Papers by Mariana Castells
Annals of Allergy, Asthma & Immunology, 2021
New England Journal of Medicine, 2021
Blood, 2020
Introduction: Systemic mastocytosis (SM) is a rare clonal mast cell (MC) neoplasm characterized b... more Introduction: Systemic mastocytosis (SM) is a rare clonal mast cell (MC) neoplasm characterized by MC accumulation and is primarily driven by the KIT D816V mutation. The D816V mutation is located in the activation loop of the KIT receptor tyrosine kinase resulting in constitutive activation of the receptor, causing aberrant MC proliferation and hyperactivation. MC mediator release can lead to severe clinical manifestations including skin, gastrointestinal, neurocognitive, skeletal, and systemic symptoms. Indolent SM is the most common subtype of SM; abnormal activation of mast cells leads to debilitating symptoms, poor quality of life, and has life-threatening consequences such as anaphylaxis. Although symptomatic treatments are used to control symptom severity (eg, cromolyn sodium, antihistamines, leukotriene inhibitors, omalizumab), there are no approved disease-modifying therapies to reduce MC burden and activation. Avapritinib is a potent, selective tyrosine kinase inhibitor tha...
The Journal of Allergy and Clinical Immunology: In Practice, 2020
test TB-Tuberculosis TEN-Toxic epidermal necrolysis TKI-Tyrosine kinase inhibitor UFH-Unfractiona... more test TB-Tuberculosis TEN-Toxic epidermal necrolysis TKI-Tyrosine kinase inhibitor UFH-Unfractionated heparin vWD-von Willebrand disease lengthened hospital stays, and increased risk for resistant organisms such as vancomycin-resistant Enterococcus, Clostridium difficile, and methicillin-resistant Staphylococcus aureus. 6,7 Despite the frequency of reported allergy, avoidance of penicillin is not necessary in the vast majority of individuals. Approximately 90% to 95% of patients with a reported penicillin allergy can tolerate a rechallenge after an appropriate allergy evaluation has been performed. 8,9 The discrepancy between reported and actual penicillin allergy may be explained by the waning of penicillin IgE antibodies over time or by the misclassification of an adverse reaction or infectious manifestation as a drug reaction. 10-12 Sensitization to penicillin has been reported to decrease every 10 years, and after 20 years fewer than 1% of patients with initial clinical symptoms compatible with an allergic reaction continue to maintain their sensitivity. Therefore, a formal allergy evaluation is recommended by both North American and European guidelines to optimize patient management. 13-15 Major symptoms of hypersensitivity. Hypersensitivity reactions to penicillin are classifiable as immediate or nonimmediate according to their clinical manifestation, time since the last drug administration, and the onset of symptoms. 16,17 Immediate reactions are predominantly IgE-mediated. They can occur within 6 hours after the last drug administration but typically occur within 1 hour of the first dose of a new treatment course. 17,18 Symptoms of an acute hypersensitivity reaction include urticaria, angioedema, conjunctivitis, respiratory symptoms (rhinitis, bronchospasm, cough, dyspnea), gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), and/or anaphylaxis. 16 Nonimmediate reactions occur more than 1 hour after the initial drug exposure, and they often develop days to weeks after medication initiation. Manifestations of nonimmediate reactions include maculopapular or morbilliform exanthems, particularly during treatment with amoxicillin or ampicillin. In addition, penicillins can elicit delayed urticaria/angioedema, exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), and more severe bullous exanthems such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Furthermore, hematologic alterations may occur with certain penicillins, such as methicillin and ampicillin, and can cause interstitial nephritis, pneumonitis, hepatitis, and/or vasculitis with or without signs of serum sickness including joint involvement. The combination of skin eruptions, visceral involvement, hematologic alteration, fever, and lymphadenopathy is termed drug-induced hypersensitivity syndrome or drug rash (or reaction) with eosinophilia and systemic symptoms (DRESS). The pathogenic mechanisms involved in nonimmediate reactions are heterogeneous. Allergic maculopapular exanthems are T-cellemediated diseases, in which drug-specific cytotoxic CD4 T cells migrate into the skin. These T cells then produce IL-5 and kill keratinocytes that present MHC class II molecules in a perforin-dependent manner. 19,20 Diagnosis. Based on the clinical history and presenting symptoms, there are distinct diagnostic approaches for an immediate reaction and for a nonimmediate reaction to penicillin. For patients with a history of TEN, SJS, DRESS, interstitial nephritis, or hemolytic anemia, reexposure through either drug challenge or desensitization is contraindicated, unless there are special circumstances.
Journal of Allergy and Clinical Immunology, Feb 1, 2018
Annals of Allergy, Asthma & Immunology, 2019
Anaphylaxis is considered idiopathic when there is no known trigger. The signs and symptoms of id... more Anaphylaxis is considered idiopathic when there is no known trigger. The signs and symptoms of idiopathic anaphylaxis (IA) are identical to those of anaphylaxis because of a known cause and can include cutaneous, circulatory, respiratory, gastrointestinal, and neurologic symptoms. Idiopathic anaphylaxis can be a frustrating disease for patients and health care providers. Episodes are unpredictable, and differential diagnosis is challenging. Current anaphylaxis guidelines have little specific guidance regarding differential diagnosis and long-term management of IA. Therefore, the objective of the Idiopathic Anaphylaxis Yardstick is to use published data and the authors' combined clinical experience to provide practical recommendations for the diagnosis and management of patients with IA.
Current Opinion in Allergy & Clinical Immunology, 2018
Purpose of review Recognize the presentation of anaphylaxis for prompt management and treatment a... more Purpose of review Recognize the presentation of anaphylaxis for prompt management and treatment and to provide tools for the diagnosis of the underlying cause(s) and set up a long-term treatment to prevent recurrence of anaphylaxis. Recent findings The recent description of phenotypes provides new insight and understanding into the mechanisms and causes of anaphylaxis through a better understanding of endotypes and biomarkers for broad clinical use. Summary Anaphylaxis is the most severe hypersensitivity reaction and can lead to death. Epinephrine is the first-line treatment of anaphylaxis and it is life-saving. Patients with first-line therapy-induced anaphylaxis are candidates for desensitization to increase their quality of life and life expectancy. Desensitization is a breakthrough novel treatment for patients with anaphylaxis in need of first-line therapy, including chemotherapy, mAbs, aspirin and others. Ultrarush with venom immunotherapy should be considered in patients who present with life-threatening anaphylaxis after Hymenoptera sting with evidence of IgEmediated mechanisms. Food desensitization is currently being expanded to provide increased safety to adults and children with food-induced anaphylaxis.
The Journal of Allergy and Clinical Immunology: In Practice, 2019
Journal of Allergy and Clinical Immunology, 2019
International Journal of Molecular Sciences, 2017
Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding... more Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross reactivity with environmental allergens. Avoidance of the offending allergenic drug may impact disease management, quality of life, and life expectancy. Precision medicine provides new tools for the understanding and management of hypersensitivity reactions (HSRs), as well as a personalized treatment approach for IgE (Immunoglobuline E) and non-IgE mediated HSRs with drug desensitization (DS). DS induces a temporary hyporesponsive state by incremental escalation of sub-optimal doses of the offending drug. In vitro models have shown evidence that IgE desensitization is an antigen-specific process which blocks calcium flux, impacts antigen/IgE/FcεRI complex internalization and prevents the acute and late phase reactions as well as mast cell mediator release. Through a "bench to bedside" approach, in vitro desensitization models help elucidate the molecular pathways involved in DS, providing new insights to improved desensitization protocols for all patients. The aim of this review is to summarize up to date information on the drug HSRs, the IgE mediated mechanisms of desensitization, and their clinical applications.
The Journal of allergy and clinical immunology, 2018
Clinics (Sao Paulo, Brazil), May 17, 2018
To assess the incidence of intra-operative immediate hypersensitivity reactions and anaphylaxis. ... more To assess the incidence of intra-operative immediate hypersensitivity reactions and anaphylaxis. A cross-sectional observational study was conducted at the Department of Anesthesiology, University of São Paulo School of Medicine, Hospital das Clínicas, São Paulo, Brazil, from January to December 2010. We developed a specific questionnaire to be completed by anesthesiologists. This tool included questions about hypersensitivity reactions during anesthesia and provided treatments. We included patients with clinical signs compatible with immediate hypersensitivity reactions. Hhypersensitivity reactions were categorized according to severity (grades I-V). American Society of Anesthesiologists physical status classification (ASA 1-6) was analyzed and associated with the severity of hypersensitivity reactions. In 2010, 21,464 surgeries were performed under general anesthesia. Anesthesiologists answered questionnaires on 5,414 procedures (25.2%). Sixty cases of intra-operative hypersensiti...
Allergy, Jan 6, 2017
Drug hypersensitivity reactions (DHRs) represent growing health problem worldwide, affecting more... more Drug hypersensitivity reactions (DHRs) represent growing health problem worldwide, affecting more than 7% of the general population and represent an important public health problem. However, knowledge in DHRs morbidity and mortality epidemiological data is still not optimal and international comparable standards remain poorly accessed. Institutional databases worldwide increasingly use the WHO International Classification of Diseases (ICD) system to classify diagnoses, health services utilization and death data. The misclassification of disorders in the ICD system contributes to a lack of ascertainment and recognition of their importance for healthcare planning and resource allocation. It also hampers clinical practice and prevention actions. To further inform the allergy community and to ensure that the revision process is transparent as advised in the WHO ICD-11 revision agenda, we report the advances and use of the pioneering "Drug hypersensitivity" subsection of ICD-11...
Journal of Allergy and Clinical Immunology, 2017
The journal of allergy and clinical immunology. In practice
Rapid drug desensitization (RDD) has become a cornerstone in the management of immediate drug hyp... more Rapid drug desensitization (RDD) has become a cornerstone in the management of immediate drug hypersensitivity reactions (DHRs) to chemotherapeutic agents. Because of the inherent risk of anaphylaxis during RDD, biomarkers to predict patients at risk of developing such severe reactions are needed. The basophil activation test (BAT) has been used in DHRs as a diagnostic tool. We evaluated basophil CD63 and CD203c expression (BAT) as a biomarker to assess the safety and effectiveness of RDD in platinum compounds-allergic patients. Patients allergic to platinum compounds (n = 15) undergoing RDD were assessed through clinical history, skin testing, serum tryptase levels, and BAT. BAT was performed immediately before RDD, assessing CD203c and CD63 expression on basophils. BAT was also performed in 6 patients tolerant to platinum compounds and in 6 healthy volunteers. BAT was positive to CD203c or CD63 in 11 out of 15 patients allergic to platinum compounds (73%), with increased expressio...
The World Allergy Organization journal, 2017
World Allergy Organization Journal, 2016
One of the major concerns in the practice of allergy is related to the safety of procedures for t... more One of the major concerns in the practice of allergy is related to the safety of procedures for the diagnosis and treatment of allergic disease. Management (diagnosis and treatment) of hypersensitivity disorders involves often intentional exposure to potentially allergenic substances (during skin testing), deliberate induction in the office of allergic symptoms to offending compounds (provocation tests) or intentional application of potentially dangerous substances (allergy vaccine) to sensitized patients. These situations may be associated with a significant risk of unwanted, excessive or even dangerous reactions, which in many instances cannot be completely avoided. However, adverse reactions can be minimized or even avoided if a physician is fully aware of potential risk and is prepared to appropriately handle the situation. Information on the risk of diagnostic and therapeutic procedures in allergic diseases has been accumulated in the medical literature for decades; however, except for allergen specific immunotherapy, it has never been presented in a systematic fashion. Up to now no single document addressed the risk of the most commonly used medical procedures in the allergy office nor attempted to present general requirements necessary to assure the safety of these procedures. Following review of available literature a group of allergy experts within the World Allergy Organization (WAO), representing various continents and areas of allergy expertise, presents this report on risk associated with diagnostic and therapeutic procedures in allergology and proposes a consensus on safety requirements for performing procedures in allergy offices. Optimal safety measures including appropriate location, type and required time of supervision, availability of safety equipment, access to specialized emergency services, etc. for various procedures have been recommended. This document should be useful for allergists with already established practices and experience as well as to other specialists taking care of patients with allergies.
The Journal of allergy and clinical immunology, Jan 15, 2015
Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized ... more Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 ...
Clinical & Experimental Allergy, 2015
We congratulate Powell et al. for the development of the ‘BSACI guideline for the management of c... more We congratulate Powell et al. for the development of the ‘BSACI guideline for the management of chronic urticaria and angioedema’, which is enlightening, and recognize the importance of NSAID as a trigger of angioedema. Recently, an international panel of HAE experts proposed a classification for ‘angioedema without wheals’. However, this classification did not include angioedema induced or exacerbated by NSAIDs, and the pathophysiological mechanisms of general angioedema were not completely addressed. Although NSAID-induced or NSAID-exacerbated angioedema usually is associated with urticaria, it can also present as the sole manifestation of NSAID intolerance. In our experience, NSAIDs are a major cause of drug-induced anaphylaxis and the major cause of angioedema without urticaria. We reviewed the records of 290 patients who sought medical assistance due to adverse drug reactions at the Adverse Drug Reaction Outpatient Facility of the ‘Hospital das Cl inicas’, University of S~ao Paulo School of Medicine, during 2013 and 2014. Patients who seek our hospital for chronic urticaria or aspirin-exacerbated respiratory disease were not included in the study. Forty-two percent of the patients (n = 122) had immediate hypersensitivity reactions (HSRs) to NSAIDs, with an average age of 40.8 years old, and 77.1% were female. Isolated cutaneous angioedema was observed in 27.9% (Fig. 1), and a ‘familiar form’ of HSRs to NSAIDs was observed in 11.5% of the cases. Patients presenting with simultaneous respiratory and cutaneous reactions, also called blended reactions, were counted as anaphylaxis cases. Two major pathophysiological mechanisms of angioedema have been described: one induced by the activation of mast cells and/or basophils, resulting in release of histamine and other mediators (histaminergic angioedema), and other due to an excess of bradykinin (bradykinin-mediated or non-histaminergic angioedema), as seen in hereditary angioedema, acquired angioedema with C1-INH deficiency (lymphoproliferative and autoimmune disorders) and in angioedema induced by angiotensin-converting enzyme inhibitors. HAE results from genetic mutations leading to C1-INH protein or function deficiency, or from the recently described mutations of factor XII. Based on ours’ and others’ observations, we propose a classification of Angioedema based on endotypes (Fig. 2). Classifications based on endotypes provide insight into the aetiology and/or pathophysiological mechanism of diseases. The paradigm of personalized medicine is based on the principle that external stimuli (environment) induce diverse clinical manifestations (phenotypes), mediated by distinct pathophysiological processes (endotypes) in different individuals (genotypes)’. This angioedema classification based on endotypes (Fig. 2) includes the main causes of angioedema and is in agreement with the new information on the pathophysiology of the disease. Furthermore, it is consistent with angioedema consensus, and the ‘hypersensitivity reactions to non-steroidal anti-inflammatory drugs’ consensus. The high rate of patients with HSRs to NSAIDs with isolated angioedema emphasizes the importance of including this type of angioedema in the classification. The understanding of angioedema subtypes and endotypes will allow the developing of new treatments for more effective disease management. Classification of angioedema by endotypes may identify patient groups that will benefit most from new and existing treatments
Journal of Allergy and Clinical Immunology, 2015
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Papers by Mariana Castells