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Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers. [ABSTRACT FROM AUTHOR]

Background: The neuropeptide U (NMU) has been proven to elicit the release of mediators from mast cells (MCs) through its receptor NMUR1 in allergic inflammatory models. However, little is known about the correlations between NMU and MCs in human allergic rhinitis (AR). Objective: The objective of this study is to investigate the expressions of NMU and NMUR1 in the tryptase + MCs and the peripheral blood leukocytes (PBLs) in human nasal mucosa with AR. Methods: Specimens of nasal mucosa from patients with AR (n = 10) and control patients without AR (n = 8) were collected and soaked in frozen tissue liquid solution (OCT) in tum. Cryostat sections were prepared for immunofluorescence staining. Tryptase was used as a marker to detect mast cells and other tryptase + immune cells. The expression of NMU and NMUR1 was respectively determined by double staining using a confocal microscope. Results: Neither NMU nor NMUR1 were detected in the tryptase + mast cells in the human nasal mucosa. To our surprise, both NMU and NMUR1 were co-expressed with tryptase in the PBLs within peripheral blood vessels in AR and controls. Conclusion: Our findings showed that NMU could not influence human nasal tryptase + mast cells directly through NMUR1 in AR. The co-expression of both NMU and NMUR1 with tryptase in the PBLs provided new insight into the potential roles of NMU and tryptase in the circulation PBLs, and the infiltrated PBLs may promote nasal allergic inflammation by producing tryptase and NMU. [ABSTRACT FROM AUTHOR]

Background: A diagnosis of hereditary angioedema (HAE) with normal C1 esterase inhibitor (HAE-nl-C1-INH) can be challenging and pharmacologic management is not well defined. Objective: The objective was to discuss practical considerations in the clinical management of HAE-nl-C1-INH by using illustrative clinical vignettes to highlight and/or address select challenges. Methods: This was a narrative review. Results: Symptoms of HAE-nl-C1-INH overlap with HAE types I and II; the heterogeneity of presentation and symptom burden are diagnostic challenges. A patient history, with particular attention to whether urticaria or other symptoms of mast cell mediator release are present, is important because such symptoms would strongly suggest a mast cell–mediated pathway. A family history of angioedema is informative but a lack thereof does not rule out diagnosis. Expected laboratory findings would be normal for C4, C1-INH level and function, and Complement 1q; a genetic mutational analysis may be helpful, but current assays do not include all known mutations; most cases are categorized as unknown. To align with guideline-directed treatment approaches, the following stepwise approach is suggested for suspected HAE-nl-C1-INH: (1) thoroughly investigate the possibility of response to histaminergic and/or mast cell–targeting treatments; (2) if patients with normal C4, C1-INH level and/or function fail adequate trials with histamine/mast cell-directed therapy or have a mutation that suggests bradykinin pathway involvement, follow HAE type I and II treatment guidelines. Response to medications approved for HAE types I/ II provides compelling support for a high clinical suspicion of HAE-nl-C1-INH. De-labeling an HAE-nl-C1-INH diagnosis may be appropriate if the initial diagnosis was made without adequate evaluation or if new information and/or testing indicates that the patient does not actually have HAE. Conclusion: Key unmet needs in HAE-nl-C1-INH include lack of confirmatory biomarker(s) for diagnosis and lack of prospective controlled clinical studies of pharmacologic products in this patient population. [ABSTRACT FROM AUTHOR]

Systemic mastocytosis is characterized by expansion of clonal mast cells in various tissues. Several biomarkers with diagnostic and therapeutic potential have recently been characterized in mastocytosis, such as the serum marker tryptase and the immune checkpoint molecule PD-L1. We aimed to investigate whether serum levels of other checkpoint molecules are altered in systemic mastocytosis and whether these proteins are expressed in mastocytosis infiltrates in the bone marrow. Levels of different checkpoint molecules were analyzed in serum of patients with different categories of systemic mastocytosis and healthy controls and correlated to disease severity. Bone marrow biopsies from patients with systemic mastocytosis were stained to confirm expression. Serum levels of TIM-3 and galectin-9 were increased in systemic mastocytosis, particularly in advanced subtypes, compared with healthy controls. TIM-3 and galectin-9 levels were also found to correlate with other biomarkers of systemic mastocytosis, such as serum tryptase and KIT D816V variant allele frequency in the peripheral blood. Moreover, we observed expression of TIM-3 and galectin-9 in mastocytosis infiltrates in bone marrow. Together, our results demonstrate for the first time that serum levels of TIM-3 and galectin-9 are increased in advanced systemic mastocytosis. Moreover, TIM-3 and galectin-9 are expressed in bone marrow infiltrates in mastocytosis. These findings provide a rationale for exploring TIM-3 and galectin-9 as diagnostic markers and eventually therapeutic targets in systemic mastocytosis, particularly in advanced forms. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) has been shown to play a central role in the initiation and persistence of allergic responses. We evaluated whether tezepelumab, a human monoclonal anti-TSLP antibody, improved the efficacy of subcutaneous allergen immunotherapy (SCIT) and promoted the development of tolerance in patients with allergic rhinitis. We conducted a double-blind parallel design trial in patients with cat allergy. A total of 121 patients were randomized to receive either intravenous tezepelumab plus subcutaneous cat SCIT, cat SCIT alone, tezepelumab alone, or placebo for 52 weeks, followed by 52 weeks of observation. Nasal allergen challenge (NAC), skin testing, and blood and nasal samples were obtained throughout the study. At week 52, the NAC-induced total nasal symptom scores (TNSS) (calculated as area under the curve [AUC 0-1h ] and as peak score [Peak 0-1h ] during the first hour after NAC) were significantly reduced in patients receiving tezepelumab/SCIT compared to SCIT alone. At week 104, one year after stopping treatment, the primary end point TNSS AUC 0-1h was not significantly different in the tezepelumab/SCIT group compared to SCIT alone, while TNSS Peak 0-1h was significantly lower in those receiving combination treatment versus SCIT. Transcriptomic analysis of nasal epithelial samples demonstrated that treatment with the combination of SCIT/tezepelumab, but neither monotherapy, caused persistent downregulation of a gene network related to type 2 inflammation that was associated with improvement in NAC responses. Inhibition of TSLP augments the efficacy of SCIT during therapy and may promote tolerance after a 1-year course of treatment. (ClinicalTrials.gov NCT02237196). [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: The causes of anaphylaxis in a general hospital may differ from those occurring in a community setting. Underlying diseases in admitted patients and vague presenting symptoms can make the diagnosis of anaphylaxis difficult. Serum tryptase measurements may provide valuable evidence for diagnosing anaphylaxis in admitted patients. Materials and Methods: This study was designed as a retrospective study of 53 patients with an anaphylaxis episode at a Korean tertiary care general hospital. Tryptase levels were measured at baseline and different time points from the onset of anaphylaxis. Results: Drugs (42 cases; 79.2%) and foods (10 cases; 18.9%) were the most common causes of anaphylaxis. In drug-induced anaphylaxis, antibiotics (24.5%), anticancer medications, which included monoclonal antibodies (22.6%), and contrast agents (11.3%) were the most frequent causes. The muscle relaxant eperisone (5.7%), neuromuscular blocking agent rocuronium (5.7%), and its antagonist sugammadex (3.8%) were other frequent triggering agents. Wheat-dependent exercise-induced anaphylaxis was the most common entity in food-induced anaphylaxis. Tryptase concentrations were higher in patients with higher grades of anaphylaxis, as well as in accidental anaphylaxis, compared to meticulously provoked anaphylaxis. Overall diagnostic sensitivity was higher for tryptase algorithm criteria (=[1.2×baseline+2] µg/L: 71.4%) than for abnormal tryptase level criteria (=11.4 µg/L: 52.8%). Conclusion: The triggers of anaphylaxis in a Korean tertiary care hospital were diverse, including beta-lactam antibiotics, anticancer medications, contrast medias, eperisone, nonsteroidal anti-inflammatory drugs, rocuronium, sugammadex, and wheat. Tryptase measurements provided valuable evidence for diagnosis, and the sensitivity of algorithm criteria was superior to that of the abnormal value criteria. [ABSTRACT FROM AUTHOR]

Mast cells are implicated in the pathogenesis of asthma, but the underlying mechanisms are not fully elucidated. Under asthmatic conditions, mast cells can relocalize to the epithelial layer and may thereby affect the functional properties of the airway epithelial cells. Activated mast cells release large quantities of proteases from their secretory granules, including chymase and tryptase. Here we investigated whether these proteases may affect airway epithelial cells. Primary small airway epithelial cells were treated with tryptase or chymase, and the effects on epithelial cell viability, proliferation, migration, cytokine output, and transcriptome were evaluated. Airway epithelial cells were relatively refractory to tryptase. In contrast, chymase had extensive effects on multiple features of the epithelial cells, with a particular emphasis on processes related to extracellular matrix (ECM) remodeling. These included suppressed expression of ECM-related genes such as matrix metalloproteinases, which was confirmed at the protein level. Further, chymase suppressed the expression of the fibronectin gene and also caused degradation of fibronectin released by the epithelial cells. Chymase was also shown to suppress the migratory capacity of the airway epithelial cells and to degrade the cell-cell contact protein E-cadherin on the epithelial cell surface. Our findings suggest that chymase may affect the regulation of ECM remodeling events mediated by airway epithelial cells, with implications for the impact of mast cells in inflammatory lung diseases such as asthma. [ABSTRACT FROM AUTHOR]

Introduction: Placental pathology and pregnancy complications are associated with unfavorable regulation of the maternal immune system. Although much research has been performed towards the role of immune cells like macrophages and T cells in this context, little is known about the presence and function of mast cells (MC). MC can be sub classified in tryptase-positive (MCT) and tryptase- and chymase-positive (MCTC). This study investigates the presence of MC in the decidua of pregnancies complicated by fetal growth restriction (FGR) and stillbirth (SB).Methods: Placental tissue from FGR (n = 250), SB (n = 64) and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to the Amsterdam Placental Workshop Group criteria. Tissue sections were stained for tryptase and chymase. Decidual MC were counted manually, and the results were expressed as number of cells/mm2 decidual tissue.Results: A significant lower median number of MCTC was found in the decidua of FGR (0.40 per mm2; p < 0.001) and SB (0.51 per mm2; p < 0.05) compared to healthy controls (1.04 per mm2). No difference in MCT number (1.19 per mm2, 1.88 per mm2 and 1.37 per mm2 respectively) was seen between the groups. There was no difference in number of MCT and MCTC between placental pathological lesions.Discussion: Our findings suggest a shift in decidual MC balance towards MCT in pregnancy complications. No difference in numbers of MC subtypes was found to be related to histopathologic lesions. [ABSTRACT FROM AUTHOR]

Copyright of Revue Francaise d'Allergologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Parmi les cellules immunitaires participant à la réaction allergique, les mastocytes et les éosinophiles occupent une place majeure. Cependant, ces cellules jouent aussi un rôle de premier plan dans l'immunité innée. Ici, nous proposons une courte revue des connaissances actuelles sur l'ontogénie, la physiologie et la physiopathologie de ces deux types cellulaires. Mast cells and eosinophils are prominent players of allergic reactions. However, these cells also make significant contributions to the innate immune defense. Here, we provide a concise update on the ontogeny, physiology and pathophysiology of mast cells and eosinophils. [ABSTRACT FROM AUTHOR]

Low molybdate (MoO 4) exposure via drinking water in mature rats infected with Nippostrongylus brasiliensis raised liver and plasma copper (Cu) concentrations. The possibility that anthelmintic effects were attributable to conversion of MoO 4 to tetrathiomolybdate (MoS 4) in a non-ruminant species was investigated by giving three groups of 18 immature rats drinking water containing 70 mg Mo l−1 as MoO 4 (group A), 5 mg Mo l−1 as MoS 4 (group B) or no supplement (group C), while receiving a commercial cubed diet. After 41 days, 12 rats from each group were inoculated subcutaneously with 2,000 L3-stage N. brasiliensis larvae. Subgroups were killed 7, 8 or 9 days post infection (dpi), when adult worms are normally expelled, and enzyme markers for the inflammatory response to infection were measured in plasma or liver. Male rats given MoS 4 prior to infection grew more slowly than those given MoO 4. Eight dpi, females given MoS 4 had lost more bodyweight than those in group C, while those given MoO 4 had gained weight. Mean worm counts at 7 dpi were 160, 65 and 250 ± 30.6 (SE), respectively, in groups C, A and B, and differed significantly from each other (P <0.05) but only rats given MoO 4 remained infected 9 dpi (mean worm count 52 ± 16.4): Faecal egg counts followed a broadly similar pattern. Both Mo sources pre-empted increases in liver and duodenal superoxide dismutase activity, induced by infection 7 and 9 dpi, respectively, in group C and enlarged the femur: neither source prevented hypertrophy of the small intestine and a rise in serum mast cell protease concentration caused by infection. Since data for plasma Cu concentration and caeruloplasmin oxidase activity, reported separately, indicated MoO 4 was thiolated in vivo , differences between Mo sources may be attributable to differences in the degree of thiolation, extent of thiomolybdate exposure and rates of thiomolybdate degradation at critical times in host or parasite development. Adding a little molybdenum (Mo) as tetrathiomolybdate (MoS 4 ; 5 mg Mo l−1) or more as molybdate (MoO 4 ; 70 mg Mo l−1) to drinking water of immature rats, infected with Nippostrongylus brasiliensis , decreased liver superoxide dismutase activity (LSOD) 7 days after infection: both sources increased femur length (FL) but had opposite effects on worm count (WC). Cellular immunity may have been compromised by MoS 4 but stimulated by MoO 4 that had been partially thiolated by sulphide generated in the large intestine. [Display omitted] [ABSTRACT FROM AUTHOR]

Les mastocytes peuvent être activés dans de nombreuses conditions physiologiques et pathologiques. Les troubles d'activation mastocytaire sont classés comme primaires – associés à une population monoclonale mastocytaire –, ou secondaires (avec un nombre normal de mastocytes dits hyperréactifs), ou encore idiopathiques. Le syndrome d'activation mastocytaire (MCAS, Mast Cell Activation Syndrome) est caractérisé par une libération inappropriée et excessive par les mastocytes de médiateurs engendrant divers symptômes pouvant concerner plusieurs apparats, voire provoquer des réactions à type d'anaphylaxie à répétition. Nous avons voulu apporter des réponses claires aux questions suivantes pour aider la prise en charge globale des patients atteints de MACS : quelles sont la définition et la classification actuelles du MCAS ? Quels sont les critères diagnostiques, cliniques et biologiques à utiliser ? Quelles sont les stratégies thérapeutiques à mettre en œuvre ? Le but de ce travail est de présenter les connaissances actuelles concernant les MCAS, pour apporter une aide au processus diagnostique et thérapeutique de ces pathologies. Mast cells may be activated secondary to different physiological and pathological conditions. Mast cell activation disorders are classified as primary – associated with a monoclonal mast cell population – or secondary (with a normal number of so-called hyperreactive mast cells), or even idiopathic. Mast Cell Activation Syndrome (MCAS) is characterized by an inappropriate and excessive release of mast cells mediators, leading to clinical symptoms that may affect several body systems, or even cause repeated anaphylaxis. We wanted to provide clear answers to the following questions to help the overall management of patients presenting with MACS: what is the current definition and classification of MCAS? Which diagnostic, clinical and laboratory criteria should be used? What are the most comment therapeutic strategies? The aim of the present work is to present current knowledge on MCAS, to aid clinicians in the diagnostic and therapeutic process of these conditions. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to evaluate the preliminary diagnosis, demographic characteristics, and outcomes of patients whose serum total tryptase levels were measured while in a tertiary pediatric hospital and to ascertain the role of serum tryptase levels in the etiology, diagnosis, severity, and course of systemic anaphylaxis. Methods: Patients ages between 1 month and 17 years who were followed up in the pediatric emergency department or as inpatients and with a diagnosis of immediate-type reactions between September 1, 2019, and August 31, 2021, were included in the study. Patient data were obtained retrospectively by examination of medical records and patient observation forms. Results: It was determined that serum tryptase levels were measured in a total of 310 patients during the study period. One hundred and fifty-five patients who met the defined diagnostic criteria were named as the anaphylaxis group and their data were detailed. The serum tryptase elevation was detected in 15.5% of the patients among the samples that met the anaphylaxis diagnostic criteria. No relationship was found between the serum total tryptase levels, the triggering factor, and the severity of anaphylaxis. Discussion: Anaphylaxis is a complex syndrome that involves different phenotypes that develop with various triggers in which different immunologic pathways, cell types, and mediators play a role. Serial measurements, including the basal value measured at least 24 hours after the symptoms disappear, are useful to confirm the diagnosis and guide the diagnostic tests during the follow-up, especially allergy evaluation. [ABSTRACT FROM AUTHOR]

Copyright of Revue Francaise d'Allergologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Mast cells (MCs) have a profound impact on allergic asthma. Under such conditions, MCs undergo degranulation, resulting in the release of exceptionally large amounts of MC-restricted proteases. However, the role of these proteases in asthma is only partially understood. We sought to test our hypothesis that MC proteases can influence the functionality of human lung fibroblasts (HLFs). Primary HLFs were treated with MC chymase or tryptase, followed by assessment of parameters related to fibroblast function. HLFs underwent major morphologic changes in response to chymase, showing signs of cellular contraction, but were refractory to tryptase. However, no effects of chymase on HLF viability or proliferation were seen. Chymase, but not tryptase, had a major impact on the output of extracellular matrix–associated compounds from the HLFs, including degradation of fibronectin and collagen-1, and activation of pro–matrix metalloprotease 2. Further, chymase induced the release of various chemotactic factors from HLFs. In line with this, conditioned medium from chymase-treated HLFs showed chemotactic activity on neutrophils. Transcriptome analysis revealed that chymase induced a proinflammatory gene transcription profile in HLFs, whereas tryptase had minimal effects. Chymase, but not tryptase, has a major impact on the phenotype of primary airway fibroblasts by modifying their output of extracellular matrix components and by inducing a proinflammatory phenotype. [ABSTRACT FROM AUTHOR]

The last 2 years yielded a proliferation of high-quality asthma research. These include new understandings of the incidence and natural history of asthma, findings on the effects of exposure to air pollution, allergens, and intake of acetaminophen, soy isoflavones, and polyunsaturated fatty acids, and exposure to microbial products. The past 2 years have benefited from great strides in determining potential mechanisms of asthma development and asthma exacerbations. These novel understandings led to identification and development of exciting new avenues for potential therapeutic intervention. Finally, there has been significant progress made in the development of tools to facilitate the diagnosis of asthma and measurement of airway physiology and in precision diagnostic approaches. Asthma guidelines were updated and new insights into the pharmacologic management of patients, including biologics, were reported. We review the most notable advances in the natural history of asthma, risk factors for the development of asthma, underlying mechanisms, diagnostic approaches, and treatments. Although greater knowledge of the mechanisms underlying responses and nonresponses to novel therapeutics and across asthma phenotypes would be beneficial, the progress over just the past 2 years has been immense and impactful. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Mast cells (MCs) are known to be involved in several physiological and pathological processes in humans and animals. Recently, their potential role in tumor development and angiogenesis has been investigated, arising interesting results to be potentially applied in clinics. Mast cells' granules contain a huge quantity of protease enzymes that, through different mechanisms, induce the formation of new microvessels, feeding tumor burden. Among them, tryptase and chymase are the most abundant enzymes: tryptase is well known for its multiple activities, on the contrary, the role of chymase in pancreatic cancer angiogenesis has not been investigated yet. PATIENTS AND METHODS: Our research aims to correlate to each other and to angiogenesis four different tissue parameters (MCs density positive to chymase, MCs area positive to chymase, microvascular density and endothelial area) together with the main clinical-pathological characteristics in 52 patients surgically resected for pancreatiCDuctal adenocarcinoma, employing immunohistochemistry and image analysis system. RESULTS: All reported tissue parameters match to confirm the correlation between chymase enzyme and angiogenesis in pancreatic cancer. CONCLUSIONS: This evidence could become a starting point for a new potential therapeutic route exploiting chymase inhibitors as a novel anti-angiogenetic strategy in pancreatic cancer patients. [ABSTRACT FROM AUTHOR]

Background: There is no trial to make a diagnostic tool of allergic rhinitis (AR) utilizing biomarkers from nasal fluid. Base on previous studies, we selected following five biomarkers in nasal fluids that represent the characteristics of allergic reactions: tryptase, eosinophil cationic protein (ECP), interleukin 5 (IL-5), Clara cell protein 16 (CC16) and CC16-to-albumin ratio. Objective: This study aimed to identify biomarkers in nasal discharge that may be used in biosensors to diagnose AR as an additional diagnostic tool. Methods: Patients showed rhinorrhea and tested positive on allergic skin and specific immunoglobulin E (IgE) tests were included in the AR group. The non-AR group included individuals no dominant nasal symptoms and tested negative on allergy tests. Nasal lavage fluid samples were collected from all participants. Biomarkers in the samples were quantified using enzyme-linked immunosorbent assay. Results: Forty-five patients with AR and 28 non-AR subjects were enrolled in this study. Comparing the concentrations of biomarkers, the concentrations of tryptase and IL-5 were significantly higher in the AR group than in the NAR group. And CC16 level and CC16-to-albumin ratio were significantly lower in the AR group. In the combination of tryptase or CC16-to-albumin ratio, the sensitivity was 90.7% and the specificity was 64.3% (p = 0.013). Conclusion: The combination of "tryptase or CC16-to-albumin" could be used as a screening tool for AR. Although this diagnostic method could not replace conventional diagnostic tools, we could consider the method we proposed as an additional screening tool for patients who could not undergo allergy tests. [ABSTRACT FROM AUTHOR]

Mastocytosis is a risk factor for Hymenoptera venom anaphylaxis (HVA). Current guidelines recommend measuring tryptase in patients with HVA and that those with mastocytosis pursue lifelong venom immunotherapy (VIT). Available data on HVA and mastocytosis largely derive from European single-center studies, and the prevalence of HVA with and without mastocytosis in the United States is unknown. We sought to determine the prevalence of HVA and mastocytosis in the United States using an insurance claims database and evaluate the impact of mastocytosis on VIT in patients with HVA in a US cohort. The IBM Watson Database, consisting of insurance claims from approximately 27 million US patients in 2018, was queried to identify patients with HVA and/or mastocytosis. Furthermore, a retrospective study of 161 patients undergoing VIT between 2015 and 2018 at the University of Michigan was conducted. In the IBM Watson Database, the prevalence of HVA was 167 per 100,000 (0.167%) and the prevalence of mastocytosis 10 per 100,000 (0.010%) overall and 97 per 100,000 (0.097%) among those with HVA. Mastocytosis showed a 9.7-fold increase among patients with HVA versus the general population. In the U-M cohort, 2.6% of patients with VIT had mastocytosis. Tryptase level did not correlate with venom reaction severity but was higher in patients with systemic VIT reactions. We observed a lower US HVA prevalence than previously reported. Mastocytosis was more common in US patients with HVA, though at lower rates than previously reported. In patients with VIT there was no correlation between tryptase level and reaction severity. [ABSTRACT FROM AUTHOR]

Les examens biologiques d'allergie contribuent de façon importante au diagnostic et au suivi des maladies allergiques. L'augmentation de la prévalence de ces maladies dans la population française durant les dernières décennies et le recours de plus en plus fréquent au diagnostic biologique nécessite l'optimisation de l'utilisation de cet outil. Son utilisation rationnelle selon les données actualisées de la science et une démarche privilégiant le rapport coût/bénéfice sont à même de garantir l'efficience diagnostique. Consciente de cet enjeu, la Société française d'allergologie (SFA) a mis en place un groupe de travail multidisciplinaire pour l'actualisation des recommandations de biologie de l'allergie, les précédentes recommandations élaborées en 2005 par la Haute autorité de santé (HAS) étant devenues en partie obsolètes en raison de l'évolution des techniques et concepts. La méthodologie utilisée est celle des recommandations pour la pratique clinique (RPC) élaborée par la HAS, même si le texte n'a pas été labellisé par celle institution. Le groupe de travail a rédigé 73 recommandations gradées et un préambule comportant 6 questions d'ordre général. Bien que non exhaustives, ces 79 questions répondent aux préoccupations les plus courantes des prescripteurs qu'ils soient allergologues ou non pour la prise en charge des patients allergiques ou ayant une suspicion d'allergie, tout en tenant compte du contexte réglementaire français. Ce texte court résume ces 79 questions sans revenir sur le rationnel ni la discussion. Allergy laboratory tests make an important contribution to the diagnosis and monitoring of allergic diseases. The increase in the prevalence of these diseases in the French population in recent decades and the increasingly frequent use of biological diagnostics requires the optimization of the use of this tool. Its rational use according to updated scientific data and an approach favoring the cost/benefit ratio can guarantee diagnostic efficiency. Aware of this issue, the French Society of Allergology (SFA) has set up a multidisciplinary task force to update allergy biology recommendations, the previous recommendations drawn up in 2005 by the High Authority for Health (HAS) having become partly obsolete due to the evolution of techniques and concepts. The methodology used is that of the recommendations for clinical practice (RPC) developed by the HAS, even if the text has not been labeled by that institution. The working group drafted 73 graded recommendations and a preamble with 6 general questions. Although not exhaustive, these 79 questions answer the most common concerns of prescribers whether they are allergists or not for the management of patients with allergies or with suspected allergies, while taking into account the French regulatory context. This short text sums up these 79 questions without going back to the rational or the discussion. [ABSTRACT FROM AUTHOR]

Les examens biologiques d'allergie contribuent de façon importante au diagnostic et au suivi des maladies allergiques. L'augmentation de la prévalence de ces maladies dans la population française durant les dernières décennies et le recours de plus en plus fréquent au diagnostic biologique nécessite l'optimisation de l'utilisation de cet outil. Son utilisation rationnelle selon les données actualisées de la science et une démarche privilégiant le rapport coût/bénéfice sont à même de garantir l'efficience diagnostique. Consciente de cet enjeu, la Société française d'allergologie (SFA) a mis en place un groupe de travail multidisciplinaire pour l'actualisation des recommandations de biologie de l'allergie, les précédentes recommandations élaborées en 2005 par la Haute Autorité de santé (HAS) étant devenues en partie obsolètes en raison de l'évolution des techniques et concepts. La méthodologie utilisée est celle des recommandations pour la pratique clinique (RPC) élaborée par la HAS, même si le texte n'a pas été labellisé par celle institution. Le groupe de travail a rédigé 73 recommandations gradées et un préambule comportant 6 questions d'ordre général. Bien que non exhaustives, ces 79 questions répondent aux préoccupations les plus courantes des prescripteurs qu'ils soient allergologues ou non pour la prise en charge des patients allergiques ou ayant une suspicion d'allergie, tout en tenant compte du contexte réglementaire français. Allergy laboratory tests make an important contribution to the diagnosis and monitoring of allergic diseases. The increase in the prevalence of these diseases in the French population in recent decades and the increasingly frequent use of biological diagnostics requires the optimisation of the use of this tool. Its rational use according to updated scientific data and an approach favoring the cost/benefit ratio can guarantee diagnostic efficiency. Aware of this issue, the French society of allergology (SFA) has set up a multidisciplinary task force to update allergy biology recommendations, the previous recommendations drawn up in 2005 by the High authority for health (HAS) having become partly obsolete due to the evolution of techniques and concepts. The methodology used is that of the recommendations for clinical practice (RPC) developed by the HAS, even if the text has not been labelled by that institution. The working group drafted 73 graded recommendations and a preamble with 6 general questions. Although not exhaustive, these 79 questions answer the most common concerns of prescribers whether they are allergists or not for the management of patients with allergies or with suspected allergies, while taking into account the French regulatory context. [ABSTRACT FROM AUTHOR]

Contrairement aux allergies respiratoires, alimentaires et aux venins d'hyménoptères qui concernent des allergènes protéiques, la prise en charge des allergies aux médicaments nécessite rarement le recours aux examens biologiques pour obtenir la preuve d'un mécanisme allergique IgE-dépendant. Un nombre très restreint de dosages d'IgE spécifiques de médicaments est disponible car la grande majorité des médicaments sont des haptènes. L'utilisation rationnelle des outils biologiques disponibles selon les données actualisées de la science est à même de garantir l'efficience diagnostique. Le mésusage de la biologie de l'allergie et/ou leur interprétation erronée risque d'aboutir à des attitudes thérapeutiques inadaptées voire dangereuses. Consciente de cet enjeu, la Société française d'allergologie (SFA) a mis en place un groupe de travail multidisciplinaire pour l'actualisation des recommandations de biologie de l'allergie, les précédentes recommandations élaborées en 2005 par la Haute autorité de santé (HAS) étant devenues en partie obsolètes en raison de l'évolution des techniques et concepts. La méthodologie utilisée est celle des recommandations pour la pratique clinique (RPC) élaborée par la HAS, même si le texte n'a pas été labellisé par celle institution. Le groupe de travail a rédigé 11 recommandations gradées sur l'allergie aux médicaments. Bien que non exhaustives, ces 11 questions répondent aux préoccupations les plus courantes des prescripteurs qu'ils soient allergologues ou non pour la prise en charge des patients ayant une suspicion d'allergie aux médicaments, tout en tenant compte du contexte réglementaire français. Unlike respiratory allergies, food allergies and hymenopteran venoms which involve protein allergens, the management of drug allergies rarely requires the use of laboratory tests to obtain evidence of an IgE-dependent allergic mechanism. A very small number of drug specific IgE assays are available because drugs are mostly haptens. The rational use of the biological tools available according to updated scientific data can guarantee diagnostic efficiency. The misuse of the biology of allergy and/or their misinterpretation may lead to inappropriate or even dangerous therapeutic attitudes. Aware of this issue, the French Society of Allergology (SFA) has set up a multidisciplinary task force to update allergy biology recommendations, the previous recommendations drawn up in 2005 by the High Authority for Health (HAS) having become partly obsolete due to the evolution of techniques and concepts. The methodology used is that of the recommendations for clinical practice (RPC) developed by the HAS, even if the text has not been labeled by that institution. The working group drafted 11 graded recommendations for the management of drug allergy. Although not exhaustive, these 11 questions respond to the most common concerns of prescribers whether or not they are allergists for the management of patients with suspected drug allergy, while taking into account the French regulatory context. [ABSTRACT FROM AUTHOR]

Mastocytosis encompasses a heterogeneous group of disorders characterized by accumulation of clonal mast cells (MCs) in the skin and/or internal organs. Patients typically present with a broad variety of recurrent mediator-related clinical symptoms, including severe anaphylaxis. However, not all patients with mastocytosis experience anaphylactic reactions. We sought to identify disease-specific biomarkers in plasma that could be used to predict patients with mastocytosis with increased risk of anaphylaxis. Nineteen patients (≥18 years) and 2 control groups (11 subjects with allergic asthma and 13 healthy volunteers without history of atopy) were recruited. In total, 248 plasma proteins were analyzed by Proximity Extension Assay using Olink Proseek Multiplex panels. We identified 4 novel proteins, in addition to tryptase, E-selectin, adrenomedullin, T-cell immunoglobulin, and mucin domain 1, and CUB domain–containing protein 1/CD138 to be significantly increased in patients with mastocytosis compared with both patients with asthma and healthy controls. Furthermore, we investigated whether we could discriminate between patients with mastocytosis with or without anaphylaxis. In addition to tryptase, we identified 3 novel proteins, that is, allergin-1, pregnancy-associated plasma protein-A, and galectin-3, with significantly different levels in patients with mastocytosis with anaphylaxis compared with those without anaphylaxis. Newly identified proteomic biomarkers may be used to predict patients with mastocytosis with increased risk of anaphylaxis. [ABSTRACT FROM AUTHOR]

While eosinophilic esophagitis (EOE) is defined by histologic presence of eosinophils, a few studies have established the presence of mast cells in EOE and even shown their correlation with symptom persistence despite resolution of eosinophils. Expression of aberrant mast cell markers CD25 and CD2 have not been studied in EOE. This study quantifies the number of hotspot cells per high power field expressing CKIT/CD117, tryptase, CD25, CD2 and CD3 by immunohistochemical stains in endoscopic esophageal biopsies of the following three cohorts: (1) established and histologically confirmed EOE, (2) suspected EOE with biopsies negative for eosinophils, and (3) no history of or suspicion for EOE with histologically unremarkable biopsies. In this study, mast cells were highlighted by CKIT and tryptase in EOE, and not seen in other clinically mimicking cases. There were also significantly higher densities of CD25 and pan-T-cell marker staining in EOE cases. These findings suggest an inflammatory cellular milieu in EOE, beyond just eosinophils, that can be demonstrated by immunohistochemistry, and that invite further study into the role that these cells may play in EOE. • Mast cells by CKIT and tryptase found in eosinophilic esophagitis • Significant CD25 expression found in eosinophilic esophagitis • Significant T-cells by CD2 and CD3 found in eosinophilic esophagitis [ABSTRACT FROM AUTHOR]

Patients with systemic mastocytosis often have symptoms of mast cell activation, which is associated with elevated levels of urinary mast cell mediator metabolites. Patients with hereditary α-tryptasemia (HαT) may present with symptoms of mast cell activation. Whether levels of mast cell mediators are elevated in this patient population is not known. The purpose of this study was to determine whether patients with HαT and symptoms of mast cell activation have elevated levels of urinary mediators and compare the levels with those in patients with systemic mastocytosis. We retrospectively analyzed mast cell mediators in 63 patients with a confirmed diagnosis of HαT, 20 patients with a confirmed diagnosis of indolent systemic mastocytosis (ISM), and 23 healthy controls. All patients were referred to the Brigham and Women's Hospital Mastocytosis Center or the Mayo Clinic for evaluation of mast cell activation disorders. Our population was predominantly female (85.7%) with an average age of 53.8 years. The average baseline serum tryptase level was significantly higher in patients with ISM than in those with HαT (65.9 vs 19.3 ng/mL [ P <.01]). When compared with patients with HαT, those with ISM had statistically significant increases in their levels of urinary N-methylhistamine (P <.01) and 2,3-dinor-11β-prostaglandin F2α (P <.05). Patients with symptomatic HαT do not have elevations of mast cell urinary metabolites, suggesting that granule- and membrane-derived mediators may not drive symptoms in HαT. [ABSTRACT FROM AUTHOR]

• Systemic mastocytosis and neuroendocrine tumors may present with similar symptoms. • Co-occurrence of both diseases may be due to activating mutations in KIT. • Recognition of these distinct diseases is necessary to ensure timely treatment. Systemic mastocystosis, a disorder of clonal mast cell expansion presents with symptoms of flushing, pruritus, musculoskeletal pain, gastrointestinal cramping and vascular instability. Patients with neuroendocrine tumors may present with similar symptoms due to the release of vasoactive mediators in both diseases. We report the co-occurrence of systemic mastocytosis and a neuroendocrine pancreatic tumor for which the patient received disease-specific treatment. A 58-year-old woman with a history of indolent systemic mastocytosis and a serum tryptase of 51 ng/mL was diagnosed with a solid pancreatic lesion on ultrasound when assessing for organomegaly. Lesional biopsy was consistent with a pancreatic neuroendocrine tumor which was successfully resected. Presenting symptoms such as skin rashes, flushing, fatigue and diarrhea, are similar for systemic mastocytosis and neuroendocrine tumors. The co-occurrence of both diseases has not been previously reported. Activating mutations in KIT, which are a hallmark of systemic mastocytosis, may drive neoplastic proliferation in neuroendocrine tumors. Furthermore, mast cells infiltrating pancreatic tissue may have a trophic effect on the development of pancreatic neuroendocrine tumors. While challenging to diagnose both diseases presenting with similar symptoms, recognition of these distinct diseases is necessary to ensure timely treatment. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19–induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation–related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti–mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider. [ABSTRACT FROM AUTHOR]

Chronic inflammation of adipose tissue is associated with the pathogenesis of cardiovascular diseases. Mast cells represent an important component of the innate defense system of the organism. In our work, we quantified mast cell number in epicardial adipose tissue (EAT), subcutaneous adipose tissue (SAT), and right atrial myocardium (RA) in patients undergoing open heart surgery (n=57). Bioptic samples of EAT (n=44), SAT (n=42) and RA (n=17) were fixed by 4% paraformaldehyde and embedded into paraffin. An anti-mast cell tryptase antibody was used for immunohistochemical detection and quantification of mast cells. We also demonstrated immunohistochemically the expression of CD117 and chymase markers. In EAT of patients with coronary artery disease (CAD), higher incidence of mast cells has been found compared to patients without CAD (3.7±2.6 vs. 2.1±1.2 cells/mm2). In SAT and RA, there was no difference in the number of mast cells in CAD and non-CAD patients. Mast cells in SAT, EAT and RA expressed CD117 and chymase. An increased incidence of mast cells in EAT of CAD patients may indicate the specific role of these inflammatory cells in relation to EAT and coronary arteries affected by atherosclerosis. [ABSTRACT FROM AUTHOR]

L'allergie par hypersensibilité immédiate correspond à des manifestations aigues variées et peut poser des difficultés diagnostiques pour l'identification de l'allergène en cause et le suivi. En support de l'approche du clinicien, le biologiste propose des outils pour confirmer la nature de l'allergène et le caractériser au niveau moléculaire par l'analyse des spécificités reconnues par les IgE du patient. Cela permet de confirmer le diagnostic, d'évaluer les risques et les potentielles réactivités croisées. L'identification des composants peut aussi consolider la mise en place d'une immunothérapie et contribuer à son suivi. Dans le cas d'une réaction anaphylactique, la mesure des médiateurs libérés (tryptase et éventuellement histamine) confirme l'activation des mastocytes et/ou basophiles dont le facteur déclenchant sera à déterminer dans un second temps. Des kits de prélèvement peuvent faciliter la procédure dans les situations d'urgence. En cas de doute diagnostique et d'un risque à l'exposition à l'allergène dans un test de provocation, le test d'exploration fonctionnelle pourra être réalisé in vitro, en toute sécurité, sur les basophiles du patient. L'exploration biologique est un complément à l'analyse du clinicien et doit être menée en partenariat de façon à ne pas semer le doute devant la détection d' IgE qui ne traduit qu'une sensibilisation somme toute fréquente, par rapport à l'allergie qui est une entité clinique potentiellement grave. Immediate allergy has various clinical manifestations and can create difficulties during the diagnostic to properly identify the responsible allergen and monitor the disease. To help the allergologist, the biologist can offer lab tests to confirm the nature of the allergen and to better molecularly define it through analysis of the components recognized by patient IgEs. This strategy allows diagnosis confirmation, risk assessment and potential cross-reaction identification. Component analysis is also helpful to set up and monitor specific allergen immunotherapy. In anaphylactic reactions, measuring mediator release (tryptase and histamine if necessary) can confirm mastocyte and/or basophil activation, the triggering agent being identified later. Ready-to-use blood sampling kits may make the procedure easier in an emergency. In the event of an uncertain diagnosis and if suspected allergen exposure in a provocation test is too harmful for the patient, functional tests can be performed in vitro using patient blood basophil in complete safety. Biologic tests can therefore contribute to the clinician's diagnosis. It should be conducted in a complete partnership in order not to cast doubt in the case of IgE detection, which remains a common situation, unlike allergy that is a disease with potential serious complications. [ABSTRACT FROM AUTHOR]

Les mastocytes et les basophiles sont des cellules apparentees aux pathologies d'ordre allergique notamment par leur expression commune du Fc recepteur de haute affinite pour le IgE, FcεRI. Ces deux types cellulaires presentent egalement des caracteristiques similaires en termes de fonctions et de developpement. En plus de fonctions homeostatiques, ces cellules sont essentielles au cours des pathologies de type allergique ou infectieux. Elles presentent egalement des caracteristiques differentes mises a profit pour leur investigation clinique. Cette revue propose de resumer les diversites et les points communs de ces deux types cellulaires avec une approche ciblee sur leur contribution dans la reponse immune allergique. Mast cells and basophils are immune cells associated to allergic diseases in particular by their common expression of the Fc receptor of high affinity for IgE, FcεRI. These two cell types also exhibit similar developmental and functional characteristics. In addition to homeostatic functions, mast cells and basophils perform essential roles in metabolic, anti-infectious and allergic responses. They exhibit different characteristics that constitute a useful tool for their clinical investigation. This review summarizes the diversities and commonalities of these two cell types with a focused approach to their contribution in allergic immune response. [ABSTRACT FROM AUTHOR]

Anaphylaxis is defined as a 'severe life-threatening generalized or systemic hypersensitivity reaction'. Anaphylactic shock is characterized by generalized vasodilation and increased capillary permeability, leading to reduction in cardiac output. The pathophysiology of anaphylaxis can be described as immunologic and non-immunologic. The National Audit Project 6 (NAP 6) has recently investigated perioperative anaphylaxis and this article will outline some key updates from their report. Common triggers include antibiotics, followed by neuromuscular blocking agents, chlorhexidine and patent blue dye. Invasive lines impregnated with chlorhexidine are frequently missed as a cause of anaphylaxis. Patients at high risk of adverse outcomes include the elderly and those with pre-existing cardiopulmonary disease. The diagnosis is clinical and can be confounded by physiological changes commonly experienced after induction or airway manipulation. Key management principles include early administration of intravenous adrenaline, CPR if the systolic blood pressure is <50 mmHg and fluid resuscitation. Follow-up investigations are essential to guide future patient care and this is the responsibility of the anaesthetist. [ABSTRACT FROM AUTHOR]

Idiopathic anaphylaxis (IA) is defined as anaphylaxis without any identifiable precipitating agent or event. The clinical manifestations of IA are the same as allergen-associated (immunologic) anaphylaxis and include urticaria, angioedema, hypotension, tachycardia, wheezing, stridor, pruritus, nausea, vomiting, flushing, diarrhea, dysphagia, light-headedness, and loss of consciousness. Patients usually tend to have the same manifestations on repeated episodes. IA is a prednisone-responsive disease that is ultimately a diagnosis of exclusion. Approximately 40% of patients are atopic. Serum tryptase (or urine histamine or its metabolite) will be elevated acutely, but, if elevated in the absence of anaphylaxis, should suggest alternative diagnoses, including indolent systemic mastocytosis. A focused history, examination, and follow-up will dictate whether a patient's symptoms may be attributable to disorders that mimic anaphylaxis, such as indolent systemic mastocytosis, carcinoid syndrome, pheochromocytoma, hereditary angioedema or acquired C1 esterase inhibitor deficiency, or panic attacks. The presence of urticaria may help limit the differential diagnosis because urticaria does not usually accompany any of the above-mentioned disorders, except for indolent systemic mastocytosis. IA is classified according to the symptoms as well as the frequency of attacks. Patients who experience six or more episodes in a year, or two or more episodes in 2 months are classified as having IA-frequent (IA-F). Patients who experience fewer episodes are classified as having IA-infrequent (IA-I). This distinction is important because patients with IA-F will initially require prednisone as disease-modifying therapy, whereas most patients who with IA-I will not require prednisone. Patients with IA must carry and know when and how to self-administer epinephrine. [ABSTRACT FROM AUTHOR]

Mast cells (MCs), which are best known for their detrimental role in patients with allergic diseases, act in a diverse array of physiologic and pathologic functions made possible by the plurality of MC types. Their various developmental avenues and distinct sensitivity to (micro-) environmental conditions convey extensive heterogeneity, resulting in diverse functions. We briefly summarize this heterogeneity, elaborate on molecular determinants that allow MCs to communicate with their environment to fulfill their tasks, discuss the protease repertoire stored in secretory lysosomes, and consider different aspects of MC signaling. Furthermore, we describe key MC governance mechanisms (ie, the high-affinity receptor for IgE [FcεRI]), the stem cell factor receptor KIT, the IL-4 system, and both Ca2+- and phosphatase-dependent mechanisms. Finally, we focus on distinct physiologic functions, such as chemotaxis, phagocytosis, host defense, and the regulation of MC functions at the mucosal barriers of the lung, gastrointestinal tract, and skin. A deeper knowledge of the pleiotropic functions of MC mediators, as well as the molecular processes of MC regulation and communication, should enable us to promote beneficial MC traits in physiology and suppress detrimental MC functions in patients with disease. [ABSTRACT FROM AUTHOR]

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions. [ABSTRACT FROM AUTHOR]

Mastocytosis is a rare disease characterized by clonal proliferation of mast cells (MCs) in different organs. Clinical manifestations of mastocytosis are mostly due to release of mediators from MCs and, in many cases, such as urticaria, flushing, angioedema, and anaphylaxis, are an expression of the biological effects of mediators on endothelial cells. Chronic secretion of mediators in patients with mastocytosis can lead to alteration of endothelial function. We sought to investigate endothelial function in patients with mastocytosis using a noninvasive technique of flow-mediated dilation (FMD). Twenty-five adult patients with indolent and advanced forms of mastocytosis and 20 healthy control subjects were enrolled in the study. Ultrasound assessment of FMD was performed by measuring changes in the diameter of the brachial artery after 5 minutes of arterial occlusion. Changes in FMD were correlated with clinical parameters and serum tryptase levels. Patients with mastocytosis had lower FMD compared with healthy control subjects (P <.001). Advanced and smoldering forms showed a lower FMD compared with indolent forms (P <.001). FMD inversely correlated with age and serum tryptase levels and directly with median arterial pressure and recurrent flushing episodes. No correlation was found between FMD and osteoporosis, recurrent anaphylaxis, presence of skin lesions, and long-term antihistamine treatment. Endothelial dysfunction, as demonstrated by FMD reduction, is detectable in patients with mastocytosis and is more severe in patients with high tryptase levels and advanced disease. Endothelial function appears to be negatively influenced by MC proliferation rather than by the severity of mediator-related symptoms. [ABSTRACT FROM AUTHOR]

The roles of mast cells in allergic diseases and helminth infections are well known. However, the roles of mast cells in T. gondii infection is poorly understood. This study was focused on the production of pro-inflammatory cytokines (TNF-α, IL-4), chemokines (CXCL8, MCP-1) and nitric oxide (NO) by mast cells in response to soluble lysate of T. gondii tachyzoites. Production of CXCL8 (IL-8), MCP-1, TNF-α and IL-4 were measured by RT-PCR and ELISA. Western blot were used for detection of CXCR-1 and CXCR2. Our results showed that T. gondii lysates triggered mast cells to release CXCL8, MCP-1, TNF-α, IL-4 and to produce NO. This suggests that mast cells play an important role in inflammatory responses to T. gondii. [ABSTRACT FROM AUTHOR]

Providers caring for patients with mastocytosis are tasked with the decision to consider therapeutic options. This can come with some trepidation because information available in the public domain lists numerous mast cell (MC) activators based on data that do not discriminate between primates, rodents, and MC lines; do not consider dosage; and do not take into account previous exposure and resultant clinical findings. This being said, there is support in the literature for an enhanced MC response in some patients with mastocytosis and in cases in which there is a greater incidence of adverse reactions associated with certain antigens, such as venoms and drugs. Thus this report provides a comprehensive guide for those providers who must decide on therapeutic options in the management of patients with clonal MC disease. [ABSTRACT FROM AUTHOR]

Introduction: Many risk factors that facilitate venom allergy and increase systemic reaction severity have been described in various studies, but the data are limited regarding this issue. We aimed to evaluate the impact of total immunoglobulin E (tIgE), specific IgE, and tryptase levels on the severity of systemic reactions in patients with a history of allergic reactions to Hymenoptera stings. Method: Eighty-two patients with a history of allergic reaction to Hymenoptera venom admitted to our outpatient clinic between March 2016 and August 2017 were included. Venom-specific IgE (Apis mellifera and Vespula vulgaris), total IgE, and basal tryptase levels were measured. Skin-prick tests were performed with inhalant allergens. The levels of specific IgE, total IgE, and tryptase were compared between patients with large local reactions and systemic reactions, and the relation of these parameters with the severity of systemic reaction was evaluated. Results: There were no significant differences in the specific IgE, total IgE, and tryptase values in patients with large local reactions and a history of systemic reactions (p < 0.05). The age, basal tryptase, and V. vulgaris-specific IgE levels of patients with a grade IV reaction history were higher than those with grades I-III reaction history (p > 0.05). An important finding was that high basal tryptase levels were a risk factor for grade IV reactions (p= 0.047, 0.047 X2= 4.512). There was a strong positive correlation between total IgE levels and V. vulgaris- and A. mellifera-specific IgE values in patients with a grade IV reaction history (r= 0.94, p= 0.005; and r= 0.88, p= 0.021, respectively). Conclusion: Baseline serum tryptase levels were a risk factor for the development of severe systemic reactions in venom allergy. This risk increases with increasing age in these patients. Another notable finding was the correlation between total IgE and venom-specific IgE values in patients with severe systemic reactions. [ABSTRACT FROM AUTHOR]

Identifying the culprit medication in cases of perioperative anaphylaxis can be extremely challenging. A detailed and accurate history, coupled with the appropriate testing, plays a key role in discovering the etiology of perioperative anaphylaxis. We present the case of a 48-year-old woman with a cranial meningioma who was scheduled for surgery. Chlorhexidine, midazolam, lidocaine, propofol, fentanyl, rocuronium, and furosemide were administered during the perioperative period. She developed hypotension, urticaria, bronchospasm, and other symptoms of anaphylaxis soon after general anesthesia. The serum tryptase level obtained during anaphylaxis was 119 ng/mL (normal, <11.4 ng/mL). Epinephrine was administered, and the surgery was canceled, with no cause identified. For the next surgical attempt, she was pretreated with diphenhydramine and ranitidine, and the neuromuscular blocker was withheld. Again, she developed hypotension consistent with anaphylaxis, and epinephrine was administered. She was referred for consultation. A detailed and accurate history was obtained. The baseline serum tryptase level was 6.4 ng/mL. Skin-prick puncture tests were completed, and a diagnosis was made. The surgical team was instructed to avoid the culprit medication, and the cranial surgery was successful. Although difficult, cases of perioperative anaphylaxis can be solved with a detailed history, keen detective work, and appropriate testing. [ABSTRACT FROM AUTHOR]

La vérification d'une méthode de dosage selon la norme NF/EN/ISO 15189 requiert l'analyse des performances de la technique (répétabilité, fidélité intermédiaire, exactitude et incertitude de mesure) avant toute utilisation en routine. Les coefficients de variation (CV) des résultats de précision intra-essai et inter-essais obtenus doivent être comparés à ceux des pairs et à ceux qui pratiquent ces mêmes dosages quelle que soit la technique. En l'absence de publications nationales ou internationales pour les IgE spécifiques et la tryptase, le réseau des biologistes des centres hospitaliers AllergoBioNet a analysé les résultats fournis par 24 centres pour proposer des limites acceptables des critères de performance pour le dosage des IgE totales et spécifiques et de la tryptase. Checking a dosing method according to NF/EN/ISO 15189 standard requires analysis of the performance of the technique (repeatability, intermediate fidelity, accuracy and measurement uncertainty) before routine use and follow-up annually. The coefficients of variation (CV) of the intra-assay and inter-assays accuracy results obtained must be compared with those of peers and those who perform the same determination regardless of the technique. In the absence of national or international guidelines for monitoring the performance of specific IgE and tryptase assay, the French network of hospital laboratories AllergoBioNet analysed the results provided by 24 centers and propose recommendations for total IgE, specific IgE and tryptase assays. [ABSTRACT FROM AUTHOR]

Background: Increased numbers of mast cells that contain tryptase are found in lesional atopic dermatitis (AD) skin. The association of serum basal tryptase (sBT) with anaphylactic reactions and mast cell diseases has recently been shown in children with venom and food allergy. Objective: We aimed to identify the risk factors that predict the severity of AD and the association of sBT levels with AD and disease severity. Method: AD diagnosis was made according to Hanifin and Rajka criteria. Disease severity was scored by the objective scoring atopic dermatitis (SCORAD) index. The sBT levels were measured. Skin-prick testing, total immunoglobulin E, eosinophil percentages and counts, and a questionnaire concerning the history of atopic diseases and the risk factors of AD were applied. Results: The children, ages 0.5 to 3.0 years, with AD (n = 85) were analyzed in two groups according to the presence (AD+/atopy- [n = 55]) or absence (AD+/atopy- [n = 30]) of skin-prick test positivity. The comparisons were made with an age- and sex-matched control group (n = 82). The median (interquartile range) sBT in the AD+/atopy-, AD-/atopy, and control groups were 5.01 ng/mL (2.75- 6.79 ng/mL), 3.02 ng/mL (1.67- 4.44 ng/mL), and 2.63 ng/mL (1.31- 4.49 ng/mL), respectively (p = 0.003). The median (interquartile range) sBT levels were higher in patients with moderate-severe objective SCORAD index scores compared with the those with mild disease (3.85 ng/mL [2.04 -5.91 ng/mL] versus 2.80 ng/mL [1.83-3.48 ng/mL]; p = 0.038). Multivariate logistic regression analysis showed that an sBT level of >3.9 ng/mL (odds ratio 8.77 [95% confidence interval, 1.87- 41.18]; p = 0.006) was independently associated with an increased risk of moderate-severe AD (objective SCORAD index). Conclusion: To our knowledge, this was the first study that indicated that sBT levels may be important in the AD disease process and associated with the disease severity and atopy. [ABSTRACT FROM AUTHOR]

FcεRI is the primary receptor in mast cells that mediates allergic reactions by inducing rapid release of mediators, an adaptive immune response that might have evolved as a host defense against parasites and venoms. Yet it is apparent that mast cells are also activated through non-IgE receptors, the significance of which is just beginning to be understood. This includes the Mas-related G protein–coupled receptor X2, which might contribute to reactions to diverse antimicrobials and polybasic compounds, and the adhesion G protein–coupled receptor E2, variants of which are associated with familial vibratory urticaria and are activated by mechanical vibration. Similarly, mast cells have long been recognized as the main repository for histamine, heparin, and proteases. Recent evidence also points to new functions, modes of delivery, and mechanisms of action of mast cell proteases that add new dimensions to the roles of mast cells in human biology. In addition, exposure of mast cells to environmental cues can quantitatively and qualitatively modulate their responses and thus their effect on allergic inflammation. Illustrating this paradigm, we summarize a number of recent studies implicating the injury/tissue damage cytokine IL-33 as a modulator of allergen-induced mast cell responses. We also discuss the discovery of markers associated with transformed mast cells and new potential directions in suppressing mast cell activity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study sought to investigate the expression of interferon-λ2 (IFN-λ2) in patients with combined allergic rhinitis and nasal polyps (AR+NP), analyze the correlation between IFN-λ2 and tryptase, interleukin 10 (IL-10), and interleukin 12 (IL-12), and identify its peripheral blood cell origins. PATIENTS AND METHODS: ELISA kits were used to investigate plasma levels of IFN-λ2, tryptase, IL-10, and IL-12 in AR+NP patients and healthy controls (HC). Flow cytometry analysis was carried out to detect IFN-λ2 expression in peripheral blood leukocytes. Immunocytochemical staining was performed to detect nasal polyp IFN-λ2 expression in AR+NP patients. RESULTS: Elevated plasma IFN-λ2 levels and positive correlations between plasma IFN-λ2 and tryptase levels in AR+NP patients indicated that IFN-λ2 likely contributes to AR+NP pathogenesis. IFN-λ2 expression was upregulated in cytotoxic T cells and eosinophils in AR+NP patients. Nasal polyp mast cells and macrophages in AR+NP patients expressed IFN-λ2. CONCLUSIONS: The close correlation between IFN-λ2 expression and AR+NP may provide experimental evidence for a possible effect of IFN-λ2 against the allergic inflammatory reaction. Therefore, IFN-λ2 actions may have a potential utility for the treatment and prevention of AR+AP. [ABSTRACT FROM AUTHOR]

Background: Mast cells (MCs), the primary effector cell of the atopic response, participate in immune defense at host/environment interfaces, yet the mechanisms by which they interact with CD4+ T cells has been controversial. Objective: We used in situ-matured primary human MCs and matched CD4+ T cells to diligently assess the ability of MCs to act as antigen-presenting cells. Methods: We examined mature human skin-derived MCs using flow cytometry for expression of antigen-presenting molecules, for their ability to stimulate CD4+ T cells to express CD25 and proliferate when exposed to superantigen or to cytomegalovirus (CMV) antigen using matched T cells and MCs from CMVseropositive or CMV-seronegative donors, and for antigen uptake. Subcellular localization of antigen, HLA molecules, and tryptase was analyzed by using structured illumination microscopy. Results: Our data show that IFN-g induces HLA class II, HLA-DM, CD80, and CD40 expression on MCs, whereas MCs take up soluble and particulate antigens in an IFN-γ-independent manner. IFN-γ-primed MCs guide activation of T cells by Staphylococcus aureus superantigen and, when preincubated with CMV antigens, induce a recall CD4+ TH1 proliferation response only in CMV-seropositive donors. MCs co-opt their secretory granules for antigen processing and presentation. Consequently, MC degranulation increases surface delivery of HLA class II/peptide, further enhancing stimulation of T-cell proliferation. Conclusions: IFN-γ primes human MCs to activate T cells through superantigen and to present CMV antigen to TH1 cells, co-opting MC secretory granules for antigen processing and presentation and creating a feed-forward loop of T-cell-MC cross-activation. [ABSTRACT FROM AUTHOR]

Background: Clonal mast cell disorders are known to occur in a subset of patients with systemic reactions to Hymenoptera stings. This observation has prompted the question of whether clonal mast cell disorders also occur in patients with idiopathic anaphylaxis (IA). Objective:We sought to determine the prevalence of clonal mast cell disorders among patients with IA, criteria to identify those patients who require a bone marrow biopsy, and whether the pathogenesis of IA involves a hyperresponsive mast cell compartment. Methods: We prospectively enrolled patients with IA (≤3 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, allele-specific quantitative PCR (ASqPCR) for the KIT D816V mutation, and a bone marrow examination. Mast cells were cultured from peripheral blood CD34+ cells and examined for releasability after FcεRI aggregation. Results: Clonal mast cell disease was diagnosed in 14% of patients referred with IA. ASqPCR for the KIT D816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome. A modified overall clonal prediction model was developed by using clinical findings, a serum tryptase determination, and ASqPCR. There was no evidence of a hyperresponsive mast cell phenotype in patients with IA. Conclusion: Patients with clonal mast cell disease can present as having IA. Distinct clinical and laboratory features can be used to select those patients more likely to have an underlying clonal mast cell disorder (monoclonal mast cell activation syndrome or systemic mastocytosis) and thus candidates for a bone marrow biopsy. [ABSTRACT FROM AUTHOR]

Résumé La mastocytose systémique est une pathologie à risque de réactions allergiques. L’anaphylaxie aux venins d’hyménoptères y est particulièrement fréquente et sévère. Notre propos est d’insister sur des points particuliers de cette association qui, s’ils sont méconnus, peuvent être à l’origine d’erreurs de diagnostic. Ces points particuliers sont les suivants : les accidents allergiques après piqûre d’hyménoptères des patients atteints de mastocytose sont souvent atypiques, le bilan allergologique montre souvent une sensibilisation faible au venin et le diagnostic d’allergie est parfois de ce fait récusé. Une démarche diagnostique rigoureuse doit donc être menée dans toutes les situations où une mastocytose est suggérée par l’histoire clinique et un taux de tryptase intercritique élevé. Les traitements de désensibilisation au venin sont la pierre angulaire pour prévenir les récidives de choc mais sont plus souvent que dans la population générale émaillés de réactions syndromiques. Une grande vigilance doit encadrer ces traitements. Mastocytosis is a risk factor for frequent and severe allergic reactions, particularly following exposure to hymenoptera venoms. It is our intention to emphasize particular aspects of this association, which, if not known, can lead to misdiagnosis. These are as follows: allergic reactions following hymenoptera stings in patients with mastocytosis are often atypical, with allergological tests frequently showing low sensitivity to venom, thus occasionally casting doubt on the diagnosis of allergy. A rigorous diagnostic procedure is systematically required whenever mastocytosis is suggested by clinical history and an elevated intercritical tryptase rate. Moreover, implementation of venom desensitization treatments constitutes the cornerstone for prevention of shock relapses but this approach is complicated by syndromic reactions that are seen more frequently than in the general population. Great vigilance is called for when administering such treatments. [ABSTRACT FROM AUTHOR]

Résumé Les pathologies mastocytaires sont liées à des anomalies du nombre et/ou de l’activation mastocytaire, systémiques ou localisées. Les anomalies quantitatives clonales, isolées ou associées à des anomalies de l’activation, sont classiquement regroupées sous le nom de mastocytose, dont la forme systémique est classée par l’OMS parmi les néoplasies myéloïdes. Les syndromes d’activation mastocytaire, dont la systématisation est récente, recoupent partiellement les anomalies quantitatives. Nous proposons ici une revue de la littérature récente sur la mastocytose et les syndromes d’activation mastocytaire, mettant l’accent sur les explorations biologiques utiles en pratiques et la manière dont elles s’intègrent dans la pratique allergologique en 2017. Mast cell disorders are underlain by abnormal numbers and/or activity of mast cells, either organ-specific or systemic. Clonal expansion of mast cells, with or without abnormal mast cell activation, belong to the WHO category of mastocytosis, a myeloid neoplasm in its systemic variant. Mast cell activation syndromes have recently become a subject of intense research. We performed a literature review on mastocytosis and mast cell activation syndromes, with special focus on laboratory work-up as a tool for allergists. [ABSTRACT FROM AUTHOR]

Résumé La prise en charge des réactions anaphylactiques périopératoires répond à des recommandations spécifiques élaborées sous l’égide de la SFAR et de la SFA et révisées en 2011. En France, l’incidence des réactions anaphylactiques d’origine allergique est estimée à 100,6 [76,2–125,3]/million d’anesthésies dans la population générale. Chez l’adulte, les substances les plus fréquemment incriminées sont les curares, suivis des antibiotiques et des colorants. Les réactions au latex sont en nette régression. La majorité des réactions apparaît dans les minutes suivant l’injection intraveineuse des produits. Lorsque la symptomatologie est d’apparition plus tardive, au cours de la période d’entretien de l’anesthésie, une allergie au latex, à un colorant, un antiseptique ou aux produits de remplissage doit être évoquée. L’expression clinique d’une réaction anaphylactique est de gravité variable. Les signes cliniques initiaux les plus fréquemment rapportés sont l’absence de pouls, un érythème, une difficulté de ventilation, une désaturation ou une baisse de la pression télé-expiratoire de CO 2 . Les signes cutanés peuvent parfois être absents. Le diagnostic du mécanisme de la réaction repose sur le dosage des médiateurs (tryptase, histamine), au moment de la réaction. En cas d’allergie, l’identification de l’agent responsable se fait par la mise en évidence d’IgE spécifiques au moment de la réaction ou à distance et sur la réalisation de tests cutanés 6 semaines après la réaction. Le traitement repose sur l’interruption de l’administration de l’allergène lorsqu’elle est possible, sur la prescription d’adrénaline à dose titrée en fonction de la gravité clinique et de la réponse au traitement et sur le remplissage vasculaire. Anaphylactic reactions occurring during the perioperative period should be investigated and treated in compliance with the guidelines published by the SFAR and the SFA in 2011. In France, the estimated incidence of allergic reactions is 100.6 [76.2–125.3]/million procedures. In adults, the most frequently incriminated substances are neuromuscular blocking agents, followed by antibiotics and dyes. In most cases, clinical symptoms occur within minutes of intravenous administration of treatments. When symptoms are delayed and occur during the surgical procedure, a reaction involving latex, a vital dye, an antiseptic or a volume-expansion fluid should be suspected. Reaction severity may vary. The most frequently reported initial symptoms are pulselessness, erythema, increased airway pressure, desaturation and decreased end-tidal CO 2 . Clinical symptoms may occur as an isolated condition, making proper diagnosis difficult. Identification of the reaction mechanism relies on determination of mediators (tryptase, histamine) at the time of the reaction. In the event of an allergic reaction, the causative drug may be identified by the detection of specific IgE using immunoassays or by skin tests performed 6 weeks after the reaction. Treatment is based on suspension of allergen administration, on administration of epinephrine carefully titrated as a function of the severity of symptoms and on volume expansion. [ABSTRACT FROM AUTHOR]

Résumé L’anaphylaxie est une urgence allergique dont la fréquence augmente constamment. Son management repose sur l’administration d’adrénaline et la coordination entre urgentistes et allergologues. L’objectif de l’étude était de déterminer l’incidence de l’anaphylaxie en 2015, d’en décrire les principales caractéristiques et d’évaluer les pratiques. Quatre centres hospitaliers lorrains ont été sélectionnés. Les dossiers médicaux informatiques des patients admis aux urgences adultes ou pédiatriques entre le 1 er janvier et le 31 décembre 2015 ont été interrogés sur leurs motifs de recours et code diagnostique. Les dossiers dont le codage était susceptible de correspondre à une réaction anaphylactique (95 codes sélectionnés) étaient revus individuellement par un investigateur allergologue, puis inclus en cas de confirmation. Un questionnaire standardisé a permis le recueil des données épidémiologiques, caractéristiques cliniques et prise en charge des patients. L’anaphylaxie représente 0,16 % des passages aux urgences pour 2015, avec une incidence de 34 pour 100 000 personnes-année en Lorraine. La présentation clinique est influencée significativement par l’âge, le facteur étiologique, certains cofacteurs (asthme, comorbidité cardiovasculaire, médications), et la gravité de la réaction. En cas d’anaphylaxie sévère, le recours à l’adrénaline n’était que de 32,4 % (48/148), et 4 fois sur 10 la durée de surveillance hospitalière était inférieure à 6 heures. Une orientation vers l’allergologue était proposée chez 57,9 % (187/323) des patients. L’anaphylaxie est une cause non exceptionnelle d’admission aux urgences. Les recommandations sont encore trop peu appliquées, et une meilleure connaissance de la pathologie et de sa prise en charge est nécessaire pour les professionnels gérant l’urgence. Anaphylaxis is an allergic emergency, and its frequency increases in all countries since the 2000s. Epinephrine administration and allergist-emergency room interactions are the key points of its management. The objective of the study was to determine the incidence of anaphylaxis in 2015, to describe its main characteristics and to evaluate practices in Lorraine for this period. Four hospitals in Lorraine were selected. Medical records from each center's adult and pediatric emergency rooms, from 1st January to 31th December 2015, were classified based on their admission cause and diagnosis code. When data were consistent for an anaphylaxis (95 selected ICD-10 codes) record was analyzed by an allergist practitioner and included if confirmed. Epidemiological data, clinical characteristics, management assessment and orientation were provided through a standardized questionnaire. Anaphylaxis is responsible for 0.16% emergency rooms’ admissions in the participating centers in 2015; the estimated incidence in Lorraine is 34 per 100,000 person-years. Clinical presentation depends on age, etiologic agent, several cofactors (asthma, cardiovascular comorbidities, treatments) and reaction's gravity. When anaphylaxis was serious (Ring-Messmer's grade ≥ 3), epinephrine use was only 32.4% (48/148) and observation duration was less than 6 hours 4 times on 10. An allergist referral was proposed in 57.9% (187/323) patients. Anaphylaxis is not a rare cause for emergency rooms’ admission in Lorraine. Therefore guidelines are insufficiently followed and a better knowledge of the pathology and its management is necessary for emergency healthcare practitioners. [ABSTRACT FROM AUTHOR]