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Diagnosis (Berlin, Germany) May 2021The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis,... (Review)
Review
The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.
Topics: Consensus; Humans; Mast Cells; Mastocytosis
PubMed: 32324159
DOI: 10.1515/dx-2020-0005 -
American Journal of Hematology Apr 2021Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs. (Review)
Review
OVERVIEW
Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs.
DIAGNOSIS
The major criterion is presence of multifocal clusters of spindled MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC CD25 expression, and presence of KITD816V mutation.
RISK STRATIFICATION
Establishing SM subtype as per the World Health Organization classification system is an important first step. Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Identification of poor-risk mutations (ie, ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Recently, clinical and hybrid clinical-molecular risk models have been developed to more accurately assign prognosis in SM patients.
MANAGEMENT
Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease-related organ dysfunction. High response rates have been seen with small-molecule inhibitors that target mutant-KIT, including midostaurin (Food and Drug Administration approved) or avapritinib (investigational). Other options for MC cytoreduction include cladribine or interferon-α, although head-to-head comparisons are lacking. Treatment of SM-AHN primarily targets the AHN component, particularly if an aggressive disease such as acute myeloid leukemia is present. Allogeneic stem cell transplant can be considered in such patients, or in those with relapsed/refractory advanced SM. Imatinib has a limited therapeutic role in SM; effective cytoreduction is limited to those with imatinib-sensitive KIT mutations.
Topics: Adult; Algorithms; Animals; Bone Marrow; Disease Management; Disease Models, Animal; Drugs, Investigational; Gain of Function Mutation; Hematologic Neoplasms; Humans; Hydroxyurea; Interleukin-2 Receptor alpha Subunit; Kaplan-Meier Estimate; Leukemia, Mast-Cell; Mast Cells; Mastocytosis, Systemic; Mice; Mice, Transgenic; Mutation, Missense; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Risk Assessment; Tryptases
PubMed: 33524167
DOI: 10.1002/ajh.26118 -
International Journal of Molecular... Oct 2021Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by... (Review)
Review
Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (HαT) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients.
Topics: Animals; Humans; Mast Cell Activation Disorders; Mast Cells; Mastocytosis
PubMed: 34681933
DOI: 10.3390/ijms222011270 -
Veterinary and Comparative Oncology Sep 2012In preparing this document the Authors aimed to pool current information on canine and feline mast cell disease. The information was gathered from international studies... (Review)
Review
In preparing this document the Authors aimed to pool current information on canine and feline mast cell disease. The information was gathered from international studies and a emphasis was placed on material and opinion with a strong evidence base. We intend it to form the basis of our understanding in this disease at the current time and we anticipate that it will be particularly useful for the general practitioner. It should be emphasized that the authors are presenting this work from a European perspective.
Topics: Animals; Cat Diseases; Cats; Dog Diseases; Dogs; Mast Cells; Mastocytosis; Paraneoplastic Syndromes
PubMed: 22882486
DOI: 10.1111/j.1476-5829.2012.00341.x -
Journal of Investigational Allergology... Dec 2021The diagnosis of mast cell activation syndrome (MCAS) is defined by 3 criteria: (1) typical clinical signs and symptoms of acute, recurrent (episodic), and systemic mast... (Review)
Review
The diagnosis of mast cell activation syndrome (MCAS) is defined by 3 criteria: (1) typical clinical signs and symptoms of acute, recurrent (episodic), and systemic mast cell activation (MCA); (2) increase in tryptase level to >20% + 2 ng/mL within 1-4 hours after onset of the acute crisis; and (3) response of MCA symptoms to antimediator therapy. Classification of MCAS requires highly sensitive and specific methodological approaches for the assessment of clonal bone marrow mast cells at low frequencies. The Spanish Network on Mastocytosis score has been used successfully as a predictive model for selecting MCAS candidates for bone marrow studies based on a high probability of an underlying clonal mast cell disorder. In this article, we propose a diagnostic algorithm and focus on the practical evaluation and management of patients with suspected MCAS.
Topics: Anaphylaxis; Humans; Mast Cell Activation Syndrome; Mast Cells; Mastocytosis; Neoplasm Recurrence, Local; Tryptases
PubMed: 33541851
DOI: 10.18176/jiaci.0675 -
Annual Review of Pathology Jan 2023Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may... (Review)
Review
Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may present as cutaneous mastocytosis or systemic mastocytosis (SM). On the basis of histopathological and molecular features, clinical variables, and organ involvement, SM is divided into indolent SM, smoldering SM, SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Each variant is defined by unique diagnostic criteria and a unique spectrum of clinical presentations. A key driver of MC expansion and disease evolution is the oncogenic machinery triggered by mutant forms of . The genetic background, additional somatic mutations, and comorbidities also contribute to the course and prognosis. Patients with SM may also suffer from mediator-related symptoms or even an MC activation syndrome. This article provides an update of concepts on the genetics, etiology, and pathology of mastocytosis, with emphasis on diagnostic criteria and new treatment concepts.
Topics: Humans; Mastocytosis; Mast Cells; Mastocytosis, Systemic; Prognosis; Proto-Oncogene Proteins c-kit
PubMed: 36270293
DOI: 10.1146/annurev-pathmechdis-031521-042618 -
Immunology and Allergy Clinics of North... Aug 2018Hereditary alpha tryptasemia is an autosomal dominant genetic trait caused by increased germline copies of TPSAB1 encoding alpha-tryptase. Individuals with this trait... (Review)
Review
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.
Topics: Connective Tissue; Disease Progression; Gene Dosage; Gene Duplication; Gene Expression Regulation; Genes, Dominant; Genotype; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Mast Cells; Mastocytosis; Quantitative Trait Loci; Skin; Tryptases
PubMed: 30007465
DOI: 10.1016/j.iac.2018.04.003 -
International Archives of Allergy and... 2022Mast cell activation syndromes (MCASs) are defined by systemic severe and recurrent mast cell activation, usually in form of anaphylaxis, a substantial, event-related... (Review)
Review
Mast cell activation syndromes (MCASs) are defined by systemic severe and recurrent mast cell activation, usually in form of anaphylaxis, a substantial, event-related increase of the serum tryptase level beyond the individual's baseline and a response of the symptomatology to drugs directed against mast cells, mast cell-derived mediators, or mediator effects. A number of predisposing genetic conditions, underlying allergic and other hypersensitivity states, and related comorbidities can contribute to the clinical manifestation of MCASs. These conditions include hereditary alpha tryptasemia, mastocytosis with an expansion of clonal KIT-mutated mast cells, atopic diathesis, and overt IgE-dependent and IgE-independent allergies. Several of these conditions have overlapping definitions and diagnostic criteria and may also develop concomitantly in the same patient. However, although criteria and clinical features overlap, each of these conditions is characterized by a unique constellation of variables and diagnostic criteria. Since two, three, or more conditions can coexist in the same patient, with obvious clinical implications, it is of crucial importance to diagnose the variant of MCAS precisely and to take all accompanying, underlying and potentially complicating conditions, and comorbidities into account when establishing the management plan. Indeed, most of these patients require multidisciplinary investigations and only a personalized treatment approach can lead to an optimal management plan providing an optimal quality of life and low risk of anaphylaxis.
Topics: Anaphylaxis; Humans; Immunoglobulin E; Mast Cell Activation Syndrome; Mast Cells; Mastocytosis; Quality of Life; Tryptases
PubMed: 35605594
DOI: 10.1159/000524532 -
The Journal of Allergy and Clinical... Apr 2019Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related... (Review)
Review
Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient. In such cases, histamine receptor blockers and other mediator-targeting drugs can usually control MCA. In severe cases, an MCA syndrome (MCAS) may be diagnosed. However, overt MCAS is an unusual condition, and many patients referred because of suspected MCAS are diagnosed with other diseases (autoimmune, neoplastic, or infectious) unrelated to MCA or suffer from MCA-related (eg, allergic) disorders and/or comorbidities without fulfilling criteria of an overt MCAS. These considerations are important as more and more patients are informed that they may have MCA or even MCAS without completing a thorough medical evaluation. In fact, in several instances, symptoms are misinterpreted as MCA/MCAS, and other clinically relevant conditions are not thoroughly pursued. The number of such referrals is increasing. To avoid such unnecessary referrals and to prevent misdiagnoses, we here propose a diagnostic algorithm through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded. In addition, the algorithm proposed should help guide the investigating care providers to consider the 2 principal diagnoses that may underlie MCAS, namely, severe allergy and systemic mastocytosis accompanied by severe MCA. Although validation is required, we anticipate that this algorithm will facilitate the management of patients with suspected MCAS.
Topics: Algorithms; Diagnosis, Differential; Humans; Hypersensitivity, Immediate; Mastocytosis; Mastocytosis, Systemic; Proto-Oncogene Proteins c-kit; Tryptases
PubMed: 30737190
DOI: 10.1016/j.jaip.2019.01.006 -
Virology Journal Oct 2022Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as "long-COVID" or "Post-COVID syndrome" (PCS).... (Review)
Review
Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as "long-COVID" or "Post-COVID syndrome" (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.
Topics: COVID-19; Fatigue; Female; Histamine Antagonists; Humans; Inflammation Mediators; Mastocytosis; SARS-CoV-2
PubMed: 36210445
DOI: 10.1186/s12985-022-01891-2