RESUMEN
The application of advances in personalized medicine requires the support of in vitro diagnostic techniques aimed at the accurate, fast, sensitive, and precise determination of selected biomarkers. Herein, a novel optical centrifugal microfluidic device is developed for clinical analysis and point-of-care diagnostics. Based on compact disc technology, the integrated biophotonic system enables multiple immunoassays in miniaturized mode. The disposable microfluidic discs are made in cyclic olefin copolymer (COP), containing arrays of immobilized probes. In the developed approach, up to six patient samples can each be tested simultaneously. A portable instrument (<2 kg) controls the assay and the high-sensitive reproducible optical detection in transmission mode. Also, the instrument incorporates specific functionalities for personalized telemedicine. The device (analytical method, disc platform, reader, and software) has been validated to diagnose IgE-mediated drug allergies, such as amoxicillin and penicillin G. The total and specific IgE to ß-lactam antibiotics were determined in human serum from patients (25 µL). The excellent analytical performances (detection limit 0.24 ng/mL, standard deviation 7-20 %) demonstrated that the developed system could have the potential for a broader impact beyond the allergy field, as it applies to other IVD tests.
Asunto(s)
Biomarcadores , Inmunoglobulina E , Humanos , Biomarcadores/sangre , Inmunoglobulina E/sangre , Inmunoensayo/métodos , Dispositivos Laboratorio en un Chip , Límite de Detección , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/sangre , Técnicas Analíticas Microfluídicas/instrumentación , Amoxicilina/sangreRESUMEN
PURPOSE OF REVIEW: The purpose of this narrative review was to summarize data and official recommendations purporting to paired tryptase determination in patients experiencing drug-induced anaphylaxis, published between January 1, 2023 and June 1, 2024. RECENT FINDINGS: Three main lines of evidence obtained through paired acute and baseline tryptase determination were identified: diagnostic criterion for hypersensitivity reactions involving systemic mast cell activation; differential diagnostic criterion for hypersensitivity reactions involving other mechanisms of immediate reactions; and added value of acute and baseline tryptase levels for personalized management following drug-induced anaphylaxis: cause, risk of recurrence, underlying mast cell conditions including hereditary α-tryptasemia, familial clusters. SUMMARY: The implementation of existing guidelines which consensually recommend paired tryptase measurement is a persistent unmet need hampering optimal diagnosis of drug-induced anaphylaxis and patient management. Another major unmet need is the lack of standardized recommendations for hereditary α-tryptasemia testing and counselling. Progress in this field is seen at a rapid pace, requiring significant efforts of continued medical education for practicing clinicians and laboratory specialists worldwide.
Asunto(s)
Anafilaxia , Hipersensibilidad a las Drogas , Triptasas , Humanos , Anafilaxia/diagnóstico , Anafilaxia/sangre , Anafilaxia/inmunología , Triptasas/sangre , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/inmunología , Hipersensibilidad a las Drogas/sangre , Mastocitos/inmunología , Guías de Práctica Clínica como AsuntoRESUMEN
Background: Perioperative hypersensitivity reaction (HR) is an IgE-FcϵRI-mediated hypersensitivity reaction with degranulation and activation of mast cells and basophils. Several studies have focused on assessing the degranulation and activation of mast cells and basophils to diagnose and predict the prognosis of drug induced HR. However, it is challenging to isolate sufficiently pure mast cells and basophils from human sources to investigate. Effective biomarkers to assess mast cells and basophils activation in vivo could potentially have high diagnostic and prognostic values. In the present study, we investigated EVs pelleted from serum in patients with succinylated gelatin induced HR. Methods: Extracellular vesicles (EVs) were isolated using a total exosome isolation kit and ultracentrifugation, characterized by Western blot, transmission electron microscopy, and nanoparticle tracking analysis. Basophils were isolated from fresh peripheral blood by negative selection using Basophil Isolation Kit II. Human mast cell line was stimulated with IL4. The expression levels of proteins related to the hypersensitive response were evaluated by Western blotting and flow Cytometer. Histamine and tryptase levels were tested using a commercial ELISA kit, and gene expression of inflammatory mediators was evaluated by qRT-PCR. The receiver operating characteristic (ROC) curve was used to evaluate the specificity and sensitivity of biomarker in predicting HR. Results: The concentration of EVs and protein expression level of CD63, FcϵRI, CD203c and tryptase were significantly (p< 0.05) increased in HR samples. The expression level of mast cell/basophil specific CD203c were significantly increased in EVs derived from serum and basophils of HR patients, and the CD203c+-EVs production in mast cells is dramatically increased in the presence of IL4, which positively correlated with histamine, tryptase and inflammatory mediators. Moreover, the ROC curve of EVs concentration and CD203c expression indicated that CD203c+-EVs had a strong diagnostic ability for HR. Conclusion: Serum CD203c+-EVs serves as a novel diagnostic and prognostic biomarker for HR.
Asunto(s)
Hipersensibilidad a las Drogas/diagnóstico , Vesículas Extracelulares/metabolismo , Gelatina/efectos adversos , Hidrolasas Diéster Fosfóricas/sangre , Sustitutos del Plasma/efectos adversos , Pirofosfatasas/sangre , Succinatos/efectos adversos , Adulto , Anciano , Basófilos/efectos de los fármacos , Basófilos/inmunología , Basófilos/metabolismo , Biomarcadores/sangre , Estudios de Casos y Controles , Degranulación de la Célula/efectos de los fármacos , Línea Celular , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Femenino , Histamina/metabolismo , Liberación de Histamina/efectos de los fármacos , Humanos , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/metabolismo , Persona de Mediana Edad , Periodo Perioperatorio , Valor Predictivo de las Pruebas , Pronóstico , Triptasas/metabolismoRESUMEN
Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.
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Anafilaxia/sangre , Atracurio/efectos adversos , Hipersensibilidad a las Drogas/sangre , Morfina/efectos adversos , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/metabolismo , Rocuronio/efectos adversos , Vancomicina/efectos adversos , Animales , Atracurio/sangre , Degranulación de la Célula/efectos de los fármacos , Hipersensibilidad a las Drogas/inmunología , Humanos , Inmunoglobulina E/metabolismo , Mastocitos/inmunología , Morfina/sangre , Rocuronio/sangre , Vancomicina/sangreRESUMEN
The diagnosis of a drug hypersensitivity reaction (DHR) is complex. The first step after taking the clinical history is to look for a sensitization to confirm or exclude the diagnosis and to identify the culprit drug. Skin tests are the primary means of detecting sensitization in DHR, but are associated with a risk for a severe reaction and may be contraindicated. In vitro tests offer the potential to support or confirm a diagnosis of DHR and influence medical decision making. For immediate-type DHR, a few validated assays for measurement of specific IgE (sIgE) are commercially available to a limited number of drugs. In addition, several home-made sIgE radioimmunoassays have been used in other studies. The sensitivity of the sIgE assay is drug-dependant and generally low (0-85%) for betalactams and reported heterogeneous for other drugs ranging from 26% for chlorhexidine and 44% for suxamethonium to 92% for chlorhexidine. However, as all these studies included patients, in whom DHR was confirmed only by skin tests and not by provocation, the results have to be interpreted carefully and may be unreliable. Determination of mediators during an acute phase of a reaction may indirectly support the diagnosis of a DHR by demonstrating mast cell and basophil mediator release. Negative in vitro tests do not exclude a DHR or imputability of a drug, but a positive result may support causality and eliminate the necessity for a drug provocation test. Unfortunately, evidence is limited with a lack of well-controlled studies in larger numbers of well-phenotyped patients, which results in susceptibility for bias and a need for future multicenter studies.
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Basófilos/efectos de los fármacos , Degranulación de la Célula/efectos de los fármacos , Hipersensibilidad a las Drogas/diagnóstico , Liberación de Histamina/efectos de los fármacos , Hipersensibilidad Inmediata/diagnóstico , Inmunoglobulina E/sangre , Pruebas Inmunológicas , Mastocitos/efectos de los fármacos , Animales , Especificidad de Anticuerpos , Basófilos/inmunología , Basófilos/metabolismo , Biomarcadores/sangre , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Humanos , Hipersensibilidad Inmediata/sangre , Hipersensibilidad Inmediata/inmunología , Mastocitos/inmunología , Mastocitos/metabolismo , Valor Predictivo de las Pruebas , Factores de RiesgoRESUMEN
Immediate drug hypersensitivity reactions (IDHRs) constitute a significant health issue with serious consequences of diagnostic error. The primary diagnostics to document IDHRs usually consists of quantification of drug-specific IgE (sIgE) antibodies and skin tests. Unfortunately, the positive predictive value (PPV) and negative predictive value (NPV) of these tests are not absolutely, which leaves room for new tests. Over the last two decades, the basophil activation test (BAT), in which ex vivo activation of individual basophils is quantified by flow cytometry, has emerged as a reliable complementary diagnostic to document IDHRs, to explore allergenic recognition, to study cross-reactivity and to monitor therapy. However, the BAT is technically challenging requiring specialized personnel and equipment, fresh samples and the technique is lost as a diagnostic in patients showing a non-responder status of their cells. By consequence, the BAT has still not entered mainstream application. In contrast, mast cell activation tests (MATs) use serum samples that can be frozen, stored, and shipped to a recognized reference centre experienced in mast cell (MC) lines and/or cultures and capable of offering batch testing with necessary quality controls. This review does not only highlight the use of the BAT and MAT as diagnostics in IDHRs, but also outlines the potential of both techniques in further exploring and unveiling the mechanisms that govern drug-induced basophil and MC activation and degranulation.
Asunto(s)
Prueba de Desgranulación de los Basófilos , Basófilos/inmunología , Degranulación de la Célula , Hipersensibilidad a las Drogas/diagnóstico , Citometría de Flujo , Mastocitos/inmunología , Basófilos/efectos de los fármacos , Basófilos/metabolismo , Biomarcadores/sangre , Degranulación de la Célula/efectos de los fármacos , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Humanos , Inmunoglobulina E/sangre , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Proteínas del Tejido Nervioso/sangre , Fenotipo , Valor Predictivo de las Pruebas , Receptores Acoplados a Proteínas G/sangre , Receptores de Neuropéptido/sangreRESUMEN
In patients with drug hypersensitivity reactions, confirmation of causality frequently facilitates decision on a continuation or withdrawal of a given treatment. Unfortunately, identification of the culprit drug often proves difficult. In vivo methods possess well-known disadvantages like low sensitivity of skin tests or the risk of relapse during drug provocation tests. Therefore, laboratory assays are of great interest as they may improve causal diagnosis without putting patients at risk. In this article, the mechanistic principles and methodological issues of the enzyme-linked immunospot (ELISpot) assay were recapped the context of drug hypersensitivity reactions. A review of ELISpot application in causal diagnosis of drug hypersensitivity was based on literature search. The main findings are: (i) ELISpot assay has a good performance in the detection of drug-specific response. (ii) ELISpot results seem to be not substantially impacted by the type of drug or phenotype of the reaction. (iii) Testing within 30 days since the episode of drug hypersensitivity reaction shows a better performance than in later recovery phase. (iv) Data from pediatric population are too scarce to draw any conclusions. (v) Differences in laboratory protocols and in criteria used in the assessment of ELISpot plates along with the issue of the technical feasibility and reproducibility may limit the use of this assay in the routine diagnostic of drug hypersensitivity reactions.
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Hipersensibilidad a las Drogas/diagnóstico , Ensayo de Immunospot Ligado a Enzimas , Biomarcadores/sangre , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Humanos , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Factores de TiempoAsunto(s)
Anafilaxia/inducido químicamente , Antineoplásicos Inmunológicos/efectos adversos , Cetuximab/efectos adversos , Disacáridos/inmunología , Hipersensibilidad a las Drogas/etiología , Inmunoglobulina E/sangre , Sustitutos del Plasma/efectos adversos , Poligelina/efectos adversos , Adulto , Anafilaxia/sangre , Anafilaxia/diagnóstico , Anafilaxia/inmunología , Biomarcadores/sangre , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/inmunología , Epítopos , Humanos , Masculino , Factores de RiesgoRESUMEN
BACKGROUND: Obesity is a chronic low-grade inflammation state associated with several diseases. OBJECTIVE: To investigate a potential link between drug allergy and obesity, exploring whether the association depends on the type (immediate vs nonimmediate) or the severity of the reaction. METHODS: Anthropometric measurements, bioimpedance, and biochemical analysis, including serum adipokines, were performed in 90 consecutive adult patients studied for suspected drug allergy. Logistic regression models were developed to identify predictors of drug allergy. RESULTS: A total of 84 patients completed the diagnostic workup (78.6% women; mean age 39.58 ± 13.3 years). Drug allergy was confirmed in 39 patients and excluded in 45 (controls). Regarding body mass index, 42.2% had normal weight and 55.3% were overweight/obese. A total of 58% of women and 41% of men fulfilled the criteria for central obesity. Patients with drug allergy exhibited considerably higher body mass index, waist and hip circumferences, waist-hip ratio, fat mass, body fat percentage (BFP), trunk fat mass, leptin levels, and leptin-adiponectin ratio than controls. Similar results were obtained in the subgroup with immediate reactions, compared with the nonimmediate or unknown reactions. The higher the BFP and the number of reactions, the greater the odds of drug allergy (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01-1.14 and OR, 2.82; 95% CI, 1.31-6.10, respectively). An immediate reaction was also a predictor of drug allergy (OR, 3.81; 95% CI, 1.30-11.14, P = .02), compared with nonimmediate or unknown reactions. In patients with drug allergy, BFP was a predictor of having an immediate reaction (OR, 1.12; 95% CI, 1.02-1.24, P = .02). CONCLUSION: Our study illustrates, for the first time, evidence of a link between obesity and drug allergy, particularly immediate reactions. The BFP emerged as a potential predictor of drug allergy.
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Adipoquinas/sangre , Hipersensibilidad a las Drogas/sangre , Obesidad/sangre , Sobrepeso/sangre , Tejido Adiposo , Adiposidad , Adulto , Antropometría , Biomarcadores/sangre , Índice de Masa Corporal , Femenino , Humanos , Leptina/sangre , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Relación Cintura-CaderaRESUMEN
Neutralizing antibodies (inhibitors) against factor VIII/IX (FVIII/FIX) poses a serious and challenging complication in the hemophilia treatment. Allergic reaction is more common in hemophilia B and always companion with FIX inhibitors, but it is rare in hemophilia A (HA). So far only few cases demonstrated FVIII-specific allergic response in hemophilia A. Coexistence of allergic reactions with inhibitors was contraindicated for immune tolerance induction (ITI) regimen which is the only proven therapy to eliminate inhibitor. We report a rare case of a 11-year-old boy with moderate HA who developed high titer inhibitor and severe allergic reaction to both plasma derived and recombinant FVIII concentrates. Inhibitor was eliminated with the use of prednisone. Further desensitization protocol by administering rFVIII of increasing does from 0.01 IU/kg to 40 IU/kg with a pre-determined time schedule allowed patient tolerance to the normal dose and infusion time to FVIII.
Asunto(s)
Desensibilización Inmunológica , Hipersensibilidad a las Drogas/terapia , Factor VIII/efectos adversos , Anticuerpos Neutralizantes/sangre , Niño , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Hemofilia A/sangre , Hemofilia A/tratamiento farmacológico , Hemofilia A/inmunología , Humanos , Inmunoglobulina E/sangre , Masculino , Proteínas Recombinantes/efectos adversosRESUMEN
BACKGROUND: Many patients report questionable drug hypersensitivity reactions (DHR) to betalactam antibiotics. A workup is required for objectivation. Direct drug provocation tests (DPTs) omitting a prior allergy workup are increasingly recommended as the primary diagnostic approach. However, apart from the risk of severe side effects, DPTs often are a scarce resource in overloaded healthcare-systems. We investigated how many cases can be solved by drug-specific history, drug-specific IgE, and skin tests obviating the need for DPT. METHODS: We conducted a chart review in a retrospective cohort of 932 patients in an allergy outpatient centre from 2016 to 2017. Patients had been submitted to drug-specific history and specific IgE-, skin prick-, intradermal- and patch-tests with early and late readings with a series of penicillins and cephalosporins but DPTs were no option. RESULTS: Overall, positive in vitro and/or skin tests were found in 96/932 (10.3%) patients. Drug-specific IgE was detected in 40/932 (4.3%) patients, 61/787 (7.8%) patients had positive skin tests. In vitro tests to Pencillin V showed the highest rate of positivity 24/479 (5.0%) and early readings of ampicillin the highest amongst the skin tests (3/49, 6.1%). Immediate skin tests were more often positive than delayed ones (75:45). The combination of all parameters including drug-specific history solved 346/932 (37.1%) cases while 586/932 (62.9%) remained unresolved. Self-reported DHR could be less often confirmed in females and young children (p < 0.05). CONCLUSIONS: Testing with betalactams applying simple, cheap, and safe skin and blood tests can solve a third of DHR-cases on a high throughput scale.
Asunto(s)
Antibacterianos/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , beta-Lactamas/efectos adversos , Adolescente , Adulto , Antibacterianos/inmunología , Niño , Preescolar , Reacciones Cruzadas , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Femenino , Humanos , Inmunoglobulina E/sangre , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Pruebas Cutáneas , Triptasas/sangre , Adulto Joven , beta-Lactamas/inmunologíaRESUMEN
BACKGROUND: Chronic rhinosinusitis may be associated with nasal polyposis. Recurrence of disease is often observed and may be due to an intolerance of acetylsalicylic acid. Sex hormones are known to modulate allergic reactions and inflammation. Whether they may be involved in the development and progression of nasal polyposis has not been investigated yet. AIM: Examine the relationship between levels of sex hormones and nasal polyposis. METHODS: Hormonal levels (estradiol, testosterone and progesterone) in patients with nasal polyposis (n = 26) with or without acetylsalicylic acid-intolerance were determined and compared to hormonal levels in patients with septal deviation (n = 35). Cone-beam computed tomography scans were analysed by using scores as defined by Lund and Mackay and by Kennedy. RESULTS: Our results show a 5 times greater odds (p = 0.01) for developing nasal polyposis in the presence of lowered estradiol plasma levels than in the presence of normal / elevated levels. When analyzing females and males separately, a 6 times greater odds for females to develop nasal polyposis in the presence of lowered estradiol plasma levels was calculated (p = 0.02). Thus, females are more likely to develop nasal polyposis when they have lowered estradiol levels than males. In addition, female patients showed an increased risk for developing ASA intolerance (p = 0.01). CONCLUSION: Variation of sex hormones may be involved in nasal polyposis. Further studies including more patients to validate the presented results are required. SIGNIFICANCE: Retrospective clinical investigation suggesting a correlation between varying sex hormones and nasal polyposis.
Asunto(s)
Aspirina/efectos adversos , Hipersensibilidad a las Drogas/epidemiología , Estradiol/sangre , Pólipos Nasales/inmunología , Progesterona/sangre , Testosterona/sangre , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Tomografía Computarizada de Haz Cónico , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Estradiol/inmunología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mucosa Nasal/diagnóstico por imagen , Pólipos Nasales/sangre , Pólipos Nasales/diagnóstico , Progesterona/inmunología , Recurrencia , Estudios Retrospectivos , Rinitis/sangre , Rinitis/inducido químicamente , Rinitis/epidemiología , Rinitis/inmunología , Sinusitis/sangre , Sinusitis/inducido químicamente , Sinusitis/epidemiología , Sinusitis/inmunología , Testosterona/inmunología , Adulto JovenRESUMEN
OBJECTIVE: This study aimed to investigate the correlation of L-asparaginase (L-asp) activity, anti-L-asp antibody, asparagine and glutamine levels with the risks of adverse events (AEs), especially anaphylaxis, in pediatric acute lymphoblastic leukemia (ALL) patients who underwent polyethylene glycol-conjugated L-asp (PEG-asp)-contained treatment. METHODS: Plasma samples were collected from 91 pediatric ALL patients who underwent PEG-asp-contained treatment on the 7th day after drug administration. Plasma L-asp activity, anti-L-asp antibody level, asparagine level and glutamine level were detected. Meanwhile, AEs related to PEG-asp administration were recorded. RESULTS: AEs occurred in 13 (14.3%) patients, among which 7 (7.7%) patients had anaphylaxis, while another 6 patients had non-anaphylaxis AEs (including 4 (4.4%) patients who had acute pancreatitis, 1 (1.1%) patient who had abdominal pain and diarrhea, as well as 1 (1.1%) patient who had nausea and vomiting). L-asp activity was decreased, while asparagine and glutamine levels were increased in patients with AEs compared to patients without AEs, and ROC curves showed that they were correlated with higher AEs risk. Notably, further analyses revealed that L-asp activity, anti-L-asp antibody, asparagine and glutamine levels were highly correlated with anaphylaxis risk, but they were not associated with the risk of non-anaphylactic AEs. CONCLUSION: The measurement of L-asp activity, anti-L-asp antibody level, asparagine level and glutamine level might assist the prevention of anaphylaxis-related AEs in pediatric ALL patients who underwent PEG-asp-contained treatment.
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Anafilaxia/sangre , Anafilaxia/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/sangre , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Adolescente , Factores de Edad , Anafilaxia/diagnóstico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/antagonistas & inhibidores , Asparagina/sangre , Biomarcadores/sangre , Niño , Preescolar , Hipersensibilidad a las Drogas/diagnóstico , Femenino , Glutamina/sangre , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pronóstico , Curva ROCAsunto(s)
Anticuerpos Antivirales/sangre , Antígenos Virales/inmunología , Betacoronavirus/inmunología , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Determinación de Punto Final/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Pandemias , Neumonía Viral/diagnóstico , Glicoproteína de la Espiga del Coronavirus/inmunología , Anticuerpos/sangre , Anticuerpos Antivirales/inmunología , COVID-19 , Prueba de COVID-19 , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/diagnóstico , Determinación de Punto Final/normas , Ensayo de Inmunoadsorción Enzimática/normas , Reacciones Falso Negativas , Reacciones Falso Positivas , Humanos , Distribución Normal , Pruebas en el Punto de Atención , Reproducibilidad de los Resultados , SARS-CoV-2 , Sensibilidad y EspecificidadAsunto(s)
Atorvastatina/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Troponina I/sangre , Troponina T/sangre , Anciano , Diagnóstico Diferencial , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/etiología , Reacciones Falso Positivas , Femenino , Humanos , Infarto del Miocardio/sangre , Infarto del Miocardio/diagnósticoAsunto(s)
Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/diagnóstico , Inmunoglobulina E/sangre , Rocuronio/efectos adversos , Rocuronio/sangre , Basófilos/efectos de los fármacos , Humanos , Fármacos Neuromusculares no Despolarizantes/efectos adversos , Fármacos Neuromusculares no Despolarizantes/sangre , Reproducibilidad de los Resultados , Estudios Retrospectivos , Pruebas Cutáneas/métodos , Pruebas Cutáneas/estadística & datos numéricosRESUMEN
BACKGROUND: Immediate drug hypersensitivity reactions are an increasing public health issue and a frequent cause of life-threatening anaphylaxis. Conventional confirmatory testing include skin tests and, for a few drugs, quantification of drug-specific immunoglobulin E (IgE) antibodies. However, none of these tests are absolutely predictive for the clinical outcome, and can yield false-negative and false-positive results. We performed a proof-of-concept study to assess whether a mast cell activation test could improve diagnosis of IgE-mediated chlorhexidine hypersensitivity, a common cause of perioperative anaphylaxis. METHODS: Human mast cells were generated from CD34+ progenitor cells and sensitised with patients' sera to become IgE+ human mast cells (dMCIgE+), and then incubated with chlorhexidine to assess degranulation. We compared the diagnostic performance of this mast cell activation test with serum from patients with and without positive skin test and basophil activation test to chlorhexidine. RESULTS: In dMC sensitised with sera from patients with a positive skin test and basophil activation test to chlorhexidine showed drug-specific and concentration-dependent degranulation upon stimulation with chlorhexidine, determined by surface upregulation of the degranulation marker CD63. In contrast, dMC sensitised with sera from patients with a negative skin test and basophil activation test to chlorhexidine were unresponsive in the mast cell activation test. CONCLUSIONS: Our study suggests that the mast cell activation test can be used to diagnose IgE/FcεRI-dependent immediate drug hypersensitivity reactions. It also shows potential to assess the clinical relevance of drug-specific IgE antibodies in their ability to elicit mast cell degranulation, and therefore discriminate between allergy and sensitisation. Extended studies are required to verify whether this technique can be used in other causes of perioperative anaphylaxis.
Asunto(s)
Clorhexidina/efectos adversos , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad Inmediata/sangre , Hipersensibilidad Inmediata/diagnóstico , Mastocitos/inmunología , Adulto , Anciano , Clorhexidina/inmunología , Hipersensibilidad a las Drogas/inmunología , Femenino , Humanos , Hipersensibilidad Inmediata/inmunología , Masculino , Mastocitos/metabolismo , Persona de Mediana EdadRESUMEN
The PD-1-targeting IgG4 antibody pembrolizumab has significant anti-tumor activity in a proportion of stage IV melanoma patients. A subset of patients develop anti-drug antibodies (ADA) which can form immune complexes (IC) with pembrolizumab. Although IC can induce powerful, Fc-mediated, immune-regulatory effects, their functional impact during pembrolizumab treatment is unclear. The functional effects of IC generated in vitro using pembrolizumab and patient-derived ADA was, therefore, investigated. Screening identified a patient whose trough serum samples from three treatment cycles contained both ADA with neutralizing activity and low levels of pembrolizumab. This patient responded well to therapy over 2 years and had ongoing, infusion-related, hypersensitivity reactions despite the later absence of detectable ADA. The components of IC were mimicked by forming a complex of pembrolizumab by absorption onto a solid phase with or without subsequent exposure to the ADA+ patient sera. Complexes comprised of pembrolizumab alone significantly inhibited TLR4 (LPS)-driven IL-10 production by PBMC and stimulated the generation of reactive oxygen species by granulocytes. In contrast, soluble and solid-phase F(ab´)2 fragments of pembrolizumab had no effect demonstrating the requirement for cross-linked Fc regions. IC containing pembrolizumab and ADA could additionally induce complement and NK activation. The results of this study demonstrate that, when oligomerized, the Fc region of pembrolizumab alone can provide immuno-regulatory signals. Furthermore, IC containing both pembrolizumab and patient-generated ADA can induce additional signals. These Fc-mediated signals may modulate both hypersensitivity reactions and anti-tumor responses associated with pembrolizumab therapy.
Asunto(s)
Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Neutralizantes/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Neutralizantes/sangre , Complejo Antígeno-Anticuerpo/sangre , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Femenino , Humanos , Leucocitos Mononucleares , Masculino , Melanoma/sangre , Melanoma/inmunología , Melanoma/secundario , Persona de Mediana Edad , Cultivo Primario de Células , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Anti-rituximab antibodies (ARA) are associated not only with adverse events, such as infusion reactions (IR) and serum sickness, but also with rituximab efficacy. However, the clinical relevance of ARA in children with steroid-dependent nephrotic syndrome (SDNS) remains unknown. METHODS: We retrospectively reviewed clinical outcomes of 13 children with complicated SDNS receiving repeated single-dose rituximab treatments at 375 mg/m2 to assess whether ARA formation could impact toxicity and efficacy of additional rituximab. Pre-rituximab 22 samples collected from patients who developed IR during the second or subsequent rituximab doses were measured by electrochemiluminescence analysis. RESULTS: ARA were identified in 5 of 13 patients (9 of 22 samples). Median time to recovery of CD19+ B cells to > 1% of total lymphocytes and median relapse-free time after rituximab treatment were significantly shorter in the 9 ARA-positive samples than the 13 ARA-negative samples (41 vs. 100 days, p < 0.01 and 119 vs. 308 days, p < 0.05, respectively). Kaplan-Meier analysis showed that time to CD19+ B cell recovery after rituximab was significantly shorter in ARA-positive samples than in ARA-negative samples (p < 0.005). Severe IR developed in two ARA-positive patients and serum sickness in one ARA-positive patient. CONCLUSIONS: The incidence of ARA formation was high in the pre-rituximab samples of patients with complicated SDNS who developed IR during the second or subsequent rituximab doses, suggesting that ARA formation might have an unfavorable impact on the toxicity and efficacy of additional rituximab doses in these patients.
Asunto(s)
Anticuerpos/sangre , Hipersensibilidad a las Drogas/epidemiología , Glucocorticoides/uso terapéutico , Síndrome Nefrótico/tratamiento farmacológico , Rituximab/inmunología , Anticuerpos/inmunología , Antígenos CD19 , Linfocitos B/inmunología , Linfocitos B/metabolismo , Niño , Preescolar , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/inmunología , Resistencia a Medicamentos/inmunología , Femenino , Humanos , Incidencia , Lactante , Infusiones Intravenosas , Masculino , Síndrome Nefrótico/sangre , Síndrome Nefrótico/inmunología , Estudios Retrospectivos , Rituximab/administración & dosificación , Rituximab/efectos adversos , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Basophil activation test (BAT) and immunoassays are the most widely used in vitro tests to diagnose IgE-mediated allergic reactions to penicillin. However, studies to determine if one test is interdependent from another are limited. OBJECTIVE: The present study aimed to measure the agreement between BAT and immunoassay in diagnosis of penicillin allergy. METHOD: BAT was performed using penicillin G (Pen G), penicillin V (Pen V), penicilloyl-polylysine (PPL), minor determinant mix (MDM), amoxicillin (Amx) and ampicillin (Amp) in 25 patients. Immunoassay of total IgE (tIgE) and specific IgE (sIgE) antibodies to Pen G, Pen V, Amx and Amp were quantified. Skin prick test (SPT) using PPL-MDM, Amx, Amp and Clavulanic acid were also performed. RESULTS: Minimal agreement was observed between BAT and immunoassay (k=0.25). Of two BAT-positive patients, one patient is positive to Amx (59.27%, SI=59) and Amp (82.32%, SI=82) but sIgE-negative to all drug tested. This patient is also SPT-positive to both drugs. Another patient is BAT-positive to Pen G (10.18%, SI=40), Pen V (25.07%, SI=100) and Amp (19.52%, SI=79). In sIgE immunoassay, four patients were sIgE-positive to at least one of the drugs tested. The sIgE level of three patients was between low and moderate and they were BAT-negative. One BAT-positive patient had a high level of sIgE antibodies (3.50-17.5kU/L) along with relatively high specific to total IgE ratio ≥0.002 (0.004-0.007). CONCLUSIONS: The agreement between BAT and immunoassay is minimal. Performing both tests provides little increase in the sensitivity of allergy diagnosis work-up for immediate reactions to penicillin.