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.

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.

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.

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

Abstract 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.

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.

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.

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.

Handgrip strength as a diagnostic tool for frailty risk in elderly patients with moderate to severe asthma.

OBJECTIVE: To evaluate handgrip strength (HGS) as a diagnostic tool for frailty risk in elderly patients with asthma, as well as to investigate the prevalence of frailty in this population. METHODS: This was a cross-sectional study including 96 patients ≥ 60 years of age diagnosed with moderate to severe asthma and treated at a tertiary referral center in Brazil. We measured HGS using a calibrated hydraulic hand dynamometer. We used a frailty scale and the AUC to assess the diagnostic accuracy of the HGS test. RESULTS: The median age of participants was 67 years. Most (78%) were women and non-White (91%) of low socioeconomic status. HGS identified those at risk for frailty, with an AUC of 71.6% (61.5-80.4%; p < 0.002), as well as a sensitivity of 73.58% and a specificity of 67.53%, on the basis of a cutoff of ≤ 19 kgf. CONCLUSIONS: HGS appears to be a simple, reliable tool for clinicians to determine frailty risk in older asthma patients in a point-of-care setting.

Another case of preventable death from asthma.

INTRODUCTION: Asthma prevalence is 262 million globally, with more than 1,000 deaths each day, most of them preventable. We were performing a longitudinal study, in Brazil, with the objective to following up patients who had a severe asthma attack and attended an emergency room (ATTACK Study). Here we present a case of a 28-year-old woman presenting what was considered moderate asthma, enrolled in ATTACK, who subsequently died of asthma. CASE STUDY: The patient was initially evaluated at an emergency room (ER) with uncontrolled asthma and no regular treatment. She had an asthma diagnosis just before this visit to the ER, despite presenting symptoms of asthma since childhood. She was subsequently evaluated by a specialist, who prescribed a treatment with regular inhaled corticosteroid and an inhaled bronchodilator, if necessary. The patient was systematically monitored by telephone for six months. RESULTS: The patient did not adhere to the treatment, in spite of repeated warnings, and 6 months later had an asthma attack resulting in her death. CONCLUSION: It is important to prioritize asthma in primary health care, including building capacity health care professionals for early diagnosis, asthma management, and to educate patients with asthma patients for the identification of worsening and signs of severity, to manage the exacerbations according to a written asthma plan. This may reduce the number of premature and preventable asthma deaths.

The use of systemic corticosteroids in asthma management in Latin American countries.

The stepwise treatment approach recommended by the Global Initiative for Asthma (GINA) includes systemic corticosteroids (SCS) suggested as a final step if asthma is severe and/or difficult to treat. Yet, despite the effectiveness of SCS, they are also associated with potentially irreversible adverse outcomes such as type 2 diabetes, adrenal suppression, and cardiovascular disease. Based on recent data indicating that the risk of developing these conditions can increase after as few as 4 short-term (burst) courses of SCS, even patients with mild asthma who receive SCS occasionally for exacerbations are also at risk of these events. As a result, recent updates by GINA and the Latin American Thoracic Society recommend decreasing SCS use by optimizing administration of non-SCS therapies and/or increasing the use of alternatives, such as biologic agents. Recent and ongoing studies characterizing treatment patterns among patients with asthma have revealed alarming trends suggesting the widespread overuse of SCS around the world. In Latin America, asthma prevalence is approximately 17%, and data suggest that the majority of patients have uncontrolled disease. In this review, we summarize currently available data on asthma treatment patterns in Latin America, which indicate that SCS are prescribed to 20-40% of patients with asthma considered to be well controlled and over 50% of patients with uncontrolled disease. We also offer potential strategies to help reduce SCS use for asthma in everyday clinical practice.

Understanding and controlling asthma in Latin America: A review of recent research informed by the SCAALA programme.

Asthma is an important health concern in Latin America (LA) where it is associated with variable prevalence and disease burden between countries. High prevalence and morbidity have been observed in some regions, particularly marginalized urban populations. Research over the past 10 years from LA has shown that childhood disease is primarily non-atopic. The attenuation of atopy may be explained by enhanced immune regulation induced by intense exposures to environmental factors such as childhood infections and poor environmental conditions of the urban poor. Non-atopic symptoms are associated with environmental and lifestyle factors including poor living conditions, respiratory infections, psychosocial stress, obesity, and a diet of highly processed foods. Ancestry (particularly African) and genetic factors increase asthma risk, and some of these factors may be specific to LA settings. Asthma in LA tends to be poorly controlled and depends on access to health care and medications. There is a need to improve management and access to medication through primary health care. Future research should consider the heterogeneity of asthma to identify relevant endotypes and underlying causes. The outcome of such research will need to focus on implementable strategies relevant to populations living in resource-poor settings where the disease burden is greatest.

Single nucleotide variants in the IL33 and IL1RL1 (ST2) genes are associated with periodontitis and with Aggregatibacter actinomycetemcomitans in the dental plaque biofilm: A putative role in understanding the host immune response in periodontitis.

The Interleukin (IL)-33 is important in several inflammatory diseases and its cellular receptor is the Interleukin 1 receptor-like 1 (IL1RL1), also called suppression of tumorigenicity 2 ligand (ST2L). This study investigated associations between single nucleotide variants (SNVs) in the IL33 gene and in the IL1RL1 (ST2) gene with periodontitis. Additionally, aimed to determine the role of Aggregatibacter actinomycetemcomitans (Aa) relative amount in the subgingival biofilm in these associations. A cross-sectional study was carried out with 506 individuals that answered a structured questionnaire used to collect their health status, socioeconomic-demographic, and behavioral characteristics. Periodontal examination was performed to determine the presence and severity of periodontitis, and subgingival biofilm samples were collected to quantify the relative amount of Aa by real time polymerase chain reaction. Human genomic DNA was extracted from whole blood cells and SNV genotyping was performed. Logistic regression estimated the association measurements, odds ratio (OR), and 95% confidence interval (95%CI), between the IL33 and ST2 genes with periodontitis, and subgroup analyses assessed the relative amount of Aa in these associations. 23% of individuals had periodontitis. Adjusted measurements showed a statistically significant inverse association between two SNVs of the ST2; rs148548829 (C allele) and rs10206753 (G allele). These two alleles together with a third SNV, the rs11693204 (A allele), were inversely associated with moderate periodontitis. One SNV of the IL33 gene also showed a statistically significant inverse association with moderate periodontitis. Nine SNVs of the ST2 gene were inversely associated with the relative amount of Aa. In the high Aa subgroup, there was a direct association between 11 SNVs of the ST2 gene and moderate periodontitis and two SNVs of the ST2 gene and severe periodontitis, and eight SNVs of the ST2 gene and periodontitis. These exploratory findings of genetic variants in IL-33/ST2 axis support the concept that the different tissue responses among individuals with periodontitis may be modulated by the host's genetics, influencing the physiopathology of the disease.

Variants in interferon gamma inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) genes that modulate inflammatory response are associated with periodontitis.

OBJECTIVE: Evaluate the association of genetic variants of the interferon gamma inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) genes with periodontitis. METHODS: The study involved 117 individuals with periodontitis and 389 without periodontitis, all Brazilians, miscegenated. Individuals with periodontitis presented at least 4 teeth with ≥ 1 site with probing depth ≥ 4 mm; clinical attachment level ≥ 3 mm on the same site and bleeding upon stimulus. Genotyping was performed using the Infinium Multi-Ethnic AMR/AFR-8 Bead Chip focused on Hispanic and African American populations with approximately 2 million markers of the human genome. Multivariate logistic regression was performed to identify associations in additive, dominant and recessive models adjusted for covariates age, obesity, mouth breathing, flossing, asthma, and ancestry. RESULTS: In IFI16, the rs75985579-A is positively associated with periodontitis in the additive (Odds Ratio adjusted (ORadjusted) 2.65, 95% confidence interval (CI):1.25-5.60, p value: 0.007) and dominant models (ORadjusted 2.56, 95%CI:1.13-5.81, p value: 0.017). In AIM2, the rs76457189-G, is associated negatively with periodontitis in two genetic models evaluated, additive (ORadjusted 0.21, 95%CI:0.05-0.94, p value: 0.022) and dominant (ORadjusted 0.21, 95%CI:0.05-0.94, p value: 0.022). CONCLUSIONS: These results have shown that variants in the IFI16 and AIM2 genes are associated with periodontitis. Individuals with at least one A (adenine) allele of the rs75985579 (IFI16) are more than twice as likely to have periodontitis, while individuals with the G (guanine) allele of rs76457189 (AIM2) are less likely to be diagnosed with periodontitis, providing a negative association with periodontitis.

Serum 25-hydroxyvitamin D deficiency is associated with atopy, and sex may be an effect modifier of its association with asthma in teenagers from northeast Brazil.

OBJECTIVE: Sufficient vitamin D (25-hydroxyvitamin D [25(OH)D]) serum levels are associated with decreased asthma symptoms. Our aim was to investigate associations between vitamin D and atopy, asthma, asthma severity, and asthma phenotypes in Brazilian teenagers. METHODS: This cross-sectional study involved 942 individuals (11-19 years old) engaged in an asthma cohort. The ISAAC questionnaire was employed to diagnosis asthma and asthma severity. Serum allergen-specific immunoglobulin E (sIgE) was measured by ImmunoCap and serum 25(OH)D was measured by ELISA. We calculated the correlation between sIgE and 25(OH)D. We used multivariate logistic regression analysis to assess associations of interest. RESULTS: We found that 25(OH)D deficiency was positively associated with atopy (OR 1.45, confidence interval [CI] 1.05-2.00) and high levels of this vitamin negatively correlated with sIgE to Dermatophagoides pteronyssinus (r = -0.11, p = 0.019). The average 25(OH)D serum level was 27.0 ± 9.5 ng/ml; 366 individuals (38.8%) had a sufficient level. There was no association between 25(OH)D and asthma, asthma severity or asthma phenotypes in the population. However, sex was a possible effect modifier of the association between vitamin D and asthma: insufficiency in asthmatic women (86%) was higher than in asthmatic men (42%), and there was an association between insufficient vitamin D levels and greater asthma risk only in women (OR = 3.06, 95% CI 1.16-8.07). CONCLUSION: We have shown that vitamin D deficiency was associated with greater risk of atopy in both sexes and vitamin D insufficiency was associated with asthma only in women. There was no association between vitamin D levels and asthma phenotypes or asthma severity.

Asthma inflammatory phenotypes on four continents: most asthma is non-eosinophilic.

BACKGROUND: Most studies assessing pathophysiological heterogeneity in asthma have been conducted in high-income countries (HICs), with little known about the prevalence and characteristics of different asthma inflammatory phenotypes in low-and middle-income countries (LMICs). This study assessed sputum inflammatory phenotypes in five centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United Kingdom (UK). METHODS: We conducted a cross-sectional study of 998 asthmatics and 356 non-asthmatics in 2016-20. All centres studied children and adolescents (age range 8-20 years), except the UK centre which involved 26-27 year-olds. Information was collected using questionnaires, clinical characterization, blood and induced sputum. RESULTS: Of 623 asthmatics with sputum results, 39% (243) were classified as eosinophilic or mixed granulocytic, i.e. eosinophilic asthma (EA). Adjusted for age and sex, with NZ as baseline, the UK showed similar odds of EA (odds ratio 1.04, 95% confidence interval 0.37-2.94) with lower odds in the LMICs: Brazil (0.73, 0.42-1.27), Ecuador (0.40, 0.24-0.66) and Uganda (0.62, 0.37-1.04). Despite the low prevalence of neutrophilic asthma in most centres, sputum neutrophilia was increased in asthmatics and non-asthmatics in Uganda. CONCLUSIONS: This is the first time that sputum induction has been used to compare asthma inflammatory phenotypes in HICs and LMICs. Most cases were non-eosinophilic, including in settings where corticosteroid use was low. A lower prevalence of EA was observed in the LMICs than in the HICs. This has major implications for asthma prevention and management, and suggests that novel prevention strategies and therapies specifically targeting non-eosinophilic asthma are required globally.

Handgrip strength as a diagnostic tool for frailty risk in elderly patients with moderate to severe asthma / Força de preensão manual como ferramenta diagnóstica de risco de fragilidade em pacientes idosos com asma moderada a grave

ABSTRACT Objective: To evaluate handgrip strength (HGS) as a diagnostic tool for frailty risk in elderly patients with asthma, as well as to investigate the prevalence of frailty in this population. Methods: This was a cross-sectional study including 96 patients ≥ 60 years of age diagnosed with moderate to severe asthma and treated at a tertiary referral center in Brazil. We measured HGS using a calibrated hydraulic hand dynamometer. We used a frailty scale and the AUC to assess the diagnostic accuracy of the HGS test. Results: The median age of participants was 67 years. Most (78%) were women and non-White (91%) of low socioeconomic status. HGS identified those at risk for frailty, with an AUC of 71.6% (61.5-80.4%; p < 0.002), as well as a sensitivity of 73.58% and a specificity of 67.53%, on the basis of a cutoff of ≤ 19 kgf. Conclusions: HGS appears to be a simple, reliable tool for clinicians to determine frailty risk in older asthma patients in a point-of-care setting.

RESUMO Objetivo: Avaliar a força de preensão manual (FPM) como ferramenta diagnóstica de risco de fragilidade em pacientes idosos com asma e investigar a prevalência de fragilidade nessa população. Métodos: Estudo transversal com 96 pacientes com idade ≥ 60 anos e diagnóstico de asma moderada a grave, atendidos em um centro terciário de referência no Brasil. Medimos a FPM com um dinamômetro hidráulico manual calibrado. Usamos uma escala de fragilidade e a ASC para avaliar a precisão diagnóstica do teste de FPM. Resultados: A mediana da idade dos participantes foi de 67 anos. A maioria eram mulheres (78%) não brancas (91%) cujo nível socioeconômico era baixo. O ponto de corte de FPM ≤ 19 kgf identificou os participantes que apresentavam risco de fragilidade, com ASC = 71,6% (61,5-80,4%; p < 0,002), sensibilidade = 73,58% e especificidade = 67,53%. Conclusões: A FPM parece ser uma ferramenta simples e confiável para determinar, no próprio local de atendimento médico, o risco de fragilidade em pacientes idosos com asma.

Impact of frailty in elderly patients with moderate to severe asthma.

Frailty assessment has been identified as critical approach in chronic respiratory diseases with substantial impact in the health status and functionality in later life. Aging modifies the immune response leading to a chronic pro-inflammatory state and increased susceptibility to airway infections. Since epigenetic changes, airway epithelium dysfunction and inflammatory cytokine activity seem to be more pronounced in the immunosenescence, elderly asthmatics are at higher risk of poor clinical outcomes. Therefore, we hypothesize that frailty would be associated with the degree of asthma control in elderly patients with moderate to severe asthma. The aims of this study are to investigate association between frailty and asthma control in patients over 60 years old to estimate the prevalence of frailty in this study population. We plan to conduct a cross-sectional study with at least 120 patients above 60 years old with diagnostic of moderate to severe asthma according to Global Initiative for Asthma (GINA) guidelines, treated at a referral outpatient clinic. We defined asthma control by the six-domain Asthma Control Questionnaire (ACQ-6) and frailty phenotype in accordance with Fried scale and visual scale of frailty (VS-Frailty). We hope to analyze the multidimensional relationships between frailty and asthma and contribute to innovative therapeutic plans in geriatric asthma.

Rationally designed hypoallergenic mutant variants of the house dust mite allergen Der p 21.

BACKGROUND: Allergic diseases figure among the most common immune-mediated diseases worldwide, affecting more than 25% of the world's population. Allergic reactions can be triggered by house dust mite (HDM) allergens, of which the so-called group 21 of allergens is considered as clinically relevant. METHODS: Herein, we used a structural bioinformatics and immunoinformatics approach to design hypoallergenic mutant variants of the Der p 21 allergen of Dermatophagoides pteronyssinus, which were then recombinantly expressed in bacteria and tested for their IgE-reactivities. For this, we scanned the wild-type Der p 21 protein for all possible single amino acid substitutions in key IgE-binding regions that could render destabilization of the major epitope regions. RESULTS: Four main substitutions (D82P, K110G, E77G, and E87S) were selected to build mutant variants of the Der p 21 allergen, which were produced in their recombinant forms; two of these variants showed reduced reactivity with IgE. Molecular dynamic simulations and immune simulations demonstrated the overall effects of these mutations on the structural stability of the Der p 21 allergen and on the profile of immune response induced through immunotherapy. CONCLUSIONS: When produced in their recombinant forms, two of the Der p 21 mutant variants, namely proteins K110G and E87S, showed significantly reduced IgE reactivities against sera from HDM-allergic individuals (n = 20; p < 0.001). GENERAL SIGNIFICANCE: This study successfully translated a rational in silico mutagenesis design into low IgE-binding mutant variants of the allergen rDer p 21. These novel hypoallergens are promising to compose next-generation allergen-immunotherapy formulations in near future.