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1.
J Investig Allergol Clin Immunol ; 33(5): 383-391, 2023 Oct 16.
Article in English | MEDLINE | ID: mdl-36000827

ABSTRACT

BACKGROUND: Vine cultivation is widely distributed in La Rioja, Spain (37% of all crops) and is associated with exposure of the general population to vine pollen. The aims of this study were to investigate the prevalence of sensitization to Vitis vinifera pollen in persons with respiratory allergy in the general population and to identify the allergens involved. MATERIALS AND METHODS: The study population comprised patients who came to the hospital between September 2019 and January 2020 with suspected respiratory allergy. All patients underwent skin prick testing with a panel of standardized aeroallergens, profilin, lipid transfer protein (LTP), and V vinifera pollen extract and prick-prick testing with fresh grapes. The in vitro study included specific IgE by ImmunoCap and ELISA, allergenic profile by immunoblot with individual sera from patients positive to V vinifera pollen extract, and 2D immunoblot with a pool of sera. The spots recognized by IgE were identified using mass spectrometry. RESULTS: A total of 151 patients were included. Of these, 124 were positive to some of the allergens tested. Thirty-four (27.4%) were positive to vine pollen in the skin prick tests. The serology study revealed positive results in 20 patients. Five vine pollen allergens were identified, and profilin was the most prevalent (30%). The other 4 allergens could be considered specific to this pollen. CONCLUSIONS: Sensitization to vine pollen was frequent in the general population in a vine growing area. The clinical relevance of this finding is unknown owing to sensitization to other pollens in the vine pollen-positive patients. Five new vine pollen allergens were identified.

2.
J. investig. allergol. clin. immunol ; 33(5): 383-391, 2023. tab, graf
Article in English | IBECS | ID: ibc-226552

ABSTRACT

Background: Vine cultivation is widely distributed in La Rioja, Spain (37% of all crops) and is associated with exposure of the general population to vine pollen. The aims of this study were to investigate the prevalence of sensitization to Vitis vinifera pollen in persons with respiratory allergy in the general population and to identify the allergens involved. Materials and Methods: The study population comprised patients who came to the hospital between September 2019 and January 2020 with suspected respiratory allergy. All patients underwent skin prick testing with a panel of standardized aeroallergens, profilin, lipid transfer protein (LTP), and V vinifera pollen extract and prick-prick testing with fresh grapes. The in vitro study included specific IgE by ImmunoCap and ELISA, allergenic profile by immunoblot with individual sera from patients positive to V vinifera pollen extract, and 2D immunoblot with a pool of sera. The spots recognized by IgE were identified using mass spectrometry. Results: A total of 151 patients were included. Of these, 124 were positive to some of the allergens tested. Thirty-four (27.4%) were positive to vine pollen in the skin prick tests. The serology study revealed positive results in 20 patients. Five vine pollen allergens were identified, and profilin was the most prevalent (30%). The other 4 allergens could be considered specific to this pollen. Conclusions: Sensitization to vine pollen was frequent in the general population in a vine growing area. The clinical relevance of this finding is unknown owing to sensitization to other pollens in the vine pollen–positive patients. Five new vine pollen allergens were identified (AU)


Antecedentes: El cultivo de la vid está ampliamente distribuido en La Rioja (37% de los cultivos), lo que supone una exposición de la población general al polen de esta planta. El objetivo de este estudio fue investigar la prevalencia de sensibilización al polen de Vitis vinifera en la población general con alergia respiratoria e identificar los alérgenos implicados. Materiales y métodos: Se incluyeron en el estudio pacientes que acudieron al hospital entre septiembre de 2019 y enero de 2020 con sospecha de alergia respiratoria. A todos ellos se les realizó una prueba cutánea con el panel de aeroalérgenos estandarizados, profilina, LTP, extracto de polen de V. vinifera y Prick prick con uva. El estudio in vitro incluyó IgE específica mediante ImmunoCap y ELISA, perfil alergénico por inmunoblot con sueros individuales de pacientes positivos al extracto de polen de V. vinifera e inmunoblot 2D con un pool de sueros. Las proteínas reconocidas por la IgE fueron identificadas por espectrometría de masas. Resultados: Se incluyeron un total de 151 pacientes. De ellos, 124 fueron positivos a algunos de los alérgenos analizados. 34 (27,4%) fueron positivos a polen de vid por prueba cutánea. 20 fueron positivos tras el estudio serológico. Se identificaron 5 alérgenos del polen de la vid, siendo la profilina el más prevalente (30%). Los otros 4 alérgenos podrían considerarse específicos de este polen. Conclusión: Se detectó una alta sensibilización al polen de vid en la población general en una zona de viñedos. Se desconoce la relevancia clínica debido a la sensibilización a otros pólenes en los pacientes positivos a polen de vid. Se identificaron 5 nuevos alérgenos del polen de la vid (AU)


Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle Aged , Aged , Rhinitis, Allergic, Seasonal/diagnosis , Vitis/adverse effects , Vitis/immunology , Allergens , Enzyme-Linked Immunosorbent Assay
3.
J Investig Allergol Clin Immunol ; 31(5): 385-403, 2021 Oct 25.
Article in English | MEDLINE | ID: mdl-33653682

ABSTRACT

The controlled drug provocation test (DPT) is currently considered the gold standard for the diagnosis of drug allergy. Adverse drug reactions (ADRs) are an increasingly common presenting complaint in both primary and specialized care. In Spain, ADRs are usually assessed via the allergology department, which rules out immunological mechanisms in up to 90% of cases. An adequate approach to ADRs clearly impacts the costs and efficacy of the treatments prescribed by other specialists. Consequently, if we did not use DPTs, patients would require more expensive, more toxic, and less effective treatments in many cases. In recent years, many new drugs have been developed. This document is intended to be a practical guideline for the management of DPTs according to the vision of the Spanish Allergology Society. The diagnostic work-up begins with a detailed clinical history. Skin tests are only useful for some medications, and in most cases the diagnosis can only be confirmed by DPT. Although cross-reactivity is common, DPTs can confirm the diagnosis and help to find an alternative drug. Programmed individualized patient management based on the type of drug to be studied and the patient´s comorbidities usually enables a solution to be found in most cases.


Subject(s)
Drug Hypersensitivity , Drug-Related Side Effects and Adverse Reactions , Pharmaceutical Preparations , Drug Hypersensitivity/diagnosis , Humans , Skin Tests , Spain
4.
J Investig Allergol Clin Immunol ; 31(4): 292-307, 2021 Jul 26.
Article in English | MEDLINE | ID: mdl-33461956

ABSTRACT

The consumption of quinolones as first-line treatment has increased in recent years, leading to an increase in the incidence of hypersensitivity reactions (HSRs) to this antibiotic group. Both diagnosis and management of HSRs to quinolones are complex and controversial. These practical guidelines aim to provide recommendations for effective clinical practice. The recommendations were drafted by an expert panel that reviewed the literature regarding HSRs to quinolones and analyzed controversies in this area. Most HSRs to quinolones are immediate and severe. The risk for HSRs is higher in patients who report allergy to ß-lactams, moxifloxacininduced anaphylaxis, and immediate reactions than in patients who report reactions to quinolones inducing other symptoms. The usefulness of skin tests in diagnosing HSRs to quinolones is controversial, with sensitivity and specificity varying between studies. Most in vitro tests are produced in-house, with no validated commercial options. The basophil activation test has proven useful for diagnosing immediate reactions, albeit with diverse results regarding sensitivity. Drug provocation testing is currently the gold standard for confirming or excluding the diagnosis and for finding safe alternatives, although it is contraindicated in patients with severe reactions. Cross-reactivity between quinolones has proven controversial in several studies, with the lowest cross-reactivity reported for levofloxacin. Desensitization may be considered in allergy to quinolones when no other alternatives are available.


Subject(s)
Allergens/adverse effects , Anti-Allergic Agents/adverse effects , Desensitization, Immunologic/methods , Drug Hypersensitivity/diagnosis , Drug-Related Side Effects and Adverse Reactions/diagnosis , Quinolones/adverse effects , Allergens/immunology , Anti-Allergic Agents/therapeutic use , Basophil Degranulation Test , Cross Reactions , Drug Hypersensitivity/drug therapy , Drug Hypersensitivity/etiology , Drug-Related Side Effects and Adverse Reactions/drug therapy , Humans , Practice Guidelines as Topic , Quinolones/therapeutic use , Skin Tests
5.
J. investig. allergol. clin. immunol ; 31(5): 385-403, 2021. tab, ilus
Article in English | IBECS | ID: ibc-216382

ABSTRACT

The controlled drug provocation test (DPT) is currently considered the gold standard for the diagnosis of drug allergy. Adverse drug reactions (ADRs) are an increasingly common presenting complaint in both primary and specialized care. In Spain, ADRs are usually assessed via the allergology department, which rules out immunological mechanisms in up to 90% of cases. An adequate approach to ADRs clearly impacts the costs and efficacy of the treatments prescribed by other specialists. Consequently, if we did not use DPTs, patients would require more expensive, more toxic, and less effective treatments in many cases. In recent years, many new drugs have been developed. This document is intended to be a practical guideline for the management of DPTs according to the vision of the Spanish Allergology Society. The diagnostic work-up begins with a detailed clinical history. Skin tests are only useful for some medications, and in most cases the diagnosis can only be confirmed by DPT. Although cross-reactivity is common, DPTs can confirm the diagnosis and help to find an alternative drug. Programmed individualized patient management based on the type of drug to be studied and the patient's comorbidities usually enables a solution to be found in most cases (AU)


La prueba de exposición controlada a fármacos (DPT) se considera actualmente el estándar de oro para el diagnóstico de alergia amedicamentos. Las reacciones adversas inducidas por medicamentos (RAM) son un motivo creciente de consulta tanto en atención primariacomo especializada. Las consultas de Alergología en España son las que habitualmente estudian estas RAM y descartan mecanismosinmunológicos implicados hasta en el 90% de los casos consultados. Un abordaje adecuado de estos casos repercute de una maneraevidente en los costes y la eficacia de los tratamientos requeridos por otros especialistas, de modo que, si no empleáramos los DPT, lospacientes requerirían tratamientos más costosos, más tóxicos y menos eficaces en la mayoría de los casos.En los últimos años se han desarrollado un gran número de nuevos fármacos y este documento pretende ser una guía práctica en lagestión de las DPT con la visión de la Sociedad Española de Alergología. El trabajo de diagnóstico comienza con un historial detalladodel paciente. Las pruebas cutáneas solo son útiles en algunos medicamentos y, en la mayoría de los casos, el diagnóstico solo puedeconfirmarse mediante el DPT. Aunque suele haber reactividad cruzada, las DPT pueden confirmar el diagnóstico y también contribuir aencontrar un fármaco alternativo tolerable. El manejo individual de los pacientes de forma programada, teniendo en cuenta tanto eltipo de fármaco a estudiar como las comorbilidades del paciente, suele permitir encontrar una solución para la mayoría de los pacientes (AU)


Subject(s)
Humans , Drug Hypersensitivity/diagnosis , Drug-Related Side Effects and Adverse Reactions , Pharmaceutical Preparations , Societies, Medical , Skin Tests , Spain
6.
J. investig. allergol. clin. immunol ; 31(4): 292-307, 2021. ilus, tab
Article in English | IBECS | ID: ibc-215221

ABSTRACT

The consumption of quinolones as first-line treatment has increased in recent years, leading to an increase in the incidence of hypersensitivity reactions (HSRs) to this antibiotic group. Both diagnosis and management of HSRs to quinolones are complex and controversial. These practical guidelines aim to provide recommendations for effective clinical practice. The recommendations were drafted by an expert panel that reviewed the literature regarding HSRs to quinolones and analyzed controversies in this area. Most HSRs to quinolones are immediate and severe. The risk for HSRs is higher in patients who report allergy to ß-lactams, moxifloxacininduced anaphylaxis, and immediate reactions than in patients who report reactions to quinolones inducing other symptoms. The usefulness of skin tests in diagnosing HSRs to quinolones is controversial, with sensitivity and specificity varying between studies. Most in vitro tests are produced in-house, with no validated commercial options. The basophil activation test has proven useful for diagnosing immediate reactions, albeit with diverse results regarding sensitivity. Drug provocation testing is currently the gold standard for confirming or excluding the diagnosis and for finding safe alternatives, although it is contraindicated in patients with severe reactions. Cross-reactivity between quinolones has proven controversial in several studies, with the lowest cross-reactivity reported for levofloxacin. Desensitization may be considered in allergy to quinolones when no other alternatives are available (AU)


Subject(s)
Humans , Anti-Allergic Agents/therapeutic use , Desensitization, Immunologic/methods , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/drug therapy , Basophil Degranulation Test , Cross Reactions , Skin Tests
7.
J Investig Allergol Clin Immunol ; 28(2): 106-112, 2018.
Article in English | MEDLINE | ID: mdl-29235434

ABSTRACT

OBJECTIVE: To investigate the prevalence of and factors associated with the presence of α-gal-specific IgE in a risk group of foresters and forest workers from La Rioja, Spain and in a control group. METHODS: The study population comprised 169 workers and 100 individuals who did not recall having had tick bites. A questionnaire including demographic data and number of tick bites per year was completed by a physician. α-Gal sIgE was assessed using ImmunoCAP with serum samples that had been taken in 2010. In 2015, second serum specimens were taken from all but 1 of the workers, who had positive specific IgE to α-gal in 2010. These new samples were tested for IgE to the α-gal epitope and to mammalian meat. RESULTS: The prevalence of positive sIgE to α-gal was 15% in the risk population and 4% in the control population. α-Gal sIgE positivity was associated with the number of tick bites per year and with seniority. Thirteen out of 21 patients sensitized to α-gal in 2010 showed positive specific IgE to α-gal in serum samples from 2015. Eleven had specific IgE to mammalian meat, but none reported symptoms of meat allergy. CONCLUSIONS: The prevalence of α-gal sIgE antibodies in this risk population was higher than in the control group and was associated with the number of tick bites per year and with seniority. None of the workers sensitized to mammalian meat developed meat allergy, possibly owing to the low levels of sIgE to α-gal.


Subject(s)
Immunoglobulin E/immunology , alpha-Galactosidase/immunology , Adult , Allergens/immunology , Epitopes/immunology , Female , Forests , Humans , Male , Meat , Prevalence , Spain , Tick Bites/immunology
8.
J. investig. allergol. clin. immunol ; 28(2): 106-112, 2018. tab
Article in English | IBECS | ID: ibc-173569

ABSTRACT

Objective: To investigate the prevalence of and factors associated with the presence of alfa-gal-specific IgE in a risk group of foresters and forest workers from La Rioja, Spain and in a control group. Methods: The study population comprised 169 workers and 100 individuals who did not recall having had tick bites. A questionnaire including demographic data and number of tick bites per year was completed by a physician. alfa-Gal sIgE was assessed using ImmunoCAP with serum samples that had been taken in 2010. In 2015, second serum specimens were taken from all but 1 of the workers, who had positive specific IgE to alfa-gal in 2010. These new samples were tested for IgE to the alfa-gal epitope and to mammalian meat. Results: The prevalence of positive sIgE to alfa-gal was 15% in the risk population and 4% in the control population. alfa-Gal sIgE positivity was associated with the number of tick bites per year and with seniority. Thirteen out of 21 patients sensitized to alfa-gal in 2010 showed positive specific IgE to alfa-gal in serum samples from 2015. Eleven had specific IgE to mammalian meat, but none reported symptoms of meat allergy. Conclusion: The prevalence of alfa-gal sIgE antibodies in this risk population was higher than in the control group and was associated with the number of tick bites per year and with seniority. None of the workers sensitized to mammalian meat developed meat allergy, possibly owing to the low levels of sIgE to alfa-gal


Objetivo: Estudiar la prevalencia de IgE específica a alfa-gal y los factores asociados en el grupo de riesgo de agentes forestales y retenes de incendios de La Rioja respecto a un grupo control. Métodos: Se incluyeron 169 trabajadores y 100 personas que referían no haber sufrido picaduras de garrapata. Cumplimentaron un cuestionario dirigido en el que se recogieron datos demográficos y número de picaduras de garrapata al año. Se realizó determinación de IgE específica a alfa-gal mediante la ténica InmunoCAP utilizando muestras serológicas extraídas en 2010. En 2015 se llevó a cabo nueva extracción serológica a todos los trabajadores sensibilizados a α-gal en muestra de 2010 excepto a uno. Se realizó nueva determinación de IgE específica a alfa-gal y a carne de mamíferos. Resultados: La prevalencia de IgE específica a alfa-gal en la población de riesgo fue del 15% vs. 4% en el grupo control. La positividad de la IgE específica a alfa-gal se asoció con el número de picaduras al año y con la antigüedad el puesto de trabajo. Trece de los pacientes sensibilizados en 2010 seguían sensibilizados en 2015. Once de ellos mostraban IgE específica frente a carnes sin manifestar síntomas de alergia. Conclusión: La prevalencia de IgE específica a alfa-gal en población de riesgo española fue superior a la del grupo control y se asoció al número de picaduras-año y a la antigüedad en el puesto de trabajo. Ninguno de los trabajadores sensibilizados a carnes, desarrolló alergia, probablemente por los niveles discretos de IgE específica a alfa-gal


Subject(s)
Humans , Hypersensitivity, Immediate/diagnosis , Hypersensitivity, Immediate/epidemiology , Immunoglobulin E/analysis , Epitopes/analysis , Epitopes/immunology , Tick Bites/diagnosis , Anaphylaxis/immunology , Tick Bites/immunology , Forestry , Surveys and Questionnaires , 28599
11.
J Investig Allergol Clin Immunol ; 24(5): 308-23, 2014.
Article in English | MEDLINE | ID: mdl-25345301

ABSTRACT

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity reactions. These reactions include various clinical entities with different mechanisms leading to the release of inflammatory mediators. Characterization of patients based on clinical manifestations and suspected underlying mechanisms is critical for implementation of adequate diagnostic procedures and patient management. Our objectives were to prepare a systematic review of available scientific evidence and to provide general guidelines for the diagnosis and management of patients with hypersensitivity reactions to NSAIDs. We also propose a practical algorithm for the diagnosis of specific types of hypersensitivity to NSAIDs and provide recommendations for the management of hypersensitive patients.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Drug Hypersensitivity/diagnosis , Practice Guidelines as Topic , Algorithms , Drug Hypersensitivity/therapy , Humans , Skin Tests
12.
J Investig Allergol Clin Immunol ; 24(4): 212-25; quiz 1p following 225, 2014.
Article in English | MEDLINE | ID: mdl-25219103

ABSTRACT

Strictly speaking, biological drugs are defined as drugs obtained using biotechnology that act on the immune system. They encompass monoclonal antibodies, fusion proteins, and cytokines. Although they are restricted to specific diseases, they have been increasingly used in recent years, with the consequent reporting of adverse reactions, many of which occur during the postmarketing phase. Because of the characteristics of adverse reactions, a new classification has been proposed. Hypersensitivity reactions are beta-type reactions and include infusion reactions and injection site reactions. In some cases, an immune mechanism mediated by IgE, IgG, or T cells is involved. Clinical symptoms vary widely, from skin reactions to anaphylaxis. Diagnostic studies are based on skin tests and in vitro tests (specific IgE, basophil activation test). Most are not standardized and are conducted in small groups of patients, thus making it impossible to obtain sensitivity and specificity values. With some biological drugs, desensitization protocols have proven successful. In this review, we discuss hypersensitivity reactions to biological drugs and the diagnostic tests used to assess these reactions.


Subject(s)
Antibodies, Monoclonal/adverse effects , Cytokines/adverse effects , Drug Hypersensitivity/etiology , Recombinant Fusion Proteins/adverse effects , Animals , Humans , Tumor Necrosis Factor-alpha/antagonists & inhibitors
15.
J. investig. allergol. clin. immunol ; 24(5): 308-323, ago. 2014. tab, ilus
Article in English | IBECS | ID: ibc-128318

ABSTRACT

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity reactions. These reactions include various clinical entities with different mechanisms leading to the release of inflammatory mediators. Characterization of patients based on clinical manifestations and suspected underlying mechanisms is critical for implementation of adequate diagnostic procedures and patient management. Our objectives were to prepare a systematic review of available scientific evidence and to provide general guidelines for the diagnosis and management of patients with hypersensitivity reactions to NSAIDs. We also propose a practical algorithm for the diagnosis of specific types of hypersensitivity to NSAIDs and provide recommendations for the management of hypersensitive patients (AU)


Los antiinflamatorios no esteroideos (AINE) es el grupo farmacológico que más frecuentemente ha sido relacionado con las reacciones de hipersensibilidad. Estos cuadros incluyen entidades clínicas muy variadas, producidas por diferentes mecanismos, tanto inmunológicos como no inmunológicos. La caracterización de los pacientes que presentan estas reacciones se fundamenta, en las manifestaciones clínicas y la sospecha del mecanismo subyacente que la ha producido, lo que conduce a la puesta en práctica del procedimiento diagnóstico adecuado y la posterior orientación del paciente. El objetivo de este trabajo es elaborar una revisión sistemática, con las pruebas científicas disponibles, facilitando las directrices generales de diagnóstico y en consecuencia la actitud a tomar en este tipo de pacientes. Se propone un algoritmo práctico de diagnóstico para cada tipo específico de hipersensibilidad a AINE, así como proporcionar las recomendaciones a seguir en el manejo de los pacientes sensibilizados (AU)


Subject(s)
Humans , Male , Female , Practice Guidelines as Topic , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Drug Hypersensitivity/diagnosis , Algorithms , Drug Hypersensitivity/therapy , Skin Tests/methods , Skin Tests/trends , Skin Tests
16.
J. investig. allergol. clin. immunol ; 24(4): 212-225, jul. 2014. tab
Article in English | IBECS | ID: ibc-126720

ABSTRACT

Strictly speaking, biological drugs are defined as drugs obtained using biotechnology that act on the immune system. They encompass monoclonal antibodies, fusion proteins, and cytokines. Although they are restricted to specific diseases, they have been increasingly used in recent years, with the consequent reporting of adverse reactions, many of which occur during the postmarketing phase. Because of the characteristics of adverse reactions, a new classification has been proposed. Hypersensitivity reactions are beta-type reactions and include infusion reactions and injection site reactions. In some cases, an immune mechanism mediated by IgE, IgG, or T cells is involved. Clinical symptoms vary widely, from skin reactions to anaphylaxis. Diagnostic studies are based on skin tests and in vitro tests (specific IgE, basophil activation test). Most are not standardized and are conducted in small groups of patients, thus making it impossible to obtain sensitivity and specificity values. With some biological drugs, desensitization protocols have proven successful. In this review, we discuss hypersensitivity reactions to biological drugs and the diagnostic tests used to assess these reactions (AU)


En sentido estricto se consideran fármacos biológicos aquellos fármacos obtenidos por biotecnología que actúan en el propio sistema inmune. Engloban básicamente anticuerpos monoclonales, proteínas de fusión y citocinas. Aunque su indicación está restringida a determinadas enfermedades, su uso ha ido en aumento en los últimos años y en consecuencia también la comunicación de reacciones adversas, muchas de ellas observadas post comercialización. Debido a sus características se ha propuesto una nueva clasificación para las reacciones adversas, en la que, las reacciones de hipersensibilidad corresponden a las reacciones de tipo be incluyen reacciones de infusión y reacciones localizadas en el punto de inyección del fármaco. En algunas de estas reacciones se ha demostrado la participación de un mecanismo de hipersensibilidad inmune, bien sea mediado por IgE, IgG o por células T. Los síntomas clínicos que presentan los pacientes son muy variados, desde síntomas cutáneos a anafilaxia. Los estudios diagnósticos se basan en pruebas cutáneas, y en pruebas in vitro (IgE específica, TAB). La mayoría de pruebas no están estandarizadas y están realizadas en pequeños grupos de pacientes, lo que no permite obtener valores de sensibilidad y especificidad. Con algunos de estos fármacos se han aplicado protocolos de desensibilización con buenos resultados. En este artículo se revisan las reacciones de hipersensibilidad inducidas por los fármacos biológicos así como las pruebas utilizadas para el diagnóstico (AU)


Subject(s)
Humans , Male , Female , Pharmaceutical Preparations/adverse effects , Biotechnology , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/therapy , Skin Tests , Antibodies, Monoclonal , Signs and Symptoms
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