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BACKGROUND: Rhinovirus (RV) infections trigger wheeze episodes in children. Thus, understanding of the lung inflammatory response to RV in children with wheeze is important. OBJECTIVES: This study sought to examine the associations of RV on bronchoalveolar lavage (BAL) granulocyte patterns and biomarkers of inflammation with age in children with treatment-refractory, recurrent wheeze (n = 616). METHODS: Children underwent BAL to examine viral nucleic acid sequences, bacterial cultures, granulocyte counts, and phlebotomy for both general and type-2 inflammatory markers. RESULTS: Despite the absence of cold symptoms, RV was the most common pathogen detected (30%), and when present, was accompanied by BAL granulocytosis in 75% of children. Compared to children with no BAL pathogens (n = 341), those with RV alone (n = 127) had greater (P < .05) isolated neutrophilia (43% vs 16%), mixed eosinophils and neutrophils (26% vs 11%), and less pauci-granulocytic (27% vs 61%) BAL. Children with RV alone furthermore had biomarkers of active infection with higher total blood neutrophils and serum C-reactive protein, but no differences in blood eosinophils or total IgE. With advancing age, the log odds of BAL RV alone were lower, 0.82 (5th-95th percentile CI: 0.76-0.88; P < .001), but higher, 1.58 (5th-95th percentile CI: 1.01-2.51; P = .04), with high-dose daily corticosteroid treatment. CONCLUSIONS: Children with severe recurrent wheeze often (22%) have a silent syndrome of lung RV infection with granulocytic bronchoalveolitis and elevated systemic markers of inflammation. The syndrome is less prevalent by school age and is not informed by markers of type-2 inflammation. The investigators speculate that dysregulated mucosal innate antiviral immunity is a responsible mechanism.
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BACKGROUND: Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear. OBJECTIVE: We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID. METHODS: We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different TH- cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively. RESULTS: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21-secreting FOXP3-CD25hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3-CD25+ cells that represented likely CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi Tfh cells greatly outnumbered regulatory cells. CONCLUSIONS: Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID.
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BACKGROUND: Dupilumab is a monoclonal antibody that targets the interleukin (IL)-4 receptor alpha subunit, thus blocking the effects of IL-4 and IL-13, and has shown efficacy in treating various conditions including asthma, atopic dermatitis, eosinophilic esophagitis, and others. Because of its immune modulatory effects, clinical trials that studied dupilumab did not allow patients to receive live vaccines during the clinical trials because of an abundance of caution, and thus package inserts recommend that patients who are being treated with dupilumab should avoid live vaccines. Because dupilumab is now approved for use in patients from 6 months of age for the treatment of atopic dermatitis, this reported contraindication is now posing a clinical dilemma for patients and clinicians. OBJECTIVE: To perform a systematic review of literature on the safety and efficacy of vaccinations in patients who are receiving dupilumab and to provide expert guidance on the use of vaccines in patients who are receiving dupilumab. METHODS: A systematic review of the literature was performed, and an expert Delphi Panel was assembled. RESULTS: The available literature on patients who received vaccinations while using dupilumab overall suggests that live vaccines are safe and that the vaccine efficacy, in general, is not affected by dupilumab. The expert Delphi panel agreed that the use of vaccines in patients receiving dupilumab was likely safe and effective. CONCLUSION: Vaccines (including live vaccines) can be administered to patients receiving dupilumab in a shared decision-making capacity.
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Anticorpos Monoclonais Humanizados , Vacinas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Consenso , Técnica Delphi , Dermatite Atópica/tratamento farmacológico , Vacinação/efeitos adversos , Vacinas/efeitos adversos , Vacinas/uso terapêuticoRESUMO
PURPOSE: Immunoglobulin E deficiency (IgED) (defined as IgE < 2 IU/mL) is enriched in patients with primary antibody deficiency (PAD). We hypothesized that selective IgED (sIgED) is a more sensitive predictor of the development of PAD than declining IgG, as IgE production typically requires two class switch recombination (CSR) events in contrast to IgG. Thus, the inability of patients with sIgED to mount an appropriate antibody response to a T-cell independent antigen or evidence of aberrant induction of É germ line (ÉGL) or IgE heavy chain (IgEHC) transcripts in vitro would support the concept that sIgED is a biomarker for emerging PAD. METHODS: We compared pre- and post-polysaccharide vaccination titers in healthy patients with sIgED without a history of recurrent infections or autoimmunity (n = 20) and in healthy controls (HCs) (n = 17). Subsequently, we assessed in vitro induction of εGL and IgEHC transcripts in patients with sIgED and HC (n = 6) in response to IL-4 + CD40L stimulation. RESULTS: Thirty percent of patients with sIgED did not have a robust vaccine response compared to 0% of HCs (p = 0.017). Individuals with sIgED with an abnormal vaccine response demonstrated persistent germline mRNA expression in their B-cells at day 5, with lower levels of IgEHC, compared to both HCs and sIgED participants with a normal vaccine response. CONCLUSION: Patients with sIgED are more likely to have abnormal antibody responses to a T cell-independent antigen and may have dysregulated CSR machinery. Following individuals with sIgED longitudinally may be beneficial in the early identification of PAD.
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Agamaglobulinemia , Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Vacinas , Humanos , Imunoglobulina E , Imunoglobulina G , Síndromes de Imunodeficiência/imunologia , Polissacarídeos/imunologia , Doenças da Imunodeficiência Primária/imunologiaRESUMO
BACKGROUND: There is increasing recognition of a type 2 (T2) inflammatory pattern in a subset of patients with chronic obstructive pulmonary disease (COPD) or emphysema, characterized by blood and airway eosinophilia. The mechanism underlying this is not well established. The recognition that CD125 (interleukin [IL]-5 receptor alpha) is expressed on some lung neutrophils and eosinophils in patients with asthma led us to speculate that CD125 may also be expressed on lung neutrophils in patients with COPD or emphysema. OBJECTIVE: To interrogate the expression of CD125 on lung neutrophils (and, when present, eosinophils) in patients with COPD/emphysema and identify a meaningful biomarker to predict neutrophil CD125 expression, including other markers of T2 inflammation. METHODS: We obtained blood and bronchoalveolar lavage (BAL) samples from patients with physician-diagnosed COPD/emphysema undergoing a clinically indicated bronchoscopy. RESULTS: We found that a highly variable percentage of BAL neutrophils indeed expressed surface CD125 (0%-78.7%), with obvious clustering of CD125high and CD125low patterns. No correlation was found with clinical characteristics, blood or BAL eosinophil or neutrophil counts, BAL cytokines, or BAL eosinophil CD125 expression. CONCLUSION: We conclude that, similar to asthma, lung neutrophils from patients with COPD display interleukin-5 receptor alpha (CD125) on their surface. This along with the frequent presence of IL-4 and IL-5 in airway fluid further suggests a possible role of the T2 pathway in contributing to COPD severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03984799.
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Asma , Enfisema , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Pulmão , Neutrófilos , Líquido da Lavagem BroncoalveolarRESUMO
Newborn screening (NBS) for severe combined immunodeficiency (SCID) can identify infants with non-SCID T cell lymphopenia (TCL). The purpose of this study was to characterize the natural history and genetic findings of infants with non-SCID TCL identified on NBS. We analyzed data from 80 infants with non-SCID TCL in the mid-Atlantic region between 2012 and 2019. 66 patients underwent genetic testing and 41 (51%) had identified genetic variant(s). The most common genetic variants were thymic defects (33%), defects with unknown mechanisms (12%) and bone marrow production defects (5%). The genetic cohort had significantly lower median initial CD3+, CD4+, CD8+ and CD4/CD45RA+ T cell counts compared to the non-genetic cohort. Thirty-six (45%) had either viral, bacterial, or fungal infection; only one patient had an opportunistic infection (vaccine strain VZV infection). Twenty-six (31%) of patients had resolution of TCL during the study period.
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Linfopenia , Imunodeficiência Combinada Severa , Lactente , Recém-Nascido , Humanos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Triagem Neonatal , Testes Genéticos , Linfopenia/genética , Linfopenia/diagnóstico , Linfócitos TRESUMO
PURPOSE OF REVIEW: In recent years, there has been a dramatic increase in the number of recognized inborn errors of immunity (IEI), many of which present in childhood. This review discusses diagnostic approaches for some of the more common presentations of IEI in childhood. RECENT FINDINGS: Implementation of newborn screening (NBS) using the T cell receptor excision circle (TREC) assay has led to the timely identification of patients with severe combined immunodeficiency (SCID) as well as both syndromic and nonsyndromic forms of T cell lymphopenia, including DiGeorge syndrome. Improvements in the availability of immunophenotyping assays, genetic testing and advanced diagnostic techniques such as the artificial thymic organoid system can improve diagnostic clarity and impact management plans. Diagnostic improvements in humoral immunodeficiency include development of novel assays to quantify and functionally evaluate polysaccharide vaccine response. SUMMARY: IEI represent a rapidly growing field, particularly in paediatrics. Use of state-of-the-art diagnostic testing can facilitate rapid identification of IEI, hopefully allowing for initiation of prompt treatment and improved patient outcomes.
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Síndromes de Imunodeficiência , Imunodeficiência Combinada Severa , Recém-Nascido , Humanos , Criança , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Triagem Neonatal/métodos , Síndromes de Imunodeficiência/genética , Testes GenéticosRESUMO
OBJECTIVE: To summarize the pitfalls associated with defining exactly what constitutes an "impaired" antibody response to polysaccharide antigens and the importance of documenting actual pyogenic infections before making a diagnosis of an immune deficiency. Specific antibody deficiency is an immune deficiency defined by the presence of normal quantitative levels of immunoglobulins, but impaired antibody responses to polysaccharide antigens, in patients presenting with frequent otosinopulmonary infections with pyogenic bacteria. DATA SOURCES: PubMed review using the following keywords: specific antibody deficiency, pneumococcal vaccination, Salmonella vaccination, infectious sinusitis. STUDY SELECTION: This review focused on key studies that have been utilized to define what constitutes a "normal" humoral immune response to pneumococcal and Salmonella vaccination in healthy subjects and on published studies defining current expert opinion. RESULTS: Published studies demonstrate wide variability in response to pneumococcal vaccination in healthy individuals, making it daunting to define what constitutes an abnormal response. These challenges are exacerbated by striking laboratory variability in reporting results. CONCLUSION: Clinical examinations in individuals with self-reported recurrent acute sinusitis or lower respiratory infections need to document an infectious etiology with pyogenic bacteria and must rule out an underlying primary airway inflammatory disorder before consideration is made regarding the presence of an immune deficiency. In addition, decision making regarding diagnosis and treatment of patients who are examined for humoral immunodeficiency should not hinge solely on the strict application of defined cutoffs for "normal" response to a single polysaccharide vaccine, but rather a global assessment of humoral immune function in the context of the clinical presentation.
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Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Sinusite , Humanos , Anticorpos Antibacterianos , Vacinas Pneumocócicas , Streptococcus pneumoniae , Vacinação , Sinusite/diagnóstico , Sinusite/complicaçõesRESUMO
BACKGROUND: Alcohol hypersensitivity (AH), an exacerbation of respiratory symptoms in response to alcohol consumption, is common in aspirin-exacerbated respiratory disease and other forms of chronic rhinosinusitis (CRS). We speculated that these reactions relate to the activation of innate immune cells including basophils and, in particular, platelet-adherent basophils by polyphenolic compounds contained within eliciting alcoholic beverages. OBJECTIVE: We investigated the absolute numbers of these cells in patients with AH and the ability of relevant polyphenolic compounds to cause cellular activation. METHODS: Data were collected from 412 consecutive adults presenting to a tertiary care sinonasal clinic in whom the presence of AH was elicited. The CRS phenotype was determined and results from complete blood cell count and differential were analyzed. A subset of patients was invited to donate blood samples that were used to explore the ability of relevant compounds associated with alcohol consumption to activate platelet-nonadherent and platelet-adherent basophils. Activation was quantified by flow cytometry as up-regulated expression of CD63 and as secretion of lipid metabolites. RESULTS: Of the 412 patients enrolled, 69 (16.7%) endorsed having AH. Significantly higher platelet counts were seen in patients reporting AH. Red wine extract and several polyphenolic compounds produced basophil activation and this was primarily observed among platelet-adherent basophils. Platelet activation was further established as the release of thromboxane B2. CONCLUSION: The presence of AH is associated with significantly higher platelet levels and compounds present in alcoholic beverages can directly mediate both their activation and the activation of platelet-adherent basophils.
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Asma Induzida por Aspirina , Hipersensibilidade , Sinusite , Basófilos , Plaquetas , Citometria de Fluxo , Humanos , Sinusite/metabolismo , Tetraspanina 30RESUMO
BACKGROUND: Our previous studies revealed the presence of interleukin-5 (IL-5) receptor alpha chain (IL-5Rα, CD125) on neutrophils in a murine model of influenza and in the lung fluid of children with severe asthma. OBJECTIVE: To further evaluate the functional characteristics and effects of clinical factors and inflammatory variables on neutrophil surface IL-5Rα abundance in lung fluid and blood. METHODS: IL-5Rα expression was quantified by flow cytometry performed on purified neutrophils from blood and bronchoalveolar lavage fluid samples obtained from healthy controls and individuals with asthma. Expression was further confirmed by immunohistochemistry. Functional signaling through the IL-5Rα was evaluated by measurement of IL-5-inducible modulation of neutrophil surface CD62L and IL-5Rα expression. RESULTS: IL-5Rα was consistently present but at a variable magnitude on blood and lung neutrophils. Expression on lung neutrophils was significantly higher than that on blood cells (p"?>P < .001) where their expression was higher in the presence of airway pathogens, especially with respiratory viruses. Increased receptor expression occurred in response to the translocation of preformed receptors from intracellular stores. Receptors were functional as revealed by IL-5-mediated down-regulation of CD62L and the feed-forward up-regulation of reception expression. CONCLUSION: In addition to the expression on eosinophils and basophils, the IL-5Rα is consistently and abundantly expressed on the surface of blood and especially air space neutrophils. These observations support the concept that some of the efficacy of IL-5/IL-5R-targeting biologics observed in asthma may reflect their ability to target neutrophilic air space inflammation.
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Asma , Subunidade alfa de Receptor de Interleucina-5/metabolismo , Neutrófilos , Humanos , Interleucina-5 , Pulmão , Neutrófilos/metabolismoRESUMO
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.
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Asma , Infecções por Picornaviridae , Rinite Alérgica , Humanos , Imunidade Inata , Rinite Alérgica/complicações , Rhinovirus , Carga ViralRESUMO
BACKGROUND: Asthma is a complex heterogeneous disease occurring in adults and children that is characterized by distinct inflammatory patterns. While numerous studies have been performed in adults, little is known regarding the heterogeneity of severe asthma in children, particularly inflammatory signatures involving the air spaces. OBJECTIVE: We sought to determine the relationship of bronchoalveolar lavage (BAL) cytokine/chemokine expression patterns in children with severe therapy-resistant asthma stratified according to neutrophilic versus nonneutrophilic BAL inflammatory cell patterns. METHODS: Children with severe asthma with inadequate symptom control despite therapy underwent diagnostic bronchoscopy and BAL. Inflammatory cytokine/chemokine concentrations were determined using a multiplex protein bead assay. RESULTS: Analysis of BAL constituents with an unbiased clustering approach revealed distinct cytokine/chemokine patterns, and these aligned with pathways associated with type 2 innate lymphoid cells, monocytes, neutrophil trafficking, and T effector cells. All cytokines examined (n = 27) with 1 exception (vascular endothelial growth factor) were overexpressed with BAL neutrophilia compared with nonneutrophilic asthma, and this was confirmed in a cross-validation analysis. Cytokines specifically responsible for Th17 (IL-17, IL-6, G-CSF) and Th1 differentiation and expression (IL-12, TNF-α, IFN-γ) were enhanced in the neutrophilic cohorts. Neutrophilic groups were also characterized by higher prevalence of bacterial and viral pathogens; however, cytokine expression patterns manifested independently of pathogen expression. CONCLUSIONS: The results demonstrate that children with refractory asthma and neutrophilic inflammation had a BAL cytokine pattern consistent with a mixed Th17/Th1/Th2 response. In contrast, nonneutrophilic asthma presented independently of cytokine overexpression.
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Asma/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Granulócitos/imunologia , Neutrófilos/imunologia , Adolescente , Líquido da Lavagem Broncoalveolar/citologia , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.
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Testes Genéticos , Doenças da Imunodeficiência Primária , Asma , Humanos , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/terapia , Estados UnidosRESUMO
BACKGROUND: Circulatory diseases continue to be the greatest cause of mortality for Australian Aboriginal and Torres Strait Islander people, and a major cause of persistently lower life expectancy compared with non-Aboriginal Australians. The limited information that exists on atrial fibrillation (AF) prevalence in Aboriginal and Torres Strait Islander communities is mostly based on hospital admission data. This shows AF as principal or additional admission diagnosis was 1.4 times higher compared to non-Aboriginal Australians, a higher incidence of AF across the adult life span after age 20 years and a significantly higher prevalence among younger patients. Our study estimates the first national community prevalence and age distribution of AF (including paroxysmal) in Australian Aboriginal people. A handheld single-lead electrocardiograph (ECG) device (iECG), known to be acceptable in this population, was used to record participant ECGs. METHODS: This co-designed, descriptive cross-sectional study was conducted in partnership with 16 Aboriginal Community Controlled Health organisations at their facilities and/or with their services delivered elsewhere. The study was also conducted at one state community event. Three (3) Australian jurisdictions were involved: New South Wales, Western Australia and the Northern Territory. Study sites were located in remote, regional and urban areas. Opportunistic recruitment occurred between June 2016 and December 2017. People <45 years of age were excluded. RESULTS: Thirty (30) of 619 Aboriginal people received a 'Possible AF' and 81 an 'Unclassified' result from a hand-held smartphone ECG device. A final diagnosis of AF was made in 29 participants (4.7%; 95%CI 3.0-6.4%), 25 with known AF (five paroxysmal), and four with previously unknown AF. Three (3) of the four with unknown AF were aged between 55-64 years, consistent with a younger age of AF onset in Aboriginal people. Estimated AF prevalence increased with age and was higher in those aged >55 years than the general population (7.2% compared with 5.4%). Slightly more men than women were diagnosed with AF. CONCLUSIONS: This study is a significant contribution to the evidence which supports screening for AF in Aboriginal and Torres Strait Islander people commencing at a younger age than as recommended in the Australian guidelines (>65 years). We recommend the age of 55 years. Consideration should be given to the inclusion of AF screening in the Australian Government Department of Health annual 'Aboriginal and Torres Strait Islander Health Assessment'. CLINICAL TRIAL REGISTRATION: ACTRN12616000459426.
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Fibrilação Atrial/etnologia , Eletrocardiografia , Serviços de Saúde do Indígena/organização & administração , Programas de Rastreamento/métodos , Havaiano Nativo ou Outro Ilhéu do Pacífico , Fibrilação Atrial/diagnóstico , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales/epidemiologia , PrevalênciaRESUMO
BACKGROUND: Rhinovirus (RV) infections exacerbate asthma in part by enhancing an allergic state, and these exacerbations can be mitigated via administration of anti-IgE. OBJECTIVE: We investigated the presence of local IgE production in the nose of allergic and non-allergic subjects and assessed whether this was enhanced by RV. METHODS: Local production of specific IgE was determined by comparing ratios of specific to total IgE concentrations between nasal and serum samples. Our initial studies were performed in subjects presenting to the emergency department for allergic and non-allergic respiratory complaints. Subsequently, we investigated influences of experimental RV infection on nasal sIgE production in an allergic cohort. RESULTS: We found evidence of local sIgE production to Dermatophagoides pteronyssinus in 30.3% and to Blomia tropicalis in 14.6% of allergic subjects. None of the non-allergic subjects demonstrated local IgE. Subjects with active RV infection were more than twice as likely to have local sIgE (45% vs 14%), and subjects with local sIgE being produced were ~3 times more likely to be having an asthma exacerbation. Experimental RV infection was able to induce local sIgE production. CONCLUSION: These studies confirm local IgE production in a large subset of allergic subjects and demonstrate that allergic asthmatics with local IgE are more likely to develop an asthma exacerbation when infected with RV. Our RV challenge studies demonstrate that at least some allergic asthmatics can be induced to secrete locally generated IgE in their nasal airway after RV infection.
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Imunoglobulina E/imunologia , Mucosa Nasal/imunologia , Infecções por Picornaviridae/imunologia , Rinite Alérgica/imunologia , Rhinovirus/imunologia , Animais , Criança , Dermatophagoides pteronyssinus/imunologia , Feminino , Humanos , Masculino , Rinite Alérgica/virologiaRESUMO
OBJECTIVE: To update the reader on recently proposed common variable immune deficiency (CVID) diagnostic criteria, newly uncovered CVID pathobiology, freshly identified CVID-related genes, and novel CVID therapies. DATA SOURCES: PubMed Central. STUDY SELECTIONS: We selected 60 clinical and translational research articles that have shaped CVID diagnostic criteria, introduced personalized therapies, and advanced our understanding of CVID biology and genetics. We have incorporated recent articles and older published work that are foundational to the modern understanding of this protean disease. RESULTS: CVID has proven to be a heterogenous group of antibody deficiency diseases driven by defects in diverse biologic processes, including B-cell development, activation, tolerance, class-switch recombination, somatic hypermutation, and lymphoproliferation. Recent genetic advances have enabled identification of several CVID-related gene defects that may contribute to patients' infectious and noninfectious symptoms. CONCLUSION: Improved understanding of the aberrant biologic processes that drive CVID and the disease's genetic basis may be useful in directing therapeutic decisions, especially in cases complicated by autoimmune, lymphoproliferative, and inflammatory features.
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Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , HumanosRESUMO
BACKGROUND: The pathogenesis of severe asthma in childhood remains poorly understood. OBJECTIVE: We sought to construct the immunologic landscape in the airways of children with severe asthma. METHODS: Comprehensive analysis of multiple cell types and mediators was performed by using flow cytometry and a multiplex assay with bronchoalveolar lavage (BAL) specimens (n = 68) from 52 highly characterized allergic and nonallergic children (0.5-17 years) with severe treatment-refractory asthma. Multiple relationships were tested by using linear mixed-effects modeling. RESULTS: Memory CCR5+ TH1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN-γ+IL-17+ and IFN-γ-IL-17+ subsets constituted secondary TH types, and BAL fluid CD8+ T cells were almost exclusively IFN-γ+. The TH17-associated mediators IL-23 and macrophage inflammatory protein 3α/CCL20 were highly expressed. Despite low TH2 numbers, TH2 cytokines were detected, and TH2 skewing correlated with total IgE levels. Type 2 innate lymphoid cells and basophils were scarce in BAL fluid. Levels of IL-5, IL-33, and IL-28A/IFN-λ2 were increased in multisensitized children and correlated with IgE levels to dust mite, ryegrass, and fungi but not cat, ragweed, or food sources. Additionally, levels of IL-5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE+FcεRI+ myeloid dendritic cells were present in BAL fluid. CONCLUSIONS: The lower airways of children with severe asthma display a dominant TH1 signature and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms and warrant further assessment of the pathogenicity of TH1 cells in patients with severe asthma.
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Asma/imunologia , Células Th1/imunologia , Adolescente , Asma/complicações , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Lactente , Pulmão/imunologia , MasculinoRESUMO
Although small prior studies have suggested that IgE can be low in common variable immunodeficiency (CVID), the workup for patients with recurrent infections and suspected hypogammaglobulinemia does not include the routine measurement of serum IgE. We sought to test the hypothesis that low/undetectable serum IgE is characteristic of CVID by comparing the frequency of low/undetectable serum IgE in healthy controls and patients with CVID. We measured total serum IgE in a large multi-center cohort of patients with CVID (n = 354) and compared this to large population-based cohorts of children and adults. We further compared IgE levels in patients with CVID to those with other forms of humoral immunodeficiency, and in a subset, measured levels of allergen-specific serum IgE and IgG subclasses. Lastly, we evaluated for the presence of IgE in commercially available immunoglobulin replacement therapy (IgRT) products. An undetectable serum IgE (< 2 IU/ml) occurs in only 3.3% (95% CI, 1.9-5.7%) of the general population. In contrast, an undetectable IgE occurs in 75.6% (95% CI, 65.6-85.7%) of patients with CVID. Conversely, a high IgE (> 180 IU/ml) is very uncommon in CVID (0.3% of patients). IgE is > 2 IU/ml in 91.2% of patients with secondary hypogammaglobulinemia, and thus, an IgE < LLOD is suggestive of a primary humoral immunodeficiency. Allergen-specific IgE is not detectable in 96.5% of patients with CVID. Sufficient quantities of IgE to change the total serum IgE are not contained in IgRT. The IgG1/IgG4 ratio is increased in subjects with low IgE, regardless of whether they are controls or have CVID. These findings support the routine measurement of serum IgE in the workup of patients with hypogammaglobulinemia.
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Biomarcadores , Imunodeficiência de Variável Comum/diagnóstico , Imunoglobulina E/sangue , Adolescente , Adulto , Alérgenos/imunologia , Criança , Estudos de Coortes , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Feminino , Humanos , Imunização , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Isotipos de Imunoglobulinas/sangue , Isotipos de Imunoglobulinas/imunologia , Masculino , Sensibilidade e Especificidade , Adulto JovemRESUMO
Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS's recommendations for the use of genetic testing in light of these issues.