RESUMO
Multi-omics (genomics, transcriptomics, epigenomics, proteomics, metabolomics, etc.) research approaches are vital for understanding the hierarchical complexity of human biology and have proven to be extremely valuable in cancer research and precision medicine. Emerging scientific advances in recent years have made high-throughput genome-wide sequencing a central focus in molecular research by allowing for the collective analysis of various kinds of molecular biological data from different types of specimens in a single tissue or even at the level of a single cell. Additionally, with the help of improved computational resources and data mining, researchers are able to integrate data from different multi-omics regimes to identify new prognostic, diagnostic, or predictive biomarkers, uncover novel therapeutic targets, and develop more personalized treatment protocols for patients. For the research community to parse the scientifically and clinically meaningful information out of all the biological data being generated each day more efficiently with less wasted resources, being familiar with and comfortable using advanced analytical tools, such as Google Cloud Platform becomes imperative. This project is an interdisciplinary, cross-organizational effort to provide a guided learning module for integrating transcriptomics and epigenetics data analysis protocols into a comprehensive analysis pipeline for users to implement in their own work, utilizing the cloud computing infrastructure on Google Cloud. The learning module consists of three submodules that guide the user through tutorial examples that illustrate the analysis of RNA-sequence and Reduced-Representation Bisulfite Sequencing data. The examples are in the form of breast cancer case studies, and the data sets were procured from the public repository Gene Expression Omnibus. The first submodule is devoted to transcriptomics analysis with the RNA sequencing data, the second submodule focuses on epigenetics analysis using the DNA methylation data, and the third submodule integrates the two methods for a deeper biological understanding. The modules begin with data collection and preprocessing, with further downstream analysis performed in a Vertex AI Jupyter notebook instance with an R kernel. Analysis results are returned to Google Cloud buckets for storage and visualization, removing the computational strain from local resources. The final product is a start-to-finish tutorial for the researchers with limited experience in multi-omics to integrate transcriptomics and epigenetics data analysis into a comprehensive pipeline to perform their own biological research.This manuscript describes the development of a resource module that is part of a learning platform named ``NIGMS Sandbox for Cloud-based Learning'' https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox [16] at the beginning of this Supplement. This module delivers learning materials on the analysis of bulk and single-cell ATAC-seq data in an interactive format that uses appropriate cloud resources for data access and analyses.
Assuntos
Computação em Nuvem , Epigenômica , Humanos , Epigenômica/métodos , Epigênese Genética , Transcriptoma , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Software , Mineração de Dados/métodosRESUMO
Coronavirus disease 2019 (COVID-19) has claimed millions of lives since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and lung disease appears the primary cause of death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an ex vivo human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors. Two cytokines in particular, IP-10 and IL-8, were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei, not only inhibited virus replication but also production of pro-inflammatory cytokines, and thus ameliorated the histopathological changes caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs. IMPORTANCE: Here, established an ex vivo human precision-cut lung slice platform for assessing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral replication kinetics, innate immune response, disease progression, and antiviral drugs. Using this platform, we identified early induction of specific cytokines, especially IP-10 and IL-8, as potential predictors for severe coronavirus disease 2019 (COVID-19), and uncovered a hitherto unrecognized phenomenon that while infectious virus disappears at late times of infection, viral RNA persists and lung histopathology commences. This finding may have important clinical implications for both acute and post-acute sequelae of COVID-19. This platform recapitulates some of the characteristics of lung disease observed in severe COVID-19 patients and is therefore a useful platform for understanding mechanisms of SARS-CoV-2 pathogenesis and for evaluating the efficacy of antiviral drugs.
Assuntos
Antivirais , COVID-19 , Citocinas , Pulmão , SARS-CoV-2 , Replicação Viral , Humanos , Pulmão/virologia , Pulmão/patologia , Pulmão/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Antivirais/farmacologia , COVID-19/virologia , COVID-19/patologia , Citocinas/metabolismo , Replicação Viral/efeitos dos fármacos , Imunidade Inata , Tratamento Farmacológico da COVID-19RESUMO
The human microbiome associated with the respiratory tract is diverse, heterogeneous, and dynamic. The diversity and complexity of the microbiome and the interactions between microorganisms, host cells, and the host immune system are complex and multifactorial. Furthermore, the lymphatics provide a direct highway, the gut-lung axis, for the gut microbiome to affect outcomes related to respiratory disease and the host immune response. Viral infections in the airways can also alter the presence or absence of bacterial species, which might increase the risks for allergies and asthma. Viruses infect the airway epithelium and interact with the host to promote inflammatory responses that can trigger a wheezing illness. This immune response may alter the host's immune response to microbes and allergens, leading to T2 inflammation. However, exposure to specific bacteria may also tailor the host's response long before the virus has infected the airway. The frequency of viral infections, age at infection, sampling season, geographic location, population differences, and preexisting composition of the microbiota have all been linked to changes in microbiota diversity and stability. This review aims to evaluate the current reported evidence for microbiome interactions and the influences that viral infection may have on respiratory and gut microbiota, affecting respiratory outcomes in children.
Assuntos
Asma , Microbiota , Viroses , Vírus , Criança , Humanos , Pulmão/microbiologia , BactériasRESUMO
BACKGROUND: Infection with rhinovirus (RV) is a major risk factor for disease exacerbations in patients with allergic asthma. This study analysed a broad set of cytokines in the noses of children and adults with asthma during RV infection in order to identify immunophenotypes that may link to virus-induced episodes. METHODS: Nasal wash specimens were analysed in children (n = 279 [healthy, n = 125; stable asthma, n = 64; wheeze, n = 90], ages 2-12) who presented to a hospital emergency department, and in adults (n = 44 [healthy, n = 13; asthma, n = 31], ages 18-38) who were experimentally infected with RV, including a subset who received anti-IgE. Cytokines were measured by multiplex bead assay and data analysed by univariate and multivariate methods to test relationships to viral load, allergic status, airway inflammation, and clinical outcomes. RESULTS: Analysis of a core set of 7 cytokines (IL-6, CXCL8/IL-8, IL-15, EGF, G-CSF, CXCL10/IP-10 and CCL22/MDC) revealed higher levels in children with acute wheeze versus those with stable asthma or controls. Multivariate analysis identified two clusters that were enriched for acutely wheezing children; one displaying high viral load ("RV-high") with robust secretion of CXCL10, and the other displaying high IgE with elevated EGF, CXCL8 and both eosinophil- and neutrophil-derived mediators. Broader assessment of 39 cytokines confirmed that children with acute wheeze were not deficient in type 1 anti-viral responses. Analysis of 18 nasal cytokines in adults with asthma who received RV challenge identified two clusters; one that was "RV-high" and linked to robust induction of anti-viral cytokines and anti-IgE; and the other associated with more severe symptoms and a higher inflammatory state featuring eosinophil and neutrophil factors. CONCLUSIONS: The results confirm the presence of different immunophenotypes linked to parameters of airway disease in both children and adults with asthma who are infected with RV. Such discrepancies may reflect the ability to regulate anti-viral responses.
Assuntos
Asma , Infecções por Enterovirus , Infecções por Picornaviridae , Adolescente , Adulto , Quimiocina CXCL10 , Criança , Pré-Escolar , Análise por Conglomerados , Citocinas , Infecções por Enterovirus/complicações , Fator de Crescimento Epidérmico , Fator Estimulador de Colônias de Granulócitos , Humanos , Interleucina-15 , Interleucina-6 , Interleucina-8 , Infecções por Picornaviridae/complicações , Infecções por Picornaviridae/diagnóstico , Sons Respiratórios , Rhinovirus , Adulto JovemRESUMO
Human rhinovirus (HRV) is the most common causative agent for the common cold and its respiratory symptoms. For those with asthma, cystic fibrosis, or chronic obstructive pulmonary disease, HRVs can lead to severe and, at times, fatal complications. Furthermore, an array of innate and adaptive host immune responses leads to varying outcomes ranging from subclinical to severe. In this review, we discuss the viral pathogenesis and host immune responses associated with this virus. Specifically, we focus on the immune responses that might skew a T-helper type 2 response, including alarmins, in those with allergic asthma. We also discuss the role of a poor innate immune response with interferons. Finally, we consider therapeutic options for HRV-associated exacerbations of asthma, including biologics and intranasal sprays on the basis of the current literature.
Assuntos
Asma , Infecções por Picornaviridae , Humanos , Rhinovirus , Interferons , Imunidade InataRESUMO
BACKGROUND: Viral infections, especially those caused by rhinovirus, are the most common cause of asthma exacerbations. Previous studies have argued that impaired innate antiviral immunity and, as a consequence, more severe infections contribute to these exacerbations. OBJECTIVE: These studies explored the innate immune response in the upper airway of volunteers with allergic rhinitis and asthma in comparison to healthy controls and interrogated how these differences corresponded to severity of infection. METHODS: Volunteers with allergic rhinitis, those with asthma, and those who are healthy were inoculated with rhinovirus A16 and monitored for clinical symptoms. Tissue and nasal wash samples were evaluated for antiviral signature and viral load. RESULTS: Both subjects with allergic rhinitis and asthma were found to have more severe cold symptoms. Subjects with asthma had worsened asthma control and increased bronchial hyperreactivity in the setting of higher fractional exhaled breath nitric oxide and blood eosinophils. These studies confirmed reduced expression of interferons and virus-specific pattern recognition receptors in both cohorts with atopy. Nevertheless, despite this defect in innate immunity, volunteers with allergic rhinitis/asthma had reduced rhinovirus concentrations in comparison to the controls. CONCLUSION: These results confirm that the presence of an allergic inflammatory disorder of the airway is associated with reduced innate immune responsive to rhinovirus infection. Despite this, these volunteers with allergy have reduced viral loads, arguing for the presence of a compensatory mechanism to clear the infection. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02910401.
Assuntos
Asma , Infecções por Picornaviridae , Rinite Alérgica , Humanos , Imunidade Inata , Rinite Alérgica/complicações , Rhinovirus , Carga ViralRESUMO
BACKGROUND: Although viral infection is known to be associated with asthma exacerbations, prior research has not identified reliable predictors of acute symptom severity in virus-related asthma exacerbations (VRAEs). OBJECTIVE: To determine the effect of asthma control and viral infection on the severity of current illness and evaluate biomarkers related to acute symptoms during asthma exacerbations. METHODS: We prospectively enrolled 120 children with physician-diagnosed asthma and current wheezing who presented to Arkansas Children's Hospital emergency department. The asthma control test (ACT) stratified controlled (ACT > 19) and uncontrolled (ACT ≤ 19) asthma, whereas pediatric respiratory symptom scores evaluated symptoms. Nasopharyngeal swabs were obtained for viral analysis, and inflammatory mediators were evaluated by nasal filter paper and Luminex assays. RESULTS: There were 33 children with controlled asthma and 87 children with uncontrolled asthma. In those with uncontrolled asthma, 77% were infected with viruses during VRAE compared with 58% of those with controlled asthma. Uncontrolled subjects with VRAE had more acute symptoms compared with the controlled subjects with VRAE or uncontrolled subjects without a virus. The uncontrolled subjects with VRAE and allergy had the highest acute symptom scores (3.363 point pediatric respiratory symptom; P = .04). Children with asthma with higher symptom scores had more periostin (P = .02). CONCLUSION: Detection of respiratory viruses is frequent in those with uncontrolled asthma. Uncontrolled subjects with viruses have more acute symptoms during exacerbations, especially in those with allergy. Periostin was highest in subjects with the most acute symptoms, regardless of control status. Taken together, these data imply synergy between viral infection and allergy in subjects with uncontrolled asthma when considering acute asthma symptoms and nasal inflammation during an exacerbation of asthma.
Assuntos
Asma , Hipersensibilidade , Viroses , Asma/diagnóstico , Criança , Serviço Hospitalar de Emergência , Humanos , Hipersensibilidade/complicações , Sons Respiratórios , Viroses/complicaçõesRESUMO
Over the past decade, there have been substantial advances in our understanding about how viral infections regulate asthma. Important lessons have been learned from birth cohort studies examining viral infections and subsequent asthma and from understanding the relationships between host genetics and viral infections, the contributions of respiratory viral infections to patterns of immune development, the impact of environmental exposure on the severity of viral infections, and how the viral genome influences host immune responses to viral infections. Further, there has been major progress in our knowledge about how bacteria regulate host immune responses in asthma pathogenesis. In this article, we also examine the dynamics of bacterial colonization of the respiratory tract during viral upper respiratory tract infection, in addition to the relationship of the gut and respiratory microbiomes with respiratory viral infections. Finally, we focus on potential interventions that could decrease virus-induced wheezing and asthma. There are emerging therapeutic options to decrease the severity of wheezing exacerbations caused by respiratory viral infections. Primary prevention is a major goal, and a strategy toward this end is considered.
Assuntos
Asma , Sons Respiratórios , Infecções Respiratórias , Viroses , Animais , Asma/tratamento farmacológico , Asma/genética , Asma/imunologia , Asma/virologia , Progressão da Doença , Microbioma Gastrointestinal , Genoma Viral , Humanos , Prevenção Primária , Sons Respiratórios/genética , Sons Respiratórios/imunologia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Infecções Respiratórias/prevenção & controle , Viroses/tratamento farmacológico , Viroses/genética , Viroses/imunologia , Viroses/prevenção & controleRESUMO
BACKGROUND: Rhinovirus frequently causes asthma exacerbations among children and young adults who are allergic. The interaction between allergen and rhinovirus-induced symptoms and inflammation over time is unclear. OBJECTIVE: Our aim was to compare the response to an experimental inoculation with rhinovirus-16 in allergic asthmatics with the response in healthy controls and to evaluate the effects of administrating omalizumab before and during the infection. METHODS: Two clinical trials were run in parallel. In one of these trials, the response to an experimental inoculation with rhinovirus-16 among asthmatics with high levels of total IgE was compared to the response in healthy controls. The other trial compared the effects of administering omalizumab versus placebo to asthmatics in a randomized, double-blind placebo-controlled investigation. The primary outcome for both trials compared lower respiratory tract symptoms (LRTSs) between study groups over the first 4 days of infection. RESULTS: Frequent comparisons of symptoms, lung function, and blood eosinophil counts revealed differences that were more pronounced among allergic asthmatics than among controls by days 2 and 3 after virus inoculation. Additionally, an augmentation of upper respiratory tract symptom scores and LRTS scores occurred among the atopic asthmatics versus the controls during the resolution of symptoms (P < .01 for upper respiratory symptom tract scores and P < .001 for LRTS scores). The beneficial effects of administering omalizumab on reducing LRTSs and improving lung function were strongest over the first 4 days. CONCLUSIONS: LRTSs and blood eosinophil counts were augmented and lung function was reduced among allergic asthmatics early after rhinovirus inoculation but increased late in the infection during symptom resolution. The effect of administering omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection.
Assuntos
Antialérgicos/uso terapêutico , Asma/imunologia , Imunoglobulina E/metabolismo , Omalizumab/uso terapêutico , Infecções por Picornaviridae/imunologia , Sistema Respiratório/patologia , Rhinovirus/fisiologia , Adulto , Asma/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Imunoglobulina E/imunologia , Masculino , Infecções por Picornaviridae/tratamento farmacológico , Efeito Placebo , Testes de Função Respiratória , Sistema Respiratório/virologia , Adulto JovemRESUMO
Rhinovirus (RV) exposure evokes exacerbations of asthma that markedly impact morbidity and mortality worldwide. The mechanisms by which RV induces airway hyperresponsiveness (AHR) or by which specific RV serotypes differentially evoke AHR remain unknown. We posit that RV infection evokes AHR and inflammatory mediator release, which correlate with degrees of RV infection. Furthermore, we posit that rhinovirus C-induced AHR requires paracrine or autocrine mediator release from epithelium that modulates agonist-induced calcium mobilization in human airway smooth muscle. In these studies, we used an ex vivo model to measure bronchoconstriction and mediator release from infected airways in human precision cut lung slices to understand how RV exposure alters airway constriction. We found that rhinovirus C15 (RV-C15) infection augmented carbachol-induced airway narrowing and significantly increased release of IP-10 (IFN-γ-induced protein 10) and MIP-1ß (macrophage inflammatory protein-1ß) but not IL-6. RV-C15 infection of human airway epithelial cells augmented agonist-induced intracellular calcium flux and phosphorylation of myosin light chain in co-cultured human airway smooth muscle to carbachol, but not after histamine stimulation. Our data suggest that RV-C15-induced structural cell inflammatory responses are associated with viral load but that inflammatory responses and alterations in agonist-mediated constriction of human small airways are uncoupled from viral load of the tissue.
Assuntos
Sinalização do Cálcio , Infecções por Enterovirus/fisiopatologia , Enterovirus/fisiologia , Músculo Liso/virologia , Hipersensibilidade Respiratória/etiologia , Asma/virologia , Carbacol/farmacologia , Células Cultivadas , Quimiocina CXCL10/metabolismo , Enterovirus/genética , Enterovirus/isolamento & purificação , Infecções por Enterovirus/virologia , Histamina/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Cadeias Leves de Miosina/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , RNA Viral/análise , Hipersensibilidade Respiratória/virologia , Carga ViralRESUMO
BACKGROUND: Food insecurity (FI), limited availability of or access to nutritional foods, is linked to poor child/caregiver health. We examined FI in food-allergic and non-food-allergic children to determine whether dietary limitations associated with food allergy increases risk of FI. METHODS: Food-allergic and non-food-allergic children (1-17 years) were recruited from Arkansas Children's Hospital allergy/asthma clinics. The USDA Food Security Survey, the Newest Vital Sign Health Literacy (HL) questionnaire, and the Food Allergy Impact Scale QOL survey were administered. Logistic regression and analysis of covariance models were utilized for data analysis. RESULTS: Subjects (n = 650) included 325 food-allergic and 325 non-food-allergic children. Overall rate of FI was 21.5% (food allergic 22.2% and non-food allergic 20.9%) with no significant difference in the prevalence of FI between groups (OR = 1.30; 95% CI 0.86-1.96; P = 0.21). FI was increased in households of children with both milk and egg allergy when compared to those without food allergy and those with single food allergy (OR = 2.5; 95% CI 1.4-4.6; P = 0.003). Mean HL rates were higher in the food-secure vs food-insecure groups (mean diff = 0.31; 95% CI 0.03-0.59; P = 0.03). Among food-allergic children, QOL was better in the food-secure vs food-insecure group (mean diff = 0.61; 95% CI 0.002-1.23; P = 0.049). CONCLUSION: Food allergy to milk and egg was associated with increased risk of household FI. Food-insecure participants had lower HL than their food-secure counterparts. Further work is needed to define risks associated with FI among food-allergic children to improve screening and management strategies.
Assuntos
Hipersensibilidade Alimentar/complicações , Abastecimento de Alimentos/estatística & dados numéricos , Letramento em Saúde/estatística & dados numéricos , Adolescente , Arkansas , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Prevalência , Qualidade de Vida , Fatores de Risco , Inquéritos e Questionários , Atenção Terciária à Saúde/estatística & dados numéricosAssuntos
Asma , Biomarcadores , Viroses , Humanos , Asma/epidemiologia , Asma/diagnóstico , Biomarcadores/sangue , Viroses/imunologia , Viroses/diagnóstico , Fatores de RiscoRESUMO
Epidemiologic studies have demonstrated an association between acetaminophen (APAP) use and the development of asthma symptoms. However, few studies have examined relationships between APAP-induced signaling pathways associated with the development of asthma symptoms. We tested the hypothesis that acute APAP exposure causes airway hyper-responsiveness (AHR) in human airways. Precision cut lung slice (PCLS) airways from humans and mice were used to determine the effects of APAP on airway bronchoconstriction and bronchodilation and to assess APAP metabolism in lungs. APAP did not promote AHR in normal or asthmatic human airways ex vivo. Rather, high concentrations mildly bronchodilated airways pre-constricted with carbachol (CCh), histamine (His), or immunoglobulin E (IgE) cross-linking. Further, the addition of APAP prior to bronchoconstrictors protected the airways from constriction. Similarly, in vivo treatment of mice with APAP (200 mg/kg IP) resulted in reduced bronchoconstrictor responses in PCLS airways ex vivo. Finally, in both mouse and human PCLS airways, exposure to APAP generated only low amounts of APAP-protein adducts, indicating minimal drug metabolic activity in the tissues. These findings indicate that acute exposure to APAP does not initiate AHR, that high-dose APAP is protective against bronchoconstriction, and that APAP is a mild bronchodilator.
Assuntos
Acetaminofen/farmacologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Pulmão/efeitos dos fármacos , Acetaminofen/administração & dosagem , Acetaminofen/efeitos adversos , Albuterol/farmacologia , Animais , Asma/fisiopatologia , Broncodilatadores/efeitos adversos , Carbacol/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Relação Dose-Resposta a Droga , Humanos , Pulmão/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Estresse Oxidativo/efeitos dos fármacos , Hipersensibilidade Respiratória/induzido quimicamenteRESUMO
Rhinovirus (RV) exposure has been implicated in childhood development of wheeze evoking asthma and exacerbations of underlying airways disease. Studies such as the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) and Childhood Origins of ASThma (COAST) have identified RV as a pathogen inducing severe respiratory disease. RVs also modulate airway hyperresponsiveness (AHR), a key characteristic of such diseases. Although potential factors underlying mechanisms by which RV induces AHR have been postulated, the precise mechanisms of AHR following RV exposure remain elusive.A challenge to RV-related research stems from inadequate models for study. While human models raise ethical concerns and are relatively difficult in terms of subject recruitment, murine models are limited by susceptibility of infection to the relatively uncommon minor group (RV-B) serotypes, strains that are generally associated with infrequent clinical respiratory virus infections. Although a transgenic mouse strain that has been developed has enhanced susceptibility for infection with the common major group (RV-A) serotypes, few studies have focused on RV in the context of allergic airways disease rather than understanding RV-induced AHR. Recently, the receptor for the virulent RV-C CDHR3, was identified, but a dearth of studies have examined RV-C-induced effects in humans.Currently, the mechanisms by which RV infections modulate airway smooth muscle (ASM) shortening or excitation-contraction coupling remain elusive. Further, only one study has investigated the effects of RV on bronchodilatory mechanisms, with only speculation as to mechanisms underlying RV-mediated modulation of bronchoconstriction.
Assuntos
Hipersensibilidade Respiratória/fisiopatologia , Hipersensibilidade Respiratória/virologia , Rhinovirus/isolamento & purificação , Rhinovirus/fisiologia , Poluentes Atmosféricos/efeitos adversos , Animais , Asma/epidemiologia , Asma/fisiopatologia , Asma/virologia , Técnicas de Cocultura , Humanos , Hipersensibilidade Respiratória/epidemiologiaRESUMO
PURPOSE OF REVIEW: Pediatric chronic rhinosinusitis (CRS) is a common disorder that carries significant morbidity. The diagnosis requires sinus symptoms that persist despite standard medical therapy greater than 3 months. Viral infections, allergies, and anatomic differences in children lead to chronic obstruction of the osteomeatal complex. RECENT FINDINGS: Chronic rhinosinusitis as a diagnosis is a conglomeration of multiple phenotypes and endotypes. As such, the diagnosis and management are complex. New survey studies provide some consensus on prevalence and management of this disease in children. In this review, we highlight the differential diagnosis of pediatric CRS, including non-eosinophilic/infectious variants, eosinophilic variants with and without nasal polyps, allergic fungal sinusitis, aspirin-exacerbated respiratory disease, primary immunodeficiency, and disorders of mucociliary clearance. Further, we detail treatment options that should be considered. Finally, we feature emerging potential treatment options of CRS, including anti-immunoglobulin E, interleukin-5, and interleukin-4 receptor alpha subunit.
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Rinite/diagnóstico , Rinite/terapia , Sinusite/diagnóstico , Sinusite/terapia , Criança , Diagnóstico Diferencial , Humanos , Pólipos Nasais/diagnóstico , Rinite/etiologia , Sinusite/etiologiaRESUMO
A 300-year (1700-2007) chronological record of environmental perchlorate, reconstructed from high-resolution analysis of a central Greenland ice core, shows that perchlorate levels in the post-1980 atm were two-to-three times those of the pre-1980 environment. While this confirms recent reports of increased perchlorate in Arctic snow since 1980 compared with the levels for the prior decades (1930-1980), the longer Greenland record demonstrates that the Industrial Revolution and other human activities, which emitted large quantities of pollutants and contaminants, did not significantly impact environmental perchlorate, as perchlorate levels remained stable throughout the 18th, 19th, and much of the 20th centuries. The increased levels since 1980 likely result from enhanced atmospheric perchlorate production, rather than from direct release from perchlorate manufacturing and applications. The enhancement is probably influenced by the emission of organic chlorine compounds in the last several decades. Prior to 1980, no significant long-term temporal trends in perchlorate concentration are observed. Brief (a few years) high-concentration episodes appear frequently over an apparently stable and low background (â¼1 ng kg-1). Several such episodes coincide in time with large explosive volcanic eruptions including the 1912 Novarupta/Katmai eruption in Alaska. It appears that atmospheric perchlorate production is impacted by large eruptions in both high- and low-latitudes, but not by small eruptions and nonexplosive degassing.
Assuntos
Percloratos , Erupções Vulcânicas , Alaska , Regiões Árticas , Monitoramento Ambiental , Groenlândia , Atividades HumanasRESUMO
BACKGROUND: In children with eosinophilic esophagitis (EoE) foods are the most common disease triggers, but environmental allergens are also suspected culprits. OBJECTIVE: To determine the effects of environmental allergen sensitization on response to treatment in children with EoE in the southeastern United States. METHODS: Patients 2 to 18 years old who were referred to the Arkansas Children's Hospital Eosinophilic Gastrointestinal Disorders Clinic from January 2012 to January 2016 were enrolled in a prospective, longitudinal cohort study with collection of demographics, clinical symptoms, medical history, allergy sensitization profiles, and response to treatment over time. Comparisons were made between complete responders (peak esophageal eosinophil count <15 per high-power field [HPF]) and nonresponders (>25 eosinophils per HPF) after treatment with diet elimination alone, swallowed corticosteroids alone, or diet elimination and swallowed corticosteroids. Sensitization patterns to environmental allergens found in the southeastern United States were analyzed for the effect on treatment response. RESULTS: A total of 223 individuals were enrolled. Of these, 182 had environmental allergy profiling and at least one endoscopy while receiving proton pump inhibitor (PPI) therapy. Twenty-nine individuals had PPI-responsive EoE and were excluded from further analysis, leaving 123 individuals with non-PPI-responsive EoE who were further analyzed; 72 (58.5%) were complete responders and 33 (26.8%) were nonresponders. Seventeen individuals (13.8%) were partial responders (≥1 but ≤25 eosinophils per HPF) and excluded from further analysis. Nonresponders were more likely to be sensitized to perennial allergens (P = .02). There was no significant difference in response based on seasonal allergen sensitization. Individuals with mold or cockroach sensitization were more likely to fail combination diet and swallowed corticosteroid treatment (P = .02 and P = .002). CONCLUSION: Perennial allergen and mold sensitization may lead to nonresponse to EoE treatment in some patients. Additional studies are needed to further understand the effect of environmental allergens on EoE. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01779154.
Assuntos
Alérgenos/imunologia , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/terapia , Eosinófilos/imunologia , Esôfago/patologia , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Adolescente , Arkansas , Criança , Pré-Escolar , Exposição Ambiental , Feminino , Humanos , Imunização/efeitos adversos , Estudos Longitudinais , Masculino , Material Particulado/imunologia , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Estações do Ano , Resultado do TratamentoRESUMO
The human rhinovirus (HRV) is commonly associated with loss of asthma symptom control requiring escalation of care and emergency room visits in many patients. While the association is clear, the mechanisms behind HRV-induced asthma exacerbations remain uncertain. Immune dysregulation via aberrant immune responses, both deficient and exaggerated, have been proposed as mechanisms for HRV-induced exacerbations of asthma. Epithelium-derived innate immune cytokines that bias Th2 responses, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), have also been implicated as a means to bridge allergic conditions with asthma exacerbations. In this review, we discuss the literature supporting these positions. We also discuss new and emerging biotherapeutics that may target virus-induced exacerbations of asthma.
Assuntos
Asma/imunologia , Rhinovirus/imunologia , Animais , Asma/tratamento farmacológico , Citocinas/imunologia , Humanos , Hipersensibilidade/imunologia , Interleucina-17/imunologia , Interleucina-33 , Interleucinas/imunologia , Linfopoietina do Estroma do TimoRESUMO
RATIONALE: Most virus-induced attacks of asthma are caused by rhinoviruses (RVs). OBJECTIVES: To determine whether people with asthma are susceptible to an increased viral load during RV infection. METHODS: Seventy-four children (4-18 yr old) were enrolled; 28 with wheezing, 32 with acute rhinitis, and 14 without respiratory tract symptoms. Nasal washes were evaluated using quantitative polymerase chain reaction for RV to judge viral load along with gene sequencing to identify strains of RV. Soluble intercellular adhesion molecule-1, IFN-λ1, and eosinophil cationic protein in nasal washes, along with blood eosinophil counts and total and allergen-specific IgE in sera, were also evaluated. Similar assessments were done in 24 young adults (16 with asthma, 8 without) who participated in an experimental challenge with RV (serotype 16). MEASUREMENTS AND MAIN RESULTS: Fifty-seven percent of wheezing children and 56% with acute rhinitis had nasal washes testing positive for RV. The geometric mean of viral loads by quantitative polymerase chain reaction in washes from wheezing children was 2.8-fold lower, but did not differ significantly from children with rhinitis (7,718 and 21,612 copies of viral RNA per microliter nasal wash, respectively; P = 0.48). The odds for wheezing were increased if children who tested positive for RV were sensitized to one or more allergens (odds ratio, 3.9; P = 0.02). Similarly, neither peak nor cumulative viral loads differed significantly in washes from adults with asthma compared with those without asthma during the experimental RV challenge. CONCLUSIONS: During acute symptoms, children infected with RV enrolled for wheezing or acute rhinitis had similar viral loads in their nasal washes, as did adults with and without asthma infected with RV-16 experimentally.
Assuntos
Asma/virologia , Infecções por Picornaviridae/virologia , Sons Respiratórios/etiologia , Rinite/virologia , Rhinovirus/isolamento & purificação , Carga Viral , Doença Aguda , Adolescente , Asma/sangue , Asma/complicações , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Progressão da Doença , Proteína Catiônica de Eosinófilo/sangue , Eosinófilos/metabolismo , Feminino , Humanos , Imunoglobulina E/sangue , Molécula 1 de Adesão Intercelular/sangue , Interferons , Interleucinas/sangue , Contagem de Leucócitos , Modelos Logísticos , Masculino , Líquido da Lavagem Nasal/virologia , Razão de Chances , Infecções por Picornaviridae/sangue , Infecções por Picornaviridae/complicações , Infecções por Picornaviridae/diagnóstico , Reação em Cadeia da Polimerase , RNA Viral/análise , Sons Respiratórios/fisiologia , Rinite/sangue , Rhinovirus/genética , Adulto JovemRESUMO
Anaphylaxis and urticaria are commonly seen in both primary care and allergy clinics. Foods, drugs, and insects are frequent culprits for immediate reactions; however, the trigger for recurring and/or chronic episodes is often unclear. We present a 56-year-old male with recurrent symptoms of urticaria, angioedema, and anaphylaxis found to be triggered by sensitization to galactose-alpha 1, 3-galactose (alpha-gal), a novel food allergen.