Short-chain fatty acid acetate triggers antiviral response mediated by RIG-I in cells from infants with respiratory syncytial virus bronchiolitis.

BACKGROUND: Gut microbiota-derived short-chain fatty-acid (SFCA) acetate protects mice against RSV A2 strain infection by increasing interferon-ß production and expression of interferon-stimulated genes (ISGs). However, the role of SFCA in RSV infection using strains isolated from patients is unknown. METHODS: We first used RSV clinical strains isolated from infants hospitalized with RSV bronchiolitis to investigate the effects of in vitro SCFA-acetate treatment of human pulmonary epithelial cells. We next examined whether SCFA-acetate treatment is beneficial in a mouse model of RSV infection using clinical isolates. We sought to investigate the relationship of gut microbiota and fecal acetate with disease severity among infants hospitalized with RSV bronchiolitis, and whether treating their respiratory epithelial cells with SCFA-acetate ex-vivo impacts viral load and ISG expression. We further treated epithelial cells from SARS-CoV-2 infected patients with SCFA-acetate. FINDINGS: In vitro pre-treatment of A549 cells with SCFA-acetate reduced RSV infection with clinical isolates and increased the expression of RIG-I and ISG15. Animals treated with SCFA-acetate intranasally recovered significantly faster, with reduction in the RSV clinical isolates viral load, and increased lung expression of IFNB1 and the RIG-I. Experiments in RIG-I knockout A549 cells demonstrated that the protection relies on RIG-I presence. Gut microbial profile was associated with bronchiolitis severity and with acetate in stool. Increased SCFA-acetate levels were associated with increasing oxygen saturation at admission, and shorter duration of fever. Ex-vivo treatment of patients' respiratory cells with SCFA-acetate reduced RSV load and increased expression of ISGs OAS1 and ISG15, and virus recognition receptors MAVS and RIG-I, but not IFNB1. These SCFA-acetate effects were not found on cells from SARS-CoV-2 infected patients. INTERPRETATION: SCFA-acetate reduces the severity of RSV infection and RSV viral load through modulation of RIG-I expression. FUNDING: FAPERGS (FAPERGS/MS/CNPq/SESRS no. 03/2017 - PPSUS 17/2551-0001380-8 and COVID-19 20/2551-0000258-6); CNPq 312504/2017-9; CAPES) - Finance Code 001.

Association between interleukin-10 polymorphisms and CD4+CD25+FOXP3+ T cells in asthmatic children

Abstract Objective: The aim of this study was to evaluate the association between possible functional interleukin-10 (IL-10) polymorphisms, IL-10 expression and regulatory T cells (Tregs) frequency, and/or asthma severity in a sample of children and adolescents. Methods: This is a nested case-control genetic association study. The study sample consisted of children and adolescents aged 8-14 from public schools. Four polymorphisms of the IL-10 gene (rs1518111, rs3024490, rs3024496, rs3024491) were genotyped in asthmatic subjects and controls using real-time PCR. Tregs cells and IL-10 were analyzed in peripheral blood mononuclear cells by flow cytometry. The severity of asthma was defined according to the Global Initiative for Asthma (GINA) guideline. Results: One hundred twenty-three asthmatic subjects and fifty-eight controls participated in the study. The single nucleotide polymorphism (SNP) rs3024491 (T allele) showed association with asthma severity, presenting a higher frequency in patients in the moderate asthma group. The T allele of variant rs3024491 also showed an association with reduced IL-10 levels (p = 0.01) and with increased Tregs frequency (p = 0.01). The other variants did not present consistent associations. Conclusions: Our results suggest that moderate asthma is associated with a higher frequency of the T allele in the SNP rs3024491. In addition, the variant rs3024491 (TT) was associated with a reduction in IL-10 production and an increased percentage of Tregs cells, suggesting possible mechanisms that influence asthma severity.

Association between interleukin-10 polymorphisms and CD4+CD25+FOXP3+ T cells in asthmatic children.

OBJECTIVE: The aim of this study was to evaluate the association between possible functional interleukin-10 (IL-10) polymorphisms, IL-10 expression and regulatory T cells (Tregs) frequency, and/or asthma severity in a sample of children and adolescents. METHODS: This is a nested case-control genetic association study. The study sample consisted of children and adolescents aged 8-14 from public schools. Four polymorphisms of the IL-10 gene (rs1518111, rs3024490, rs3024496, rs3024491) were genotyped in asthmatic subjects and controls using real-time PCR. Tregs cells and IL-10 were analyzed in peripheral blood mononuclear cells by flow cytometry. The severity of asthma was defined according to the Global Initiative for Asthma (GINA) guideline. RESULTS: One hundred twenty-three asthmatic subjects and fifty-eight controls participated in the study. The single nucleotide polymorphism (SNP) rs3024491 (T allele) showed association with asthma severity, presenting a higher frequency in patients in the moderate asthma group. The T allele of variant rs3024491 also showed an association with reduced IL-10 levels (p=0.01) and with increased Tregs frequency (p=0.01). The other variants did not present consistent associations. CONCLUSIONS: Our results suggest that moderate asthma is associated with a higher frequency of the T allele in the SNP rs3024491. In addition, the variant rs3024491 (TT) was associated with a reduction in IL-10 production and an increased percentage of Tregs cells, suggesting possible mechanisms that influence asthma severity.

OM-85 BV for primary prevention of recurrent airway infections: a pilot randomized, double-blind, placebo-controlled study.

OBJECTIVE: To compare the frequency of respiratory tract infections in children treated with OM-85 BV and placebo during the 3-month therapy period, and observation for a further 3 months after treatment. METHODS: A randomized, double-blind, placebo-controlled trial was conducted with 54 children (6 months to 5 years old) with no past history of recurrent respiratory infections attending daycare center. Family members were instructed to administer one capsule per day for 10 consecutive days, for 3 months of OM-85 BV or placebo. Telephone interviews were conducted every 30 days. RESULTS: There was no significant difference in the number of respiratory infections between the groups. The mean number of respiratory tract infection in the OM-85 BV Group in the first 3 months was 0.92±0.87, and in the Placebo Group was 0.74±1.02, and at 6 months it was 1.62±1.47 and 1.03±1.34, respectively. CONCLUSION: OM-85 BV was not effective in the primary prevention of respiratory tract infections. Although most authors recommend the use of this immunostimulant in children with a history of recurrent respiratory infections, more studies are needed to define its usefulness in the primary prevention of respiratory infections in healthy children exposed to few risk factors.

Azithromycin administered for acute bronchiolitis may have a protective effect on subsequent wheezing. / A azitromicina administrada para bronquiolite aguda pode ter um efeito de proteção na sibilância recorrente.

OBJECTIVE: A significant proportion of the infants developed recurrent wheezing after an acute bronchiolitis (AB) event. Recent studies have demonstrated protection for recurrent wheeze and lower respiratory morbidity in infants treated with azithromycin during an acute respiratory wheezing. The aim of the present study was to test the hypothesis that administration of azithromycin during an AB event reduces subsequent wheezing and hospital re-admissions. METHODS: This is a secondary analysis of a randomized, double-blinded, placebo-controlled trial, including unpublished data of wheezing and hospitalizations during the initial 6 months following admission for acute viral bronchiolitis. The study was performed in a tertiary University hospital. Infants (<12 months of age) hospitalized with AB were randomized to receive either azithromycin or placebo, administered orally, for 7 days. Families were contacted by telephone at 3 and 6 months after the initial acute event and answered to a standardized questionnaire in order to identify recurrent wheezing and hospital readmissions. RESULTS: One hundred and four patients were included (Azithromycin group, n= 50; placebo group, n=54). Considering the total of patients contacted 3 months after hospitalization (n=70), the recurrence rate of wheezing in the azithromycin group was significantly lower than in the placebo group (RR = 0.48; CI = 0.24-0.98; p = 0.038). CONCLUSION: Azithromycin significantly reduces the risk of subsequent wheezing between 0 and 3 months after hospital admission due to acute bronchiolitis irrespective of the presence of respiratory syncytial virus.

OBJETIVO: Uma proporção significativa de lactentes desenvolve sibilância recorrente após um evento de bronquiolite aguda (BA). Estudos recentes demonstraram proteção para sibilância recorrente e menor morbidade respiratória em lactentes tratados com azitromicina durante uma crise de sibilância. O objetivo do presente estudo foi testar a hipótese de que a administração de azitromicina durante um evento BA reduz sibilos e reinternações hospitalares subsequentes. MÉTODOS: Trata-se de uma análise secundária de um estudo randomizado, duplo-cego, controlado por placebo, incluindo dados não publicados de sibilância e hospitalizações durante os seis meses iniciais após a internação por bronquiolite aguda. O estudo foi realizado em um hospital universitário terciário. Os bebês (<12 meses de idade) hospitalizados com BA foram randomizados para receber azitromicina ou placebo, administrados por via oral, por sete dias. As famílias foram contatadas por telefone aos três e seis meses após o evento agudo inicial, e responderam a um questionário padronizado para identificar sibilos recorrentes e reinternações hospitalares. RESULTADOS: Cento e quatro pacientes foram incluídos (grupo Azitromicina, n=50; grupo Placebo, n=54). Considerando o total de pacientes contatados com sucesso três meses após a hospitalização (n=70), a taxa de recorrência de sibilância no grupo da azitromicina foi significativamente menor do que no grupo placebo (RR=0,48; CI=0,24-0.98; p=0,038). CONCLUSÕES: A azitromicina reduziu significativamente o risco de sibilância subsequente entre zero e três meses após a admissão hospitalar por bronquiolite aguda.

OM-85 BV for primary prevention of recurrent airway infections: a pilot randomized, double-blind, placebo-controlled study / OM-85 BV para prevenção primária de infecções recorrentes das vias aéreas: estudo piloto, randomizado, duplo-cego, placebo-controlado

ABSTRACT Objective To compare the frequency of respiratory tract infections in children treated with OM-85 BV and placebo during the 3-month therapy period, and observation for a further 3 months after treatment. Methods A randomized, double-blind, placebo-controlled trial was conducted with 54 children (6 months to 5 years old) with no past history of recurrent respiratory infections attending daycare center. Family members were instructed to administer one capsule per day for 10 consecutive days, for 3 months of OM-85 BV or placebo. Telephone interviews were conducted every 30 days. Results There was no significant difference in the number of respiratory infections between the groups. The mean number of respiratory tract infection in the OM-85 BV Group in the first 3 months was 0.92±0.87, and in the Placebo Group was 0.74±1.02, and at 6 months it was 1.62±1.47 and 1.03±1.34, respectively. Conclusion OM-85 BV was not effective in the primary prevention of respiratory tract infections. Although most authors recommend the use of this immunostimulant in children with a history of recurrent respiratory infections, more studies are needed to define its usefulness in the primary prevention of respiratory infections in healthy children exposed to few risk factors.

RESUMO Objetivo Comparar a frequência de infecções do trato respiratório em crianças tratadas com OM-85 BV e placebo durante o período de terapia de 3 meses, e observação por mais 3 meses após o tratamento. Métodos Foi realizado estudo randomizado, duplo-cego, controlado por placebo com 54 crianças (6 meses a 5 anos) sem história prévia de infecções respiratórias recorrentes, que frequentavam creches. Os membros da família foram instruídos a administrar uma cápsula por dia durante 10 dias consecutivos, durante 3 meses, de OM-85 BV ou placebo. Entrevistas telefônicas foram realizadas a cada 30 dias. Resultados Não houve diferença significativa no número de infecções respiratórias entre os grupos. O número médio de infecções do trato respiratório no Grupo OM-85 BV nos primeiros 3 meses foi de 0,92±0,87 e, no Grupo Placebo, de 0,74±1,02, e aos 6 meses foi de 1,62±1,47 e 1,03±1,34, respectivamente. Conclusão O OM-85 BV não foi eficaz na prevenção primária de infecções do trato respiratório. Embora a maioria dos autores recomende o uso deste imunoestimulante em crianças com história de infecções respiratórias recorrentes, mais estudos são necessários para definir sua utilidade na prevenção primária de infecções respiratórias em crianças saudáveis expostas a poucos fatores de risco.

A azitromicina administrada para bronquiolite aguda pode ter um efeito de proteção na sibilância recorrente / Azithromycin administered for acute bronchiolitis may have a protective effect on subsequent wheezing

RESUMO Objetivo Uma proporção significativa de lactentes desenvolve sibilância recorrente após um evento de bronquiolite aguda (BA). Estudos recentes demonstraram proteção para sibilância recorrente e menor morbidade respiratória em lactentes tratados com azitromicina durante uma crise de sibilância. O objetivo do presente estudo foi testar a hipótese de que a administração de azitromicina durante um evento BA reduz sibilos e reinternações hospitalares subsequentes. Métodos Trata-se de uma análise secundária de um estudo randomizado, duplo-cego, controlado por placebo, incluindo dados não publicados de sibilância e hospitalizações durante os seis meses iniciais após a internação por bronquiolite aguda. O estudo foi realizado em um hospital universitário terciário. Os bebês (<12 meses de idade) hospitalizados com BA foram randomizados para receber azitromicina ou placebo, administrados por via oral, por sete dias. As famílias foram contatadas por telefone aos três e seis meses após o evento agudo inicial, e responderam a um questionário padronizado para identificar sibilos recorrentes e reinternações hospitalares. Resultados Cento e quatro pacientes foram incluídos (grupo Azitromicina, n=50; grupo Placebo, n=54). Considerando o total de pacientes contatados com sucesso três meses após a hospitalização (n=70), a taxa de recorrência de sibilância no grupo da azitromicina foi significativamente menor do que no grupo placebo (RR=0,48; CI=0,24-0.98; p=0,038). Conclusões A azitromicina reduziu significativamente o risco de sibilância subsequente entre zero e três meses após a admissão hospitalar por bronquiolite aguda.

ABSTRACT Objective A significant proportion of the infants developed recurrent wheezing after an acute bronchiolitis (AB) event. Recent studies have demonstrated protection for recurrent wheeze and lower respiratory morbidity in infants treated with azithromycin during an acute respiratory wheezing. The aim of the present study was to test the hypothesis that administration of azithromycin during an AB event reduces subsequent wheezing and hospital re-admissions. Methods This is a secondary analysis of a randomized, double-blinded, placebo-controlled trial, including unpublished data of wheezing and hospitalizations during the initial 6 months following admission for acute viral bronchiolitis. The study was performed in a tertiary University hospital. Infants (<12 months of age) hospitalized with AB were randomized to receive either azithromycin or placebo, administered orally, for 7 days. Families were contacted by telephone at 3 and 6 months after the initial acute event and answered to a standardized questionnaire in order to identify recurrent wheezing and hospital readmissions. Results One hundred and four patients were included (Azithromycin group, n= 50; placebo group, n=54). Considering the total of patients contacted 3 months after hospitalization (n=70), the recurrence rate of wheezing in the azithromycin group was significantly lower than in the placebo group (RR = 0.48; CI = 0.24-0.98; p = 0.038). Conclusion Azithromycin significantly reduces the risk of subsequent wheezing between 0 and 3 months after hospital admission due to acute bronchiolitis irrespective of the presence of respiratory syncytial virus.