcomes between RCTs limited analysis. CONCLUSIONS: This is the first systematic analysis of associations between patient traits and differential treatment outcomes in mild asthma. Although the traits analysed were not found to significantly interact with relative treatment response, inconsistent reporting from the RCTs prevented assessment of some of the most clinically relevant traits and outcomes, such as adherence. More consistent reporting of respiratory RCTs would provide more comparable data and aid future analyses.

Overprescription of short-acting ß2 agonists: reflections from the SABINA study in Brazil.

OBJECTIVE: To assess prescription patterns for short-acting b2 agonists (SABAs) and other asthma medications in asthma patients treated by specialists and participating in the SABA use IN Asthma (SABINA) study in Brazil. METHODS: This was an observational, cross-sectional study conducted at five sites in different regions of Brazil. The primary endpoints were to record SABA prescriptions and obtain data on over-the-counter (OTC) SABA purchases at the pharmacy. RESULTS: Data on 218 asthma patients were analyzed. Of those 218 patients, 80.3% were prescribed SABAs in addition to their maintenance therapy, with a mean of 11.2 SABA canisters in the previous 12 months. Of those patients, 71.4% were prescribed ≥ 3 canisters and 42.2% were prescribed ≥ 10 canisters. None of the patients were prescribed SABA monotherapy. A total of 14.2% of the patients reported purchasing SABAs OTC at a pharmacy without a prescription. Of those, 48.4% purchased ≥ 3 SABA canisters. A fixed-dose combination of an inhaled corticosteroid and a long-acting b2 agonist was prescribed to 95.0% of the patients. In the year before the study visit, 45.0% of the patients received at least one course of oral corticosteroid burst treatment. Asthma was well controlled in 43.1% of the patients, partly controlled in 34.9%, and uncontrolled in 22.0%. Patients reported a mean of 1.1 severe asthma exacerbations, with 49.1% experiencing 1 or more severe exacerbations. CONCLUSIONS: Overprescription and OTC purchases of SABAs are common in Brazil, possibly leading to the need for courses of oral corticosteroids. The health care community should collaborate to implement evidence-based recommendations and promote health education to improve asthma management in Brazil.

Asthma and rhinitis control in adolescents and young adults: A real-world MASK-air study.

BACKGROUND: In allergic rhinitis and asthma, adolescents and young adult patients are likely to differ from older patients. We compared adolescents, young adults and adults on symptoms, control levels, and medication adherence. METHODS: In a cross-sectional study (2015-2022), we assessed European users of the MASK-air mHealth app of three age groups: adolescents (13-18 years), young adults (18-26 years), and adults (>26 years). We compared them on their reported rhinitis and asthma symptoms, use and adherence to rhinitis and asthma treatment and app adherence. Allergy symptoms and control were assessed by means of visual analogue scales (VASs) on rhinitis or asthma, the combined symptom-medication score (CSMS), and the electronic daily control score for asthma (e-DASTHMA). We built multivariable regression models to compare symptoms or medication accounting for potential differences in demographic characteristics and baseline severity. RESULTS: We assessed 965 adolescent users (15,252 days), 4595 young adults (58,161 days), and 15,154 adult users (258,796 days). Users of all three age groups displayed similar app adherence. In multivariable models, age groups were not found to significantly differ in their adherence to rhinitis or asthma medication. These models also found that adolescents reported lower VAS on global allergy, ocular, and asthma symptoms (as well as lower CSMS) than young adults and adults. CONCLUSIONS: Adolescents reported a better rhinitis and asthma control than young adults and adults, even though similar medication adherence levels were observed across age groups. These results pave the way for future studies on understanding how adolescents control their allergic diseases.

Systematic literature review of traits and outcomes reported in randomised controlled trials of asthma with regular dosing of inhaled corticosteroids with short-acting ß2-agonist reliever, as-needed ICS/formoterol, or ICS/formoterol maintenance and reliever therapy.

INTRODUCTION: Asthma treatments based solely on diagnostic label do not benefit patients equally. To identify patient traits that may be associated with improved treatment response to regular inhaled corticosteroid (ICSs) dosing with short-acting ß2-agonist reliever or ICS/formoterol-containing therapy, a systematic literature review (SLR) was conducted. METHODS: Searches of databases including MEDLINE and Embase identified randomised controlled trials (RCTs) of patients with asthma, aged ≥12 years, published 1998-2022, containing ≥1 regular ICS dosing or ICS/formoterol-containing treatment arm, and reporting patient traits and outcomes of interest. Relevant data was extracted and underwent a feasibility assessment to determine suitability for meta-analysis. RESULTS: The SLR identified 39 RCTs of 72,740 patients and 90 treatment arms, reporting 11 traits and 11 outcomes. Five patient traits (age, body mass index, FEV1, smoking history, asthma control) and five outcomes (exacerbation rate, lung function, asthma control, adherence, time to first exacerbation) were deemed feasible for inclusion in meta-analyses due to sufficient comparable reporting. Subgroups of clinical outcomes stratified by levels of patient traits were reported in 16 RCTs. CONCLUSION: A systematic review of studies of regular ICS dosing with SABA or ICS/formoterol-containing treatment strategies in asthma identified consistent reporting of five traits and outcomes, allowing exploration of associations with treatment response. Conversely, many other traits and outcomes, although being potentially relevant, were inconsistently reported and limited subgroup reporting meant analyses of treatment response for subgroups of traits was not possible. We recommend more consistent measurement and reporting of clinically relevant patient traits and outcomes in respiratory RCTs.

Overprescription of short-acting β2 agonists: reflections from the SABINA study in Brazil / Prescrição excessiva de β2-agonistas de curta duração: reflexões a partir do estudo SABINA no Brasil

ABSTRACT Objective: To assess prescription patterns for short-acting b2 agonists (SABAs) and other asthma medications in asthma patients treated by specialists and participating in the SABA use IN Asthma (SABINA) study in Brazil. Methods: This was an observational, cross-sectional study conducted at five sites in different regions of Brazil. The primary endpoints were to record SABA prescriptions and obtain data on over-the-counter (OTC) SABA purchases at the pharmacy. Results: Data on 218 asthma patients were analyzed. Of those 218 patients, 80.3% were prescribed SABAs in addition to their maintenance therapy, with a mean of 11.2 SABA canisters in the previous 12 months. Of those patients, 71.4% were prescribed ≥ 3 canisters and 42.2% were prescribed ≥ 10 canisters. None of the patients were prescribed SABA monotherapy. A total of 14.2% of the patients reported purchasing SABAs OTC at a pharmacy without a prescription. Of those, 48.4% purchased ≥ 3 SABA canisters. A fixed-dose combination of an inhaled corticosteroid and a long-acting b2 agonist was prescribed to 95.0% of the patients. In the year before the study visit, 45.0% of the patients received at least one course of oral corticosteroid burst treatment. Asthma was well controlled in 43.1% of the patients, partly controlled in 34.9%, and uncontrolled in 22.0%. Patients reported a mean of 1.1 severe asthma exacerbations, with 49.1% experiencing 1 or more severe exacerbations. Conclusions: Overprescription and OTC purchases of SABAs are common in Brazil, possibly leading to the need for courses of oral corticosteroids. The health care community should collaborate to implement evidence-based recommendations and promote health education to improve asthma management in Brazil.

RESUMO Objetivo: Avaliar os padrões de prescrição de short-acting b2 agonists (SABAs, b2-agonistas de curta duração) e outros medicamentos para asma em pacientes tratados por especialistas e participantes do estudo SABA use IN Asthma (SABINA) no Brasil. Métodos: Trata-se de um estudo transversal observacional realizado em cinco locais em diferentes regiões do Brasil. Os desfechos primários foram registrar as prescrições de SABAs e obter dados a respeito da compra de SABAs sem receita médica na farmácia. Resultados: Foram analisados dados a respeito de 218 pacientes com asma. Dos 218 pacientes, 80,3% receberam prescrição de SABA além da terapia de manutenção, com uma média de 11,2 frascos de SABA nos 12 meses anteriores. Destes, 71,4% receberam prescrição de ≥ 3 frascos e 42,2% receberam prescrição de ≥ 10 frascos. Nenhum dos pacientes recebeu prescrição de monoterapia com SABA. Do total de pacientes, 14,2% relataram que compraram SABAs sem receita médica na farmácia. Destes, 48,4% compraram ≥ 3 frascos de SABA. Foram prescritas doses fixas combinadas de corticosteroide inalatório e b2-agonista de longa duração para 95,0% dos pacientes. No ano anterior à visita do estudo, 45,0% dos pacientes receberam pelo menos um ciclo de tratamento de curta duração com corticosteroide oral. A asma estava bem controlada em 43,1% dos pacientes, parcialmente controlada em 34,9% e não controlada em 22,0%. Os pacientes relataram uma média de 1,1 exacerbações graves da asma, sendo que 49,1% apresentaram uma ou mais exacerbações graves. Conclusões: A prescrição excessiva e a compra de SABAs sem receita médica são comuns no Brasil e possivelmente levam à necessidade de uso de corticosteroides orais. A comunidade de profissionais de saúde deve colaborar para implantar recomendações baseadas em evidências e promover a educação em saúde para melhorar o manejo da asma no Brasil.

Aeroallergen sensitization patterns among patients with chronic rhinitis with or without concomitant asthma.

OBJECTIVES: The aim of this study was to explore the differences in the pattern of allergen sensitization in CR individuals without or with asthma, according to asthma severity. METHODS: A total of 1066 adults were evaluated. Asthma and chronic/allergic rhinits were identified by specialists, questionnaries and skin-prick test. The phenotypic characterization was avaliable from skin-prick test to an aeroallergen extended panel, total IgE and pulmonary function. Using questionnaires and clinical evaluation, participants were classified into the groups: chronic rhinitis alone (CRA) and chronic rhinitis + asthma, the latter subdivided into CR + mild asthma (CRMA) and CR + moderate to severe asthma (CRMSA). Aerollergen sensitization was defined by a positive prick test to one or more allergens associated with nasal symptoms and/or asthma. The association between CR and asthma was evaluated by multivariable logistic regression. The evidence of effect modification of pattern of sensitization in CR on the association with asthma severity and outcomes was examined by introducing interactions terms in the logistic regression models adjusting for confounders. RESULTS: Frequency of sensitization to aeroallergens was higher in association with asthma in comparison to CRA (CRMA 70.4%; CRMSA 65.0%; CRA 47.0%; p = 0.000). Similarly, the presence of asthma was associated to aeroallergen multiple sensitization (51.5%) (OR = 2.10, 95% CI 1.27-3.50). Additionally, the sensitization to mites, cockroaches, animal epithelium, grasses, and molds, were higher in asthma (56.8%, 24.3%, 12%, 7.13% and 10.3%, respectively). Sensitization to Alternaria alternata, Cladosporium herbarum and dog epithelium was exclusive in asthma groups. A concomitant asthma diagnosis was directly associated with a positive allergen sensitization at least one allergen (62.7%, OR = 2.45, 95% CI 1.80-3.34) and polissensitization (51.5%, OR = 2.10, 95% CI 1.27-3.50). CONCLUSION: Asthma is associated with multiple allergen sensitization among patients with CR. Some unique profiles of aeroallergen sensitization were observed in patients with CR and asthma. Nevertheless, no difference was found in the sensitization in relation to asthma severity, which suggest atopy is not the main underlying mechanism for asthma severity among patients with CR. LEVEL OF EVIDENCE: Level 3.

Aedes aegypti D7 long salivary proteins modulate blood feeding and parasite infection.

Mosquito saliva facilitates blood meal acquisition through pharmacologically active compounds that prevent host hemostasis and immune responses. Here, we generated two knockout (KO) mosquito lines by CRISPR/Cas9 to functionally characterize D7L1 and D7L2, two abundantly expressed salivary proteins from the yellow fever mosquito vector Aedes aegypti. The D7s bind and scavenge biogenic amines and eicosanoids involved in hemostasis at the bite site. The absence of D7 proteins in the salivary glands of KO mosquitoes was confirmed by mass spectrometry, enzyme-linked immunosorbent assay, and fluorescence microscopy of the salivary glands with specific antibodies. D7-KO mosquitoes had longer probing times than parental wildtypes. The differences in probing time were abolished when mutant mice resistant to inflammatory insults were used. These results confirmed the role of D7 proteins as leukotriene scavengers in vivo. We also investigated the role of D7 salivary proteins in Plasmodium gallinaceum infection and transmission. Both KO lines had significantly fewer oocysts per midgut. We hypothesize that the absence of D7 proteins in the midgut of KO mosquitoes might be responsible for creating a harsh environment for the parasite. The information generated by this work highlights the biological functionality of salivary gene products in blood feeding and pathogen infection. IMPORTANCE During blood feeding, mosquitoes inject saliva into the host skin, preventing hemostasis and inflammatory responses. D7 proteins are among the most abundant components of the saliva of blood-feeding arthropods. Aedes aegypti, the vector of yellow fever and dengue, expresses two D7 long-form salivary proteins: D7L1 and D7L2. These proteins bind and counteract hemostatic agonists such as biogenic amines and leukotrienes. D7L1 and D7L2 knockout mosquitoes showed prolonged probing times and carried significantly less Plasmodium gallinaceum oocysts per midgut than wild-type mosquitoes. We hypothesize that reingested D7s play a vital role in the midgut microenvironment with important consequences for pathogen infection and transmission.

The heat shock protein Hsc70-3 mediates an anti-apoptotic response critical for Plasmodium evasion of Anopheles gambiae immunity.

IMPORTANCE: Malaria transmission by Anopheles gambiae mosquitoes is very effective, in part because the parasite expresses a surface protein called Pfs47 that allows it to evade the mosquito immune system. Here we investigate how this protein changes the response of mosquito midgut epithelial cells to invasion by the parasite. Pfs47 is known to interact with P47Rec, a mosquito midgut receptor. We found that Pf47Rec inhibits caspase-mediated apoptosis by interacting with the Hsc70-3. This disrupts nitration of midgut epithelial cells invaded by the parasite and the release of hemocyte-derived microvesicles, which are critical for effective activation of the mosquito complement system that eliminates the parasite.

Design of smart nanoparticles for the electrochemical detection of 3,4-methylenedioxymethamphetamine to allow in field screening by law enforcement officers.

A portable and highly sensitive sensor was designed for the specific detection of 3,4-methyl-enedioxy-methamphetamine (MDMA), in a range of field-testing situations. The sensor can detect MDMA in street samples, even when other controlled substances drugs, or adulterants are present. In this work, we report for the first time a sensor using electroactive molecularly imprinted polymer nanoparticles computationally designed to recognize MDMA and then produced using solid phase synthesis. A composite comprising chitosan, reduced graphene oxide, and molecularly imprinted polymer nanoparticles synthesized for MDMA for the first time was immobilized on screen-printed carbon electrodes. The sensors displayed a satisfactory sensitivity (106.8 nA × µM-1 ), limit of detection (1.6 nM; 0.31 ng/mL), and recoveries (92-99%). The accuracy of the results was confirmed through validation using Ultra-High Performance Liquid Chromatography coupled with tandem Mass Spectrometry (UPLC-MS/MS). This technology could be used in forensic analysis and make it possible to selectively detect MDMA in street samples.

Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper.

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nano-technologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime.

BAFF system expression in double negative 2, activated naïve and activated memory B cells in systemic lupus erythematosus.

Introduction: B cell activating factor (BAFF) has an important role in normal B cell development. The aberrant expression of BAFF is related with the autoimmune diseases development like Systemic Lupus Erythematosus (SLE) for promoting self-reactive B cells survival. BAFF functions are exerted through its receptors BAFF-R (BR3), transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) that are reported to have differential expression on B cells in SLE. Recently, atypical B cells that express CD11c have been associated with SLE because they are prone to develop into antibody-secreting cells, however the relationship with BAFF remains unclear. This study aims to analyze the BAFF system expression on CXCR5- CD11c+ atypical B cell subsets double negative 2 (DN2), activated naïve (aNAV), switched memory (SWM) and unswitched memory (USM) B cells. Methods: Forty-five SLE patients and 15 healthy subjects (HS) were included. Flow cytometry was used to evaluate the expression of the receptors in the B cell subpopulations. Enzyme-linked immunosorbent assay (ELISA) was performed to quantify the soluble levels of BAFF (sBAFF) and IL-21. Results: We found increased frequency of CXCR5- CD11c+ atypical B cell subpopulations DN2, aNAV, SWM and USM B cells in SLE patients compared to HS. SLE patients had increased expression of membrane BAFF (mBAFF) and BCMA receptor in classic B cell subsets (DN, NAV, SWM and USM). Also, the CXCR5+ CD11c- DN1, resting naïve (rNAV), SWM and USM B cell subsets showed higher mBAFF expression in SLE. CXCR5- CD11c+ atypical B cell subpopulations DN2, SWM and USM B cells showed strong correlations with the expression of BAFF receptors. The atypical B cells DN2 in SLE showed significant decreased expression of TACI, which correlated with higher IL-21 levels. Also, lower expression of TACI in atypical B cell DN2 was associated with high disease activity. Discussion: These results suggest a participation of the BAFF system in CXCR5- CD11c+ atypical B cell subsets in SLE patients. Decreased TACI expression on atypical B cells DN2 correlated with high disease activity in SLE patients supporting the immunoregulatory role of TACI in autoimmunity.

Genetic variants associated with SARS-CoV-2 infection also affect lung function and asthma severity.

Background: Host genetic factors may be associated with COVID-19 unfavourable outcomes. The first genome-wide association study (GWAS) conducted in individuals with respiratory failure due to COVID-19 revealed susceptibility loci close to six genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1) and the ABO blood-group gene. We aimed to investigate how polymorphisms in those genes could relate to lung function and severe asthma in a Brazilian population. Methods: DNA samples of 784 individuals following the ProAR (Programa para Controle da Asma e Rinite Alérgica da Bahia) were genotyped by the Multi-Ethnic Global Array panel with ∼2 million polymorphisms (Illumina). Polymorphisms in SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1 and the ABO blood-group gene were evaluated. Logistic regression for severe asthma, airway obstruction and lack of FEV1 reversibility was performed using PLINK software 1.9, in the additive model and was adjusted for sex, age and PCA-1. Pairwise Linkage disequilibrium analyses were performed using Haploview 4.2. The haplotypes and gene score analyses were performed in the SNPstat tool. In silico functions of polymorphisms were analysed using rSNPbase and RegulomeDB plataforms. Results: We identified the rs8176733 (G allele) and rs8176725 (A allele) in the ABO blood-group gene as risk factors for severe asthma, lower pulmonary obstruction and lack of FEV1 reversibility. Polymorphisms in CCR9 are risk factors for both severe asthma (A allele of rs34338823) and airway obstruction (A allele of rs6806802). The markers rs13079478 (A allele) and rs75817942 (A allele) in FYCO1 are related to more severe asthma and a lack of FEV1 reversibility, respectively. We identified the A allele of both rs35731912 and rs34338823 in LZTFL1 as risk factors for severe asthma. The marker rs6806802 (C allele) was associated with airway obstruction and rs7614952 (A allele), rs7625839 (G allele) and rs112509260 (A allele) are related to a lack of FEV1 reversibility. The A allele of rs2531747 in the SLC6A20 gene is also associated with severe asthma. Conversely, polymorphisms in XCR1 play a protective role in relation to severe asthma (A allele of rs2036295) and airway obstruction (A allele of rs2036295). Additionally, we found that individuals with a higher number of risk alleles have a greater risk of severe asthma, airway obstruction and FEV1 reversibility. Conclusion: Our study suggests that polymorphisms in genes associated with respiratory failure in SARS-CoV-2-infected individuals are associated with greater susceptibility to severe asthma and reduced lung function in subjects with asthma.

The rs2601796 variant in ADCY9 gene is associated with severe asthma and less bronchodilator response.

Asthma is a respiratory disease caused by the interaction of genetic and environmental factors. The adenylyl cyclase type 9 (ADCY9) enzyme produces the cyclic-adenosinemonophosphate (cAMP), important mediator involved in bronchodilation and immunomodulatory response. The aim of this study was to investigate if rs2601796 and rs2532019 variants in the ADCY9 gene are associated with asthma and lung function. The study comprised 1,052 subjects. Logistic regressions were done using PLINK 1.9 adjusted by sex, age, BMI, smoke and principal components. Bronchodilator responsiveness was assessed using the percentage of difference in FEV1 before and after the bronchodilator use. The in silico analysis for gene expression was performed in the GTEx Portal. The variant rs2601796 (AA/AG genotype) was positively associated with asthma severity (OR: 1.60 IC95%: 1.08-2.39) and with obstruction in individuals with severe asthma (OR: 3.10, IC95%: 1.11-8.62). Individuals with severe asthma and the AA/AG genotype of rs2601796 had less responsiveness to bronchodilators and also a lower expression of ADCY9 in lung and whole blood. The variant rs2532019 (TT/GT genotype) also downregulated the ADCY9 gene expression, but no significant association with the studied phenotypes was found. Thus, the variant in ADCY9 was associated with worse asthma outcomes, including a lower response to bronchodilators, likely due to the impact on its gene expression rate. This variant may be useful in the future to assist in personalized management of patients with asthma.

Impairment of EQ-5D-5L Domains According to Allergic Rhinitis and Asthma Control: A MASK-air Real-World Study.

BACKGROUND: EQ-5D-5L (EuroQOL, 5 Domains, 5 Levels) is a widely used health-related quality-of-life instrument, comprising 5 domains. However, it is not known how each domain is impacted by rhinitis or asthma control. OBJECTIVE: To assess the association between rhinitis or asthma control and the different EQ-5D-5L domains using data from the MASK-air mHealth app. METHODS: In this cross-sectional study, we assessed data from all MASK-air users (2015-2021; 24 countries). For the levels of each EQ-5D-5L domain, we assessed rhinitis and asthma visual analog scales (VASs) and the combined symptom-medication score (CSMS). We built ordinal multivariable models assessing the adjusted association between VAS/CSMS values and the levels of each EQ-5D-5L domain. Finally, we compared EQ-5D-5L data from users with rhinitis and self-reported asthma with data from users with rhinitis alone. RESULTS: We assessed 5354 days from 3092 users. We observed an association between worse control of rhinitis or asthma (higher VASs and CSMS) and worse EQ-5D-5L levels. In multivariable models, all VASs and the CSMS were associated with higher levels of pain/discomfort and daily activities. For anxiety/depression, the association was mostly observed for rhinitis-related tools (VAS nose, VAS global, and CSMS), although the presence of self-reported asthma was also associated with worse anxiety/depression. Worse mobility ("walking around") was particularly associated with VAS asthma and with the presence of asthma. CONCLUSIONS: A worse rhinitis control and a worse asthma control are associated with higher EQ-5D-5L levels, particularly regarding pain/discomfort and activity impairment. Worse rhinitis control is associated with worse anxiety/depression, and poor asthma control with worse mobility.

PDE4D gene variants and haplotypes are associated with asthma and atopy in Brazilian children.

PDE4D (Phosphodiesterase 4D) gene encodes a hydrolase of cyclic AMP. PDE4D genetic variants have been associated with asthma susceptibility. Therefore, this study aimed to investigate the association between PDE4D variants (and haplotypes) with asthma and atopy in a Brazilian population. The study comprised 1,246 unrelated participants from the SCAALA (Social Changes Asthma and Allergy in Latin America) program. Genotyping was performed using the Illumina 2.5 Human Omni bead chip. Multivariate logistic regression was used to investigate the association between PDE4D variants and asthma/atopy phenotypes in PLINK 1.09 software. Twenty-four SNVs in PDE4D were associated with atopy or asthma. The rs6898082 (A) variant increased asthma susceptibility (OR 2.76; CI 99% 1.26-6.03) and was also related to a greater PDE4D expression in the GTEx database. Also, the variant rs6870632 was further associated with asthma in meta-analysis with a replication cohort. In addition, the variants rs75699812 (C), rs8007656 (G), and rs958851 (T) were positively associated with atopy. Moreover, these variants formed an atopy risk haplotype (OR 1.82; CI 99% 1.15-2.88). Also, these variants were related to lower levels of IL-10. Functional in silico assessment showed that some PDE4D SNVs may have an impact on gene regulation and expression. Variants in the PDE4D are positively associated with asthma and allergy markers. It is possible that these variants lead to alteration in PDE4D expression and therefore impact immunity and pulmonary function.

Evaluation of Serum Levels of Cytokines in Acute Apical Abscess: A Longitudinal Observational Study.

INTRODUCTION: Cytokine levels are related to the aethiopathogenia of acute apical abscesses (AAA); however, the specific cytokine profiles in these cases are unclear. This study aimed to investigate the changes in systemic cytokine levels in patients with AAA and trismus onset, postantibiotic treatment, and postroot canal disinfection. METHODS: In total, 46 AAA patients with trismus and 32 control subjects were included. After seven days of antibiotic therapy, root canal disinfection was performed in the AAA patients. The serum levels of cytokines were evaluated at basal, seven, and 14 days after endodontic treatment. Quantification of cytokines from T helper (Th) 1, Th2, Th17, and regulatory T cells profiles was determined using the BioPlex MagPix system, and the obtained data were analyzed using SPSS statistical software (P < .05). RESULTS: AAA patients showed higher tumor necrosis factor-alpha (TNF-α), interleukin (IL) -6, and IL-10 levels than control subjects, at basal measurement (P < .05); there were similar levels of interferon gamma, IL-1ß, IL-4, and IL-17 between groups (P > .05). IL-6 and IL-10 levels decreased after antibiotic treatment (P < .05), which was also associated with clinical improvement in patients with AAA and trismus. Patients with AAA had a positive correlation with higher serum levels of IL-6 and IL-10. In addition, TNF-α levels decreased only after antibiotic and endodontic treatment. CONCLUSIONS: In conclusion, patients with AAA had increased systemic serum levels of TNF-α, IL-6, and IL-10. Moreover, increased levels of IL-6 and IL-10 are associated with acute inflammatory symptoms. However, IL-6 and IL-10 levels decreased after antibiotic treatment, while TNF-α levels decreased after antibiotic and endodontic treatment.

BAFFR expression in circulating T follicular helper (CD4+CXCR5+PD-1+) and T peripheral helper (CD4+CXCR5-PD-1+) cells in systemic lupus erythematosus.

BACKGROUND: Circulating T follicular helper (cTfh) and T peripheral helper (Tph) subpopulations are shown to be higher in systemic lupus erythematosus (SLE) patients and have been involved in promoting extrafollicular B cell responses. However, a possible association with the B cell activating factor (BAFF), a cytokine mainly related to B cell responses and disease activity in SLE, has not been investigated. Therefore, this study aimed to evaluate the association of cTfh and Tph subpopulations with the BAFF system expression and clinical activity in SLE patients. METHODS: This study included 43 SLE patients and 12 healthy subjects (HS). The identification of cTfh (CD4+CXCR5+PD-1+), Tph (CD4+CXCR5-PD-1+) cells, expression of membrane-bound BAFF (mBAFF), BAFFR, TACI, BCMA, and intracellular IL-21 was performed by flow cytometry. Serum levels of IL-21, CXCL13, and BAFF were analyzed using ELISA. The SLEDAI-2K score was used to evaluate disease activity in SLE patients. RESULTS: Compared with HS, SLE patients showed a significantly increased percentage of cTfh and Tph cells, higher in patients with clearly active disease. SLE patients had markedly higher IL-21-producing cTfh and Tph cells than HS. Both subpopulations were positively correlated with the disease activity in SLE patients. Tph cells were negatively correlated with CD19+CXCR5+ B cells and positively correlated with CD19+CXCR5- B cells. A low expression of mBAFF and their receptors TACI and BCMA was found on cTfh and Tph cells in SLE patients and HS. However, SLE patients with clearly active disease showed decreased expression of BAFFR on cTfh and Tph subpopulations than patients with mildly active/nonactive disease. Serum IL-21, CXCL13, and BAFF levels were higher in SLE patients than in HS. Levels of CXCL13 were correlated with disease activity. Non-significant correlations were observed among T cell subpopulations and IL-21, CXCL13, and BAFF levels. CONCLUSIONS: This study emphasizes the importance of cTfh and Tph cells in SLE pathogenesis. Besides the importance of IL-21, our results suggest that BAFFR could play a role in cTfh and Tph subpopulations in the autoimmunity context.

A network meta-analysis of the association between patient traits and response to regular dosing with ICS/long-acting ß2-agonist plus short-acting ß2 agonist reliever or maintenance and reliever therapy for asthma.

INTRODUCTION: Current treatment for moderate-severe asthma with inhaled corticosteroid (ICS)-based therapy can follow two strategies: a single inhaler maintenance and reliever therapy (MART) regimen, or regular dosing with ICS/long-acting ß2-agonist used as maintenance therapy plus a separate short acting ß2-agonist reliever inhaler. It would be clinically useful to understand the potential of patient traits to influence regular dosing or MART treatment outcomes. OBJECTIVES: A systematic literature review (SLR) and meta-analysis was conducted to identify specific patient traits that may predict improved clinical outcomes with regular dosing or MART. RESULTS: The SLR identified 28 studies in patients with moderate-severe asthma assessing regular dosing or MART treatments and reporting the traits and outcomes of interest. Network meta-regressions found no significant difference in the relative efficacy of regular dosing as compared with MART on any of the clinical outcomes (exacerbation rate, time to first exacerbation, FEV1, reliever use and adherence) for any of the patient traits (baseline lung function, baseline ACQ, age, BMI, and smoking history) evaluated. However, some trends towards traits influencing treatment efficacy were identified. Inconsistent reporting of traits and outcomes was observed between trials. CONCLUSIONS: The analysed patient traits evaluated in this study were associated with similar efficacy for the analysed outcomes to either regular dosing or MART; however, trends from the data observed encourage future analyses for possible identification of additional traits, or a combination of traits, that may be of interest. More comparable reporting of clinically important traits and outcomes would improve future analyses.