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BACKGROUND: Non-sedating H1 -antihistamines (nsAH) are the most commonly used treatment for chronic spontaneous urticaria (CSU). Many patients use them as on-demand (OD) therapy rather than a maintenance treatment. Here, we compared OD versus daily maintenance treatment with the nsAH rupatadine, assessed the efficacy of rupatadine updosing, and investigated potential long-term disease-modifying effects. METHODS: This multicenter, randomized study consisted of 2 weeks of screening, 8 weeks of double-blind treatment, and 6 weeks of treatment-free follow-up (OD allowed). Adult patients were randomized to 10 mg rupatadine OD or 10 mg rupatadine daily. At Week 4, if patients did not have a complete response, they switched from 10 to 20 mg rupatadine daily or underwent sham updosing (patients on 10 mg rupatadine OD). The primary aim was to compare CSU disease activity at the end of follow-up between daily versus OD. Additionally, we assessed the efficacy of rupatadine updosing. Major outcomes were disease activity, CSU-related quality of life (QoL), and disease control. RESULTS: At Week 4, disease activity and QoL significantly improved in daily versus OD-treated patients. Updosing of rupatadine did not improve the mean disease activity, but the number of complete responders increased during updosing from 5% to 22%. At the end of follow-up, the disease activity of patients treated OD versus daily was not significantly different. CONCLUSIONS: Daily rupatadine treatment significantly improved CSU disease activity and QoL during treatment versus OD treatment but not after discontinuation of rupatadine, indicating the benefits of a daily maintenance nsAH schedule.
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Urticaria Crónica , Urticaria , Adulto , Humanos , Urticaria/tratamiento farmacológico , Urticaria/diagnóstico , Calidad de Vida , Enfermedad Crónica , Resultado del TratamientoRESUMEN
Epistasis refers to the dependence of a mutation on other mutation(s) and the genetic context in general. In the context of human disorders, epistasis complicates the spectrum of disease symptoms and has been proposed as a major contributor to variations in disease outcome. The nonadditive relationship between mutations and the lack of complete understanding of the underlying physiological effects limit our ability to predict phenotypic outcome. Here, we report positive epistasis between intragenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)-the gene responsible for cystic fibrosis (CF) pathology. We identified a synonymous single-nucleotide polymorphism (sSNP) that is invariant for the CFTR amino acid sequence but inverts translation speed at the affected codon. This sSNP in cis exhibits positive epistatic effects on some CF disease-causing missense mutations. Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity. The most robust effect was observed when the sSNP was present in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon. Functional studies revealed that synergistic alteration in ribosomal velocity is the underlying mechanism; alteration of translation speed likely increases the time window for establishing crucial domain-domain interactions that are otherwise perturbed by each individual mutation.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Epistasis Genética , Biosíntesis de Proteínas , Secuencia de Aminoácidos/genética , Codón/genética , Fibrosis Quística/patología , Humanos , Mutación Missense/genética , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genéticaRESUMEN
BACKGROUND: Chronic spontaneous urticaria (CSU) is a rare, heterogeneous, severely debilitating, and often poorly controlled skin disease resulting in an itchy eruption that can be persistent. Antihistamines and omalizumab, an anti-IgE mAb, are the only licensed therapies. Although CSU pathogenesis is not yet fully understood, mast cell activation through the IgE:high-affinity IgE receptor (FcεRI) axis appears central to the disease process. OBJECTIVE: We sought to model CSU pathophysiology and identify in silico the mechanism of action of different CSU therapeutic strategies currently in use or under development. METHODS: Therapeutic performance mapping system technology, based on systems biology and machine learning, was used to create a CSU interactome validated with gene expression data from patients with CSU and a CSU model that was used to evaluate CSU pathophysiology and the mechanism of action of different therapeutic strategies. RESULTS: Our models reflect the known role of mast cell activation as a central process of CSU pathophysiology, as well as recognized roles for different therapeutic strategies in this and other innate and adaptive immune processes. They also allow determining similarities and differences between them; anti-IgE and Bruton tyrosine kinase inhibitors play a more direct role in mast cell biology through abrogation of FcεRI signaling activity, whereas anti-interleukins and anti-Siglec-8 have a role in adaptive immunity modulation. CONCLUSION: In silico CSU models reproduced known CSU and therapeutic strategies features. Our results could help advance understanding of therapeutic mechanisms of action and further advance treatment research by patient profile.
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Antialérgicos , Urticaria Crónica , Urticaria , Humanos , Inmunoglobulina E , Urticaria/tratamiento farmacológico , Urticaria/genética , Biología de Sistemas , Urticaria Crónica/tratamiento farmacológico , Receptores de IgE , Omalizumab/uso terapéutico , Inmunosupresores/uso terapéutico , Enfermedad Crónica , Antialérgicos/farmacología , Antialérgicos/uso terapéuticoRESUMEN
This work provides psychometric data on the validity and reliability of the Spanish adaptation of the Pet Bereavement Questionnaire (PBQ), as well as information on the intensity of bereavement in the Spanish population. The study evaluated 333 Spanish participants of legal age (M = 31.5; SD = 11.6), mostly women (76.3%). Confirmatory factor analysis (CFA) tested the adequacy of three different structures present in literature, finding better fit indexes for a model that kept the original three-factor structure (grief, guilt, and anger) but rearranged 2 of the 16 items. Around 70% of participants reported signs of intense bereavement on the grief scale, with higher means among women. The results confirm adequate psychometric qualities of the PBQ, offering healthcare professionals a tool to evaluate bereavement intensity after the loss of a companion animal in Spanish samples.
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Carbon black nanomaterial (CB-NM), as an industrial product with a large number of applications, poses a high risk of exposure, and its impact on health needs to be assessed. The most common testing platform for engineered (E)NMs is in vitro toxicity assessment, which requires prior ENM dispersion, stabilization, and characterization in cell culture media. Here, asymmetric flow field-flow fractionation (AF4) coupled to UV-Vis and dynamic light scattering (DLS) detectors in series was used for the study of CB dispersions in cell culture media, optimizing instrumental variables and working conditions. It was possible to disperse CB in a non-ionic surfactant aqueous solution due to the steric effect provided by surfactant molecules attached on the CB surface which prevented agglomeration. The protection provided by the surfactant or by culture media alone was insufficient to ensure good dispersion stability needed for carrying out in vitro toxicity studies. On the other hand, cell culture media in combination with the surfactant improved dispersion stability considerably, enabling the generation of shorter particles and a more favourable zeta potential magnitude, leading to greater stability due to electrostatic repulsion. It was demonstrated that the presence of amino acids in the culture media improved the monodisperse nature and stability of the CB dispersions, and resulted in a turn towards more negative zeta potential values when the pH was above the amino acid isoelectric point (IEP). Culture media used in real cell culture scenarios were also tested, and in vitro toxicity assays were developed optimizing the compatible amount of surfactant.
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Fraccionamiento de Campo-Flujo , Nanoestructuras , Surfactantes Pulmonares , Técnicas de Cultivo de Célula , Medios de Cultivo , Fraccionamiento de Campo-Flujo/métodos , Nanoestructuras/toxicidad , Nanoestructuras/química , Tamaño de la Partícula , Hollín/toxicidad , Tensoactivos/toxicidad , Punto IsoeléctricoRESUMEN
Chronic spontaneous urticaria (CSU) is a debilitating mast cell-driven disease characterized by recurrent wheals and/or angioedema. Substantial progress has been made in dissecting the 2 main autoimmune mechanisms that drive the pathogenesis of CSU. Type I autoimmune (autoallergic) CSU is associated with IgE antibodies against autoantigens, for example, thyroid peroxidase and IL-24. Type IIb autoimmune CSU is mediated by autoantibodies that activate mast cells, for example, via IgE and FcεRI, and is present in less than 10% of patients with CSU when strict criteria are used, that is, triple positivity of autologous serum skin test, immunoassays for IgG autoantibodies, and basophil activation tests. A subpopulation of patients with CSU has both types. Type IIb autoimmune CSU is characterized by higher disease severity, concomitant autoimmune diseases, low levels of total IgE, elevated levels of IgG-anti-thyroid peroxidase, basopenia, eosinopenia, poor response to antihistamines and to omalizumab, and a good response to cyclosporine. Novel targeted therapies for CSU are under development such as ligelizumab, an anti-IgE, fenebrutinib and remibrutinib, Bruton's tyrosine kinase inhibitors, and dupilumab, an anti-IL-4Rα. Further studies should investigate the overlap between autoallergic and type IIb autoimmune CSU, optimize the diagnosis of both autoimmune endotypes using easy-to-perform, noninvasive, and inexpensive markers, and assess differences in response to therapy.
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Urticaria Crónica , Urticaria , Autoanticuerpos , Enfermedad Crónica , Urticaria Crónica/diagnóstico , Urticaria Crónica/tratamiento farmacológico , Humanos , Inmunoglobulina E , Inmunoglobulina G , Urticaria/diagnóstico , Urticaria/tratamiento farmacológicoRESUMEN
BACKGROUND: Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as "may contain traces of" is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. METHODS: MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. RESULTS: In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. CONCLUSION: Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement "this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product" for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.
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Anafilaxia , Hipersensibilidad a los Alimentos , Alérgenos/análisis , Anafilaxia/diagnóstico , Anafilaxia/etiología , Anafilaxia/prevención & control , Animales , Huevos , Hipersensibilidad a los Alimentos/diagnóstico , Etiquetado de Alimentos , HumanosRESUMEN
BACKGROUND: As the use of multiplex-specific immunoglobulin E (sIgE) detection methods becomes increasingly widespread, proper comparative validation assessments of emerging new platforms are vital. OBJECTIVE: To evaluate the clinical and technical performance of a newly introduced microarray platform, Allergy Explorer (ALEX) (MacroArray Diagnostics), in the diagnosis of pollen (cypress, grass, olive), dust mite (Dermatophagoides pteronyssinus), mold (Alternaria alternata), fruit (apple, peach), and nut (walnut, hazelnut and peanut) allergies and to compare it with those of the ImmunoCAP Immuno Solid-phase Allergen Chip (ISAC) 112 microarray and the ImmunoCAP singleplex method (ThermoFisher Scientific). METHODS: We enrolled 153 patients with allergy and 16 controls without atopy. The sIgE assays were conducted using ISAC112, ALEX version 2 (ALEX2), and ImmunoCAP for whole extracts and major components. Technical validation of ALEX2 was performed by measuring repeatability and interassay, interbatch, and interlaboratory reproducibility. RESULTS: When measured globally (detection by 1 or more allergen components), ALEX2 had adequate sensitivity and specificity for most of the allergens studied, comparable in general with that of ISAC112 (except for olive pollen and walnut) and similar to that of ImmunoCAP whole extract measurements. Component-by-component analysis revealed comparable results for all techniques, except for Ole e 1 and Jug r 3, in both ISAC112 and ImmunoCAP comparisons, and Alt a 1, when compared with ISAC112. Continuous sIgE levels correlate with sIgE by ImmunoCAP. Good reproducibility and repeatability were observed for ALEX2. CONCLUSION: ALEX2 has sound technical performance and adequate diagnostic capacity, comparable in general with that of ISAC112 and ImmunoCAP.
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Alérgenos , Inmunoglobulina E , Animales , Humanos , Polen , Pyroglyphidae , Reproducibilidad de los ResultadosRESUMEN
Nanotechnology is science, engineering and technology conducted at the nanoscale, which is about 1-100 nm. It has led to the development of nanomaterials, which behave very differently from materials with larger scales and can have a wide range of applications in biomedicine. The physical and chemical properties of materials of such small compounds depend mainly on the size, shape, composition and functionalization of the system. Nanoparticles, carbon nanotubes, liposomes, polymers, dendrimers and nanogels, among others, can be nanoengineeried for controlling all parameters, including their functionalization with ligands, which provide the desired interaction with the immunological system, that is dendritic cell receptors to activate and/or modulate the response, as well as specific IgE, or effector cell receptors. However, undesired issues related to toxicity and hypersensitivity responses can also happen and would need evaluation. There are wide panels of accessible structures, and controlling their physico-chemical properties would permit obtaining safer and more efficient compounds for clinical applications goals, either in diagnosis or treatment. The application of dendrimeric antigens, nanoallergens and nanoparticles in allergy diagnosis is very promising since it can improve sensitivity by increasing specific IgE binding, mimicking carrier proteins or enhancing signal detection. Additionally, in the case of immunotherapy, glycodendrimers, liposomes, polymers and nanoparticles have shown interest, behaving as platforms of allergenic structures, adjuvants or protectors of allergen from degradation or having a depot capacity. Taken together, the application of nanotechnology to allergy shows promising facts facing important goals related to the improvement of diagnosis as well as specific immunotherapy.
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Hipersensibilidad , Nanoestructuras , Nanotubos de Carbono , Alérgenos , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/terapia , NanotecnologíaRESUMEN
BACKGROUND: Double-blind, placebo-controlled oral food challenges are the gold standard in food allergy diagnosis. Nevertheless, proper masking of peanuts is particularly complex owing to their intense flavor and odor. Thus, it is important to use validated recipes to ensure their adequate masking during oral food challenges. OBJECTIVE: To design and validate recipes containing masked peanuts for double-blind, placebo-controlled oral food challenges. METHODS: Two types of products (cookies and a custardtype dessert) containing the masked peanuts and other ingredients with low allergenic potential were designed and validated. For this purpose, of the 24 initial cookie recipes and 12 initial custard recipes developed, those that did not exhibit significant differences in their texture were selected for sensory validation. RESULTS: Similarity triangle tests were performed using a panel of 36 selected tasters, enabling the validation of 1 pair of cookie recipes and 1 pair of custard-type dessert recipe, both with low allergenic potential and suitable for those with celiac disease and for vegans. CONCLUSION: The validated recipes are of clinical and research interest because they allow to confirm a peanut allergy and detect a wide range of tolerated threshold doses, which makes it possible to provide specific indications for each patient.
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Alérgenos/administración & dosificación , Culinaria/métodos , Hipersensibilidad al Cacahuete/diagnóstico , Arachis , Libros de Cocina como Asunto , Método Doble Ciego , Alimentos/efectos adversos , HumanosRESUMEN
BACKGROUND: Evidence from the scientific literature shows a significant variation in greenhouse gas (GHG) emissions from the diet, according to the type of food consumed. We aim to analyze the relationship between the daily dietary GHG emissions according to red meat, fruit and vegetables consumption and their relationship with risk of total mortality, and incident risk of chronic diseases. METHODS: We examined data on the EPIC-Spain prospective study, with a sample of 40 621 participants. Dietary GHG emission values were calculated for 57 food items of the EPIC study using mean emission data from a systematic review of 369 published studies. RESULTS: Dietary GHG emissions (kgCO2eq/day), per 2000 kcal, were 4.7 times higher in those with high red-meat consumption (>140 g/day) than those with low consumption (<70 g/day). The average dietary GHG emissions were similar in males and females, but it was significantly higher in youngest people and in those individuals with lower educational level, as well as for northern EPIC centers of Spain. We found a significant association with the risk of mortality comparing the third vs. the first tertile of dietary GHG emissions [hazard ratio (HR) 1.095; 95% confidence interval (CI) 1.007-1.19; trend test 0.037]. Risk of coronary heart disease (HR 1.26; 95% CI 1.08-1.48; trend test 0.003) and risk of type 2 diabetes (HR 1.24; 95% CI 1.11-1.38; trend test 0.002) showed significant association as well. CONCLUSIONS: Decreasing red-meat consumption would lead to reduce GHG emissions from diet and would reduce risk of mortality, coronary heart disease and type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Gases de Efecto Invernadero , Enfermedad Crónica , Dieta , Femenino , Efecto Invernadero , Gases de Efecto Invernadero/análisis , Humanos , Masculino , Estudios Prospectivos , España/epidemiologíaRESUMEN
Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, and it has been stated that extracellular vesicles (EVs) secreted by MSCs (EVMSC) are able to recapitulate the immunosuppressive properties of parental cells. As a next step, clinical trials to corroborate preclinical studies should be performed. However, effective dose in large mammals, including humans, is quite high and EVs industrial production is hindered by the proliferative senescence that affects MSCs during massive cell expansion. We generated a genetically modified MSC cell line overexpressing hypoxia-inducible factor 1-alpha and telomerase to increase the therapeutic potency of EVMSC and facilitate their large-scale production. We also developed a cytokine-based preconditioning culture medium to prime the immunomodulatory response of secreted EVs (EVMSC-T-HIFc). We tested the efficacy of this system in vitro and in a delayed-type hypersensitivity mouse model. MSC-T with an HIF-1α-GFP lentiviral vector (MSC-T-HIF) can be effectively expanded to obtain large amounts of EVs without major changes in cell phenotype and EVs composition. EVMSC-T-HIFc suppressed the proliferation of activated T-cells more effectively than did EVs from unmodified MSC in vitro, and significantly blunted the ear-swelling response in vivo by inhibiting cell infiltration and improving tissue integrity. We have developed a long-lived EV source that secretes high quantities of immunosuppressive EVs, facilitating a more standard and cost-effective therapeutic product.
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Vesículas Extracelulares/trasplante , Hipersensibilidad Tardía/terapia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Inmunomodulación , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Linfocitos T/inmunología , Animales , Línea Celular , Proliferación Celular , Células Cultivadas , Citocinas/farmacología , Pulpa Dental/citología , Vesículas Extracelulares/inmunología , Vectores Genéticos/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Lentivirus/genética , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ingeniería de Proteínas/métodos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Linfocitos T/fisiología , Telomerasa/genética , Telomerasa/metabolismo , Adulto JovenRESUMEN
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-HIF) and conditioned with pro-inflammatory stimuli release EVs (EVMSC-T-HIFC) with potent immunomodulatory activity. We tested the efficacy of EVMSC-T-HIFC to repolarize M1 macrophages (Mφ1) to M2-like macrophages (Mφ2-like) by analyzing surface markers and cytokines and performing functional assays in co-culture, including efferocytosis and T-cell proliferation. We also studied the capacity of EVMSC-T-HIFC to dampen the inflammatory response of activated endothelium and modulate fibrosis. Finally, we tested the therapeutic capacity of EVMSC-T-HIFC in an acute colitis model. EVMSC-T-HIFc induced the repolarization of monocytes from Mφ1 to an Mφ2-like phenotype, which was accompanied by reduced inflammatory cytokine release. EVMSC-T-HIFc-treated Mφ1 had similar effects of immunosuppression on activated peripheral blood mononuclear cells (PBMC) as Mφ2, and reduced the adhesion of PBMCs to activated endothelium. EVMSC-T-HIFc also prevented myofibroblast differentiation of TGF-ß-treated fibroblasts. Finally, administration of EVMSC-T-HIFc promoted healing in a TNBS-induced mouse colitis model in terms of preserving colon length and intestinal mucosa architecture and altering the ratio of Mφ1/ Mφ2 infiltration. In conclusion, EVMSC-T-HIFC have effective anti-inflammatory properties, making them potential therapeutic agents in cell free-based therapies for the treatment of Crohn's disease and likely other immune-mediated inflammatory diseases.
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Enfermedad de Crohn/terapia , Vesículas Extracelulares/trasplante , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Células Madre Mesenquimatosas/metabolismo , Animales , Adhesión Celular , Polaridad Celular , Enfermedad de Crohn/inducido químicamente , Enfermedad de Crohn/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Vesículas Extracelulares/genética , Vesículas Extracelulares/inmunología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Telomerasa/metabolismo , Ácido Trinitrobencenosulfónico/efectos adversos , Adulto JovenRESUMEN
This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (CSU), the expanding spectrum of patient-reported outcome measures (PROMs) for assessing CU disease activity, impact, and control, as well as future treatment options for CU. This update is needed, as several recently reported findings have led to significant advances in these areas. Some of these key discoveries were first presented at past meetings of the Collegium Internationale Allergologicum (CIA). New evidence shows that the prevalence of CSU is geographically heterogeneous, high in all age groups, and increasing. Several recent reports have helped to better characterize two endotypes of CSU: type I autoimmune (or autoallergic) CSU, driven by IgE to autoallergens, and type IIb autoimmune CSU, which is due to mast cell (MC)-targeted autoantibodies. The aim of treatment in CU is complete disease control with absence of signs and symptoms as well as normalization of quality of life (QoL). This is best monitored by the use of an expanding set of PROMs, to which the Angioedema Control Test, the Cholinergic Urticaria Quality of Life Questionnaire, and the Cholinergic Urticaria Activity Score have recently been added. Current treatment approaches for CU under development include drugs that inhibit the effects of signals that drive MC activation and accumulation, drugs that inhibit intracellular pathways of MC activation and degranulation, and drugs that silence MCs by binding to inhibitory receptors. The understanding, knowledge, and management of CU are rapidly increasing. The aim of this review is to provide physicians who treat CU patients with an update on where we stand and where we will go. Many questions and unmet needs remain to be addressed, such as the development of routine diagnostic tests for type I and type IIb autoimmune CSU, the global dissemination and consistent use of PROMs to assess disease activity, impact, and control, and the development of more effective and well-tolerated long-term treatments for all forms of CU.
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Urticaria Crónica , HumanosRESUMEN
Here we report a Spanish family in which two members, mother and daughter, present with a phenotype of mild non transfusion-dependent thalassemia (NTDT) due to compound heterozygosity for δß-thalassemia (δß-thal) and the α gene triplication ααα-3.7. They carry the most prevalent form of δß-thal in Spain, the so-called Spanish δß0-thal, which consists of a deletion of 114 kb that affects the δ and ß genes. A mild microcytic anemia [hemoglobin (Hb) 10.6 g/dL and mean corpuscular volume (MCV) 72.8 fL, and Hb 10.9 g/dL and MCV 70.0 fL, respectively], hypocromia [mean corpuscular Hb (MCH), 23.4 and 22.6 pg, respectively], increased red blood cell (RBC) distribution width (RDW) (20.0 and 21.9%, respectively), high fetal Hb (Hb F) (23.7 and 21.6%, respectively) with Hb A2 within the normal range, and splenomegaly, were present in the affected subjects. In areas were δß-thal is prevalent, the interaction with triplicated α-globin genes should be suspected in cases of mild NTDT if Hb F is high and Hb A2 is not increased.
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Mutación , Globinas alfa/genética , Talasemia beta/diagnóstico , Talasemia beta/genética , Adolescente , Adulto , Anciano , Alelos , Análisis Mutacional de ADN , Índices de Eritrocitos , Femenino , Genotipo , Hemoglobinas Anormales/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , España , Globinas beta/genética , Talasemia beta/sangreRESUMEN
BACKGROUND: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU. METHODS: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). RESULTS: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non-aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti-TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively. CONCLUSIONS: aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management.
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Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Biomarcadores , Urticaria Crónica/inmunología , Urticaria Crónica/metabolismo , Adolescente , Adulto , Anciano , Anticuerpos Antiidiotipos/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/diagnóstico , Basófilos/inmunología , Basófilos/metabolismo , Urticaria Crónica/diagnóstico , Femenino , Liberación de Histamina , Humanos , Inmunoglobulina G/inmunología , Yoduro Peroxidasa/inmunología , Proteínas de Unión a Hierro/inmunología , Masculino , Persona de Mediana Edad , Fenotipo , Receptores de IgE/metabolismo , Evaluación de Síntomas , Adulto JovenRESUMEN
BACKGROUND: The daily diary Urticaria Activity Score (UAS) and its weekly score (UAS7) are widely used to assess signs and symptoms in patients with chronic spontaneous urticaria (CSU). The objective of this study was to assess the psychometric properties of a Spanish version of the once-daily UAS. METHODS: Observational study in patients ≥18 years old receiving usual care for CSU (daily or almost daily occurrence of generalized hives or angioedema for ≥6 weeks). Patients were included consecutively and completed the UAS, EQ-5D, and the Chronic Urticaria Quality of Life scale (CU-Q2oL) at two study visits 6 weeks apart. On each occasion, the UAS was completed once-daily for 7 consecutive days to be able to calculate the UAS7 score. Psychometric properties of reliability, construct validity, and responsiveness were assessed. The Minimal Important Difference (MID) was estimated for the UAS7 using anchor- and distribution-based approaches. RESULTS: Data from 166 patients was available for analysis (mean age 49 years, 65.7% female). Floor (5.4% of patients with the lowest possible score) and ceiling (1.2%) effects were low; 15% of patients had missing values. Internal consistency and test-retest reliability were good (Cronbach's alpha of 0.83 and an ICC of 0.84, respectively). Convergent validity was demonstrated through the pattern of correlations with the EQ-5D and CU-Q2oL and known groups' validity was demonstrated by the instrument's ability to discriminate between patients with different overall levels of urticaria severity, with between-group effect-sizes (ES) ranging from 0.36 to 1.19. The UAS7 proved responsive to change with effect sizes ranging from 0.3 to 1.52 in patients reporting improvement or deterioration in overall urticaria status. The MID for the UAS7 score was estimated at 7-8 points, on a scale of 0-42. CONCLUSIONS: The Spanish version of the UAS score has demonstrated a robust psychometric performance in patients with CSU managed in conditions of usual care. It can therefore be considered a suitable instrument to assess disease activity in clinical practice in Spanish-speaking patients. The Spanish version's reliability and validity are similar to those reported for other language versions of the once- and twice-daily variants of the UAS.
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Medición de Resultados Informados por el Paciente , Calidad de Vida , Urticaria/psicología , Adulto , Anciano , Enfermedad Crónica/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Psicometría , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , España , Traducciones , Urticaria/fisiopatologíaRESUMEN
BACKGROUND: Bronchoscopy is a safe technique for diagnosing peripheral pulmonary lesions (PPLs), and virtual bronchoscopic navigation (VBN) helps guide the bronchoscope to PPLs. OBJECTIVES: We aimed to compare the diagnostic yield of VBN-guided and unguided ultrathin bronchoscopy (UTB) and explore clinical and technical factors associated with better results. We developed a diagnostic algorithm for deciding whether to use VBN to reach PPLs or choose an alternative diagnostic approach. METHODS: We compared diagnostic yield between VBN-UTB (prospective cases) and unguided UTB (historical controls) and analyzed the VBN-UTB subgroup to identify clinical and technical variables that could predict the success of VBN-UTB. RESULTS: Fifty-five cases and 110 controls were included. The overall diagnostic yield did not differ between the VBN-guided and unguided arms (47 and 40%, respectively; p = 0.354). Although the yield was slightly higher for PPLs ≤20 mm in the VBN-UTB arm, the difference was not significant (p = 0.069). No other clinical characteristics were associated with a higher yield in a subgroup analysis, but an 85% diagnostic yield was observed when segmentation was optimal and the PPL was endobronchial (vs. 30% when segmentation was suboptimal and 20% when segmentation was optimal but the PPL was extrabronchial). CONCLUSIONS: VBN-guided UTB is not superior to unguided UTB. A greater impact of VBN-guided over unguided UTB is highly dependent on both segmentation quality and an endobronchial location of the PPL. Segmentation quality should be considered before starting a procedure, when an alternative technique that may improve yield can be chosen, saving time and resources.