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Human cytomegalovirus (CMV) is a widespread persistent herpes virus requiring lifelong immune surveillance to maintain latency. Such long-term interactions with the immune system may be associated with deleterious effects including immune exhaustion and senescence. Regarding the COVID-19 pandemic, we asked whether CMV-specific cellular and humoral activity could influence immune responses toward SARS-CoV-2 and/or disease severity. All adults with mild (n = 15) and severe (n = 14) COVID-19 were seropositive for anti-CMV IgG, but negative for IgM antibodies. Antibody titers did not correlate with COVID-19 severity. Six patients presented elevated frequencies of CMV-specific CD4 + and CD8 + T cells producing IFNγ, IL-17, and TNFα, designated as CMV high responders (hiT CMV). In comparison to low CMV responders, hiT CMV individuals exhibited higher frequencies of SARS-CoV-2-specific CD4 + IL-17 + and CD8 + IFNγ + , IL-17 + or TNFα + T cells. These results indicate that high frequencies of CMV-specific T cells may be associated with a SARS-CoV-2-reactive profile skewed toward Th17-dominated immunity.

Objective To evaluate the accuracy of an antibody point-of-care lateral flow immunoassay (LFI - Wondfo Biotech Co., Guangzhou, China) in a pediatric population. Methods Children and adolescents (2 months to 18 years) with signs and symptoms suggestive of acute SARS-CoV-2 infection were prospectively investigated with nasopharyngeal RT-PCR and LFI at the emergency room. RT-PCR was performed at baseline, and LFI at the same time or scheduled for those with less than 7 days of the clinical picture. Overall accuracy, sensitivity and specificity were assessed, as well as according to the onset of symptoms (7-13 or ≥14 days) at the time of LFI test. Results In 175 children included, RT-PCR and LFI were positive in 51 (29.14%) and 36 (20.57%), respectively. The overall sensitivity, specificity, positive and negative predictive value was of 70.6% (95%CI 56.2-82.5), 96.8% (95%CI 91.9-99.1), 90.0% (95%CI 77.2-96.0), and 88.9% (95%CI 83.9-92.5), respectively. At 7-13 and ≥14 days after the onset of symptoms, sensitivity was 60.0% (95%CI 26.2-87.8) and 73.2% (95%CI 57.1-85.8) and specificity was 97.9% (95%CI 88.7-99.9) and 96.1% (95%CI 89.0-99.2), respectively. Conclusion Despite its high specificity, in the present study, the sensitivity of LFI in children was lower (around 70%) than most reports in adults. In acute care settings, although a positive result is informative, a negative LFI test cannot rule out COVID-19 in children.

Supplemental Digital Content is available in the text., Background: The viral dynamics and the role of children in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not completely understood. Our aim was to evaluate reverse transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) values among children with confirmed SARS-CoV-2 compared with that of adult subjects. Methods: Patients (from 2 months to ≤18 years of age and adults) with signs and symptoms of acute SARS-CoV-2 infection for less than 7 days were prospectively enrolled in the study from May to November 2020. All participants performed RT-PCR assay for SARS-CoV-2 detection; Ct values of ORF1ab, N and S gene targets and the average of all the 3 probes were used as surrogates of viral load. Results: There were 21 infants (2 months to

IntroductionThe high burden of respiratory syncytial virus (RSV) infection in young children disproportionately occurs in low- and middle-income countries (LMICs). The PROUD (Preventing RespiratOry syncytial virUs in unDerdeveloped countries) Taskforce of 24 RSV worldwide experts assessed key needs for RSV prevention in LMICs, including vaccine and newer preventive measures.MethodsA global, survey-based study was undertaken in 2021. An online questionnaire was developed following three meetings of the Taskforce panellists wherein factors related to RSV infection, its prevention and management were identified using iterative questioning. Each factor was scored, by non-panellists interested in RSV, on a scale of zero (very-low-relevance) to 100 (very-high-relevance) within two scenarios: (1) Current and (2) Future expectations for RSV management.ResultsNinety questionnaires were completed: 70 by respondents (71.4% physicians; 27.1% researchers/scientists) from 16 LMICs and 20 from nine high-income (HI) countries (90.0% physicians; 5.0% researchers/scientists), as a reference group. Within LMICs, RSV awareness was perceived to be low, and management was not prioritised. Of the 100 factors scored, those related to improved diagnosis particularly access to affordable point-of-care diagnostics, disease burden data generation, clinical and general education, prompt access to new interventions, and engagement with policymakers/payers were identified of paramount importance. There was a strong need for clinical education and local data generation in the lowest economies, whereas upper-middle income countries were more closely aligned with HI countries in terms of current RSV service provision.ConclusionSeven key actions for improving RSV prevention and management in LMICs are proposed.

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.

BACKGROUND AND OBJECTIVE: The knowledge about the impact of the nonpharmacological measures to control the COVID-19 pandemic can give insight into ways in which they can also be applied for other respiratory diseases. To assess the impact of containment measures of the COVID-19 pandemic on pneumonia hospitalizations in children from 0 to 14 years of age in Brazil. METHODS: Data from hospital admissions for pneumonia were obtained from the Department of Informatics of Brazilian Public Health System database in the period of 2015-2020 and analyzed by macroregions and age groups. To evaluate the effect of containment measures, on the incidence of pneumonia, the absolute reduction and relative reduction were calculated by analyzing the subsets 2015-2019 vs. 2020. RESULTS: Comparing the subsets of April-August 2015-2019 vs. April-August 2020 for Brazil (total), there was an significant reduction in the average incidence of hospitalizations, with numbers ranging from -82% [IRR 0.17 (0.14-0.21)] for

OM-85 is a bacterial lysate from common respiratory tract pathogens, with an excellent safety profile, widely used to prevent recurrent respiratory tract infections. Several studies have been reporting the antiviral roles of OM-85. Here we demonstrated the effect of ex-vivo OM-85 exposure in nasopharyngeal cells collected from COVID-19 patients. OM-85 decreased the SARS-CoV-2 N1 gene expression and increased RIG-I (DDX58) gene expression in these cells. These data support the antiviral effect of OM-85 against SARS-CoV-2.

Respiratory syncytial virus (RSV) is a seasonal pathogen responsible for the highest percentage of viral bronchiolitis in pediatric patients. There are currently no vaccine available and therapeutic methods to mitigate the severity of RSV bronchiolitis are limited. OM-85, an oral standardized bacterial lysate isolated from human respiratory strains and widely used to prevent recurrent infections and/or exacerbations in populations at risk, has been shown to be effective and safe in children and adults. Here, we demonstrate that airway administration of OM-85 in Balb/c mice prior to infection prevents RSV-induced disease, resulting in inhibition of viral replication associated with less perivascular and peribronchial inflammation in the lungs. These protective effects are dose and time-dependent with complete protection using 1mg dose of OM-85 only four times intranasally. Mechanistic insights using this topical route in the airways revealed increased alveolar macrophages, a selective set of tolerogenic DCs, Treg and Th1 expansion in the lung, even in the absence of infection, contributing to a better Th1/Th2 balance and preventing ILC2 recruitment in the airways and associated inflammatory sequelae. OM-85 preventive treatment also improved antiviral response by increasing IFNβ and its responsive genes in the lung. In vitro, OM-85 protects against RSV infection in a type I interferon pathway. Our animal model data suggest that intranasal use of OM-85 should be considered as a potential prophylactic product to prevent RSV bronchiolitis once human studies confirm these findings.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1 year. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV-specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via interleukin (IL) 21 secretion. In this study, we evaluated whether RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL-21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL-21/interleukin-21 receptor (IL-21R) in Tfh cells and upregulated programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) and B cells. PD-L1 blockade during infection recovered IL-21R expression in Tfh cells and increased the secretion of IL-21 in a DC-dependent manner. IL-21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs in the lung. It also decreased regulatory follicular T cells, and increased Tfh cells, B cells, antibody avidity and neutralization capacity, leading to an overall improved anti-RSV humoral response in infected mice. Passive immunization with purified immunoglobulin G from IL-21-treated RSV-infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD-L1 expression on antigen-presenting cells, highlighting the importance of an IL-21-PD-L1 axis for the generation of protective responses to RSV infection.

Background Interventions to tackle the coronavirus disease 2019 (COVID-19) pandemic may affect the burden of other respiratory diseases. Considering the repercussions of these unique social experiences to infant health, this study aims to assess the early impact of social distancing due to the COVID-19 pandemic in hospital admissions for acute bronchiolitis. Methods Data from hospitalizations of acute bronchiolitis in infants Results There was a significant reduction in all comparisons, ranging from −78% (incidence rate ratio [IRR], 0.22 [95% confidence interval {CI}, .20–.24]) in 2016 vs 2020 to −85% (IRR, 0.15 [95% CI, .13–.16]) in 2019 vs 2020, for the data from Brazil. For analyses by macroregions, the reduction varied from −58% (IRR, 0.41 [95% CI, .37–.45]) in the Midwest in 2016 vs 2020 to −93% (IRR, 0.07 [95% CI, .06–.08]) in the South in 2019 vs 2020. Conclusions There was a significant reduction in hospitalization for acute bronchiolitis in children 70% for most analysis. Our data suggest an important impact of social distancing on reducing the transmission of viruses related to acute bronchiolitis. Such knowledge may guide strategies for prevention of viral spread.

During chronic inflammatory disease, such asthma, leukocytes can invade the central nervous system (CNS) and together with CNS-resident cells, generate excessive reactive oxygen species (ROS) production as well as disbalance in the antioxidant system, causing oxidative stress, which contributes a large part to neuroinflammation. In this sense, the aim of this study is to investigate the effects of treatment with neostigmine, known for the ability to control lung inflammation, on oxidative stress in the cerebral cortex of asthmatic mice. Female BALB/cJ mice were submitted to asthma model induced by ovalbumin (OVA). Control group received only Dulbecco's phosphate-buffered saline (DPBS). To evaluate neostigmine effects, mice received 80 μg/kg of neostigmine intraperitoneally 30 min after each OVA challenge. Our results revealed for the first time that treatment with neostigmine (an acetylcholinesterase inhibitor that no crosses the BBB) was able to revert ROS production and change anti-oxidant enzyme catalase in the cerebral cortex in asthmatic mice. These results support the communication between the peripheral immune system and the CNS and suggest that acetylcholinesterase inhibitors, such as neostigmine, should be further studied as possible therapeutic strategies for neuroprotection in asthma.

Although the clinical course of the COVID-19 in adults has been extensively described, the impact of the co-detection of SARS-CoV-2 and rhinovirus on severity outcomes is not understood.This study aimed to compare the risk of hospitalization of outpatients with COVID-19 with and without the co-detection of rhinovirus in southern Brazil. Secondarily, such risk was also compared between all individuals with COVID-19 and those with single rhinovirus infection.Outpatients (gt;18 years) with acute signs of cough, fever, or sore throat were prospectively enrolled at two emergency departments from May to September 2020. Sample collection was performed to detect SARS-CoV-2 and other 20 respiratory pathogens. Participants were followed for 28 days through telephone interviews.1,047 participants were screened and 1,044 were included. Of these, 4.9% were lost during follow-up, and 993/1,044 (95.1%) were included in severity-related analysis. Rhinovirus was the most prevalent pathogen (25.0%, 248/993), followed by SARS-CoV-2 (22.6%, 224/993), with coinfection of these two viruses occurring in 91/993 (9.2%) participants. The risk of COVID-19-related hospitalizations were not different between individuals with and without co-detection of rhinovirus (9.9% vs. 7.6%, respectively, P = 0.655). Conversely, subjects with COVID-19 had a higher hospitalization risk than single rhinovirus infection (8.3 vs 0.4%, respectively, P lt; 0.001).The co-detection of SARS-CoV-2 and rhinovirus did not change the risk of hospitalizations in adults. Furthermore, COVID-19 was more severe than single rhinovirus infection.

Background The World Health Organization recommends tuberculosis (TB) preventive treatment (TPT) for all people living with HIV (PLH) and household contacts (HHC) of index TB patients. Tests for TB infection (TBI) or to rule out TB disease (TBD) are preferred, but if not available, this should not be a barrier if access to these tests is limited for high-risk people, such as PLH and HHC under 5 years old. There is equipoise on the need for these tests in different risk populations, especially HHC aged over 5. Methods This superiority cluster-randomized multicenter trial with three arms of equal size compares, in Benin and Brazil, three strategies for HHC investigation aged 0–50: (i) tuberculin skin testing (TST) or interferon gamma release assay (IGRA) for TBI and if positive, chest X-Ray (CXR) to rule out TBD in persons with positive TST or IGRA; (ii) same as (i) but GeneXpert (GX) replaces CXR; and (iii) no TBI testing. CXR for all; if CXR is normal, TPT is recommended. All strategies start with symptom screening. Clusters are defined as HHC members of the same index patients with newly diagnosed pulmonary TBD. The main outcome is the proportion of HHC that are TPT eligible who start TPT within 3 months of the index TB patient starting TBD treatment. Societal costs, incidence of severe adverse events, and prevalence of TBD are among secondary outcomes. Stratified analyses by age (under versus over 5) and by index patient microbiological status will be conducted. All participants provide signed informed consent. The study was approved by the Research Ethic Board of the Research Institute of the McGill University Health Centre, the Brazilian National Ethical Board CONEP, and the “Comité Local d’Éthique Pour la Recherche Biomédicale (CLERB) de l’Université de Parakou,” Benin. Findings will be submitted for publication in major medical journals and presented in conferences, to WHO and National and municipal TB programs of the involved countries. Discussion This randomized trial is meant to provide high-quality evidence to inform WHO recommendations on investigation of household contacts, as currently these are based on very low-quality evidence. Trial registration ClinicalTrials.gov NCT04528823.

In 2020, a unique social experience was provided by the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2. Interventions to tackle the pandemic may affect the burden of other respiratory diseases.This study aims to assess the impact of the COVID-19 mitigation strategies on hospitalizations for asthma in children aged between 1 and 14 years, adults aged between 20 and 59 years, and elderly older than 60 years.Data from hospital admissions for asthma were obtained from the Department of Informatics of Brazilian Public Health System database in the period between January 2016 and December 2020 and analyzed by age groups. To evaluate the effect of containment measures on the incidence of asthma and respiratory system diseases (total), the absolute reduction and relative reduction were calculated by analyzing the subsets from 2016 to 2019 versus 2020.There was a significant reduction in the average incidence of hospitalizations in 2020, with numbers ranging from -59% (incidence rate ratio, 0.41 [0.37-0.45]) for age 1 to 14 years (prepandemic 1,393.2/100,000 vs pandemic 574.9/100.000), -37% (incidence rate ratio, 0.63 [0.49-0.80]) for age 20 to 59 years (prepandemic 160.2/100,000 vs pandemic 101.1/100,000), and -60% (incidence rate ratio, 0.40 [0.33-0.47]) for older than 60 years (prepandemic 460.6/100,000 vs pandemic 185.3/100,000).Ashtma hospitalizations decreased in 2020, especially in the pediatric group and the older group during the COVID-19 pandemic, which may be associated with the reduction in the incidence of many respiratory viral infections.

COVID-19 manifests as a milder disease in children than adults, but the underlying mechanisms are not fully characterized. Here we assess the difference in cellular or humoral immune responses of pediatric and adult COVID-19 patients to see if these factors contribute to the severity dichotomy. Children’s non-specific immune profile is dominated by naive lymphocytes and HLA-DRhighCX3CR1low dendritic cells; meanwhile, children show strong specific antibody and T cell responses for viral structural proteins, with their T cell responses differing from adults by having weaker CD8+TNF+ T cells responses to S peptide pool but stronger responses to N and M peptide pools. Finally, viral mRNA is more abundant in pediatric patients. Our data thus support a scenario in which SARS-CoV-2 infected children contribute to transmission yet are less susceptible to COVID-19 symptoms due to strong and differential responses to the virus., Children often show milder COVID-19 symptoms, but the underlying mechanistic insights are still lacking. Here the authors profile both pediatric and adult cohorts of COVID-19 patients in Brazil to find that children exhibit higher viral load but stronger and biased cellular immunity, thereby serving clues for the differential responses in children.

Gut microbiota-derived short-chain fatty-acid (SFCA) acetate protects mice against RSV A2 strain infection by increasing interferon-β production and expression of interferon-stimulated genes (ISGs). However, the role of SFCA in RSV infection using strains isolated from patients is unknown.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.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.SCFA-acetate reduces the severity of RSV infection and RSV viral load through modulation of RIG-I expression.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.

BackgroundThe emergence of SARS-CoV-2 variants is a current public health concern possibly impacting COVID-19 disease diagnosis, transmission patterns and vaccine effectiveness.ObjectivesTo describe the SARS-CoV-2 lineages circulating early pandemic among samples with S gene dropout and characterize a novel mutation in receptor-binding domain (RBD) of viral spike protein.Study designAdults and children older than 2 months with signs and symptoms of COVID-19 were prospectively enrolled from May to October 2020 in Porto Alegre, Brazil. All participants performed RT-PCR assays for diagnosing SARS-CoV-2, samples with S gene dropout and Ct < 30 (cycle threshold) were submitted to whole genome sequencing (WGS), and homology modeling and physicochemical properties analysis were performed.Results484/1,557 participants tested positive for SARS-CoV-2. The S gene dropout was detected in 7.4% (36/484) as early as May, and a peak was observed in early August. WGS was performed in 8 samples. The B.1.1.28, B.1.91 and B.1.1.33 lineages were circulating in early pandemic. The RBD novel mutation (Y380Q) was found in one sample occurring simultaneously with C379W and V395A, and the B.1.91 lineage in the spike protein.ConclusionMutations in the SARS-CoV-2 spike region were detected early in the COVID-19 pandemic in Southern Brazil, regarding the B.1.1.28, B.1.91 and B.1.1.33 lineages identified. The novel mutation (Y380Q) with C379W, modifies important RBD properties, which may interfere with the binding of neutralizing antibodies (CR3022, EY6A, H014, S304).HighlightsCharacterization of novel mutation (Y380Q) in RBD of SARS-CoV-2 spike proteinThe Y380Q and C379W modify important properties in the SARS-CoV-2 RBD regionThe RBD mutations may interfere with the binding of neutralizing antibodiesThe B.1.1.28, B.1.91 and B.1.1.33 lineages were circulating in early pandemic

Background/ObjectivesThe aim of this study was to evaluate the association between obesity and hospitalization in mild COVID-19 adult outpatients in Brazil.Subjects/MethodsAdults with signs and symptoms suggestive of acute SARS-CoV-2 infection who sought two hospitals (one public and one private) emergency department (ED) were prospectively enrolled. Patients with confirmed COVID-19 at inclusion were followed by phone calls at day (D) D7, D14 and D28. Multivariable logistic regression models were employed to explore the association between obesity and other potential predictors for hospitalization.ResultsA total of 1,050 participants were screened, 310 were diagnosed with COVID-19 by RT-PCR. Median age was 37.4 (IQR 29.8-45.0) years, and 186 (60.0%) were female. Duration of symptoms was 3.0 (IQR 2.0-5.0) days, and 10.0 (IQR 8.0-12.0) was the median number of symptoms at inclusion. A total of 98 (31.6%) were obese, and 243 (78.4%) had no previous medical conditions. Twenty three participants (23/310, 7.4%) required hospitalization during the period. After adjusting, obesity (BMI≥30.0 kg/m2) (OR=2.69, 95%CI 1.63-4.83, PConclusionsObesity, followed by aging, was the main factor associated with hospital admission for COVID-19 in a young population in a low-middle income country. Our findings highlighted the need for actions to promote additional protection for obese population, such as vaccination, and to encourage lifestyle changes.

Respiratory syncytial virus (RSV) is the major cause of infection in children up to 2 years old and reinfection is very common among patients. Tissue damage in the lung caused by RSV leads to an immune response and infected cells activate multiple signaling pathways and massive production of inflammatory mediators like macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine. Therefore, we sought to investigate the role of MIF during RSV infection in macrophages. We evaluated MIF expression in BALB/c mice-derived macrophages stimulated with different concentrations of RSV by Western blot and real-time PCR. Additionally, different inhibitors of signaling pathways and ROS were used to evaluate their importance for MIF expression. Furthermore, we used a specific MIF inhibitor, ISO-1, to evaluate the role of MIF in viral clearance and in RSV-induced TNF-α, MCP-1 and IL-10 release from macrophages. We showed that RSV induces MIF expression dependently of ROS, 5-LOX, COX and PI3K activation. Moreover, viral replication is necessary for RSV-triggered MIF expression. Differently, p38 MAPK in only partially needed for RSV-induced MIF expression. In addition, MIF is important for the release of TNF-α, MCP-1 and IL-10 triggered by RSV in macrophages. In conclusion, we demonstrate that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.

Epidemiological evidence that COVID-19 manifests as a milder disease in children compared to adults has been reported by numerous studies, but the mechanisms underlying this phenomenon have not been characterized. It is still unclear how frequently children get infected, and/or generate immune responses to SARS-CoV-2. We have performed immune profiling of pediatric and adult COVID-19 patients in Brazil, producing over 38 thousand data points, asking if cellular or humoral immune responses could help explain milder disease in children. In this study, pediatric COVID-19 patients presented high viral titers. Though their non-specific immune profile was dominated by naive, non-activated lymphocytes, their dendritic cells expressed high levels of HLA-DR and were low in CX3CR1, indicating competence to generate immune responses that are not targeted to inflamed tissue. Finally, children formed strong specific antibody and T cell responses for viral structural proteins. Children’s T cell responses differed from adults in that their CD8+ TNFα+ T cell responses were low for S peptide but significantly higher against N and M peptide pools. Altogether, our data support a scenario in which SARS-CoV-2 infected children may contribute to transmission, though generating strong and differential responses to the virus that might associate with protection in pediatric COVID-19 presentation.

Epidemiological evidence that COVID-19 manifests as a milder disease in children compared to adults has been reported by numerous studies, but the mechanisms underlying this phenomenon have not been characterized. It is still unclear how frequently children get infected, and/or generate immune responses to SARS-CoV-2. We have performed immune profiling of pediatric and adult COVID-19 patients in Brazil, producing over 38 thousand data points, asking if cellular or humoral immune responses could help explain milder disease in children. In this study, pediatric COVID-19 patients presented high viral titers. Though their non-specific immune profile was dominated by naive, non-activated lymphocytes, their dendritic cells expressed high levels of HLA-DR and were low in CX3CR1, indicating competence to generate immune responses that are not targeted to inflamed tissue. Finally, children formed strong specific antibody and T cell responses for viral structural proteins. Children’s T cell responses differed from adults in that their CD8+ TNFα+ T cell responses were low for S peptide but significantly higher against N and M peptide pools. Altogether, our data support a scenario in which SARS-CoV-2 infected children may contribute to transmission, though generating strong and differential responses to the virus that might associate with protection in pediatric COVID-19 presentation.

Background: Respiratory syncytial virus (RSV) and influenza are prevalent seasonal community viruses. Although not completely understood, SARS-CoV-2 may have the same means of transmission. Preventive social measures aimed at preventing SARS-CoV-2 spread could impact transmission of other respiratory viruses as well. The aim of this study is to report the detection of RSV and influenza during the period of social distancing due to COVID-19 pandemic in a heavily affected community. Methods: Prospective study with pediatric and adult populations seeking care for COVID-19-like symptoms during the fall and winter of 2020 at two hospitals in Southern Brazil. RT-PCR tests for SARS-CoV-2, influenza A (Flu A), influenza B (Flu B) and respiratory syncytial virus (RSV) was performed for all participants. Results: 1435 suspected COVID-19 participants (1137 adults, and 298 children). were included between May and August. Median age was 37.7 years (IQR = 29.6-47.7), and 4.92 years (IQR = 1.96-9.53), for the adult and child cohorts, respectively. SARS-CoV-2 was positive in 469 (32.7%) while influenza and RSV were not detected at all. Conclusions: Measures to reduce SARS-CoV-2 transmission likely exerted a huge impact in the spread of alternate respiratory pathogens. These findings contribute to the knowledge about the dynamics of virus spread. Further, it may be considered for guiding therapeutic choices for these other viruses.

Background: Gut microbiota-derived short-chain fatty-acid (SFCA) acetate protects mice againstRSV A2 strain infection by increasing interferon-β production and expression of interferonstimulated genes (ISGs). However, the role of SFCAs 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 acetate treatment in human pulmonary epithelial cells. We next examined whether 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 acetate ex-vivo impacts upon viral load and ISG expression. We further treated epithelial cells from SARS-CoV-2 infected patients with acetate. Findings: In vitro pre-treatment of A549 cells with acetate reduced RSV load after infection with clinical isolates and increased the expression of RIG-I and ISG15. Animals treated with acetate intranasally recovered significantly faster, with reduction in the RSV clinical isolates viral load, and increased lung expression of IFNB1 and the RIG-I receptor. 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 acetate levels were associated with increasing oxygen saturation at admission, and shorter duration of fever. Ex-vivo treatment of patients’ respiratory cells with acetate reduced RSV load and increased expression of ISGs OAS1 and ISG15, and virus recognition receptors MAVS and RIG-I, but not IFNB1. These acetate effects were not found on cells from SARS-CoV-2 infected patients. Interpretation: Acetate reduces the severity of RSV infection and RSV viral load through modulation of RIG-I expression. Funding: This study was supported by Rio Grande do Sul Research Foundation FAPERGS (FAPERGS/MS/CNPq/SESRS no. 03/2017 - PPSUS 17/2551-0001380-8 and COVID-19 20/2551-0000258-6), CNPq 312504/2017-9 and by Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) - Finance Code 001. P.B., C.V.B. and L.A.B. would like to acknowledge financial support given by CNPq/FAPERGS/CAPES/BNDES to the National Institute of Science and Technology on Tuberculosis (INCT-TB), Brazil [grant numbers: 421703- 2017-2/17-1265-8/14.2.0914.1). Declaration of Interest: The authors declare no competing interests. Ethical Approval: All animal procedures were performed in accordance with protocols approved by CEUA/UNICAMP (protocols 4022-1 and 4599-1).

Severe therapy-resistant asthma (STRA) is closely associated with distinct clinical and inflammatory pheno-endotypes, which may contribute to the development of age-related comorbidities. Evidence has demonstrated a contribution of accelerated telomere shortening on the poor prognosis of respiratory diseases in adults. Eotaxin-1 (CCL11) is an important chemokine for eosinophilic recruitment and the progression of asthma. In the last years has also been proposed as an age-promoting factor. This study aimed to investigate the association of relative telomere length (rTL) and eotaxin-1 in asthmatic children. Children aged 8-14 years (n=267) were classified as healthy control (HC, n=126), mild asthma (MA, n=124) or severe therapy-resistant asthma (STRA, n=17). rTL was performed by qPCR from peripheral blood. Eotaxin-1 was quantified by ELISA from fresh-frozen plasma. STRA had shorter telomeres compared to HC (p=0.02) and MA (p=0.006). Eotaxin-1 levels were up-regulated in STRA [median; IQR25-75)] [(1,190 pg/mL; 108-2,510)] compared to MA [(638 pg/mL; 134-1,460)] (p=0.03) or HC [(627 pg/mL; 108-1,750)] (p

Introdução/Objetivo: Os fatores associados ao risco de hospitalização por COVID19 não são completamente conhecidos. O objetivo deste estudo foi descrever o risco de hospitalização dos participantes ambulatoriais com diagnóstico exclusivo para rinovírus, SARS-CoV-2 e codetecção entre esses dois agentes, durante a pandemia no sul do Brasil. Métodos: Participantes ambulatoriais (> 18 anos) com sinais agudos de tosse, febre ou dor de garganta foram recrutados prospectivamente nas tendas de atendimento do Hospital Moinhos de Vento e Hospital Restinga e Extremo Sul, entre maio e novembro de 2020, e foram acompanhados por 28 dias através de entrevistas telefônicas. Para a detecção de SARS-CoV-2 bem como para o painel respiratório, foi utilizada a técnica de RT-PCR. Para detecção de SARS-CoV-2 foi utilizado kit TaqManTM 2019-nCoV Assay Kit v1 (genes S, N e ORF1ab) a partir de swabs orofaríngeo e nasofaríngeo bilateral. Em coleta de outro swab nasofaríngeo foi realizado painel respiratório para detecção de: Bordetella pertussis; Chlamydophila pneumoniae; Mycoplasma pneumoniae; adenovírus; bocavírus; coronavírus tipos HKU1, 229E, NL63 e OC43; vírus influenza A tipos H1 e H3; vírus influenza B; enterovírus humano; metapneumovírus humano; vírus parainfluenza tipos 1, 2 e 3; RSV tipos A e B; e rinovírus). Todas as amostras foram analisadas no Laboratório de Biologia Molecular do Hospital Moinhos de Vento. Resultados: Foram recrutados 609 participantes, com idade mediana de 36 anos, sendo a maioria mulheres (63,2%). 282 (46,4%) participantes tiveram detectado apenas rinovírus, seguido por 234 (38,4%) com SARS-CoV-2 exclusivamente. A codetecção entre estes dois agentes ocorreu em 93 (15,3%) dos 608 participantes. Deste total, 26 (4,3%) participantes necessitaram hospitalização após a busca por atendimento ambulatorial. Participantes com codetecção viral apresentaram maior proporção de hospitalização quando comparados aos participantes com SARS-CoV-2 e rinovírus detectados como agentes únicos (9,7% (9/93) vs 6,8% (16/234) vs 0,4% (1/282), p < 0.001). Entretanto, quando comparadas as proporções de coinfecção com SARS-CoV-2 (como agente único), a diferença não é significativa (9,7% (9/93) vs 6,8% (16/234), p = 0.373). Conclusão: O rinovírus foi o principal patógeno detectado em adultos, e apesar da alta prevalência não foi associado ao aumento na hospitalização, sendo o maior risco atribuído à detecção de SARS-CoV-2 nessa população.

Background Invariant natural killer T (iNKT) cells play complex functions in the immune system, releasing both Th1 and Th2 cytokines. The role of iNKT cells in human asthma is still controversial and never described in severe therapy-resistant asthma in children. The objective of this work was to analyse iNKT frequency in peripheral blood of children with severe therapy-resistant asthma (STRA), compared to children with milder asthma and healthy controls. Methods Children with asthma ( n = 136) (non-severe and STRA) from a referral centre and healthy controls ( n = 40) were recruited. Peripheral blood mononuclear cells were isolated, stained with anti-CD3 and anti-iNKT (Vα24Jα18), and analysed through flow cytometry. Atopic status was defined by measuring specific IgE in serum. Airway inflammation was assessed by induced sputum. Results Children with asthma presented an increased frequency of CD3 + iNKT + cells (median 0.38% IQR 0.18–1.9), compared to healthy controls (median 0.26% IQR 0.10–0.43) ( p = 0.025). Children with STRA also showed an increased frequency of iNKT cells (1.5% IQR 1.05–2.73) compared to healthy controls and non-severe asthmatic children (0.35% IQR 0.15–1.6; p = 0.002). The frequency of iNKT cells was not different between atopic and non-atopic children. In addition, iNKT cells were not associated with any inflammatory pattern of induced sputum studied. Conclusion Our data suggests that iNKT cells play a role in paediatric asthma, which is also associated with the severity of disease, but independent of the atopic status.

Background Severe asthma in children is a global health problem. Severe therapy-resistant asthma (STRA) in children is a major clinical challenge due to persistent symptoms despite high doses of corticosteroids and results in high public health costs. Omalizumab (anti-IgE monoclonal antibody) has been described as an effective add-on therapy in these patients. The characteristics of children with STRA from low- and middle-income countries have scarcely been reported, and no real-life study has been published on the effects of omalizumab in this group of patients. The aim of our study is to report the first clinical real-life experiences with omalizumab in Brazilian children with STRA. Methods Children (6-18 years old) from a referral center who were diagnosed with STRA were included in this retrospective study based on our clinical databases. The included children had undergone at least 6 months of omalizumab treatment and fulfilled the following initial criteria: 1) >6 years old; 2) a positive skin-prick test for at least one aeroallergen; and 3) a serum total IgE level between 30 and 1500 IU/mL. Clinical and lung function variables were analyzed before and after treatment. Results Fourteen children (mean age: 11.9 years; percentage female: 72%) were included in this study. Omalizumab treatment significantly increased control of the disease according to a standardized questionnaire administered at every visit (P

Background It is not quite well established how immune responses differ in term and preterm infants beyond the first year of life. This study aimed to evaluate aspects of the innate and adaptive immune responses in a group of preterm infants in comparison with their term peers. Methods In this cross-sectional study peripheral blood mononuclear cells (PBMC) were isolated from preterm and term children at age three years. Innate immune response was evaluated by the analysis of TLR receptors expression on CD11c+HLADRhigh cells and inflammatory cytokine production after PBMC stimulation with Toll like receptors (TLR) ligands. Adaptive immune response was evaluated by T cells’ phenotyping and function after stimulation with polyclonal conventional T cell stimulus. Conclusion We have found that the patterns of innate and adaptive immune responses at 3 years of age were not affected by the fact of the children having being born preterm or at term.

Introduction: Severe therapy-resistant asthma (STRA) is associated with a range of pheno-endotypes and adults with STRA have higher risk for developing comorbidities. Studies investigating telomere length (TL) in adults have demonstrated telomere shortening in IPF, COPD and asthma. Eotaxin-1 (CCL11), an important modulator for eosinophilic function and chemo-attraction has also been proposed an aging factor. Aims: To investigate whether differences exist in TL and CCL11 on peripheral blood cells between age-matched severe and mild asthmatic (MA) children and healthy control (HC) subjects. Methods: Relative telomere length (T/S) was quantified by qPCR (peripheral blood) from 124 children with MA, 17 STRA and 73 age-matched HC. CCL11 was quantified by ELISA. Results: T/S analyses indicated that STRA group (median 0.818, IQR25-27 0.496–1.041) had significantly shorter telomeres when compared to MA (1.083 (0.732–1.582), P=0.043). No difference was observed between T/S ratio of MA or STRA and HC (0.998, (0.630–1.740)). Higher levels of CCL11 were found among children within STRA group (1,119 pg/mL (554 - 1,401)) when compared to MA (675 (388 - 1,015) or HC children (626 (256 - 922), P=0.023) with ordered differences among classes (P=0.021). T/S ratio of STRA was inversely correlated with CCL11 (r=-0.573, P=0.011). Conclusions: This is the first report showing a decrease in TL in children with STRA and associated with up-regulation of CCL11. This study adds new evidence to the theory of accelerated aging suggesting that, telomeres attrition and CCL11, could prematurely contribute to a senescent phenotype associated with risk for appearance of comorbidities

ObjectiveWe aimed to assess the profile of respiratory viruses in young children hospitalized for acute lower respiratory tract infection (ALRI) and its association with disease severity, defined as need for pediatric intensive care unit (PICU) admission.DesignProspective observational cohort study.SettingA tertiary-care university hospital in Brazil.PatientsChildren younger than three years attending the pediatric emergency room with ALRI who were admitted to the hospital.InterventionsNone.Measurements and main resultsNasopharyngeal aspirates were collected from patients from June 1st, 2008 to May 31st, 2009within the first 48 hours of hospitalization. Nasopharyngeal aspirates were tested for 17humanrespiratory viruses by molecular and immunofluorescence based assays. Simple and multiple log-binomial regression models were constructed to assess associations of virus type with a need for PICU admission. Age, prematurity, the presence of an underlying disease and congenital heart disease were covariates. Nasopharyngeal aspirates were positive for at least one virus in 236 patients. Rhinoviruses were detected in 85.6% of samples, with a preponderance of rhinovirus C (RV-C) (61.9%). Respiratory syncytial virus was detected in 59.8% and human coronavirus (HCoV) in 11% of the samples. Co-detections of two to five viruses were found in 78% of the patients. The detection of HCoV alone (adjusted relative risk (RR) 2.18; 95% CI 1.15-4.15) or in co-infection with RV-C (adjusted RR 2.37; 95% CI 1.23-4.58) was independently associated with PICU admission.ConclusionsThe detection of HCoV alone or in co-infection with RV-C was independently associated with PICU admission in young children hospitalized for ALRI.

Community-acquired pneumonia (CAP) remains a major health problem, accounting for approximately 20% of all deaths in children younger than 5 years. Viruses are, by far, the most common cause of CAP. The introduction of conjugate vaccines for pneumococcus and H. Influenzae in the past decade has reduced the burden of bacterial disease. Currently, Streptococcus pneumoniae and Mycoplasma pneumoniae are the most prevalent bacterial agents among immunized populations, especially beyond the neonatal period. Contiguous spread for viruses and microaspiration of bacteria from the upper airways are main pathogenic mechanisms. Clinical and radiological parameters are highly variable, and diagnosis remains a challenge, especially in young children. Moreover, etiologic diagnosis is usually not possible or feasible in children. General management includes supportive measures and in the case of suspected bacterial etiology, antimicrobials are warranted. All current guidelines recommend oral Amoxicillin as the drug of choice, and IV Penicillin or Ampicillin when parenteral route is indicated for fully immunized children. Major clinical complications are tissue necrosis, pleural effusion, empyema, and lung abscess. Besides universal hygiene precautions with good sanitary conditions, immunization against Influenza, Streptococcus pneumoniae, Haemophilus influenzae type b, and Bordetella pertussis constitute the most effective strategy for CAP prevention. The prognosis for healthy children is usually good and complete recovery is the rule, although restrictive lung disease and recurrent wheezing can occur in a small subset of patients.

An imbalance in Th1/Th2 cytokine immune response has been described to influence the pathogenesis of respiratory syncytial virus (RSV) acute bronchiolitis and the severity of infection. Th2-driven response has been well described under first RSV vaccine (formalin-inactivated RSV vaccine antigens) and replicated in some conditions for RSV-infected mice, in which a Th2-dependent lung eosinophilia increases illness severity, accompanied of tissue damage. Currently, several prototypes of RSV vaccine are being tested, but there is no vaccine available so far. The advance of bioinformatics can help to solve this issue. Systems biology approaches based on network topological analysis may help to identify new genes in order to direct Th1 immune response during RSV challenge. For this purpose, network centrality analyses from high-throughput experiments were performed in order to select major genes enrolled in each T-helper immune response. Thus, genes termed Hub (B) and bottlenecks (H), which control the flow of biological information (Th1 or Th2 immune response, in this case) within the network, would be identified. As these genes possess high potential to promote Th1 immune response, they could be cloned under regulation of specific promoters in a plasmid, which will be available as a gene-transfer adjunctive to vaccines. Th1 immune response potentiated by our strategy may contribute to accelerate Th1/Th2 shift from neonatal immune system, which might favor protective immunity against RSV infection and reduce lung damage.

To assess the impact of asthma in a population of inner-city Brazilian children.In a cross-sectional study, we selected children with asthma and healthy controls from public schools (8-16 years) from a capital city of Southern Brazil. Divided into three phases, questionnaires were administered, assessing lung function, body mass index and allergic sensitization.From 2500 children initially included in the study (48.4% males; mean age of 11.42 ± 2.32 years), asthma prevalence was detected in 28.6% (715/2500). The disease was not controlled in 42.7% (305/715) of the children, with 7.6% of hospitalization rate. School absenteeism (at least one day of missing school because of asthma) and sedentary behavior were high (57.1 and 67.2%, respectively), with 47.9% of subjects requiring oral steroids in the previous year, and physical well-being significantly lower than controls, directly interfering with quality of life, and therefore in the daily activities of these students. Moreover, 38% of the parents admitted to being non-adherent to treatment with their children and 31.1 and 53.6%, respectively, believed that rescue medication and exercise might be harmful.The burden of asthma in Brazilian children seems to be substantial. New international guidelines with a special focus in developing countries settings, with more pragmatic approaches, should be a priority for discussion and implementation actions.

Despite overall progress toward achieving the Millennium Development Goals, large health discrepancies persist between developed and developing countries. The world is rapidly changing and the influences of societal change and climate change will disproportionately affect the world's most vulnerable populations, thus exacerbating current inequities. Current development strategies do not adequately address these disproportionate impacts of environmental exposures. The aim of this study was to propose a new framework to address the health consequences of environmental exposures beyond 2015. This framework is transdisciplinary and precautionary. It is based on identifying social and economic determinants of health, strengthening primary health systems, and improving the health of vulnerable populations. It incorporates deliberate plans for assessment and control of avoidable environmental exposures. It sets specific, measurable targets for health and environmental improvement.

Experimental data show that type I interferon has a key role in innate immune response against influenza infection.We compared nasal levels of interferon-α2 and β among inpatients and outpatients with influenza.Children younger than 5 years of age with influenza-like illness seeking care at the emergency department within the first 72 h of disease onset were prospectively included. Clinical and demographic data and secretions through nasal wash were obtained. Influenza infection was assessed through reverse-transcription polymerase chain reaction and nasal levels of interferon-α2 and β were measured by enzyme-linked immunosorbent assay. All patients followed until the end of the disease.One hundred patients were included, of which 24 had confirmed influenza infection, and 5 of them were hospitalized. Subtypes A (H3N2) and B were confirmed in 10 and 14 patients, respectively. Seventy-six patients without influenza, including 48% of outpatients, were recruited as controls. All hospitalized patients were significantly younger regardless of influenza status (age6 months in 59% vs. 23.2%, p 0.001). All other data were similar among the groups. Comparing median levels of interferon-α2 among children with influenza, levels were significantly higher in outpatients than in hospitalized patients and were 263.2 pg/mL (25-75 interquartile range: 58.3-634) and detectable in only one patient (90 pg/mL), respectively. The levels of interferon-α2 in controls and those of interferon-β in all groups were not detected.Higher levels of interferon-α2 in patients with less severe influenza reinforce experimental evidence about the protective role of interferon-α2 against influenza infection.

Studies have shown autophagy participation in the immunopathology of inflammatory diseases. However, autophagy role in asthma and in eosinophil extracellular traps (EETs) release is poorly understood. Here, we attempted to investigate the autophagy involvement in EETs release and in lung inflammation in an experimental asthma model. Mice were sensitized with ovalbumin (OVA), followed by OVA challenge. Before the challenge with OVA, mice were treated with an autophagy inhibitor, 3-methyladenine (3-MA). We showed that 3-MA treatment decreases the number of eosinophils, eosinophil peroxidase (EPO) activity, goblet cells hyperplasia, proinflammatory cytokines, and nuclear factor kappa B (NFκB) p65 immunocontent in the lung. Moreover, 3-MA was able to improve oxidative stress, mitochondrial energy metabolism, and Na+ , K+ -ATPase activity. We demonstrated that treatment with autophagy inhibitor 3-MA reduced EETs formation in the airway. On the basis of our results, 3-MA treatment can be an interesting alternative for reducing lung inflammation, oxidative stress, mitochondrial damage, and EETs formation in asthma.

Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants, Dietary fibers and SCFAs can exert a protective effect against respiratory syncytial virus (RSV). Here, the authors report that microbiota-derived acetate protects mice against RSV infection via GPR43- mediated type 1 interferon response induction in the lungs.

Summary Respiratory syncytial virus (RSV)-specific CD8+ T cell responses do not protect against reinfection. Activation of mammalian target of rapamycin (mTOR) impairs memory CD8+ T cell differentiation. Our hypothesis was that RSV inhibits the formation of CD8+ T cells memory responses through mTOR activation. To explore this, human and mouse T cells were used. RSV induced mTOR phosphorylation at Ser2448 in CD8 T cells. mTOR activation by RSV was completely inhibited using rapamycin. RSV-infected children presented higher mTOR gene expression on nasal washes comparing to children infected with metapneumovirus and rhinovirus. In addition, RSV-infected infants presented a higher frequency of CD8+ pmTORser2448+ T cells in nasal washes compared to RSV-negative infants. Rapamycin treatment increased the frequency of mouse CD8 RSV-M282–90 pentamer-positive T cells and the frequency of RSV-specific memory T cells precursors. These data demonstrate that RSV is activating mTOR directly in CD8 T cells, indicating a role for mTOR during the course of RSV infection.

Objective: To review the mechanisms of action of macrolides in pediatric respiratory diseases and their clinical indications. Sources: Review in the PubMed database, comprising the following terms in English: “macrolide and asthma”; “macrolide and cystic fibrosis”; “macrolide bronchiolitis and viral acute”; “macrolide and bronchiolitis obliterans” and “macrolide and non-CF bronchiectasis”. Summary of the findings: The spectrum of action of macrolides includes production of inflammatory mediators, control of mucus hypersecretion, and modulation of host-defense mechanisms. The potential benefit of macrolide antibiotics has been studied in a variety of lung diseases, such as cystic fibrosis (CF), bronchiectasis, asthma, acute bronchiolitis, and non-CF bronchiectasis. Several studies have evaluated the benefits of macrolides in asthma refractory to therapy, but the results are controversial and indications should be limited to specific phenotypes.In viral bronchiolitis, there is no consistent benefit in acute conditions, although recent data have shown an effect in recurrent wheezing prevention. In patients with CF results are also contradictory, but the consensus states there is a small clinical benefit, especially for patients infected with P. aeruginosa. There was also no positive action of macrolides in patients with post-infectious bronchiolitis obliterans. Children with non-CF bronchiectasis seem to have clear benefits regarding the use of macrolides, which showed clinical advantages in parenchyma protection and lung function. Conclusions: The long-term use of macrolides should be limited to highly selected situations, especially in patients with bronchiectasis. Careful evaluation of the benefits and potential damage are tools for their indication in specific groups. Resumo: Objetivo: revisar os mecanismos de ação de macrolídeos em doenças respiratórias pediátricas e as suas indicações clínicas. Fonte de dados: revisão na base de dados Pubmed, compreendendo os termos em inglês referente ao tema básico. Síntese dos dados: O seu espectro de ação estende-se desde a produção de mediadores inflamatórios, o controle da hipersecreção de muco e modulação de mecanismos de defesa do hospedeiro. O potencial benefício dos antibióticos macrolídeos foi estudado em doenças pulmonares como a fibrose cística, as bronquiectasias, a asma, a bronquiolite aguda e as bronquiectasias não ligadas à fibrose cística. Diversos estudos avaliaram os benefícios dos macrolídeos na asma resistente a terapia, porém, os resultados são controversos e as indicações devem ser limitadas a fenótipos específicos. Na bronquiolite viral não há benefícios consistentes nos quadros agudos, embora dados recentes mostrem um efeito na prevenção de sibilância recorrente. Em pacientes com fibrose cística os resultados também são contraditórios, mas o consenso é de que há um pequeno benefício clínico, especialmente para os pacientes infectados por P. aeruginosa. Também não foi observada ação positiva dos macrolídeos em pacientes com bronquiolite obliterante pós-infecciosa. Crianças com bronquiectasias não relacionadas à fibrose cística parecem ter claros benefícios em relação ao uso de macrolídeos, os quais mostraram vantagens clínicas, de proteção ao parênquima e na função pulmonar. Conclusões: O uso em longo prazo de macrolídeos deve ser limitado a situações altamente selecionadas, especialmente em pacientes com bronquiectasias. Avaliação cuidadosa dos benefícios e potenciais danos são ferramentas para indicação em grupos específicos. Keywords: Pulmonary diseases, Macrolides, Inflammation, Children, Adolescents, Palavras-chave: Doenças pulmonares, Macrolídeos, Inflamação, Crianças, Adolescentes

Summary Background Children's perception of their symptoms has proved reliable and relevant to disease management and should be considered when assessing their asthma control. The aim of the study is to validate the Brazilian Portuguese version of the Childhood Asthma Control Test (c-ACT) in children aged 4–11 years. Methods This is a cross-sectional study in children diagnosed with asthma undergoing treatment in a pediatric pulmonology outpatient clinic in Porto Alegre, Brazil. The translation and linguistic adaptation of the instrument were performed in accordance with international recommendations for questionnaire validation. Results A total of 105 participants were included, aged 4–11 years. Validity: all correlations between the total score and items on the questionnaire were significant and obtained values of r ≥ 0.3, and c-ACT means showed statistically significant differences between the GINA categories (P

Objective The main objective of this systematic review is to assess the effects of obesity on telomere length. Methods The following databases were searched: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), LILACS, SPORTdiscus, and Web of Science from inception to August 2014. The search was performed using the following combinations of terms: telomere AND “overweight” OR “obesity” OR “adiposity,” without language restriction. Results Sixty-three original studies were included in this systematic review, comprising 119,439 subjects. Thirty-nine studies showed either weak or moderate correlation between obesity and telomere length; however, they showed an important heterogeneity. Conclusions There is a tendency toward demonstrating negative correlation between obesity and telomere length. The selected studies showed weak to moderate correlation for the main search, and there was an important heterogeneity. For this reason, the causal relationship of obesity and telomere length remains open. Additional controlled longitudinal studies are needed to investigate this issue.

It is not currently clear whether different parasites have distinct effects on the airway inflammatory response in asthma and whether exposure in early life to helminths have a stronger impact in a potential inhibitory effect on asthma. The aim of this study is to evaluate the effect of exposure to different helminth extracts on the development of allergic pulmonary response in mice, including early-life exposure. Different helminth extracts (Angiostrongylus costaricensis, Angiostrongylus cantonensis and Ascaris lumbricoides) were studied in female adult BALB/c and C57BL/6 IL-10-deficient mice in a protocol of murine asthma, injected intraperitoneally in different periods of exposure (early, pre-sensitization and post-sensitization). Cell counts in bronchoalveolar lavage (BAL), eosinophil peroxidase (EPO) from lung tissue, cytokine levels from BAL/spleen cell cultures, and lung histology were analyzed. Airway cellular influx induced by OVA was significantly inhibited by extracts of A. cantonensis and A. lumbricoides. Extracts of A. lumbricoides and A. costaricensis led to a significant reduction of IL-5 in BAL (p

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention. Fil: Caballero, Mauricio Tomás. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Serra, M. Elina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Acosta, Patricio Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Marzec, Jacqui. Instituto de Efectividad Clínica y Sanitaria; Argentina Fil: Gibbons, Luz. Institute For Clinical Effectiveness And Health Policy, Ciudad Autonoma de Buenos Aires; Argentina Fil: Salim, Maximiliano. Hospital Evita Pueblo; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Rodriguez, Andrea. Hospital Mi Pueblo; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Reynaldi, Andrea. Unidad Asistencial "Dr. César Milstein"; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Garcia, Alejandro. Fundación para la Investigación en Infectología Infantil; Argentina. Unidad Asistencial "Dr. César Milstein"; Argentina Fil: Bado, Daniela. Unidad Asistencial "Dr. César Milstein"; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Buchholz, Ursula J.. National Institute Of Allergy And Infectious Diseases; Estados Unidos Fil: Hijano, Diego Raúl. Fundación para la Investigación en Infectología Infantil; Argentina. Vanderbilt University; Estados Unidos Fil: Coviello, Silvina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Newcomb, Dawn. Vanderbilt University; Estados Unidos Fil: Bellabarba, Miguel. Unidad Asistencial "Dr. César Milstein"; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Ferolla, Fausto Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Libster, Romina Paula. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Vanderbilt University; Estados Unidos Fil: Berenstein, Ada. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Siniawaski, Susana. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Blumetti, Valeria. Swiss Medical Center; Argentina Fil: Echavarría, Marcela Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Educación Medica E Invest.clinicas; Argentina Fil: Pinto, Leonardo. Fundación para la Investigación en Infectología Infantil; Argentina. Pontificia Universidade Católica do Rio Grande do Sul; Brasil Fil: Lawrence, Andrea. Vanderbilt University; Estados Unidos Fil: Ossorio, Maria Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); Argentina Fil: Grosman, Arnoldo. Hospital Espanol; Argentina Fil: Mateu, Cecilia Gabriela. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bayle, Carola. Hospital Nacional Professor Dr. Alejandro Posadas; Argentina Fil: Dericco, Alejandra. Hospital Nacional Professor Dr. Alejandro Posadas; Argentina Fil: Pellegrini, Mariana. Hospital Nacional Professor Dr. Alejandro Posadas; Argentina Fil: Igarza, Ignacio. Hospital Nacional Professor Dr. Alejandro Posadas; Argentina Fil: Repetto, Horacio A.. 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