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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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INTRODUCTION: Psoriasis is a papulosquamous condition characterized by type 1 (T1) inflammation, while chronic rhinosinusitis (CRS) concurrent with asthma is commonly a type 2 (T2) process. Since psoriasis is predictive for higher rates of CRS, our objective was to determine whether CRS with concurrent psoriasis would share its T1 pathogenic signature. In comparison to T1 CRS, a T2 process can be predicted by presence of more extensive sinus disease via Lund-MacKay score, reduced sense of smell, and greater concurrence of purulent drainage and pain/pressure. METHODS: Subjective measurements of CRS included the Sino-Nasal Outcome Test (SNOT-22) and objective measurements included Lund-MacKay sinus CT score and endoscopic scoring. Outcomes were compared with control subjects with CRS co-presenting with allergies, asthma, or aspirin-exacerbated respiratory disease (AERD). RESULTS: A total of 62 patients (12 CRS alone, 14 CRS/psoriasis, 12 CRS/AERD, 12 CRS/allergic asthmatic, 12 CRS/non-allergic asthmatic) were included. Comparative analysis utilizing χ2 revealed no significant differences in any factor between CRS/psoriatic patients and all other groups associated with T2 presentations. Specifically, psoriatic patients had comparable reductions in smell, similar complaints of pain/pressure, negligible purulent drainage/crusting, and comparable extent of disease on their CT scan, as well as similar blood eosinophilia. The only significant difference was in lack of productivity (p < 0.05) with trends toward reduced concentration, waking up tired, and lack of sleep parameters presumably related to systemic psoriatic manifestations. CONCLUSIONS: Despite the increased prevalence of CRS in psoriasis patients, our data suggest that when present, psoriasis does not predict the presence of a T1 process in the sinuses.
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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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Agammaglobulinemia , Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Vacunas , Humanos , Inmunoglobulina E , Inmunoglobulina G , Síndromes de Inmunodeficiencia/inmunología , Polisacáridos/inmunología , Enfermedades de Inmunodeficiencia Primaria/inmunologíaRESUMEN
BACKGROUND: Recent studies have shown deposition of immunoglobulin G4 (IgG4) and food proteins in the esophageal mucosa of eosinophilic esophagitis (EoE) patients. Our aims were to assess whether co-localization of IgG4 and major cow's milk proteins (CMPs) was associated with EoE disease activity and to investigate the proteins enriched in proximity to IgG4 deposits. METHODS: This study included adult subjects with EoE (n = 13) and non-EoE controls (n = 5). Esophageal biopsies were immunofluorescence stained for IgG4 and CMPs. Co-localization in paired samples from active disease and remission was assessed and compared to controls. The proteome surrounding IgG4 deposits was evaluated by the novel technique, AutoSTOMP. IgG4-food protein interactions were confirmed with co-immunoprecipitation and mass spectrometry. RESULTS: IgG4-CMP co-localization was higher in the active EoE group compared to paired remission samples (Bos d 4, p = .02; Bos d 5, p = .002; Bos d 8, p = .002). Co-localization was also significantly higher in the active EoE group compared to non-EoE controls (Bos d 4, p = .0013; Bos d 5, p = .0007; Bos d 8, p = .0013). AutoSTOMP identified eosinophil-derived proteins (PRG 2 and 3, EPX, RNASE3) and calpain-14 in IgG4-enriched areas. Co-immunoprecipitation and mass spectrometry confirmed IgG4 binding to multiple food allergens. CONCLUSION: These findings further contribute to the understanding of the interaction of IgG4 with food antigens as it relates to EoE disease activity. These data strongly suggest the immune complex formation of IgG4 and major cow's milk proteins. These immune complexes may have a potential role in the pathophysiology of EoE by contributing to eosinophil activation and disease progression.
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Esofagitis Eosinofílica , Adulto , Femenino , Animales , Bovinos , Humanos , Esofagitis Eosinofílica/patología , Complejo Antígeno-Anticuerpo , Inmunoglobulina G , Alérgenos , Proteínas de la LecheRESUMEN
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 , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Humanos , Pulmón , Neutrófilos , Líquido del Lavado BronquioalveolarRESUMEN
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 Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Sinusitis , Humanos , Anticuerpos Antibacterianos , Vacunas Neumococicas , Streptococcus pneumoniae , Vacunación , Sinusitis/diagnóstico , Sinusitis/complicacionesRESUMEN
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 Inducida por Aspirina , Hipersensibilidad , Sinusitis , Basófilos , Plaquetas , Citometría de Flujo , Humanos , Sinusitis/metabolismo , Tetraspanina 30RESUMEN
Chronic rhinosinusitis (CRS) is an inflammatory condition of the paranasal sinuses defined by classic symptoms, imaging findings, or endoscopic findings. There are a growing number of emerging pharmacologic therapies being evaluated to treat patients with CRS, some of which have gained indication status in the United States. There have not been updated treatment guidelines published in the United States however since 2014. This document is meant to serve as an updated expert consensus document for the pharmacologic management of patients with CRS. We review available data focusing on prospective clinical trials on oral and intranasal corticosteroids, nasal irrigation, biologics, antibiotics, and allergy immunotherapy for CRS both with and without nasal polyposis, including specific therapies for aspirin-exacerbated respiratory disease-associated CRS and allergic fungal CRS. There are multiple options to treat CRS, and clinicians should be knowledgeable on the efficacy and risks of these available therapies. Allergists-immunologists now have various therapies available to treat patients with CRS.
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Pólipos Nasales , Senos Paranasales , Rinitis , Sinusitis , Enfermedad Crónica , Humanos , Pólipos Nasales/tratamiento farmacológico , Estudios Prospectivos , Rinitis/diagnóstico , Rinitis/tratamiento farmacológico , Sinusitis/diagnóstico , Sinusitis/tratamiento farmacológicoRESUMEN
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 , Infecciones por Picornaviridae , Rinitis Alérgica , Humanos , Inmunidad Innata , Rinitis Alérgica/complicaciones , Rhinovirus , Carga ViralRESUMEN
OBJECTIVE: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Dupilumab, omalizumab, and mepolizumab are approved for use in patients with severe, uncontrolled CRSwNP. However, the lack of a consistent definition of severe CRSwNP makes the decision to initiate biologic treatment particularly complex. Furthermore, the position of each biologic in the overall management of CRSwNP remains to be clarified. DATA SOURCES: Publications reporting results of phase III trials of dupilumab, omalizumab, mepolizumab, and benralizumab in the treatment of CRSwNP. STUDY SELECTIONS: Randomized, controlled phase III trials of biologics approved for CRSwNP. RESULTS: These trials all used different enrollment criteria. We discuss the complexities of assessing CRSwNP disease severity and highlight how these impact comparisons of the populations and outcomes of the phase III biologic trials. CONCLUSION: To position biologic agents appropriately within the existing CRSwNP treatment paradigm, future trials will need to include comparable patient populations and standardized outcome measures. Such trials will help to ensure that biologic treatment is targeted appropriately to support optimal clinical outcomes.
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Productos Biológicos , Pólipos Nasales , Rinitis , Sinusitis , Corticoesteroides/uso terapéutico , Productos Biológicos/uso terapéutico , Enfermedad Crónica , Humanos , Pólipos Nasales/complicaciones , Omalizumab/uso terapéutico , Rinitis/complicaciones , Sinusitis/complicacionesRESUMEN
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 , Subunidad alfa del Receptor de Interleucina-5/metabolismo , Neutrófilos , Humanos , Interleucina-5 , Pulmón , Neutrófilos/metabolismoRESUMEN
Aspirin-exacerbated respiratory disease (AERD) is a complex inflammatory disorder that is not generally viewed as a disease involving the adaptive immune system but instead one largely driven by the innate immune system. This article focuses on the cellular dysregulation involving 4 central cell types: eosinophils, basophils, mast cells, and innate lymphoid type 2 cells. AERD can be envisioned as involving a self-perpetuating vicious circle in which mediators produced by a differentiated activated epithelial layer, such as IL-25, IL-33, and thymic stromal lymphopoietin, engage and activate each of these innate immune cells. The activation of these innate immune cells with their production of additional cytokine/chemokine and lipid mediators leads to further recruitment and activation of these innate immune cells. More importantly, numerous mediators produced by these innate immune cells provoke the epithelium to induce further inflammation. This self-perpetuating cycle of inflammation partially explains both current interventions suggested to ameliorate AERD (eg, aspirin desensitization, leukotriene modifiers, anti-IL-5/IL-5 receptor, anti-IL-4 receptor, and anti-IgE) and invites exploration of novel targets as specific therapies for this condition (prostaglandin D2 antagonists or cytokine antagonists [IL-25, IL-33, thymic stromal lymphopoietin]). Several of these interventions currently show promise in small retrospective analyses but now require definite clinical trials.
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Aspirina/efectos adversos , Asma Inducida por Aspirina/inmunología , Citocinas/inmunología , Inmunidad Innata/efectos de los fármacos , Leucocitos/inmunología , Animales , Aspirina/uso terapéutico , Asma Inducida por Aspirina/patología , Asma Inducida por Aspirina/terapia , Humanos , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Inflamación/terapia , Leucocitos/patologíaRESUMEN
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/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/inmunología , Granulocitos/inmunología , Neutrófilos/inmunología , Adolescente , Líquido del Lavado Bronquioalveolar/citología , Niño , Preescolar , Femenino , Humanos , MasculinoRESUMEN
Aspirin-exacerbated respiratory disease (AERD) is characterized by the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and an intolerance to medications that inhibit the cycloxgenase-1 enzyme. Patients with AERD on average have more severe respiratory disease compared with patients with chronic rhinosinusitis with nasal polyps and/or asthma alone. Although patients with AERD traditionally develop significant upper and lower respiratory tract symptoms on ingestion of cycloxgenase-1 inhibitors, most of these same patients report clinical benefit when desensitized to aspirin and maintained on daily aspirin therapy. This Work Group Report provides a comprehensive review of aspirin challenges, aspirin desensitizations, and maintenance aspirin therapy in patients with AERD. Identification of appropriate candidates, indications and contraindications, medical and surgical optimization strategies, protocols, medical management during the desensitization, and recommendations for maintenance aspirin therapy following desensitization are reviewed. Also included is a summary of studies evaluating the clinical efficacy of aspirin therapy after desensitization as well as a discussion on the possible cellular and molecular mechanisms explaining how this therapy provides unique benefit to patients with AERD.
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Antiinflamatorios/uso terapéutico , Aspirina/uso terapéutico , Asma Inducida por Aspirina/terapia , Desensibilización Inmunológica/métodos , Rinitis/terapia , Sinusitis/terapia , Administración Oral , Algoritmos , Alérgenos/inmunología , Animales , Antiinflamatorios/inmunología , Aspirina/inmunología , Asma Inducida por Aspirina/diagnóstico , Asma Inducida por Aspirina/inmunología , Enfermedad Crónica , Humanos , Rinitis/diagnóstico , Rinitis/inmunología , Sinusitis/diagnóstico , Sinusitis/inmunologíaRESUMEN
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.
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Antialérgicos/uso terapéutico , Asma/inmunología , Inmunoglobulina E/metabolismo , Omalizumab/uso terapéutico , Infecciones por Picornaviridae/inmunología , Sistema Respiratorio/patología , Rhinovirus/fisiología , Adulto , Asma/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Inmunoglobulina E/inmunología , Masculino , Infecciones por Picornaviridae/tratamiento farmacológico , Efecto Placebo , Pruebas de Función Respiratoria , Sistema Respiratorio/virología , Adulto JovenRESUMEN
Asthma is associated with the overproduction of leukotrienes (LTs), including LTB4. Patients with severe asthma can be highly responsive to 5-lipoxygenase (5-LO) inhibition, which blocks production of both the cysteinyl LTs and LTB4. Production of LTB4 has traditionally been ascribed to neutrophils, mononuclear phagocytes, and epithelial cells, and acts as a chemoattractant for inflammatory cells associated with asthma. The source of LTB4 is unclear, especially in eosinophilic asthma. We speculated that the benefit of 5-LO inhibition could be mediated in part by inhibition of eosinophil-derived LTB4. LTB4 concentrations were assayed in BAL fluid from patients with severe asthma characterized by isolated neutrophilic, eosinophilic, and paucigranulocytic inflammation. Expression of LTA4 hydrolase (LTA4H) by airway eosinophils was determined by immunohistochemistry (IHC). Subsequently, peripheral blood eosinophils were activated and secreted LTB4 was quantified by enzyme immunoassay. Blood eosinophil LTA4H expression was determined by flow cytometry, qPCR, and IHC. LTB4 concentrations were elevated in BAL fluid from patients with severe asthma, including those with isolated eosinophilic inflammation, and these eosinophils displayed LTA4H via IHC. LTA4H expression by blood eosinophils was confirmed by flow cytometry, IHC, and qPCR. Robust LTB4 production by blood eosinophils was observed in response to some, but not all, stimuli. We demonstrated that eosinophils express LTA4H transcripts and protein, and can be stimulated to secrete LTB4. We speculate that in many patients with asthma, eosinophil-derived LTB4 is increased, and this may contribute to the efficacy of 5-LO inhibition.
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Asma/patología , Eosinófilos/metabolismo , Epóxido Hidrolasas/metabolismo , Leucotrieno B4/biosíntesis , Araquidonato 5-Lipooxigenasa/metabolismo , Asma/inmunología , Líquido del Lavado Bronquioalveolar/citología , Niño , Preescolar , Femenino , Humanos , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Neutrófilos/citologíaRESUMEN
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.