RESUMO
BACKGROUND: Histamine-releasing factor (HRF) is implicated in allergic diseases. We previously showed its pathogenic role in murine models of asthma. OBJECTIVE: We aim to present data analysis from 3 separate human samples (sera samples from asthmatic patients, nasal washings from rhinovirus [RV]-infected individuals, and sera samples from patients with RV-induced asthma exacerbation) and 1 mouse sample to investigate correlates of HRF function in asthma and virus-induced asthma exacerbations. METHODS: Total IgE and HRF-reactive IgE/IgG as well as HRF in sera from patients with mild/moderate asthma or severe asthma (SA) and healthy controls (HCs) were quantified by ELISA. HRF secretion in culture media from RV-infected adenovirus-12 SV40 hybrid virus transformed human bronchial epithelial cells and in nasal washings from experimentally RV-infected subjects was analyzed by Western blotting. HRF-reactive IgE/IgG levels in longitudinal serum samples from patients with asthma exacerbations were also quantified. RESULTS: HRF-reactive IgE and total IgE levels were higher in patients with SA than in HCs, whereas HRF-reactive IgG (and IgG1) level was lower in asthmatic patients versus HCs. In comparison with HRF-reactive IgElow asthmatic patients, HRF-reactive IgEhigh asthmatic patients had a tendency to release more tryptase and prostaglandin D2 on anti-IgE stimulation of bronchoalveolar lavage cells. RV infection induced HRF secretion from adenovirus-12 SV40 hybrid virus transformed bronchial epithelial cells, and intranasal RV infection of human subjects induced increased HRF secretion in nasal washes. Asthmatic patients had higher levels of HRF-reactive IgE at the time of asthma exacerbations associated with RV infection, compared with those after the resolution. This phenomenon was not seen in asthma exacerbations without viral infections. CONCLUSIONS: HRF-reactive IgE is higher in patients with SA. RV infection induces HRF secretion from respiratory epithelial cells both in vitro and in vivo. These results suggest the role of HRF in asthma severity and RV-induced asthma exacerbation.
Assuntos
Asma , Infecções por Enterovirus , Infecções por Picornaviridae , Humanos , Animais , Camundongos , Histamina , Rhinovirus , Imunoglobulina E , Imunoglobulina G , Infecções por Picornaviridae/complicaçõesRESUMO
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
BACKGROUND: IgE to α-Gal is a cause of mammalian meat allergy and has been linked to tick bites in North America, Australia, and Eurasia. Reports from the developing world indicate that α-Gal sensitization is prevalent but has been little investigated. OBJECTIVE: We sought evidence for the cause(s) of α-Gal sensitization and lack of reported meat allergy among children in less developed settings in Ecuador and Kenya. METHODS: IgE to α-Gal and total IgE were assessed in children from Ecuador (n = 599) and Kenya (n = 254) and compared with children with (n = 42) and without known (n = 63) mammalian meat allergy from the southeastern United States. Information on diet, potential risk factors, and helminth infections was available for children from Ecuador. IgG4 to α-Gal and antibodies to regionally representative parasites were assessed in a subset of children. RESULTS: In Ecuador (32%) and Kenya (54%), α-Gal specific IgE was prevalent, but levels were lower than in children with meat allergy from the United States. Sensitization was associated with rural living, antibody markers of Ascaris exposure, and total IgE, but not active infections with Ascaris or Trichuris species. In Ecuador, 87.5% reported consuming beef at least once per week, including 83.9% of those who had α-Gal specific IgE. Levels of α-Gal specific IgG4 were not high in Ecuador, but were greater than in children from the United States. CONCLUSIONS: These results suggest that in areas of the developing world with endemic parasitism, α-Gal sensitization is (1) common, (2) associated with Ascaris exposure, and (3) distinguished by a low percentage of specific/total IgE compared with individuals with meat allergy in the United States.
Assuntos
Dissacarídeos/imunologia , Hipersensibilidade Alimentar/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Adolescente , Adulto , Animais , Ascaris/imunologia , Ascaris/isolamento & purificação , Criança , Pré-Escolar , Dieta , Equador/epidemiologia , Fezes/parasitologia , Feminino , Hipersensibilidade Alimentar/sangue , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/parasitologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Quênia/epidemiologia , Masculino , Prevalência , Carne Vermelha , Trichuris/isolamento & purificação , Virginia/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Allergic asthmatic subjects are uniquely susceptible to acute wheezing episodes provoked by rhinovirus. However, the underlying immune mechanisms and interaction between rhinovirus and allergy remain enigmatic, and current paradigms are controversial. OBJECTIVE: We sought to perform a comprehensive analysis of type 1 and type 2 innate and adaptive responses in allergic asthmatic subjects infected with rhinovirus. METHODS: Circulating virus-specific TH1 cells and allergen-specific TH2 cells were precisely monitored before and after rhinovirus challenge in allergic asthmatic subjects (total IgE, 133-4692 IU/mL; n = 28) and healthy nonallergic controls (n = 12) using peptide/MHCII tetramers. T cells were sampled for up to 11 weeks to capture steady-state and postinfection phases. T-cell responses were analyzed in parallel with 18 cytokines in the nose, upper and lower airway symptoms, and lung function. The influence of in vivo IgE blockade was also examined. RESULTS: In uninfected asthmatic subjects, higher numbers of circulating virus-specific PD-1+ TH1 cells, but not allergen-specific TH2 cells, were linked to worse lung function. Rhinovirus infection induced an amplified antiviral TH1 response in asthmatic subjects versus controls, with synchronized allergen-specific TH2 expansion, and production of type 1 and 2 cytokines in the nose. In contrast, TH2 responses were absent in infected asthmatic subjects who had normal lung function, and in those receiving anti-IgE. Across all subjects, early induction of a minimal set of nasal cytokines that discriminated high responders (G-CSF, IFN-γ, TNF-α) correlated with both egress of circulating virus-specific TH1 cells and worse symptoms. CONCLUSIONS: Rhinovirus induces robust TH1 responses in allergic asthmatic subjects that may promote disease, even after the infection resolves.
Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Infecções por Picornaviridae/imunologia , Rhinovirus/fisiologia , Células Th1/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Antígenos Virais/imunologia , Células Cultivadas , Citocinas/metabolismo , Suscetibilidade a Doenças , Humanos , Ativação Linfocitária , Receptor de Morte Celular Programada 1/metabolismo , Sons RespiratóriosRESUMO
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) is a major cause of common cold and an important trigger of acute episodes of chronic lung diseases. Antigenic variation across the numerous RV strains results in frequent infections and a lack of durable cross-protection. Because the nature of human CD4+ T cells that target RV is largely unknown, T cell epitopes of RV capsid proteins were analyzed, and cognate T cells were characterized in healthy subjects and those infected by intranasal challenge. Peptide epitopes of the RV-A16 capsid proteins VP1 and VP2 were identified by peptide/MHC class II tetramer-guided epitope mapping, validated by direct ex vivo enumeration, and interrogated using a variety of in silico methods. Among noninfected subjects, those circulating RV-A16-specific CD4+ T cells detected at the highest frequencies targeted 10 unique epitopes that bound to diverse HLA-DR molecules. T cell epitopes localized to conserved molecular regions of biological significance to the virus were enriched for HLA class I and II binding motifs, and constituted both species-specific (RV-A) and pan-species (RV-A, -B, and -C) varieties. Circulating epitope-specific T cells comprised both memory Th1 and T follicular helper cells, and were rapidly expanded and activated after intranasal challenge with RV-A16. Cross-reactivity was evidenced by identification of a common *0401-restricted epitope for RV-A16 and RV-A39 by tetramer-guided epitope mapping and the ability for RV-A16-specific Th1 cells to proliferate in response to their RV-A39 peptide counterpart. The preferential persistence of high-frequency RV-specific memory Th1 cells that recognize a limited set of conserved epitopes likely arises from iterative priming by previous exposures to different RV strains.
Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Proteínas do Capsídeo/imunologia , Epitopos de Linfócito T/imunologia , Memória Imunológica , Infecções por Picornaviridae/imunologia , Rhinovirus/imunologia , Adolescente , Adulto , Mapeamento de Epitopos , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The fall peak in childhood asthma exacerbations is thought to be related to an increase in viral infections and allergen exposure when children return to school. Whether the seasonality of asthma attacks among children from different geographic regions follows similar trends is unclear. OBJECTIVE: To compare seasonal trends in asthma exacerbations among school-age children who lived in different geographic locations, with different climates, within the United States. METHODS: Hospital billing data bases were examined to determine the monthly number of school-age children who were hospitalized or treated in the emergency department (ED) for asthma exacerbations. Data from four cities within three states were compared. Climate data were obtained from archives of the National Climate Data Center, U.S. Department of Commerce. RESULTS: An annual peak in asthma exacerbations was observed during the fall months (September through November) among children who lived in Charlottesville, Virginia, as well as throughout the state of Virginia. An increase in exacerbations, which peaked in November, was observed for exacerbations among children who lived in Tucson, Arizona, and Yuma, Arizona. In contrast, exacerbations among children from New Orleans, Louisiana, increased in September but remained elevated throughout the school year. Although there was annual variation in the frequency of exacerbations over time, the seasonal patterns observed remained similar within the locations from year to year. A nadir in the frequency of attacks was observed during the summer months in all the locations. CONCLUSION: Seasonal peaks for asthma exacerbations varied among the children who lived in geographic locations with different climates, and were not restricted to the beginning of the school year.
Assuntos
Asma/epidemiologia , Clima , Estações do Ano , Asma/diagnóstico , Criança , Progressão da Doença , Serviço Hospitalar de Emergência , Feminino , Geografia , Humanos , Masculino , Estados Unidos/epidemiologiaRESUMO
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
House dust mites produce potent allergens, Der p 1 and Der f 1, that cause allergic sensitization and asthma. Der p 1 and Der f 1 are cysteine proteases that elicit IgE responses in 80% of mite-allergic subjects and have proinflammatory properties. Their antigenic structure is unknown. Here, we present crystal structures of natural Der p 1 and Der f 1 in complex with a monoclonal antibody, 4C1, which binds to a unique cross-reactive epitope on both allergens associated with IgE recognition. The 4C1 epitope is formed by almost identical amino acid sequences and contact residues. Mutations of the contact residues abrogate mAb 4C1 binding and reduce IgE antibody binding. These surface-exposed residues are molecular targets that can be exploited for development of recombinant allergen vaccines.
Assuntos
Alérgenos/química , Anticorpos Monoclonais Murinos/química , Antígenos de Dermatophagoides/química , Proteínas de Artrópodes/química , Cisteína Endopeptidases/química , Epitopos/química , Imunoglobulina E/química , Alérgenos/genética , Alérgenos/imunologia , Animais , Anticorpos Monoclonais Murinos/genética , Anticorpos Monoclonais Murinos/imunologia , Antígenos de Dermatophagoides/genética , Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/imunologia , Epitopos/genética , Epitopos/imunologia , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Camundongos , Mutação , Pyroglyphidae , Vacinas/química , Vacinas/genética , Vacinas/imunologiaRESUMO
RATIONALE: IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract. OBJECTIVES: To evaluate the relationship between IgE antibodies to α-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens. METHODS: Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide, questionnaires, and serum IgE antibody assays. The results were compared with control subjects and cohorts from the emergency department in Virginia (n = 130), northern Sweden (n = 963), and rural Kenya (n = 131). MEASUREMENTS AND MAIN RESULTS: Patients in Virginia with high-titer IgE antibodies to α-gal had normal lung function, low levels of exhaled nitric oxide, and low prevalence of asthma symptoms. Among patients in the emergency department and children in Kenya, there was no association between IgE antibodies to α-gal and asthma (odds ratios, 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r = 0.83) and to asthma (P < 0.001). CONCLUSIONS: These results provide a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and further evidence that the main allergens that are causally related to asthma are those that are inhaled.
Assuntos
Anafilaxia/imunologia , Asma/imunologia , Dissacarídeos/imunologia , Imunoglobulina E/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anafilaxia/etiologia , Animais , Asma/etiologia , Estudos de Casos e Controles , Criança , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Noruega , Fatores de Risco , Espirometria , Suécia , Carrapatos/imunologia , Virginia , Adulto JovemRESUMO
BACKGROUND: The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining "exacerbation" or about how to characterize an episode's severity. OBJECTIVE: National Institutes of Health institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies. METHODS: We used comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health-organized workshop in March 2010 and finalized in September 2011. RESULTS: No dominant definition of "exacerbation" was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalizations, and (3) use of short-acting ß-agonists as quick-relief (sometimes referred to as "rescue" or "reliever") medications. CONCLUSIONS: The working group participants propose that the definition of "asthma exacerbation" be "a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome." As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Furthermore, they propose the development of a standardized, component-based definition of "exacerbation" with clear thresholds of severity for each component.
Assuntos
Asma/fisiopatologia , Asma/terapia , Índice de Gravidade de Doença , Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/prevenção & controle , Pesquisa Biomédica/normas , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Prevenção SecundáriaRESUMO
BACKGROUND: The relevance of allergic sensitization, as judged by titers of serum IgE antibodies, to the risk of an asthma exacerbation caused by rhinovirus is unclear. OBJECTIVE: We sought to examine the prevalence of rhinovirus infections in relation to the atopic status of children treated for wheezing in Costa Rica, a country with an increased asthma burden. METHODS: The children enrolled (n= 287) were 7 through 12 years old. They included 96 with acute wheezing, 65 with stable asthma, and 126 nonasthmatic control subjects. PCR methods, including gene sequencing to identify rhinovirus strains, were used to identify viral pathogens in nasal washes. Results were examined in relation to wheezing, IgE, allergen-specific IgE antibody, and fraction of exhaled nitric oxide levels. RESULTS: Sixty-four percent of wheezing children compared with 13% of children with stable asthma and 13% of nonasthmatic control subjects had positive test results for rhinovirus (P< .001 for both comparisons). Among wheezing subjects, 75% of the rhinoviruses detected were group C strains. High titers of IgE antibodies to dust mite allergen (especially Dermatophagoides species) were common and correlated significantly with total IgE and fraction of exhaled nitric oxide levels. The greatest risk for wheezing was observed among children with titers of IgE antibodies to dust mite of 17.5 IU/mL or greater who tested positive for rhinovirus (odds ratio for wheezing, 31.5; 95% CI, 8.3-108; P< .001). CONCLUSIONS: High titers of IgE antibody to dust mite allergen were common and significantly increased the risk for acute wheezing provoked by rhinovirus among asthmatic children.
Assuntos
Alérgenos/imunologia , Asma/complicações , Asma/imunologia , Imunoglobulina E/sangue , Infecções por Picornaviridae/imunologia , Pyroglyphidae/imunologia , Rhinovirus , Animais , Estudos de Casos e Controles , Criança , Epitopos/imunologia , Expiração , Feminino , Humanos , Masculino , Óxido Nítrico/análise , Infecções por Picornaviridae/complicações , Infecções por Picornaviridae/diagnóstico , Sons Respiratórios/etiologia , Rhinovirus/genética , Rhinovirus/imunologia , RiscoAssuntos
Alergia e Imunologia , Imunoglobulina E , Alergia e Imunologia/história , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Anti-Idiotípicos/metabolismo , Especificidade de Anticorpos/imunologia , História do Século XX , História do Século XXI , Humanos , Imunoglobulina E/imunologia , Imunoglobulina E/isolamento & purificação , Imunoglobulina E/metabolismo , Pesquisa/históriaRESUMO
Inquiries into the relationships between viral respiratory tract illnesses and the inception and exacerbation of asthma are being facilitated by recent advances in research approaches and technology. In this article we identify important knowledge gaps and future research questions, and we discuss how new investigational tools, including improved respiratory tract virus detection techniques, will permit current and future researchers to define these relationships and the host, virus, developmental, and environmental mechanisms that regulate them. A better understanding of these processes should facilitate the development of improved strategies for the prevention and treatment of virus-induced wheezing illnesses and asthma exacerbations and, possibly, the ultimate goal of discovering effective approaches for the primary prevention of asthma.
Assuntos
Asma/imunologia , DNA Viral/análise , Vírus Sinciciais Respiratórios/imunologia , Infecções Respiratórias/imunologia , Rhinovirus/imunologia , Idade de Início , Asma/diagnóstico , Asma/epidemiologia , Asma/genética , Comorbidade , Humanos , Patologia Molecular/métodos , Vírus Sinciciais Respiratórios/genética , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/genética , Rhinovirus/genética , Fatores de RiscoRESUMO
Antibodies of the IgG4 isotype are strongly associated with allergic disease but have several properties such as not precipitating with allergens, not activating complement and poor binding to Fcγ receptors that argue against a pro-inflammatory role. In keeping with that, IgG4 antibodies are a striking feature of the response to immunotherapy. In two naturally occurring situations IgG4 antibodies are common with low or absent IgE antibodies. The first example is children raised in a house with a cat and the second is eosinophilic esophagitis (EoE). In many population-based cohorts, the ownership of a cat in early childhood is associated with a decreased prevalence of a cat allergy at age 10. The second example (i.e., EoE) is a novel form of food allergy that is not mediated by IgE and is related to consuming cow's milk or wheat. In EoE, patients have IgG4 to milk proteins in high > 10 µg/mL or very high > 100 µg/mL titers. Enigmatically these patients are found to have deposits of IgG4 in the wall of their inflamed esophagus. The factors that have given rise to EoE remain unclear; however, changes in food processing over the past 50 years, particularly ultra-heat treatment and the high pressure homogenization of milk, represent a logical hypothesis.
RESUMO
BACKGROUND: Preschool children with treatment-refractory wheeze often require unscheduled acute care. Current guidelines advise treatment of persistent wheeze with inhaled corticosteroids. Alternative treatments targeting structural abnormalities and specific inflammatory patterns could be more effective. OBJECTIVE: To apply unsupervised analysis of lung lavage (bronchoalveolar lavage [BAL]) variables to identify clusters of preschool children with treatment-refractory wheeze. METHODS: A total of 155 children 6 years or younger underwent bronchoscopy with BAL for evaluation of airway structure, inflammatory markers, and pathogens. Variables were screened with factor analysis and sorted into clusters by Ward's method, and membership was confirmed by discriminant analysis. RESULTS: The model was repeatable in a 48-case validation sample and accurately classified 86% of cases. Cluster 1 (n = 60) had early-onset wheeze, 85% with structural abnormalities, mostly tracheamalacia, with low total IgE and agranulocytic BAL. Cluster 2 (n = 42) had later-onset wheeze, the highest prevalence of gastroesophageal reflux, little atopy, and two-third had increased BAL lipid-laden macrophages. Cluster 3 (n = 46) had mid-onset wheeze, low total IgE, and two-third had BAL viral transcripts, predominately human rhinovirus, with BAL neutrophilia. Cluster 4 (n = 7) was older, with high total IgE, blood eosinophilia, and mixed BAL eosinophils and neutrophils. CONCLUSIONS: Preschool children with recurrent wheeze refractory to inhaled corticosteroid treatment include 4 clusters: airway malacia, gastroesophageal reflux, indolent human rhinovirus bronchoalveolitis, and type-2high inflammation. The results support the risk and cost of invasive bronchoscopy to diagnose causes of treatment-refractory wheeze and develop novel therapies targeting airway malacia, human rhinovirus infection, and BAL neutrophilia in preschool children.
Assuntos
Asma , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/epidemiologia , Lavagem Broncoalveolar , Pré-Escolar , Análise por Conglomerados , Humanos , Lactente , Fenótipo , Sons RespiratóriosRESUMO
Human rhinoviruses cause the common cold and exacerbate chronic respiratory diseases. Although infection elicits neutralizing antibodies, these do not persist or cross-protect across multiple rhinovirus strains. To analyze rhinovirus-specific B cell responses in humans, we developed techniques using intact RV-A16 and RV-A39 for high-throughput high-dimensional single-cell analysis, with parallel assessment of antibody isotypes in an experimental infection model. Our approach identified T-bet+ B cells binding both viruses that account for â¼5% of CXCR5- memory B cells. These B cells infiltrate nasal tissue and expand in the blood after infection. Their rapid secretion of heterotypic immunoglobulin G (IgG) in vitro, but not IgA, matches the nasal antibody profile post-infection. By contrast, CXCR5+ memory B cells binding a single virus are clonally distinct, absent in nasal tissue, and secrete homotypic IgG and IgA, mirroring the systemic response. Temporal and spatial functions of dichotomous memory B cells might explain the ability to resolve infection while rendering the host susceptible to re-infection.
Assuntos
Linfócitos B/imunologia , Reações Cruzadas/imunologia , Imunoglobulina G/imunologia , Memória Imunológica/imunologia , Rhinovirus/imunologia , HumanosRESUMO
OBJECTIVE: To examine whether early child care exposure influences the risk for development of asthma. STUDY DESIGN: Longitudinal data from 939 children and their families from the National Institute of Child Health and Development Study of Early Child Care and Youth Development were analyzed. Exposure to other children in the primary child care setting as an infant (before 15 months) and as a toddler (16-36 months) were assessed as risk factors for persistent or late-onset asthma by age 15 via logistic regression. RESULTS: The number of children in the child-care environment when the child was a toddler was significantly associated with odds of asthma, even after adjusting for respiratory illnesses and other risk factors (P < .05). The fewer the children exposed to as toddlers, the higher the probability of persistent or late-onset asthma by age 15. CONCLUSIONS: This study supports the theory of a protective effect of exposure to other children at an early age, especially as a toddler, on the risk of asthma. This effect appears to be independent of the number of reported respiratory tract illnesses, suggesting that other protective mechanisms related to the number of children in the child care environment may be involved.