|
1
|
Karthikeyan B, James RI, Daniel J, Kumar R S, Varughese BT, Manoj D, Arakkal AL, Johnson LR. Utility of biomarkers in the postmortem diagnosis of fatal Anaphylaxis: A scoping review. Leg Med (Tokyo) 2025; 74:102610. [PMID: 40163933 DOI: 10.1016/j.legalmed.2025.102610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/25/2025] [Accepted: 03/13/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Diagnosing anaphylactic deaths is a challenging task for forensic pathologists. Although serum tryptase is considered to be a reliable biomarker, there are limitations to it. Thus, there is an urgent need to explore various other potential biomarkers which could be of diagnostic value, along with Tryptase, to diagnose anaphylactic shock at autopsy. AIM We want to systematically review the accuracy of newer postmortem biomarkers for anaphylaxis, such as chymase or eosinophilic cationic protein. Before embarking on this project, we intend to assess the feasibility of conducting systematic reviews on this topic. and identify any deficiencies in the existing literature to guide research priorities. METHODOLOGY We followed PRISMA guidelines and conducted the search in four databases, namely Medline, Scopus, EBSCO-CINAHL, and TRIP. Rayyan AI software was used to screen the articles. RESULTS A total of 6112 articles were retrieved from the search, and 5079 articles were screened after removing duplicates. Only 25 articles were finally available as per our inclusion criteria. Studies pertaining to post-mortem tryptase levels were found in large numbers, with two recently done systematic reviews on this topic. The number of studies available on other newer biomarkers was too few. More clinical studies are needed before a meta-analysis can be done. Hence, we could perform only a narrative review on the topic. DISCUSSION There is a scarcity of literature with definite cutoff levels for markers other than Tryptase. Based on the available studies, it is not possible to do diagnostic accuracy reviews at the moment. Hence, we narrate the usefulness of biomarkers like Immunoglobulin E, Chymase, Carboxypeptidase A3, Diamine Oxidase, Histamine and Eosinophilic Cationic Protein. CONCLUSION Based on the available evidence, serum tryptase is recognized as the primary biomarker for the postmortem diagnosis of anaphylactic death, with elevated levels strongly indicating anaphylaxis. Additionally, serum IgE, particularly allergen-specific IgE, is a valuable complementary biomarker. Further research is needed to understand the performance of other biomarkers.
Collapse
Affiliation(s)
- Bharath Karthikeyan
- Department of Pulmonary Medicine, Christian Medical College Vellore, Tamil Nadu, India
| | - Ranjit Immanuel James
- Department of Forensic Medicine & Toxicology, Christian Medical College Vellore, Tamil Nadu, India.
| | - Jefferson Daniel
- Department of Pulmonary Medicine, Christian Medical College Vellore, Tamil Nadu, India
| | - Senthil Kumar R
- Department of Forensic Medicine, Post-Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Benjy Tom Varughese
- Department of Forensic Medicine & Toxicology, Christian Medical College Vellore, Tamil Nadu, India
| | - Daniel Manoj
- Department of Forensic Medicine & Toxicology, Christian Medical College Vellore, Tamil Nadu, India
| | - Antony L Arakkal
- Department of Forensic Medicine & Toxicology, Christian Medical College Vellore, Tamil Nadu, India
| | - Latif Rajesh Johnson
- Department of Forensic Medicine & Toxicology, Christian Medical College Vellore, Tamil Nadu, India
| |
Collapse
|
|
2
|
Farmer I, Radia DH. Systemic Mastocytosis: State of the Art. Curr Hematol Malig Rep 2024; 19:197-207. [PMID: 39187708 DOI: 10.1007/s11899-024-00737-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2024] [Indexed: 08/28/2024]
Abstract
PURPOSE OF REVIEW Since identification of Systemic mastocytosis (SM) as a distinct disease entity by the World Health Organisation (WHO), there has been a wealth of new research in therapeutic targeting of the pathogenic C-KIT D816V mutation. RECENT FINDINGS Avapritinib, the first licensed drug in SM capable of disease modification alongside the increasingly potent, oral and highly selective KIT tyrosine kinase inhibitors (TKIs) Bezuclastinib and now Elenestinib have enabled the prospect of long-term remissions. Studies have shown improved survival and symptomatic control in patients with SM. Of great triumph, this has been achieved in an outpatient setting with apparent tolerable and minimal toxicity. The importance of molecular profiling is being demonstrated in administering combination therapies for SM with an associated haematological neoplasm (AHN), allowing more personalised and streamlined treatment regimes. This review focuses on current management strategies of SM, focusing on state-of-the-art directed therapies, the evidence behind their use with presentation of two clinical cases to highlight key messages.
Collapse
Affiliation(s)
- Isabel Farmer
- Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, SE1 7EH, UK.
| | - Deepti H Radia
- Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, SE1 7EH, UK.
| |
Collapse
|
|
3
|
Akin C, Siebenhaar F, Wechsler JB, Youngblood BA, Maurer M. Detecting Changes in Mast Cell Numbers Versus Activation in Human Disease: A Roadblock for Current Biomarkers? THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:1727-1737. [PMID: 38467332 DOI: 10.1016/j.jaip.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/09/2024] [Accepted: 03/01/2024] [Indexed: 03/13/2024]
Abstract
The pathophysiology of mast cell (MC)-driven disorders is diverse, ranging from localized reactions to systemic disorders caused by abnormal accumulation and activation in multiorgan systems. Prompt and accurate diagnosis is critically important, both for informing treatment and objective assessment of treatment outcomes. As new therapeutics are being developed to deplete MCs or silence them (eg, by engaging inhibitory receptors that block activation), new biomarkers are needed that can distinguish between MC activation versus burden. Serum tryptase is the gold standard for assessing both MC burden and activation; however, commercial tryptase assays have limitations related to timing of release, lack of discernment between inactive (α) and active (β) forms of tryptase, and interpatient variability of baseline levels. Alternative approaches to measuring MC activation include urinary MC mediators, flow cytometry-based assays or gene expression profiling. Additional markers of MC activation are needed for use in clinical diagnostics, to help selection of treatment of MC diseases, and for assessing outcomes of therapy. We review the spectrum of disorders with known or suspected MC contribution, describe the utility and limitations of current MC markers and assays, and discuss the need for new markers that can differentiate between MC activation and burden.
Collapse
Affiliation(s)
- Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Mich
| | - Frank Siebenhaar
- Institute of Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany
| | - Joshua B Wechsler
- Division of Gastroenterology, Hepatology, and Nutrition, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill
| | | | - Marcus Maurer
- Institute of Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany.
| |
Collapse
|
|
4
|
DuToit G, Smith P, Muraro A, Fox AT, Roberts G, Ring J, Worm M. Identifying patients at risk of anaphylaxis. World Allergy Organ J 2024; 17:100904. [PMID: 38966605 PMCID: PMC11223123 DOI: 10.1016/j.waojou.2024.100904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 03/31/2024] [Accepted: 04/05/2024] [Indexed: 07/06/2024] Open
Abstract
Anaphylaxis is an acute, potentially fatal, systemic hypersensitivity reaction that warrants prompt diagnosis and management. It continues to be challenging to anticipate who may be at risk of a severe, life-threatening allergic reaction. Anaphylaxis can be caused by a range of allergens, such as certain foods, medications, latex, insect stings, etc. Cofactors that augment the severity of clinical symptoms and increase the risk of poor outcomes include exercise, stress, infectious diseases, underlying mast cell disease, active allergic disease such as asthma, advanced age, intake of certain medications, history of previous anaphylaxis, and delayed or missed administration of adrenaline. According to the European Anaphylaxis Registry, food is the major elicitor of anaphylaxis, especially eggs, cow milk, and nuts, in children and adolescents. Reaction to insect venom has also been noted in young adulthood. Early recognition of signs and symptoms and prompt treatment are crucial in anaphylaxis management to avoid serious and even fatal outcomes. It is crucial for both individuals and clinicians to identify the cause of anaphylaxis. Biomarkers of anaphylaxis, such as histamine, tryptase, platelet activation factor (PAF), chymase, carboxypeptidase A3, dipeptidyl peptidase I (DPPI), basogranulin, CCL-2, hsa-miR-451a, may be useful in diagnosis and management. The purpose of this review article is to present a comprehensive overview of current evidence and expert opinions regarding the risk factors that predispose individuals to anaphylaxis. Additionally, it provides insights into potential biomarkers and genetic markers for accurate diagnosis and management. This review underscores the significance of expert guidance in enhancing patient outcomes and enabling self-management of anaphylactic episodes.
Collapse
Affiliation(s)
- George DuToit
- Pediatric Allergy King's College London and Guy's and St Thomas', London, United Kingdom
| | - Pete Smith
- Clinical School of Medicine, Griffith University, Southport, Queensland, Australia
| | - Antonella Muraro
- Food Allergy Referral Centre, Department of Woman and Child Health, Padua University Hospital, Padua, Italy
| | - Adam T. Fox
- Children's Allergy Service, Guy's and St Thomas' Hospitals NHS Foundation Trust, Westminster Bridge, London, United Kingdom
| | - Graham Roberts
- University of Southampton, Pediatric Allergy & Respiratory Medicine, Tremona Road, Southampton, United Kingdom
| | - Johannes Ring
- Technical University Munich (TUM), Dept Dermatology Allergology Biederstein, Germany
| | - Margitta Worm
- Allergologie und Immunologie, Klinik für Dermatologie, Venerologie und Allergologie, Campus Charité Mitte, Universitätsmedizin Berlin, Berlin, Germany
| |
Collapse
|
|
5
|
Kovacheva E, Gevezova M, Maes M, Sarafian V. The mast cells - Cytokines axis in Autism Spectrum Disorder. Neuropharmacology 2024; 249:109890. [PMID: 38431049 DOI: 10.1016/j.neuropharm.2024.109890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/19/2024] [Accepted: 02/24/2024] [Indexed: 03/05/2024]
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disturbance, diagnosed in early childhood. It is associated with varying degrees of dysfunctional communication and social skills, repetitive and stereotypic behaviors. Regardless of the constant increase in the number of diagnosed patients, there are still no established treatment schemes in global practice. Many children with ASD have allergic symptoms, often in the absence of mast cell (MC) positive tests. Activation of MCs may release molecules related to inflammation and neurotoxicity, which contribute to the pathogenesis of ASD. The aim of the present paper is to enrich the current knowledge regarding the relationship between MCs and ASD by providing PPI network analysis-based data that reveal key molecules and immune pathways associated with MCs in the pathogenesis of autism. Network and enrichment analyzes were performed using receptor information and secreted molecules from activated MCs identified in ASD patients. Our analyses revealed cytokines and key marker molecules for MCs degranulation, molecular pathways of key mediators released during cell degranulation, as well as various receptors. Understanding the relationship between ASD and the activation of MCs, as well as the involved molecules and interactions, is important for elucidating the pathogenesis of ASD and developing effective future treatments for autistic patients by discovering new therapeutic target molecules.
Collapse
Affiliation(s)
- Eleonora Kovacheva
- Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria; Research Institute at Medical University-Plovdiv, Plovdiv, Bulgaria
| | - Maria Gevezova
- Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria; Research Institute at Medical University-Plovdiv, Plovdiv, Bulgaria
| | - Michael Maes
- Research Institute at Medical University-Plovdiv, Plovdiv, Bulgaria; Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, 610072, China; Department of Psychiatry, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand; Cognitive Fitness and Technology Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Psychiatry, Medical University-Plovdiv, Plovdiv, Bulgaria; Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea
| | - Victoria Sarafian
- Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria; Research Institute at Medical University-Plovdiv, Plovdiv, Bulgaria.
| |
Collapse
|
|
6
|
Shin H, Lyons JJ. Alpha-Tryptase as a Risk-Modifying Factor for Mast Cell-Mediated Reactions. Curr Allergy Asthma Rep 2024; 24:199-209. [PMID: 38460022 PMCID: PMC11870015 DOI: 10.1007/s11882-024-01136-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 03/11/2024]
Abstract
PURPOSE OF REVIEW To provide an overview on the current understanding of genetic variability in human tryptases and summarize the literature demonstrating the differential impact of mature tryptases on mast cell-mediated reactions and associated clinical phenotypes. RECENT FINDINGS It is becoming increasingly recognized that tryptase gene composition, and in particular the common genetic trait hereditary alpha-tryptasemia (HαT), impacts clinical allergy. HαT has consistently been associated with clonal mast cell disorders (MCD) and has also been associated with more frequent anaphylaxis among these patients, and patients in whom no allergic trigger can be found, specifically idiopathic anaphylaxis. Additionally, more severe anaphylaxis among Hymenoptera venom allergy patients has been linked to HαT in both retrospective and prospective studies. An increased relative number of α-tryptase-encoding gene copies, even in the absence of HαT, has also been associated with systemic mastocytosis and has been shown to positively correlate with the severity of mast cell-mediated reactions to vibration and food. These findings may be due to increased generation of α/β-tryptase heterotetramers and differences in their enzymatic activity relative to β-tryptase homotetramers. HαT is a naturally occurring overexpression model of α-tryptase in humans. Increased relative α-tryptase expression modifies immediate hypersensitivity symptoms and is associated with more frequent and severe mast cell-mediated reactions, ostensibly due to increased α/β-tryptase heterotetramer production.
Collapse
Affiliation(s)
- Hannah Shin
- Division of Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jonathan J Lyons
- Division of Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
- Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA.
| |
Collapse
|
|
7
|
Valent P, Akin C, Arock M. Reversible Elevation of Tryptase Over the Individual's Baseline: Why is It the Best Biomarker for Severe Systemic Mast Cell Activation and MCAS? Curr Allergy Asthma Rep 2024; 24:133-141. [PMID: 38308674 PMCID: PMC10960756 DOI: 10.1007/s11882-024-01124-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2024] [Indexed: 02/05/2024]
Abstract
PURPOSE OF REVIEW Mast cell (MC) activation syndromes (MCAS) are conditions defined by recurrent episodes of severe systemic anaphylaxis or similar systemic events triggered by MC-derived mediators that can be measured in biological fluids. Since some symptoms of MC activation may occur due to other, non-MC etiologies and lead to confusion over diagnosis, it is of crucial importance to document the involvement of MC and their products in the patients´ symptomatology. RECENT FINDINGS The most specific and generally accepted marker of severe systemic MC activation is an event-related, transient increase in the serum tryptase level over the individual baseline of the affected individual. However, baseline concentrations of serum tryptase vary among donors, depending on the genetic background, age, kidney function, and underlying disease. As a result, it is of critical importance to provide a flexible equation that defines the diagnostic increase in tryptase qualifying as MCAS criterion in all patients, all situations, and all ranges of baseline serum tryptase. In 2012, the consensus group proposed the 120% + 2 ng/ml formula, which covers the great majority of groups, including cases with low, normal, or elevated basal serum tryptase level. This formula has been validated in subsequent studies and has proven to be a robust and consistent diagnostic criterion of MCAS. The present article is discussing the impact of this formula and possible limitations as well as alternative markers and mediators that may be indicative of MCAS.
Collapse
Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
| | - Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Michel Arock
- Platform of Molecular Analysis for Mastocytosis and MCAD (CEREMAST), Department of Biological Hematology, Pitié-Salpêtrière Hospital, AP-HP, Paris Sorbonne University, Paris, France
| |
Collapse
|
|
8
|
Keow J, Chin‐Yee B, Hsia CC, Robertson K. Urticaria pigmentosa and systemic mastocytosis. Clin Case Rep 2023; 11:e8302. [PMID: 38111510 PMCID: PMC10725995 DOI: 10.1002/ccr3.8302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/25/2023] [Accepted: 11/27/2023] [Indexed: 12/20/2023] Open
Abstract
Key Clinical Message Additional investigations for systemic involvement should be initiated once the diagnosis of cutaneous mastocytosis has been established in an adult patient. A serum tryptase can serve as a screening test for systemic mastocytosis, and persistent elevations should prompt further investigations, such as bone marrow studies. Abstract Urticaria pigmentosa (UP) is the most common form of cutaneous mastocytosis, presenting as a wide variety of macroscopic appearances. Cutaneous mastocytosis in pediatric patients usually does not present with systemic involvement, but more than half of adult patients with cutaneous mastocytosis demonstrate systemic involvement. Currently, there is no guidance surrounding systemic testing in patients with UP. A 50-year-old Caucasian male was referred to the Clinical Immunology and Allergy clinic with a history of a rash. He initially presented to hospital 12 years prior with group A beta hemolytic streptococcus bacteremia treated with multiple different antibiotics. One week following discharge, he developed erythematous brown spots on his right leg which were flat, non-pruritic, and not painful. The rash later expanded to his trunk and extremities. A skin biopsy performed 2 years prior to referral to our clinic demonstrated urticaria pigmentosa. The CD117 immunohistochemical stain showed increased perivascular and interstitial mast cells in the superficial dermis. Darier's sign was negative on physical examination, and venom testing was also negative. Although he had no symptoms of systemic involvement, his serum tryptase was elevated at 47.6 ng/mL in the context of normal kidney and liver function. A skeletal survey was normal, and an abdominal ultrasound ruled out splenomegaly. Bone marrow biopsy demonstrated a mild increase in paratrabecular and perivascular atypical mast cells, in keeping with systemic mastocytosis. Adult patients with cutaneous mastocytosis have a high likelihood of having an underlying systemic mast cell disorder. Therefore, any patient presenting with characteristic skin findings should be investigated as having a cutaneous manifestation of systemic mastocytosis. This case demonstrates the utility of serum tryptase and its role in triggering additional investigations and guiding appropriate therapy.
Collapse
Affiliation(s)
| | - Benjamin Chin‐Yee
- Division of Hematology, Department of MedicineUniversity of Western OntarioLondonOntarioCanada
- Department of History and Philosophy of ScienceUniversity of CambridgeCambridgeUnited Kingdom
| | - Cyrus C. Hsia
- Division of Hematology, Department of MedicineUniversity of Western OntarioLondonOntarioCanada
| | - Kara Robertson
- Division of Clinical Immunology and Allergy, Department of MedicineUniversity of Western OntarioLondonOntarioCanada
| |
Collapse
|
|
9
|
Valent P, Hoermann G, Bonadonna P, Hartmann K, Sperr WR, Broesby-Olsen S, Brockow K, Niedoszytko M, Hermine O, Chantran Y, Butterfield JH, Greiner G, Carter MC, Sabato V, Radia DH, Siebenhaar F, Triggiani M, Gülen T, Alvarez-Twose I, Staudinger T, Traby L, Sotlar K, Reiter A, Horny HP, Orfao A, Galli SJ, Schwartz LB, Lyons JJ, Gotlib J, Metcalfe DD, Arock M, Akin C. The Normal Range of Baseline Tryptase Should Be 1 to 15 ng/mL and Covers Healthy Individuals With HαT. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:3010-3020. [PMID: 37572755 PMCID: PMC11869997 DOI: 10.1016/j.jaip.2023.08.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/27/2023] [Accepted: 08/01/2023] [Indexed: 08/14/2023]
Abstract
Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation. To address this point, experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases met at the 2022 Annual ECNM meeting and discussed the physiological tryptase range. Based on this discussion, our faculty concluded that the normal serum tryptase range should be defined in asymptomatic controls, inclusive of individuals with HαT, and based on 2 SDs covering the 95% confidence interval. By applying this definition in a literature screen, the normal basal tryptase in asymptomatic controls (HαT-positive persons included) ranges between 1 and 15 ng/mL. This definition should avoid overinterpretation, unnecessary referrals, and unnecessary anxiety or anticipatory fear of illness in healthy individuals.
Collapse
Affiliation(s)
- Peter Valent
- Division of Haematology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
| | - Gregor Hoermann
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria; MLL Munich Leukemia Laboratory, Munich, Germany
| | | | - Karin Hartmann
- Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Wolfgang R Sperr
- Division of Haematology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Sigurd Broesby-Olsen
- Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark
| | - Knut Brockow
- Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany
| | - Marek Niedoszytko
- Department of Allergology, Medical University of Gdansk, Gdansk, Poland
| | - Olivier Hermine
- Service d'hématologie, Imagine Institute Université de Paris, Centre national de référence des mastocytoses, Hôpital Necker, Assistance publique hôpitaux de Paris, Paris, France
| | - Yannick Chantran
- Department of Biological Immunology, Saint-Antoine Hospital, Paris Sorbonne University, Paris, France
| | | | - Georg Greiner
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria; Ihr Labor, Medical Diagnostic Laboratories, Vienna, Austria
| | - Melody C Carter
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md
| | - Vito Sabato
- Faculty of Medicine and Health Sciences, Department of Immunology-Allergology-Rheumatology, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Deepti H Radia
- Guy's & St. Thomas' National Health Service (NHS) Foundation Trust, Guy's Hospital, London, UK
| | - Frank Siebenhaar
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Immunology and Allergology (IA), Berlin, Germany
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy
| | - Theo Gülen
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet, Stockholm, Sweden
| | - Ivan Alvarez-Twose
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) and CIBERONC, Hospital Virgen del Valle, Toledo, Spain
| | - Thomas Staudinger
- Department of Internal Medicine I, Intensive Care Unit, Medical University of Vienna, Vienna, Austria
| | - Ludwig Traby
- Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria
| | - Karl Sotlar
- Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Andreas Reiter
- Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
| | - Hans-Peter Horny
- Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
| | - Alberto Orfao
- Servicio Central de Citometria, Centro de Investigacion del Cancer (IBMCC CSIC/USAL) Instituto Biosanitario de Salamanca (IBSAL), CIBERONC and Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Stephen J Galli
- Department of Pathology, Department of Microbiology and Immunology, Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Lawrence B Schwartz
- Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, Virginia Commonwealth University, Richmond, Va
| | - Jonathan J Lyons
- Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, Md
| | - Jason Gotlib
- Stanford University School of Medicine/Stanford Cancer Institute, Stanford, Calif
| | - Dean D Metcalfe
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Hospital, Paris Sorbonne University, Paris, France
| | - Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Mich
| |
Collapse
|
|
10
|
Valent P, Hartmann K, Bonadonna P, Sperr WR, Niedoszytko M, Hermine O, Kluin-Nelemans HC, Sotlar K, Hoermann G, Nedoszytko B, Broesby-Olsen S, Zanotti R, Lange M, Doubek M, Brockow K, Alvarez-Twose I, Varkonyi J, Yavuz S, Nilsson G, Radia D, Grattan C, Schwaab J, Gülen T, Oude Elberink HNG, Hägglund H, Siebenhaar F, Hadzijusufovic E, Sabato V, Mayer J, Reiter A, Orfao A, Horny HP, Triggiani M, Arock M. European Competence Network on Mastocytosis (ECNM): 20-Year Jubilee, Updates, and Future Perspectives. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1706-1717. [PMID: 36868470 DOI: 10.1016/j.jaip.2023.02.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/17/2023] [Accepted: 02/13/2023] [Indexed: 03/05/2023]
Abstract
In 2002, the European Competence Network on Mastocytosis (ECNM) was launched as a multidisciplinary collaborative initiative to increase the awareness and to improve diagnosis and management of patients with mast cell (MC) disorders. The ECNM consists of a net of specialized centers, expert physicians, and scientists who dedicate their work to MC diseases. One essential aim of the ECNM is to timely distribute all available information about the disease to patients, doctors, and scientists. In the past 20 years, the ECNM has expanded substantially and contributed successfully to the development of new diagnostic concepts, and to the classification, prognostication, and treatments of patients with mastocytosis and MC activation disorders. The ECNM also organized annual meetings and several working conferences, thereby supporting the development of the World Health Organization classification between 2002 and 2022. In addition, the ECNM established a robust and rapidly expanding patient registry and supported the development of new prognostic scoring systems and new treatment approaches. In all projects, ECNM representatives collaborated closely with their U.S. colleagues, various patient organizations, and other scientific networks. Finally, ECNM members have started several collaborations with industrial partners, leading to the preclinical development and clinical testing of KIT-targeting drugs in systemic mastocytosis, and some of these drugs received licensing approval in recent years. All these networking activities and collaborations have strengthened the ECNM and supported our efforts to increase awareness of MC disorders and to improve diagnosis, prognostication, and therapy in patients.
Collapse
Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
| | - Karin Hartmann
- Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | | | - Wolfgang R Sperr
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Marek Niedoszytko
- Department of Allergology, Medical University of Gdansk, Gdansk, Poland
| | - Olivier Hermine
- Service d'Hématologie, Imagine Institute Université de Paris, INSERM U1163, Centre National de Référence des Mastocytoses, Hôpital Necker, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Hanneke C Kluin-Nelemans
- Department of Hematology, University Hospital Groningen, University of Groningen, Groningen, The Netherlands
| | - Karl Sotlar
- Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Gregor Hoermann
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria; MLL Munich Leukemia Laboratory, Munich, Germany
| | - Boguslaw Nedoszytko
- Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Poland, and Invicta Fertility and Reproductive Center, Molecular Laboratory, Sopot, Poland
| | - Sigurd Broesby-Olsen
- Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark
| | - Roberta Zanotti
- Section of Hematology, Multidisciplinary Outpatients Clinics for Mastocytosis, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Magdalena Lange
- Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk, Poland
| | - Michael Doubek
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
| | - Knut Brockow
- Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany
| | - Ivan Alvarez-Twose
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) and CIBERONC, Hospital Virgen del Valle, Toledo, Spain
| | | | - Selim Yavuz
- Division of Hematology, Istanbul Medical School, University of Istanbul, Istanbul, Turkey
| | - Gunnar Nilsson
- Department of Medicine Solna & Mastocytosis Centre, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden; Department of Medical Sciences, Uppsala University and Section of Hematology, Uppsala University Hospital, Uppsala, Sweden
| | - Deepti Radia
- Guy's & St. Thomas' NHS Foundation Trust, Guy's Hospital, London, UK
| | - Clive Grattan
- St. John's Institute of Dermatology, Guy's Hospital, London, UK
| | - Juliana Schwaab
- Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
| | - Theo Gülen
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet, Stockholm, Sweden
| | - Hanneke N G Oude Elberink
- Department of Internal Medicine, Division of Allergology, University Medical Center, Groningen University of Groningen, Groningen, The Netherlands
| | - Hans Hägglund
- Department of Medical Sciences, Uppsala University and Section of Hematology, Uppsala University Hospital, Uppsala, Sweden
| | - Frank Siebenhaar
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Emir Hadzijusufovic
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria; Department/University Clinic for Companion Animals and Horses, University Clinic for Small Animals, Internal Medicine Small Animals, University of Veterinary Medicine, Vienna, Austria
| | - Vito Sabato
- Faculty of Medicine and Health Sciences, Department of Immunology-Allergology-Rheumatology, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Jiri Mayer
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
| | - Andreas Reiter
- Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
| | - Alberto Orfao
- Servicio Central de Citometria, Centro de Investigacion del Cancer (IBMCC, CSIC/USAL) Instituto Biosanitario de Salamanca (IBSAL), CIBERONC and Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Hans-Peter Horny
- Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), Paris, France
| |
Collapse
|
|
11
|
Rymut SM, Henderson LM, Poon V, Staton TL, Cai F, Sukumaran S, Rhee H, Owen R, Ramanujan S, Yoshida K. A mechanistic PK/PD model to enable dose selection of the potent anti-tryptase antibody (MTPS9579A) in patients with moderate-to-severe asthma. Clin Transl Sci 2023; 16:694-703. [PMID: 36755366 PMCID: PMC10087065 DOI: 10.1111/cts.13483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/20/2022] [Accepted: 01/09/2023] [Indexed: 02/10/2023] Open
Abstract
Tryptase, a protease implicated in asthma pathology, is secreted from mast cells upon activation during an inflammatory allergic response. MTPS9579A is a novel monoclonal antibody that inhibits tryptase activity by irreversibly dissociating the active tetramer into inactive monomers. This study assessed the relationship between MTPS9579A concentrations in healthy subjects and tryptase levels in serum and nasal mucosal lining fluid from healthy subjects and patients with moderate-to-severe asthma. These data were used to develop a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model that quantitatively inter-relates MTPS9579A exposure and inhibition of active tryptase in the airway of patients with asthma. From initial estimates of airway tryptase levels and drug partitioning, the PK/PD model predicted almost complete neutralization of active tryptase in the airway of patients with asthma with MTPS9579A doses of 900 mg and greater, administered intravenously (i.v.) once every 4 weeks (q4w). Suppression of active tryptase during an asthma exacerbation event was also evaluated using the model by simulating the administration of MTPS9579A during a 100-fold increase in tryptase secretion in the local tissue. The PK/PD model predicted that 1800 mg MTPS9579A i.v. q4w results in 95.7% suppression of active tryptase at the steady-state trough concentration. Understanding how the exposure-response relationship of MTPS9579A in healthy subjects translates to patients with asthma is critical for future clinical studies assessing tryptase inhibition in the airway of patients with moderate-to-severe asthma.
Collapse
Affiliation(s)
- Sharon M Rymut
- Department of Clinical Pharmacology, Genentech Inc, South San Francisco, California, USA
| | - Lindsay M Henderson
- Department of Clinical Pharmacology, Genentech Inc, South San Francisco, California, USA
| | - Victor Poon
- Department of Clinical Pharmacology, Genentech Inc, South San Francisco, California, USA
| | - Tracy L Staton
- Department of Ophthalmology, Metabolism, Neurology & Immunology Biomarker Development (OMNI-BD), Genentech Inc, South San Francisco, California, USA
| | - Fang Cai
- Department of Ophthalmology, Metabolism, Neurology & Immunology Biomarker Development (OMNI-BD), Genentech Inc, South San Francisco, California, USA
| | - Siddharth Sukumaran
- Department of Preclinical and Translational PKPD, Genentech Inc, South San Francisco, California, USA
| | - Horace Rhee
- Early Clinical Development, Ophthalmology, Metabolism, Neurology Immunology (OMNI), Genentech Inc, South San Francisco, California, USA
| | - Ryan Owen
- Department of Clinical Pharmacology, Genentech Inc, South San Francisco, California, USA
| | - Saroja Ramanujan
- Department of Preclinical and Translational PKPD, Genentech Inc, South San Francisco, California, USA
| | - Kenta Yoshida
- Department of Clinical Pharmacology, Genentech Inc, South San Francisco, California, USA
| |
Collapse
|
|
12
|
Valent P, Hartmann K, Bonadonna P, Gülen T, Brockow K, Alvarez-Twose I, Hermine O, Niedoszytko M, Carter MC, Hoermann G, Butterfield JH, Lyons JJ, Sperr WR, Greiner G, Sotlar K, Kluin-Nelemans HC, Schwaab J, Lange M, George TI, Siebenhaar F, Broesby-Olsen S, Jawhar M, Nedoszytko B, Castells M, Orfao A, Gotlib J, Reiter A, Horny HP, Triggiani M, Arock M, Metcalfe DD, Akin C. Global Classification of Mast Cell Activation Disorders: An ICD-10-CM-Adjusted Proposal of the ECNM-AIM Consortium. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2022; 10:1941-1950. [PMID: 35623575 DOI: 10.1016/j.jaip.2022.05.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/04/2022] [Accepted: 05/11/2022] [Indexed: 12/18/2022]
Abstract
Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM-adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia.
Collapse
Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
| | - Karin Hartmann
- Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | | | - Theo Gülen
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet, Stockholm, Sweden
| | - Knut Brockow
- Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany
| | - Ivan Alvarez-Twose
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) and CIBERONC, Hospital Virgen del Valle, Toledo, Spain
| | - Olivier Hermine
- Service d'hématologie, Imagine Institute Université de Paris, Sorbonne, INSERM U1163, Centre national de référence des mastocytoses, Hôpital Necker, Assistance publiquehôpitaux de Paris, Paris, France
| | - Marek Niedoszytko
- Department of Allergology, Medical University of Gdansk, Gdansk, Poland
| | - Melody C Carter
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Gregor Hoermann
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria; MLL Munich Leukemia Laboratory, Munich, Germany
| | | | - Jonathan J Lyons
- Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Wolfgang R Sperr
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Georg Greiner
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, and Ihr Labor, Vienna, Austria
| | - Karl Sotlar
- Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Hanneke C Kluin-Nelemans
- Department of Haematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Juliana Schwaab
- Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
| | - Magdalena Lange
- Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk, Poland
| | - Tracy I George
- Department of Pathology, University of Utah, Salt Lake City, Utah
| | - Frank Siebenhaar
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Sigurd Broesby-Olsen
- Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark
| | - Mohamad Jawhar
- Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
| | - Boguslaw Nedoszytko
- Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk, Poland; Invicta Fertility and Reproductive Center, Molecular Laboratory, Sopot, Poland
| | - Mariana Castells
- Division of Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass
| | - Alberto Orfao
- Servicio Central de Citometria, Centro de Investigacion del Cancer (IBMCC; CSIC/USAL), Instituto Biosanitario de Salamanca (IBSAL), CIBERONC and Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Jason Gotlib
- Stanford Cancer Institute/Stanford University School of Medicine, Stanford, Calif
| | - Andreas Reiter
- Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
| | - Hans-Peter Horny
- Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), Paris, France
| | - Dean D Metcalfe
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Mich
| |
Collapse
|
|
13
|
Awan SF, Schwartz LB, Maric I, Metcalfe DD, Carter MC. Acute increases in total serum tryptase unassociated with hemodynamic instability in diffuse cutaneous mastocytosis. Ann Allergy Asthma Immunol 2022; 129:249-252. [PMID: 35568301 DOI: 10.1016/j.anai.2022.04.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/13/2022] [Accepted: 04/27/2022] [Indexed: 11/19/2022]
Affiliation(s)
- Seemal F Awan
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
| | - Larry B Schwartz
- Division of Rheumatology, Allergy and Immunology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Irina Maric
- Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Dean D Metcalfe
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Melody C Carter
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
14
|
State-of-the-Art on Biomarkers for Anaphylaxis in Obstetrics. Life (Basel) 2021; 11:life11090870. [PMID: 34575019 PMCID: PMC8467046 DOI: 10.3390/life11090870] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/21/2021] [Accepted: 08/23/2021] [Indexed: 12/25/2022] Open
Abstract
Anaphylaxis is an unpredictable systemic hypersensitivity reaction and constitutes a high risk of maternal and fetal morbidity and mortality when occurring during pregnancy. Currently, the acute management of anaphylaxis is based on clinical parameters. A total serum tryptase is only used to support an accurate diagnosis. There is a need to detect other biomarkers to further assess high-risk patients in obstetrics. Our objective is to present biomarkers in this complex interdisciplinary approach beyond obstetrician and anaesthetic management. Candidate biomarkers derive either from mediators involved in immunopathogenesis or upcoming molecules from systems biology and proteomics. Serum tryptase is determined by singleplex immunoassay method and is important in the evaluation of anaphylactic mast cell degranulation but also in the assessment of other risk factors for anaphylaxis such as systemic mastocytosis. Another category of biomarkers investigates the IgE-mediated sensitization to triggers potentially involved in the etiology of anaphylaxis in pregnant women, using singleplex or multiplex immunoassays. These in vitro tests with natural extracts from foods, venoms, latex or drugs, as well as with molecular allergen components, are useful because in vivo allergy tests cannot be performed on pregnant women in such a major medical emergency due to their additional potential risk of anaphylaxis.
Collapse
|
|
15
|
Soria-Castro R, Meneses-Preza YG, Rodríguez-López GM, Romero-Ramírez S, Sosa-Hernández VA, Cervantes-Díaz R, Pérez-Fragoso A, Torres-Ruíz JJ, Gómez-Martín D, Campillo-Navarro M, Álvarez-Jiménez VD, Pérez-Tapia SM, Chávez-Blanco AD, Estrada-Parra S, Maravillas-Montero JL, Chacón-Salinas R. Severe COVID-19 is marked by dysregulated serum levels of carboxypeptidase A3 and serotonin. J Leukoc Biol 2021; 110:425-431. [PMID: 34057753 PMCID: PMC8242632 DOI: 10.1002/jlb.4hi0221-087r] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/19/2021] [Accepted: 04/15/2021] [Indexed: 12/22/2022] Open
Abstract
The immune response plays a critical role in the pathophysiology of SARS‐CoV‐2 infection ranging from protection to tissue damage and all occur in the development of acute respiratory distress syndrome (ARDS). ARDS patients display elevated levels of inflammatory cytokines and innate immune cells, and T and B cell lymphocytes have been implicated in this dysregulated immune response. Mast cells are abundant resident cells of the respiratory tract and are able to release different inflammatory mediators rapidly following stimulation. Recently, mast cells have been associated with tissue damage during viral infections, but their role in SARS‐CoV‐2 infection remains unclear. In this study, we examined the profile of mast cell activation markers in the serum of COVID‐19 patients. We noticed that SARS‐CoV‐2‐infected patients showed increased carboxypeptidase A3 (CPA3) and decreased serotonin levels in their serum when compared with symptomatic SARS‐CoV‐2‐negative patients. CPA3 levels correlated with C‐reactive protein, the number of circulating neutrophils, and quick SOFA. CPA3 in serum was a good biomarker for identifying severe COVID‐19 patients, whereas serotonin was a good predictor of SARS‐CoV‐2 infection. In summary, our results show that serum CPA3 and serotonin levels are relevant biomarkers during SARS‐CoV‐2 infection. This suggests that mast cells and basophils are relevant players in the inflammatory response in COVID‐19 and may represent targets for therapeutic intervention.
Collapse
Affiliation(s)
- Rodolfo Soria-Castro
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico City, Mexico
| | - Yatsiri G Meneses-Preza
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico City, Mexico
| | - Gloria M Rodríguez-López
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico City, Mexico
| | - Sandra Romero-Ramírez
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.,Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Víctor A Sosa-Hernández
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.,Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Rodrigo Cervantes-Díaz
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.,Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Alfredo Pérez-Fragoso
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - José J Torres-Ruíz
- Departamento de Atención Institucional Continua y Urgencias, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Diana Gómez-Martín
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - Sonia M Pérez-Tapia
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico City, Mexico.,Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico City, Mexico
| | - Alma D Chávez-Blanco
- División de Ciencia Básica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - Sergio Estrada-Parra
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico City, Mexico
| | - José L Maravillas-Montero
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Rommel Chacón-Salinas
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico City, Mexico
| |
Collapse
|
|
16
|
Wu R, Lyons JJ. Hereditary Alpha-Tryptasemia: a Commonly Inherited Modifier of Anaphylaxis. Curr Allergy Asthma Rep 2021; 21:33. [PMID: 33970354 DOI: 10.1007/s11882-021-01010-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait and a common cause of elevated basal serum tryptase in Western populations. It is a risk factor for severe anaphylaxis among individuals with venom allergy and an established modifier of anaphylaxis and mast cell mediator-associated symptoms among patients with systemic mastocytosis. Understanding the physiology of tryptases and how this may relate to the clinical features associated with HαT is the first step in identifying optimal medical management and targets for novel therapeutics. RECENT FINDINGS HαT prevalence is increased in both clonal and non-clonal mast cell-associated disorders where it augments symptoms of immediate hypersensitivity, including anaphylaxis. The unique properties of naturally occurring α/β-tryptase heterotetramers may explain certain elements of phenotypes associated with HαT, though additional mechanisms are being evaluated. This review provides an overview of the clinical and translational studies that have identified HαT as a modifier of mast cell-associated disorders and anaphylaxis and discusses mechanisms that may potentially explain some of these clinical findings.
Collapse
Affiliation(s)
- Richard Wu
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Building 29B, Room 5NN18, MSC 1889, Bethesda, MD, 20892, USA
| | - Jonathan J Lyons
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Building 29B, Room 5NN18, MSC 1889, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
17
|
Ebo DG, De Puysseleyr LP, Van Gasse AL, Elst J, Poorten MLVD, Faber MA, Mertens C, Van Houdt M, Hagendorens MM, Sermeus L, Vitte J, Moise M, Garvey LH, Castells MC, Tacquard C, Mertes PM, Schwartz LB, Sabato V. Mast Cell Activation During Suspected Perioperative Hypersensitivity: A Need for Paired Samples Analysis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:3051-3059.e1. [PMID: 33862269 DOI: 10.1016/j.jaip.2021.03.050] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/12/2021] [Accepted: 03/27/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Perioperative hypersensitivity (POH) reactions constitute a significant clinical and diagnostic challenge. A transient increase in serum tryptase during POH reflects mast cell activation (MCA) and helps to recognize an underlying hypersensitivity mechanism. OBJECTIVE To determine the diagnostic performance of different tryptase decision thresholds based on single and paired measurements to document MCA in suspected POH. METHODS Acute serum tryptase (aST) and baseline serum tryptase (bST) samples were obtained from patients referred to our outpatients clinic because of clinical POH. Tryptase samples from controls were obtained before induction (Tt0) and 1.5 hours after induction (Tt1) in uneventful anesthesia. Different cutoff points for tryptase increase over bST and the percentage increase in tryptase (%T) were calculated and compared with existing thresholds: aST > [1.2 × (bST) + 2] (consensus formula), aST higher than 11.4 ng/mL, and aST higher than 14 ng/mL. RESULTS Patients with POH had higher bST and aST levels compared with controls (respectively 5.15 vs 2.28 ng/mL for bST and 20.30 vs 1.92 ng/mL for aST). The consensus formula and a tryptase increase over bST of greater than or equal to 3.2 ng/mL held the highest accuracies to document MCA in POH (respectively 81% and 82%). A bST of higher than 8 ng/mL was present in 4% of controls, 5% of patients with grade 1 POH, 24% of patients with grade 2 POH, 15% of patients with grade 3 POH, and 17% of patients with grade 4 POH. CONCLUSIONS Our data endorse the consensus formula for detection of MCA in POH. Furthermore, it shows that a bST of higher than 8 ng/mL was associated with occurrence of anaphylaxis.
Collapse
Affiliation(s)
- Didier G Ebo
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium; AZ Jan Palfijn Gent, Department of Immunology and Allergology, Ghent, Belgium.
| | - Leander P De Puysseleyr
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Athina L Van Gasse
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium; Faculty of Medicine and Health Sciences, Department of Paediatrics and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium
| | - Jessy Elst
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Marie-Line van der Poorten
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium; Faculty of Medicine and Health Sciences, Department of Paediatrics and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium
| | - Margaretha A Faber
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Christel Mertens
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Michel Van Houdt
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium
| | - Margo M Hagendorens
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium; Faculty of Medicine and Health Sciences, Department of Paediatrics and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium
| | - Luc Sermeus
- Department of Anaesthesia, Antwerp University Hospital, Antwerp, Belgium
| | - Joana Vitte
- Aix-Marseille University, IRD, APHM, MEPHI, IHU Méditerranée Infection, Marseille, France; IDESP, INSERM, University of Montpellier, Montpellier, France; Laboratoire d'Immunologie, CHU de Nîmes, Nîmes, France
| | - Michel Moise
- Aix-Marseille University, IRD, APHM, MEPHI, IHU Méditerranée Infection, Marseille, France; Laboratoire d'Immunologie, CHU de Nîmes, Nîmes, France
| | - Lene H Garvey
- Allergy Clinic, Department of Dermatology and Allergy, Gentofte Hospital, Gentofte, Denmark; Department of Clinical Medicine, Ha, Denmark
| | - Mariana C Castells
- Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Harvard Medical School, Boston, Mass
| | - Charles Tacquard
- Nouvel Hôpital Civil, hôpitaux universitaires de Strasbourg, service d'anesthésie-réanimation chirurgicale, Strasbourg, France
| | - Paul-Michel Mertes
- Nouvel Hôpital Civil, hôpitaux universitaires de Strasbourg, service d'anesthésie-réanimation chirurgicale, Strasbourg, France
| | - Lawrence B Schwartz
- Department of Internal Medicine, Division of Rheumatology, Allergy & Immunologie, Virginia Commonwealth University, Richmond, Va
| | - Vito Sabato
- Faculty of Medicine and Health Sciences, Department of Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology, Allergology, Rheumatology, Antwerp University Hospital, Antwerp, Belgium; AZ Jan Palfijn Gent, Department of Immunology and Allergology, Ghent, Belgium
| |
Collapse
|
|
18
|
Marcella S, Petraroli A, Braile M, Parente R, Ferrara AL, Galdiero MR, Modestino L, Cristinziano L, Rossi FW, Varricchi G, Triggiani M, de Paulis A, Spadaro G, Loffredo S. Vascular endothelial growth factors and angiopoietins as new players in mastocytosis. Clin Exp Med 2021; 21:415-427. [PMID: 33687603 PMCID: PMC8266723 DOI: 10.1007/s10238-021-00693-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 02/08/2021] [Indexed: 12/27/2022]
Abstract
Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSAKIT WT and ROSA KIT D816V and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSAKIT WT, ROSAKIT D816V and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.
Collapse
Affiliation(s)
- Simone Marcella
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Angelica Petraroli
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Mariantonia Braile
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Roberta Parente
- Division of Allergy and Clinical Immunology, University of Salerno, 84084, Fisciano, SA, Italy
| | - Anne Lise Ferrara
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy.,Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy.,Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy
| | - Luca Modestino
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Leonardo Cristinziano
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Francesca Wanda Rossi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy. .,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy. .,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy. .,Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy.
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, 84084, Fisciano, SA, Italy
| | - Amato de Paulis
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Giuseppe Spadaro
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy. .,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy. .,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy. .,Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy.
| |
Collapse
|
|
19
|
Sprinzl B, Greiner G, Uyanik G, Arock M, Haferlach T, Sperr WR, Valent P, Hoermann G. Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond. Int J Mol Sci 2021; 22:2458. [PMID: 33671092 PMCID: PMC7957558 DOI: 10.3390/ijms22052458] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/20/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and stored in secretory granules together with other pre-formed mediators. MC activation, degranulation and mediator release contribute to various immunological processes, but also to several specific diseases, such as IgE-dependent allergies and clonal MC disorders. Biologically active tryptase tetramers primarily derive from the two genes TPSB2 (encoding β-tryptase) and TPSAB1 (encoding either α- or β-tryptase). Based on the most common gene copy numbers, three genotypes, 0α:4β, 1α:3β and 2α:2β, were defined as "canonical". About 4-6% of the general population carry germline TPSAB1-α copy number gains (2α:3β, 3α:2β or more α-extra-copies), resulting in elevated basal serum tryptase levels. This condition has recently been termed hereditary alpha tryptasemia (HαT). Although many carriers of HαT appear to be asymptomatic, a number of more or less specific symptoms have been associated with HαT. Recent studies have revealed a significantly higher HαT prevalence in patients with systemic mastocytosis (SM) and an association with concomitant severe Hymenoptera venom-induced anaphylaxis. Moreover, HαT seems to be more common in idiopathic anaphylaxis and MC activation syndromes (MCAS). Therefore, TPSAB1 genotyping should be included in the diagnostic algorithm in patients with symptomatic SM, severe anaphylaxis or MCAS.
Collapse
Affiliation(s)
- Bettina Sprinzl
- Ludwig Boltzmann Institute for Hematology and Oncology at the Hanusch Hospital, Center for Medical Genetics, Hanusch Hospital, 1140 Vienna, Austria; (B.S.); (G.U.)
- Center for Medical Genetics, Hanusch Hospital, 1140 Vienna, Austria
| | - Georg Greiner
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria;
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria; (W.R.S.); (P.V.)
- Ihr Labor, Medical Diagnostic Laboratories, 1220 Vienna, Austria
| | - Goekhan Uyanik
- Ludwig Boltzmann Institute for Hematology and Oncology at the Hanusch Hospital, Center for Medical Genetics, Hanusch Hospital, 1140 Vienna, Austria; (B.S.); (G.U.)
- Center for Medical Genetics, Hanusch Hospital, 1140 Vienna, Austria
- Medical School, Sigmund Freud Private University, 1020 Vienna, Austria
| | - Michel Arock
- Department of Hematology, APHP, Pitié-Salpêtrière-Charles Foix University Hospital and Sorbonne University, 75013 Paris, France;
- Centre de Recherche des Cordeliers, INSERM, Sorbonne University, Cell Death and Drug Resistance in Hematological Disorders Team, 75006 Paris, France
| | | | - Wolfgang R. Sperr
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria; (W.R.S.); (P.V.)
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria
| | - Peter Valent
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria; (W.R.S.); (P.V.)
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria
| | - Gregor Hoermann
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria; (W.R.S.); (P.V.)
- MLL Munich Leukemia Laboratory, 81377 Munich, Germany;
| |
Collapse
|
|
20
|
Mast Cell Activation Disorders. ACTA ACUST UNITED AC 2021; 57:medicina57020124. [PMID: 33573161 PMCID: PMC7911219 DOI: 10.3390/medicina57020124] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/23/2021] [Accepted: 01/27/2021] [Indexed: 02/07/2023]
Abstract
Background and Objectives: Mast cell disorders comprise a wide spectrum of syndromes caused by mast cells' degranulation with acute or chronic clinical manifestations. Materials and Methods: In this review article we reviewed the latest findings in scientific papers about mast cell disorders with a particular focus on mast cell activation syndrome and mastocytosis in pediatric age. Results: Patients with mast cell activation syndrome have a normal number of mast cells that are hyperreactive upon stimulation of various triggers. We tried to emphasize the diagnostic criteria, differential diagnosis, and therapeutic strategies. Another primary mast cell disorder is mastocytosis, a condition with a long-known disease, in which patients have an increased number of mast cells that accumulate in different regions of the body with different clinical evolution in pediatric age. Conclusions: Mast cell activation syndrome overlaps with different clinical entities. No consensus was found on biomarkers and no clearly resolutive treatment is available. Therefore, a more detailed knowledge of this syndrome is of fundamental importance for a correct diagnosis and effective therapy.
Collapse
|
|
21
|
Valent P, Akin C, Nedoszytko B, Bonadonna P, Hartmann K, Niedoszytko M, Brockow K, Siebenhaar F, Triggiani M, Arock M, Romantowski J, Górska A, Schwartz LB, Metcalfe DD. Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine. Int J Mol Sci 2020; 21:ijms21239030. [PMID: 33261124 PMCID: PMC7731385 DOI: 10.3390/ijms21239030] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/16/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022] Open
Abstract
Mast cell activation (MCA) is seen in a variety of clinical contexts and pathologies, including IgE-dependent allergic inflammation, other immunologic and inflammatory reactions, primary mast cell (MC) disorders, and hereditary alpha tryptasemia (HAT). MCA-related symptoms range from mild to severe to life-threatening. The severity of MCA-related symptoms depends on a number of factors, including genetic predisposition, the number and releasability of MCs, organs affected, and the type and consequences of comorbid conditions. In severe systemic reactions, MCA is demonstrable by a substantial increase of basal serum tryptase levels above the individual’s baseline. When, in addition, the symptoms are recurrent, involve more than one organ system, and are responsive to therapy with MC-stabilizing or mediator-targeting drugs, the consensus criteria for the diagnosis of MCA syndrome (MCAS) are met. Based on the etiology of MCA, patients can further be classified as having i) primary MCAS where KIT-mutated, clonal, MCs are detected; ii) secondary MCAS where an underlying IgE-dependent allergy or other reactive MCA-triggering pathology is found; or iii) idiopathic MCAS, where neither a triggering reactive state nor KIT-mutated MCs are identified. Most severe MCA events occur in combined forms of MCAS, where KIT-mutated MCs, IgE-dependent allergies and sometimes HAT are detected. These patients may suffer from life-threatening anaphylaxis and are candidates for combined treatment with various types of drugs, including IgE-blocking antibodies, anti-mediator-type drugs and MC-targeting therapy. In conclusion, detailed knowledge about the etiology, underlying pathologies and co-morbidities is important to establish the diagnosis and develop an optimal management plan for MCAS, following the principles of personalized medicine.
Collapse
Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria
- Correspondence: (P.V.); (B.N.)
| | - Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI 48106, USA;
| | - Boguslaw Nedoszytko
- Department of Dermatology, Medical University of Gdansk, 80-211 Gdansk, Poland
- Correspondence: (P.V.); (B.N.)
| | | | - Karin Hartmann
- Division of Allergy, University Hospital Basel and University of Basel, 4031 Basel, Switzerland;
| | - Marek Niedoszytko
- Department of Allergology, Medical University of Gdansk, 80-211 Gdansk, Poland; (M.N.); (J.R.); (A.G.)
| | - Knut Brockow
- Department of Dermatology and Allergy Biederstein, Technical University of Munich, D-80802 Munich, Germany;
| | - Frank Siebenhaar
- Dermatological Allergology, Department of Dermatology and Allergy, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany;
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, 84131 Salerno, Italy;
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), 75005 Paris, France;
| | - Jan Romantowski
- Department of Allergology, Medical University of Gdansk, 80-211 Gdansk, Poland; (M.N.); (J.R.); (A.G.)
| | - Aleksandra Górska
- Department of Allergology, Medical University of Gdansk, 80-211 Gdansk, Poland; (M.N.); (J.R.); (A.G.)
| | - Lawrence B. Schwartz
- Department of Internal Medicine, Division of Rheumatology, Allergy & Immunology, Virginia Commonwealth University, Richmond, VA 23284, USA;
| | - Dean D. Metcalfe
- Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20852, USA;
| |
Collapse
|
|
22
|
Di Raimondo C, Del Duca E, Silvaggio D, Di Prete M, Lombardo P, Mazzeo M, Spallone G, Campione E, Botti E, Bianchi L. Cutaneous mastocytosis: A dermatological perspective. Australas J Dermatol 2020; 62:e1-e7. [PMID: 33040350 DOI: 10.1111/ajd.13443] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 12/01/2022]
Abstract
Mastocytosis is a rare disease characterised by expansion and collection of clonal mast cells in various organs including the skin, bone marrow, spleen, lymph nodes and gastrointestinal tract. The prevalence of mastocytosis has been estimated to be one in 10 000, while the estimated incidence is one per 100 000 people per year. Cutaneous mastocytosis is classified into (i) maculopapular cutaneous mastocytosis, also known as urticaria pigmentosa; (ii) diffuse cutaneous mastocytosis; and (iii) mastocytoma of the skin. In adults, cutaneous lesions are usually associated with indolent systemic mastocytosis and have a chronic evolution. Paediatric patients, on the contrary, have often cutaneous manifestations without systemic involvement and usually experience a spontaneous regression. Diagnosis of cutaneous mastocytosis may be challenging due to the rarity of the disease and the overlap of cutaneous manifestations. This short review describes pathogenesis and clinical aspects of cutaneous mastocytosis with a focus on diagnosis and currently available therapies.
Collapse
Affiliation(s)
| | - Ester Del Duca
- Department of Dermatology, University of Roma Tor Vergata, Rome, Italy
| | | | - Monia Di Prete
- Department of Anatomic Pathology, University of Rome Tor Vergata, Rome, Italy
| | - Paolo Lombardo
- Department of Dermatology, University of Roma Tor Vergata, Rome, Italy
| | - Mauro Mazzeo
- Department of Dermatology, University of Roma Tor Vergata, Rome, Italy
| | - Giulia Spallone
- Department of Dermatology, University of Roma Tor Vergata, Rome, Italy
| | - Elena Campione
- Department of Dermatology, University of Roma Tor Vergata, Rome, Italy
| | - Elisabetta Botti
- Department of Dermatology, University of Roma Tor Vergata, Rome, Italy
| | - Luca Bianchi
- Department of Dermatology, University of Roma Tor Vergata, Rome, Italy
| |
Collapse
|
|
23
|
Serrao S, Firinu D, Olianas A, Deidda M, Contini C, Iavarone F, Sanna MT, Boroumand M, Amado F, Castagnola M, Messana I, Del Giacco S, Manconi B, Cabras T. Top-Down Proteomics of Human Saliva Discloses Significant Variations of the Protein Profile in Patients with Mastocytosis. J Proteome Res 2020. [PMID: 32575983 DOI: 10.1021/acs.jproteome.0c00207.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Mastocytosis is a myeloproliferative neoplasm causing abnormal clonal mast cell accumulation in different tissues, such as skin and bone marrow. A cutaneous subtype (CM) is distinguished from a systemic one (SM); SM patients can be grouped into SM with (SM+C) or without (SM-C) additional cutaneous lesions, and their classification is often challenging. This study was purposed to highlight variations in the salivary proteome of patients with different mastocytosis subtypes and compared to healthy controls. A top-down proteomics approach coupled to a label-free quantitation revealed salivary profiles in patients different from those of controls and a down-regulation of peptides/proteins involved in the mouth homeostasis and defense, such as statherin, histatins, and acidic proline-rich proteins (aPRPs), and in innate immunity and inflammation, such as the cathepsin inhibitors, suggesting a systemic condition associated with an exacerbated inflammatory state. The up-regulation of antileukoproteinase and S100A8 suggested a protective role against the disease status. The two SM forms were distinguished by the lower levels of truncated forms of aPRPs, statherin, P-B peptide, and cystatin D and the higher levels of thymosin β4 and α-defensins 1 and 4 in SM-C patients with respect to SM+C. Data are available via ProteomeXchange with identifier PXD017759.
Collapse
Affiliation(s)
- Simone Serrao
- Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Davide Firinu
- Dipartimento di Scienze Mediche e Sanità Pubblica, Università di Cagliari, 09124 Cagliari, Italy
| | - Alessandra Olianas
- Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Margherita Deidda
- Dipartimento di Scienze Mediche e Sanità Pubblica, Università di Cagliari, 09124 Cagliari, Italy
| | - Cristina Contini
- Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Federica Iavarone
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.,Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy
| | - M Teresa Sanna
- Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Mozhgan Boroumand
- Laboratorio di Proteomica e Metabonomica-IRCCS Fondazione Santa Lucia, 100168 Roma, Italy
| | - Francisco Amado
- QOPNA, Mass spectrometry center, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Massimo Castagnola
- Laboratorio di Proteomica e Metabonomica-IRCCS Fondazione Santa Lucia, 100168 Roma, Italy
| | - Irene Messana
- Istituto di Scienze e Tecnologie Chimiche "Giulio Natta", Consiglio Nazionale delle Ricerche, 00185 Roma, Italy
| | - Stefano Del Giacco
- Dipartimento di Scienze Mediche e Sanità Pubblica, Università di Cagliari, 09124 Cagliari, Italy
| | - Barbara Manconi
- Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Tiziana Cabras
- Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| |
Collapse
|
|
24
|
Serrao S, Firinu D, Olianas A, Deidda M, Contini C, Iavarone F, Sanna MT, Boroumand M, Amado F, Castagnola M, Messana I, Del Giacco S, Manconi B, Cabras T. Top-Down Proteomics of Human Saliva Discloses Significant Variations of the Protein Profile in Patients with Mastocytosis. J Proteome Res 2020; 19:3238-3253. [PMID: 32575983 PMCID: PMC8008451 DOI: 10.1021/acs.jproteome.0c00207] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Indexed: 01/06/2023]
Abstract
Mastocytosis is a myeloproliferative neoplasm causing abnormal clonal mast cell accumulation in different tissues, such as skin and bone marrow. A cutaneous subtype (CM) is distinguished from a systemic one (SM); SM patients can be grouped into SM with (SM+C) or without (SM-C) additional cutaneous lesions, and their classification is often challenging. This study was purposed to highlight variations in the salivary proteome of patients with different mastocytosis subtypes and compared to healthy controls. A top-down proteomics approach coupled to a label-free quantitation revealed salivary profiles in patients different from those of controls and a down-regulation of peptides/proteins involved in the mouth homeostasis and defense, such as statherin, histatins, and acidic proline-rich proteins (aPRPs), and in innate immunity and inflammation, such as the cathepsin inhibitors, suggesting a systemic condition associated with an exacerbated inflammatory state. The up-regulation of antileukoproteinase and S100A8 suggested a protective role against the disease status. The two SM forms were distinguished by the lower levels of truncated forms of aPRPs, statherin, P-B peptide, and cystatin D and the higher levels of thymosin β4 and α-defensins 1 and 4 in SM-C patients with respect to SM+C. Data are available via ProteomeXchange with identifier PXD017759.
Collapse
Affiliation(s)
- Simone Serrao
- Dipartimento
di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Davide Firinu
- Dipartimento
di Scienze Mediche e Sanità Pubblica, Università di Cagliari, 09124 Cagliari, Italy
| | - Alessandra Olianas
- Dipartimento
di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Margherita Deidda
- Dipartimento
di Scienze Mediche e Sanità Pubblica, Università di Cagliari, 09124 Cagliari, Italy
| | - Cristina Contini
- Dipartimento
di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Federica Iavarone
- Dipartimento
di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Fondazione
Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy
| | - M. Teresa Sanna
- Dipartimento
di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Mozhgan Boroumand
- Laboratorio
di Proteomica e Metabonomica-IRCCS Fondazione Santa Lucia, 100168 Roma, Italy
| | - Francisco Amado
- QOPNA, Mass
spectrometry center, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Massimo Castagnola
- Laboratorio
di Proteomica e Metabonomica-IRCCS Fondazione Santa Lucia, 100168 Roma, Italy
| | - Irene Messana
- Istituto
di Scienze e Tecnologie Chimiche “Giulio Natta”, Consiglio Nazionale delle Ricerche, 00185 Roma, Italy
| | - Stefano Del Giacco
- Dipartimento
di Scienze Mediche e Sanità Pubblica, Università di Cagliari, 09124 Cagliari, Italy
| | - Barbara Manconi
- Dipartimento
di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| | - Tiziana Cabras
- Dipartimento
di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy
| |
Collapse
|
|
25
|
Kucharik AH, Chang C. The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS). Clin Rev Allergy Immunol 2020; 58:273-297. [PMID: 31267471 DOI: 10.1007/s12016-019-08755-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In recent years, an association between hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS), and postural orthostatic tachycardia syndrome (POTS) has garnered attention and patients are increasingly presenting with this triad. However, a real relationship between these entities is unclear due to a lack of scientific validity. We conducted an extensive review of the literature using two different search strategies. A narrower strategy included 88 searches of various combinations of terms for each of the three conditions, yielding 19 unique papers. A broader search included 136 searches of various combinations of terms but included all forms of EDS and yielded 40 unique papers. Of these, only four and nine papers from the narrower and broader search strategies were original research articles. None of these papers resulted from a combination of the search terms for the three conditions. All three clinical entities are controversial in either existence or pathogenesis. MCAS is a poorly defined clinical entity, and many studies do not adhere to the proposed criteria when establishing the diagnosis. Patients previously diagnosed with EDS hypermobility type may not meet the new, stricter criteria for hEDS but may for a less severe hypermobility spectrum disorder (HSD). The pathophysiology of POTS is still unclear. An evidence-based, common pathophysiologic mechanism between any of the two, much less all three conditions, has yet to be described. Our review of the literature shows that current evidence is lacking on the existence of MCAS or hEDS as separate or significant clinical entities. Studies proposing a relationship between the three clinical entities are either biased or based on outdated criteria. The reason behind the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists.
Collapse
Affiliation(s)
| | - Christopher Chang
- Florida Atlantic University, Boca Raton, FL, USA.
- Joe DiMaggio Children's Hospital, 1131 North 35th Avenue, Suite 220, Hollywood, FL, 33021, USA.
- University of California, Davis, CA, USA.
- Florida International University, Miami, FL, USA.
| |
Collapse
|
|
26
|
Yasui K, Matsuyama N, Takihara Y, Hirayama F. New insights into allergic transfusion reactions and their causal relationships, pathogenesis, and prevention. Transfusion 2020; 60:1590-1601. [DOI: 10.1111/trf.15845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/22/2020] [Accepted: 04/08/2020] [Indexed: 12/13/2022]
Affiliation(s)
- Kazuta Yasui
- Japanese Red Cross Kinki Block Blood Center Ibaraki Osaka Japan
| | | | | | - Fumiya Hirayama
- Japanese Red Cross Kinki Block Blood Center Ibaraki Osaka Japan
| |
Collapse
|
|
27
|
|
|
28
|
Lee AYS. Elevated Serum Tryptase in Non-Anaphylaxis Cases: A Concise Review. Int Arch Allergy Immunol 2020; 181:357-364. [PMID: 32126554 DOI: 10.1159/000506199] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 01/27/2020] [Indexed: 11/19/2022] Open
Abstract
One of the most important blood tests in the field of allergy, mast cell tryptase has numerous diagnostic uses, particularly for anaphylactic reactions and for the diagnosis of mastocytosis. However, there are numerous other non-anaphylactic conditions where clinicians may see elevated serum tryptase (hypertryptasemia) and the practicing clinician ought to be aware of these important differential diagnoses. Such conditions include systemic mastocytosis, hematological malignancies, and chronic kidney disease. This article provides a comprehensive, updated summary on the variety of non-anaphylactic conditions where hypertryptasemia may be seen.
Collapse
Affiliation(s)
- Adrian Y S Lee
- Department of Allergy/Clinical Immunology and SA Pathology, Flinders Medical Centre, Bedford Park, South Australia, Australia, .,College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia,
| |
Collapse
|
|
29
|
Weiler CR. Mast Cell Activation Syndrome: Tools for Diagnosis and Differential Diagnosis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2020; 8:498-506. [DOI: 10.1016/j.jaip.2019.08.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 07/30/2019] [Accepted: 08/07/2019] [Indexed: 02/07/2023]
|
|
30
|
Abstract
Mast cell activation syndrome (MCAS) is a heterogeneous and rare disorder with episodic and severe activation of mast cells. Because symptoms of mast cell activation are nonspecific, it is important to base the diagnosis on best available clinical and scientific evidence, and not make it one of exclusion. MCAS, much like the mast cell itself, as a whole is greater than the sum of its proposed diagnostic criteria. When each component is considered in isolation, criteria can seem nonspecific, and thus, a broad constellation of symptoms can be attributed to MCAS when they may be due to other disease processes.
Collapse
Affiliation(s)
- Dilawar Khokhar
- Department of Internal Medicine, Division of Allergy and Clinical Immunology, University of Michigan, 24 Frank Lloyd Wright Drive, Lobby H Suite H-2100, Ann Arbor, MI 48106, USA
| | - Cem Akin
- Department of Internal Medicine, Division of Allergy and Clinical Immunology, University of Michigan, 24 Frank Lloyd Wright Drive, Lobby H Suite H-2100, Ann Arbor, MI 48106, USA.
| |
Collapse
|
|
31
|
Le QT, Lyons JJ, Naranjo AN, Olivera A, Lazarus RA, Metcalfe DD, Milner JD, Schwartz LB. Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia. J Exp Med 2019; 216:2348-2361. [PMID: 31337736 PMCID: PMC6780998 DOI: 10.1084/jem.20190701] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/12/2019] [Accepted: 06/25/2019] [Indexed: 12/19/2022] Open
Abstract
Human α/β-tryptase heterotetramer, a previously hidden form of tryptase, explains some of the unusual clinical features of hereditary α-tryptasemia. α/β-Tryptase forms naturally in mast cells and, when secreted, activates clinically relevant proteins, likely impacting a variety of mast cell disorders. Both α-tryptase and β-tryptase are preferentially expressed by human mast cells, but the purpose of α-tryptase is enigmatic, because its tetramers lack protease activity, whereas β-tryptase tetramers are active proteases. The monogenic disorder called hereditary α-tryptasemia, due to increased α-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2α- and 2β-tryptase protomers (α/β-tryptase) form naturally in individuals who express α-tryptase. α/β-Tryptase, but not homotetramer, activates protease-activated receptor-2 (PAR2), which is expressed on cell types such as smooth muscle, neurons, and endothelium. Also, only α/β-tryptase makes mast cells susceptible to vibration-triggered degranulation by cleaving the α subunit of the EGF-like module–containing mucin-like hormone receptor-like 2 (EMR2) mechanosensory receptor. Allosteric effects of α-tryptase protomers on neighboring β-tryptase protomers likely result in the novel substrate repertoire of α/β-tryptase tetramers that in turn cause some of the clinical features of hereditary α-tryptasemia and of other disorders involving mast cells.
Collapse
Affiliation(s)
- Quang T Le
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA
| | - Jonathan J Lyons
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Andrea N Naranjo
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Ana Olivera
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Robert A Lazarus
- Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA
| | - Dean D Metcalfe
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Joshua D Milner
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Lawrence B Schwartz
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA
| |
Collapse
|
|
32
|
Mohajeri M, Kovanen PT, Bianconi V, Pirro M, Cicero AFG, Sahebkar A. Mast cell tryptase - Marker and maker of cardiovascular diseases. Pharmacol Ther 2019; 199:91-110. [PMID: 30877022 DOI: 10.1016/j.pharmthera.2019.03.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 03/01/2019] [Indexed: 12/14/2022]
Abstract
Mast cells are tissue-resident cells, which have been proposed to participate in various inflammatory diseases, among them the cardiovascular diseases (CVDs). For mast cells to be able to contribute to an inflammatory process, they need to be activated to exocytose their cytoplasmic secretory granules. The granules contain a vast array of highly bioactive effector molecules, the neutral protease tryptase being the most abundant protein among them. The released tryptase may act locally in the inflamed cardiac or vascular tissue, so contributing directly to the pathogenesis of CVDs. Moreover, a fraction of the released tryptase reaches the systemic circulation, thereby serving as a biomarker of mast cell activation. Actually, increased levels of circulating tryptase have been found to associate with CVDs. Here we review the biological relevance of the circulating tryptase as a biomarker of mast cell activity in CVDs, with special emphasis on the relationship between activation of mast cells in their tissue microenvironments and the pathophysiological pathways of CVDs. Based on the available in vitro and in vivo studies, we highlight the potential molecular mechanisms by which tryptase may contribute to the pathogenesis of CVDs. Finally, the synthetic and natural inhibitors of tryptase are reviewed for their potential utility as therapeutic agents in CVDs.
Collapse
Affiliation(s)
- Mohammad Mohajeri
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Vanessa Bianconi
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - Arrigo F G Cicero
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
33
|
Valent P, Bonadonna P, Hartmann K, Broesby-Olsen S, Brockow K, Butterfield JH, Triggiani M, Lyons JJ, Oude Elberink JNG, Arock M, Metcalfe DD, Akin C. Why the 20% + 2 Tryptase Formula Is a Diagnostic Gold Standard for Severe Systemic Mast Cell Activation and Mast Cell Activation Syndrome. Int Arch Allergy Immunol 2019; 180:44-51. [PMID: 31256161 DOI: 10.1159/000501079] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 05/20/2019] [Indexed: 12/16/2022] Open
Abstract
Mast cell activation syndrome (MCAS) is a condition characterized by recurrent episodes of clinically relevant, systemic, severe reactions to mast cell (MC)-derived mediators released in the context of anaphylaxis or another acute MC-related event. It is important to document MC involvement in these reactions in order to establish the diagnosis MCAS. The most specific and reliable marker of systemic MC activation is an acute and substantial event-related (transient) increase in the serum tryptase level over the individual's baseline value. However, the baseline level of tryptase varies depending on the underlying disease and the genetic background. For example, an estimated 3-5% of healthy individuals exhibit duplications or multiple copies of the TPSAB1 gene encoding for alpha-tryptase, and over 30% of all patients with myeloid neoplasms, including mastocytosis, have elevated basal tryptase levels. Therefore, it is of utmost importance to adjust the event-related diagnostic (MCAS-confirming) increase in tryptase over the individual baseline in a robust approach. To address this challenge, the 20% + 2 formula was proposed by the consensus group in 2012. Since then, this approach has been validated in clinical practice by independent groups and found to be sound. In the current article, we discuss the emerging importance and value of the 20% + 2 formula in clinical practice and its role as a criterion of severe systemic MC activation and MCAS.
Collapse
Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, and Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria,
| | | | - Karin Hartmann
- Division of Allergy, Department of Dermatology, University of Basel, Basel, Switzerland
| | - Sigurd Broesby-Olsen
- Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark
| | - Knut Brockow
- Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany
| | | | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy
| | - Jonathan J Lyons
- Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, Maryland, USA
| | - Joanna N G Oude Elberink
- Department of Allergology, University Medical Center of Groningen, University of Groningen, Groningen, The Netherlands
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), Paris, France
| | - Dean D Metcalfe
- Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, Maryland, USA
| | - Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Michigan, USA
| |
Collapse
|
|
34
|
Vitte J, Amadei L, Gouitaa M, Mezouar S, Zieleskiewicz L, Albanese J, Bruder N, Lagier D, Mertès PM, Mège J, Schwartz LB, Leone M. Paired acute-baseline serum tryptase levels in perioperative anaphylaxis: An observational study. Allergy 2019; 74:1157-1165. [PMID: 30793322 DOI: 10.1111/all.13752] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 11/30/2018] [Accepted: 12/21/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Anaphylaxis is recognized mainly through clinical criteria, which may lack specificity or relevance in the perioperative setting. The transient increase in serum tryptase has been proposed since 1989 as a diagnostic tool. Sampling for well-defined acute and baseline determinations has been recommended. We assessed the performance of four proposed algorithms with tightly controlled time frames for tryptase sampling, their robustness with inadequate sampling times, and the possible use of mature tryptase determination. METHODS A retrospective study was performed on 102 adult patients from the Aix-Marseille University Hospitals who had experienced a perioperative hypersensitivity reaction clinically suggesting anaphylaxis. EAACI and ICON criteria were used to diagnose anaphylaxis. Mature and total serum tryptase levels were measured. RESULTS Based on EAACI guidelines, clinical diagnostic criteria for anaphylaxis were found in 76 patients and lacking in 26. The most effective algorithm was the international consensus recommendation of 2012 that acute total tryptase levels should be greater than ([1.2×baseline tryptase] + 2] μg/L to be considered a clinically significant rise. In our cohort, this algorithm achieved 94% positive predictive value (PPV), 53% negative predictive value (NPV), 75% sensitivity, 86% specificity, and a Youden's index value of 0.61. A detectable acute mature tryptase level showed lower sensitivity, particularly in patients with acute total tryptase levels lower than 16 μg/L. Acute tryptase levels varied as a function of the clinical severity of anaphylaxis. CONCLUSION Total tryptase levels in serum discriminated between nonanaphylactic and anaphylactic events in a perioperative setting when acute and baseline levels were collected and analyzed by the consensus algorithm.
Collapse
Affiliation(s)
- Joana Vitte
- Aix‐Marseille Univ, IRD, APHM, MEPHI, IHU Méditerranée Infection Marseille France
| | | | - Marion Gouitaa
- Aix‐Marseille Univ, APHM, Hôpital Nord Service de Pneumologie Marseille France
| | - Soraya Mezouar
- Aix‐Marseille Univ, IRD, APHM, MEPHI, IHU Méditerranée Infection Marseille France
| | | | - Jacques Albanese
- Aix‐Marseille Univ, APHM, Hôpital de la Conception Service d'Anesthésie et de Réanimation Marseille France
| | - Nicolas Bruder
- Aix‐Marseille Univ, APHM, Hôpital de la Timone Service d'Anesthésie et de Réanimation Marseille France
| | - David Lagier
- Aix‐Marseille Univ, APHM, Hôpital de la Timone Service d'Anesthésie et de Réanimation Marseille France
| | - Paul M. Mertès
- Strasbourg Univ, HUS, Nouvel Hôpital Civil, FMTS Service d'Anesthésie Réanimation Strasbourg France
| | - Jean‐Louis Mège
- Aix‐Marseille Univ, IRD, APHM, MEPHI, IHU Méditerranée Infection Marseille France
| | - Lawrence B. Schwartz
- Division of Rheumatology, Allergy and Immunology Virginia Commonwealth University Richmond Virginia, VA USA
| | - Marc Leone
- Aix‐Marseille Univ, IRD, APHM, MEPHI, IHU Méditerranée Infection Marseille France
- Aix‐Marseille Univ, APHM, Hôpital Nord Marseille France
| |
Collapse
|
|
35
|
Gutjahr E, Madea B. Inflammatory reaction patterns of the lung as a response to alveolar hypoxia and their significance for the diagnosis of asphyxiation. Forensic Sci Int 2019; 297:315-325. [PMID: 30852415 DOI: 10.1016/j.forsciint.2019.02.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 01/30/2019] [Accepted: 02/12/2019] [Indexed: 10/27/2022]
Abstract
Providing evidence of asphyxia death is a challenging issue in forensic pathology. Besides helpful macroscopical signs (e.g. strangulation mark, lung edema), recent data from literature indicate that the time of protracted asphyxia suffices to trigger an increase of giant cells and a migration of inflammatory cells from the bone marrow to the lung, thus offering a help in diagnosis of asphyxia death. In search of new valid asphyxia markers, the present study examined this hypothesis and investigated the leading role of pre-existing lung tissue cells and their functional state in reaction patterns to asphyxia. In specimens of suffocated human lungs following a short (n = 13) and a long asphyxia terminal episode (n = 15), and controls (sudden cardiovascular (n = 11) and traumatic deaths (n = 7)), the count of alveolar phagocytes, megakaryocytes, giant and mast cells, using H&E and toluidine blue staining, was performed. To show macrophage activation, immunohistochemical stainings for CD68, late (25F9) and early (MRP-8/-14) stage inflammatory markers were used. Measuring concentration of tryptase in femoral blood acted as a parameter for mast cell degranulation and consequently their activation. Results showed the lack of specificity of macroscopical parameters despite an association of suffocation with heavy lung edema. No significant differences in the numbers of inflammatory cells in the lungs of different case groups were detected. The doubling of MRP-8- and a five-fold elevation of MRP-14-positive cells compared to cardiovascular controls, proved an early activation state of pre-exiting monocytes in protracted asphyxia. These activated monocytes induced the degranulation of mast cells, resulting in slightly elevated tryptase levels in suffocation compared to cardiovascular controls. In summary, the duration of asphyxia (max. 20 min in cases investigated) only suffices to cause changes on molecular level, being not detectable in any specific macroscopical or histological form in the lung. Despite a potential utility of this molecular insight in individual cases, these results point to the classic doctrine of the evaluation of a rounded overall picture, accentuating on the proof of the ligature tool and the marks of suffocation process.
Collapse
Affiliation(s)
- Ewgenija Gutjahr
- Institute of Forensic Medicine, University of Bonn, Stiftsplatz 12, 53111, Bonn, Germany.
| | - Burkhard Madea
- Institute of Forensic Medicine, University of Bonn, Stiftsplatz 12, 53111, Bonn, Germany
| |
Collapse
|
|
36
|
Willmann M, Hadzijusufovic E, Hermine O, Dacasto M, Marconato L, Bauer K, Peter B, Gamperl S, Eisenwort G, Jensen-Jarolim E, Müller M, Arock M, Vail DM, Valent P. Comparative oncology: The paradigmatic example of canine and human mast cell neoplasms. Vet Comp Oncol 2018; 17:1-10. [PMID: 30136349 PMCID: PMC6378619 DOI: 10.1111/vco.12440] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 08/14/2018] [Accepted: 08/16/2018] [Indexed: 12/13/2022]
Abstract
In humans, advanced mast cell (MC) neoplasms are rare malignancies with a poor prognosis. Only a few preclinical models are available, and current treatment options are limited. In dogs, MC neoplasms are the most frequent malignant skin tumours. Unlike low‐grade MC neoplasms, high‐grade MC disorders usually have a poor prognosis with short survival. In both species, neoplastic MCs display activating KIT mutations, which are considered to contribute to disease evolution. Therefore, tyrosine kinase inhibitors against KIT have been developed. Unfortunately, clinical responses are unpredictable and often transient, which remains a clinical challenge in both species. Therefore, current efforts focus on the development of new improved treatment strategies. The field of comparative oncology may assist in these efforts and accelerate human and canine research regarding diagnosis, prognostication, and novel therapies. In this article, we review the current status of comparative oncology approaches and perspectives in the field of MC neoplasms.
Collapse
Affiliation(s)
- Michael Willmann
- Department of Companion Animals and Horses, Clinic for Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria.,Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - Emir Hadzijusufovic
- Department of Companion Animals and Horses, Clinic for Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria.,Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Olivier Hermine
- Department of Hematology, Necker Hospital, Imagine Institute Université Paris Descartes, Sorbonne, Paris, France
| | - Mauro Dacasto
- Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy
| | | | - Karin Bauer
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Barbara Peter
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Susanne Gamperl
- Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Gregor Eisenwort
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - Erika Jensen-Jarolim
- Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.,The Interuniversity Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University Vienna, University of Vienna, Vienna, Austria
| | - Mathias Müller
- Biomodels Austria and Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | - Michel Arock
- LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France.,Laboratory of Hematology, Pitié-Salpêtrière Hospital, Paris, France
| | - David M Vail
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin.,Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - Peter Valent
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
37
|
Hunter J, Naguib M. Sugammadex-induced bradycardia and asystole: how great is the risk? Br J Anaesth 2018; 121:8-12. [DOI: 10.1016/j.bja.2018.03.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/03/2018] [Accepted: 03/05/2018] [Indexed: 12/17/2022] Open
|
|
38
|
Valent P, Akin C, Bonadonna P, Hartmann K, Broesby-Olsen S, Brockow K, Butterfield JH, Reiter A, Gotlib J, Castells M, Milner JD, Carter MC, Komarow H, Radia D, Pardanani A, Sotlar K, Triggiani M, Horny HP, Arock M, Schwartz LB, Metcalfe DD. Mast cell activation syndrome: Importance of consensus criteria and call for research. J Allergy Clin Immunol 2018; 142:1008-1010. [PMID: 29928922 DOI: 10.1016/j.jaci.2018.06.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 05/25/2018] [Accepted: 06/07/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Haematology, Medical University of Vienna, Vienna, Austria.
| | - Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Mich
| | | | - Karin Hartmann
- Department of Dermatology, University of Luebeck, Luebeck, Germany
| | - Sigurd Broesby-Olsen
- Department of Dermatology and Allergy Centre Odense University Hospital, Odense, Denmark
| | - Knut Brockow
- Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany
| | | | - Andreas Reiter
- III Medizinische Klinik, Universitäts-Medizin Mannheim, Universität Heidelberg, Mannheim, Germany
| | - Jason Gotlib
- Stanford Cancer Institute/Stanford University School of Medicine, Stanford, Calif
| | - Mariana Castells
- Division of Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass
| | - Joshua D Milner
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Melody C Carter
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Hirsh Komarow
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Deepti Radia
- Department of Haematology, Guys and St Thomas' NHS Foundation Trust, Guys Hospital, London, United Kingdom
| | | | - Karl Sotlar
- Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology University of Salerno, Salerno, Italy
| | - Hans-Peter Horny
- Institute of Pathology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Michel Arock
- LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France
| | - Lawrence B Schwartz
- Department of Internal Medicine, Division of Rheumatology, Allergy & Immunology, Virginia Commonwealth University, Richmond, Va
| | - Dean D Metcalfe
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| |
Collapse
|
|
39
|
Lyons JJ. Hereditary Alpha Tryptasemia: Genotyping and Associated Clinical Features. Immunol Allergy Clin North Am 2018; 38:483-495. [PMID: 30007465 DOI: 10.1016/j.iac.2018.04.003] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hereditary alpha tryptasemia is an autosomal dominant genetic trait caused by increased germline copies of TPSAB1 encoding alpha-tryptase. Individuals with this trait have elevated basal serum tryptase, and may present with associated multisystem complaints. Both basal serum tryptase levels and severity of clinical symptoms display a gene-dose relationship with TPSAB1, whereby higher tryptase levels and greater symptom severity are correlated with increasing numbers of alpha-encoding TPSAB1. As the functional effects of increased basal serum tryptase and/or altered tryptase gene expression are elucidated, greater insights will be gained into the symptoms associated with hereditary alpha tryptasemia and their potential therapy.
Collapse
Affiliation(s)
- Jonathan J Lyons
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N240 MSC 1889, 10 Center Drive, Bethesda, MD 20892, USA.
| |
Collapse
|
|
40
|
Matito A, Azaña JM, Torrelo A, Alvarez-Twose I. Cutaneous Mastocytosis in Adults and Children: New Classification and Prognostic Factors. Immunol Allergy Clin North Am 2018; 38:351-363. [PMID: 30007456 DOI: 10.1016/j.iac.2018.04.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The skin is one of the most frequent tissues affected in patients with mastocytosis, but cutaneous lesions are highly heterogeneous in shape, size, color, number, localization, and distribution. The World Health Organization recognizes 3 subtypes of cutaneous mastocytosis (CM): maculopapular CM (MPCM), diffuse CM, and mastocytoma of skin. An international task force of experts in mastocytosis has recently proposed subdividing MPCM into monomorphic and polymorphic, which could predict the duration of the disease in children. More research is warranted to develop an improved classification of CM that ideally should incorporate robust factors with prognostic impact on disease behavior.
Collapse
Affiliation(s)
- Almudena Matito
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Ctra. Cobisa s/n, Toledo 45071, Spain
| | - José Manuel Azaña
- Department of Dermatology, Complejo Hospitalario Universitario de Albacete, Hospital General Universitario de Albacete, C/Hermanos Falcó nº 37, Albacete 02006, Spain
| | - Antonio Torrelo
- Department of Dermatology, Hospital Infantil Universitario del Niño Jesús, Av/Menéndez Pelayo, nº 65, Madrid 28009, Spain
| | - Iván Alvarez-Twose
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Ctra. Cobisa s/n, Toledo 45071, Spain.
| |
Collapse
|
|
41
|
|
|
42
|
Paolino G, Corsetti P, Moliterni E, Corsetti S, Didona D, Albanesi M, Mattozzi C, Lido P, Calvieri S. Mast cells and cancer. GIORN ITAL DERMAT V 2017; 154:650-668. [PMID: 29192477 DOI: 10.23736/s0392-0488.17.05818-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mast cells (MCs) are a potent proangiogenic factor in tumors, they product several pro-angiogenic factors such as fibroblast growth factor 2 (FGF-2), vascular epithelial growth factor (VEGF), tryptase and chymase. Tryptase is a serine protease classified as α-tryptase and β-tryptase, both produced by MCs. Tryptase degrades the tissues, playing an important role in angiogenesis and in the development of metastases. Serum tryptase increases with age, with increased damage to cells and risk of developing a malignancy and it could be considered the expression of a fundamental role of MCs in tumor growth or, on the contrary, in the antitumor response. Many biomarkers have been developed in clinical practice for improving diagnosis and prognosis of some neoplasms. Elevated tryptase levels are found in subgroups of patients with haematologic and solid cancers. In the current review, we want to update the perspectives of tryptase as a potential biomarker in daily practice in different neoplasms.
Collapse
Affiliation(s)
| | | | | | - Serena Corsetti
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, San Vito al Tagliamento, Pordenone, Italy -
| | - Dario Didona
- First Division of Dermatology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy
| | - Marcello Albanesi
- Department of Emergency and Organ Transplantation, School of Allergology and Clinical Immunology, University of Bari Aldo Moro, Bari, Italy
| | | | - Paolo Lido
- Internal Medicine Residency Program, Tor Vergata University, Rome, Italy
| | | |
Collapse
|
|
43
|
Castells M. Diagnosis and management of anaphylaxis in precision medicine. J Allergy Clin Immunol 2017; 140:321-333. [PMID: 28780940 DOI: 10.1016/j.jaci.2017.06.012] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 06/28/2017] [Accepted: 06/29/2017] [Indexed: 12/18/2022]
Abstract
Anaphylaxis is the most severe and frightening of the allergic reactions, placing patients at high risk and demanding prompt recognition and immediate management by health care providers. Yet because its symptoms imitate those of other diseases, such as asthma and urticaria, current data suggest that its diagnosis is often missed, with underuse of tryptase measurement; its treatment is delayed, with little use of epinephrine; and its underlying cause or causes are poorly investigated. Deaths from anaphylaxis are difficult to investigate because of miscoding. Surprisingly, patients treated with new and powerful chemotherapy agents and humanized mAbs present with nonclassical symptoms of anaphylaxis, and patients may present with unrecognized clonal mast cell disorders with KIT mutations may present as Hymenoptera-induced or idiopathic anaphylaxis. The goal of this review is to recognize the presentations of anaphylaxis with the description of its current phenotypes, to provide new insight and understanding of its mechanisms and causes through its endotypes, and to address its biomarkers for broad clinical use. Ultimately, the aim is to empower allergists and heath care providers with new tools that can help alleviate patients' symptoms, preventing and protecting them against anaphylaxis.
Collapse
Affiliation(s)
- Mariana Castells
- Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
| |
Collapse
|
|
44
|
Tammaro A, Romano I, Persechino F, Parisella F, Trimarchi I, Persechino S. Plasticity of immune system vs. memory therapy IST. Allergol Immunopathol (Madr) 2017; 45:482-486. [PMID: 28549766 DOI: 10.1016/j.aller.2017.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 01/24/2017] [Indexed: 11/27/2022]
Abstract
BACKGROUND Pharmacotherapy and immunotherapy are the main treatments for allergic diseases to inhalants. OBJECTIVE This study investigates whether to repeat short cycles of immunotherapy after 3 or 5 years the from interruption of the first therapeutic cycle, lasting 3-4 years, to maintain immune memory in individuals subjected to IST. METHODS AND RESULTS We have compared two groups, one of 452 patients who, after the first treatment for 3-4 years of IST, performed a cycle of four months after three and 10 years from the suspension, and a second group of 126 individuals who have performed only the IST treatment for 3-4 years. The best results were obtained in the first group. CONCLUSIONS These results are due to the immune system's plasticity, a very important concept in clinical practice.
Collapse
|
|
45
|
Ruëff F, Mastnik S, Oppel EM. Mastzellerkrankungen bei Patienten mit Insektengiftallergie: Konsequenzen für Diagnostik und Therapie. ALLERGO JOURNAL 2017. [DOI: 10.1007/s15007-017-1354-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
46
|
Abstract
INTRODUCTION Tryptase is one of the main serine-proteinases located in the secretory granules of mast cells, and is released through degranulation, which is involved in the pathogenesis of allergic inflammatory disease, cardiovascular diseases, lung fibrosis and tumor. Therefore, inhibitors targeting tryptase may represent a new direction for the treatment of allergic inflammatory disease and other diseases. Areas covered: In this article, we discussed the history and development of tryptase inhibitors and described a variety of tryptase inhibitors via their structures and biological importance in clinical studies and drug development for tryptase-related diseases. Expert opinion: Initial tryptase inhibitors based on indole structure as the hydrophobic substituent on a benzylamine-piperidine template have low specificity and poor bioavailability. Therefore, designing new and specific inhibitors targeting tryptase should be involved in future clinical studies. Modifications toward indoles with varying N-substitution, introducing an amide bond, and growing the chain length contribute to an increase in the specific selectivity and potency of tryptase inhibitors. Tryptase has become the research hotspot to explore many related diseases. Therefore, there has been growing appreciation for the potential importance of the tryptase inhibitors as a target for treating these diseases.
Collapse
Affiliation(s)
- Wei-Wei Ni
- a Research Division of Clinical Pharmacology , the First Affiliated Hospital of Nanjing Medical University , Nanjing , Jiangsu , China
| | - Meng-Da Cao
- a Research Division of Clinical Pharmacology , the First Affiliated Hospital of Nanjing Medical University , Nanjing , Jiangsu , China
| | - Wen Huang
- a Research Division of Clinical Pharmacology , the First Affiliated Hospital of Nanjing Medical University , Nanjing , Jiangsu , China
| | - Ling Meng
- a Research Division of Clinical Pharmacology , the First Affiliated Hospital of Nanjing Medical University , Nanjing , Jiangsu , China
| | - Ji-Fu Wei
- a Research Division of Clinical Pharmacology , the First Affiliated Hospital of Nanjing Medical University , Nanjing , Jiangsu , China
| |
Collapse
|
|
47
|
Heinze A, Kuemmet TJ, Chiu YE, Galbraith SS. Longitudinal Study of Pediatric Urticaria Pigmentosa. Pediatr Dermatol 2017; 34:144-149. [PMID: 28133781 DOI: 10.1111/pde.13066] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND/OBJECTIVES Urticaria pigmentosa (UP) is the most common form of mastocytosis in children and is associated with systemic signs, symptoms, and triggers. To our knowledge, the effect of UP on children's quality of life has not been studied. The objective of the current study was to characterize the natural history, triggers, and complications of pediatric UP, identify prognostic indicators, and determine its effect on quality of life. METHODS Between 2002 and 2007, children with three or more mastocytomas diagnosed by a pediatric dermatologist were recruited during visits at the Children's Hospital of Wisconsin Dermatology Clinic (Milwaukee, WI). Research visits were conducted every 3 years and telephone interviews yearly. The Children's Dermatology Life Quality Index was administered to subjects 4 years of age and older at enrollment. Laboratory test results were collected for subjects younger than 4 years at enrollment. Subjects were followed until UP resolution or study end in August 2015. RESULTS The final cohort size was 43 subjects followed for a median of 8.1 years. Twenty-six subjects were followed through study completion. At age 12 years, 6 patients had disease resolution and 14 remained active. Patients who had disease resolution before age 12 years were more likely to be male and had fewer years of age and smaller lesions, fewer affected areas, and earlier onset. Common medications and anesthetics resulted in no serious reactions. Hymenoptera stings occurred in 51%, with no reports of anaphylaxis. No patient reported a severe effect on quality of life, with most indicating mild to no effect. CONCLUSION Severe complications are not common with historically identified triggers. Disease does not resolve before adolescence in most children. UP has a minimal effect on quality of life for most children.
Collapse
Affiliation(s)
- Adam Heinze
- Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Yvonne E Chiu
- Section of Pediatric Dermatology, Departments of Dermatology and Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Sheila S Galbraith
- Department of Dermatology, Mayo Clinic Health System, Eau Claire, Wisconsin
| |
Collapse
|
|
48
|
Valent P, Sotlar K, Blatt K, Hartmann K, Reiter A, Sadovnik I, Sperr WR, Bettelheim P, Akin C, Bauer K, George TI, Hadzijusufovic E, Wolf D, Gotlib J, Mahon FX, Metcalfe DD, Horny HP, Arock M. Proposed diagnostic criteria and classification of basophilic leukemias and related disorders. Leukemia 2017; 31:788-797. [PMID: 28090091 DOI: 10.1038/leu.2017.15] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 12/14/2016] [Accepted: 12/19/2016] [Indexed: 01/09/2023]
Abstract
Basophils form a distinct cell lineage within the hematopoietic cell family. In various myeloid neoplasms, including chronic myeloid leukemia, basophilia is frequently seen. Acute and chronic basophilic leukemias, albeit rare, have also been described. However, no generally accepted criteria and classification of basophilic leukemias have been presented to date. To address this unmet need, a series of Working Conferences and other meetings were organized between March 2015 and March 2016. The current article provides a summary of consensus statements from these meetings, together with proposed criteria to delineate acute basophilic leukemia (ABL) from chronic basophilic leukemia (CBL) and primary forms of the disease where no preceding myeloid malignancy is detected, from the more common 'secondary' variants. Moreover, the term hyperbasophilia (HB) is proposed for cases with a persistent peripheral basophil count ⩾1000 per μl of blood. This condition, HB, is highly indicative of the presence of an underlying myeloid neoplasm. Therefore, HB is an important checkpoint in the diagnostic algorithm and requires a detailed hematologic investigation. In these patients, an underlying myeloid malignancy is often found and is then labeled with the appendix -baso, whereas primary cases of ABL or CBL are very rare. The criteria and classification proposed in this article should facilitate the diagnosis and management of patients with unexplained basophilia and basophil neoplasms in routine practice, and in clinical studies.
Collapse
Affiliation(s)
- P Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - K Sotlar
- Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - K Blatt
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - K Hartmann
- Department of Dermatology, University of Luebeck, Luebeck, Germany
| | - A Reiter
- Department of Hematology and Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - I Sadovnik
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - W R Sperr
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - P Bettelheim
- Division of Laboratory Medicine, Elisabethinen Hospital Linz, Linz, Austria
| | - C Akin
- Division of Rheumatology, Immunology and Allergy, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - K Bauer
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - T I George
- Department of Pathology, University of New Mexico, Albuquerque, NM, USA
| | - E Hadzijusufovic
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.,Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - D Wolf
- Medical Clinic III for Oncology, Haematology and Rheumatology, University Hospital Bonn, Bonn, Germany
| | - J Gotlib
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - F-X Mahon
- Laboratoire d'Hématologie, CHU de Bordeaux, France
| | - D D Metcalfe
- Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, USA
| | - H-P Horny
- Institute of Pathology, Ludwig-Maximilians University, Munich, Germany
| | - M Arock
- LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France
| |
Collapse
|
|
49
|
Kim HK. The roles of mast cells in allergic inflammation and mast cell-related disorders. ALLERGY ASTHMA & RESPIRATORY DISEASE 2017. [DOI: 10.4168/aard.2017.5.5.248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Hee-Kyoo Kim
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| |
Collapse
|
|
50
|
|